Afterloading

The flexible carrier method was first used with radon seeds by Hames⁸ in 1937 and later by Morton and associates,⁹ who used cobalt sources. Afterloading was systematized by Henschke and colleagues at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. Since the early 1960s, Pierquin and colleagues¹⁰ in Europe popularized the afterloading Henschke techniques with personal modifications and contributed the use of “hairpins” for afterloading with thicker iridium wires mainly for lesions of the oral cavity and oropharynx. Several reports in the literature describe techniques and instrumentation for the use of afterloading interstitial therapy with radium and other isotopes such as tantalum wires and ¹⁹²Ir and ¹²⁵I seeds.^11–19

Removable implants are performed with either stainless-steel needles or semiflexible Teflon or nylon catheters with metallic guides. Using the one-end implant technique, stainless-steel or Teflon 16-gauge tubing is cut to the desired length. The distal end of the tubing is crimped but not closed to hold the afterloaded iridium insert in place, still allowing repositioning should it be required. A barium-impregnated plastic button or a metallic button is fitted snugly at the end. This technique is used in head and neck, breast, female urethra, and anal canal sites and for sarcomas.

Permanent Interstitial Iodine-125 Implants

A system with 10 ¹²⁵I seeds contained within a braided synthetic absorbable carrier has been developed for implants in a shallow plane of tissue or for a tumor site that is inaccessible to standard implant devices.^22,23 The ¹²⁵I seeds are spaced at 1-cm intervals, center to center. The carrier retains a half-circle, taper-point surgical needle. Each strand of 10 seeds is contained within a stainless-steel tubular ring, which effectively shields radiation. The unopened package has a surface dose rate of less than 0.2 mR/h for a loading of ten 0.5-mCi seeds. Consequently, it can be handled and stored without additional shielding.

In circumstances in which the supplied surgical needle is unsuitable, it can be replaced by a tie-on needle (e.g., a French spring-eye needle). The placement of the strands and spacing of the seeds should follow appropriate dosimetric considerations. Martinez and associates described a methodology to insert seeds into an absorbable suture²⁴ and to sterilize them for intraoperative use.²⁵ The absorbable carrier material and ¹²⁵I seeds are implanted in the tumor tissues by successive advancing of the needle and gentle pulling of the carrier. The carrier material is absorbed by body tissue; the rate depends on the nature of the implanted tissue. Intramuscular implantation studies in rats showed that the absorption of the carrier is minimal until the 40th postoperative day. Absorption is essentially complete after 60 to 90 days.

Goffinet and coworkers²⁶ at Stanford University reported on 64 intraoperative ¹²⁵I implants with absorbable Vicryl suture carriers performed in 53 patients with head and neck cancers, many of them recurrent after initial definitive radiation therapy. Among 14 patients who had received no prior therapy, local control was achieved in 10 (71%), and 5 (40%) were alive 2 to 45 months after therapy. Among 34 patients who had received prior therapy, local control was achieved in 20 (59%), and no recurrences developed in any head and neck site in 13 (38%). Complications were noted in 7 (50%) of 14 patients treated definitively, including skin ulceration and intraoral and intrapharyngeal ulceration, which usually healed. Of 34 patients who had ¹²⁵I suture implants after prior therapy, 7 (20%) had complications after the procedure. In a variation of this technique, the ¹²⁵I suture material is sewed through Gelfoam, which in turn is secured to the tumor bed with special clips.

Syed-Neblett Templates

Several Syed-Neblett templates are commercially available. These have been individualized by disease site.

Modified Perineal Template

Hockel and Muller²⁸ described a modified Syed-Neblett type of perineal template for HDR interstitial brachytherapy of gynecologic malignant disease. The template can easily be disassembled after insertion of the central needles into the pelvis, allowing cystoscopic and rectoscopic control of the needle position. Needles penetrating the bladder or the rectum can be repositioned before reassembling the template, eliminating a high-irradiation zone in tumor-free bladder and rectum walls.

Martinez Universal Perineal Interstitial Template

The Martinez Universal Perineal Interstitial Template (MUPIT) was designed to treat locally advanced or recurrent tumors in the prostate, anorectal, perineal, or gynecologic area. The device consists of two acrylic cylinders, one that can be placed in the vagina and the other in the rectum, an acrylic template with an array of holes that allows placement of the metallic guides in the tissues to be implanted, and a cover plate.²⁹ The cylinders are placed in the vagina or rectum, or both, and fastened to the templates so that a fixed geometric relationship among the tumor volume, normal structures, and source placement is preserved throughout the course of the implantation. When the MUPIT interstitial template is used, no central intracavitary sources are inserted, except in some patients requiring an intrauterine tandem (beyond the volume treated with the interstitial sources). Differential loading (using ¹⁹²Ir seeds of different activity) has always been used for the MUPIT implants to optimize LDR dose distribution.

Template versus Intracavitary Brachytherapy in Locally Advanced Gynecologic Tumors

Patients with locally advanced or recurrent gynecologic malignant tumors have relatively few treatment options. Radical surgery and traditional irradiation have been associated with high rates of local failure and can produce significant morbidity. Local recurrence rates range from 24% to 45% following radical hysterectomy for patients with large lesions.

Results with definitive irradiation using intracavitary treatment as a boost have served as a benchmark for comparison. In advanced-stage or bulky disease, however, local control rates drop to 25% to 60%. In the patterns of care study, local control in stage III disease was only 49%. Local control rates of 60% have been reported in stage II disease with lesions greater than 6 cm. Despite these aggressive therapies, local failure has been thought to be secondary to inadequate tumor clearance by surgery or inadequate coverage and/or dose inhomogeneities by radiotherapy.

In an effort to improve on these results, LDR transperineal interstitial brachytherapy techniques were developed as a supplement to external beam radiation therapy (EBRT). Prempree³⁰ used radium needle implants in conjunction with a tandem in 49 patients with stage IIIB cervical carcinoma. All patients were followed for a minimum of 5 years. The control rate in the cervix, vagina, and parametrium was 84% and the major complication rate was 8%. Gaddis and colleagues³¹ have reported the results of treating 75 patients with primary cervical carcinoma using the Syed-Neblett template. With a median follow-up of 17 months, the overall pelvic control rate was 71% (77% in stage IE/IIA, 80% in stage IIB, 54% in stage III, and 0% in stage IV). It is difficult to compare interstitial brachytherapy with traditional intracavitary treatment owing to differences in patient populations, length of follow-up, and methods of reporting results.

Monk and associates³² have reported results in 70 patients with stage II, III, or IVA cervical cancer treated with interstitial therapy using the Syed-Neblett template retrospectively compared with 61 patients with similar disease treated with intracavitary treatment. They reported similar results in stage III and IVA patients; however, patients with stage II disease had a significantly improved 5-year disease-free survival (DFS) rate (50% vs. 21%) and 5-year local control rate (61% vs. 32%) with intracavitary treatment. A greater percentage of the patients in the interstitial group had unknown tumor size (27% vs. 7%), and the stage distribution was slightly in favor of the intracavitary group.

Gupta and associates³³ reviewed the outcomes of patients with locally advanced or recurrent gynecologic cancers who were treated with LDR brachytherapy using the MUPIT. The 3-year actuarial local control rate, DFS rate, and overall survival (OS) rate for all patients were 60%, 55%, and 41%, respectively. For patients with primary cervical cancer, the 3-year actuarial local control rate was 44%. However, 12 of the 30 patients with primary cervical cancer had a disease volume of 100 cm³ or greater. In patients with recurrent disease, the control rate was 68%. The overall complication rate was 13%. These results suggest that in patients with locally advanced or recurrent disease, interstitial implants using the MUPIT applicator can produce acceptable results with acceptable rates of toxicity.

Some concern exists regarding operator variability for interstitial implants. Although patient numbers are small, Gupta and associates³³ retrospectively analyzed local control with respect to physician performing the implant. No difference in outcome was found for those patients undergoing this procedure by the senior author versus the other four operators.

In a report by Gupta and associates,³³ 41% of the patients had recurrent disease, 22% had received prior irradiation, and 26% had disease greater than 100 cm³ in volume. The 3-year local control rate with a disease volume of 100 cm³ or less was 89%. The 3-year actuarial local control rate in the 15 patients who had received prior irradiation was 49%. The major complication rate using interstitial treatment in this group of patients was only 13%.

Russell and colleagues³⁴ have reported their results with re-irradiation of recurrent gynecologic cancers using intracavitary treatment in 25 patients. They report crude local control rates of 56% and major complication rates of 50%. Similar results have been reported by Puthawala and colleagues³⁵ using interstitial implants for recurrent pelvic malignant tumors. After a minimum follow-up of 2 years in 40 patients, they reported a pelvic control rate of 67% and a grade 4 complication rate of 15%.

LDR Implants: Manual versus Remote Afterloading

Few studies compare results of intracavitary therapy with LDR remote afterloading implants with those for manual afterloading systems because there are no significant changes in isotopes or dose rates. Battermann and Szabol³⁶ reported their experience with the LDR Selectron afterloading machine for patients with cancer of the cervix using the same treatment policy as previously used for manual afterloading. Local tumor control and complications were the same for both groups.

HDR Remote Afterloading Implants: Potential Advantages Over LDR

Some of the advantages of HDR remote afterloading techniques relative to LDR manual or remote afterloading are as follows:

Fractionation and adjustment of total dose are crucial factors in lowering the frequency of complications without compromising the results of therapy with HDR systems.³⁷ Scalliet and associates³⁸ compared HDR and LDR in gynecologic brachytherapy, especially regarding the conversion of LDR total dose into equivalent HDR dose per fraction and total dose. Calculation of biologically equivalent schedules requires knowledge of repair capacity and repair kinetics of tumors and normal tissues, both of which influence the biologic effect of any radiation dose. The emerging clinical experience with HDR is equivalent to that of classic LDR. However, although treatment with LDR has proven to be quite tolerant to a lack of absolute precision, that would be disastrous with HDR techniques due to large dosages per fraction.

Pulsed-Dose-Rate Brachytherapy

Pulsed-dose-rate (PDR) brachytherapy was proposed³⁹ to exploit the advantages of HDR computer-controlled remote afterloading technology. It was noted that by varying the dwell times of the stepping source, dose optimization could be achieved, maintaining the potential benefits of LDR, including improved radiation protection. The inactive source times, when the sources are in the safe between pulses, should allow for improved nursing care and patient visiting. The pulse delivers about 0.5 Gy per 10-minute exposure every hour. As the dose rate gradually decreases because of radioactive decay of the source, somewhat longer periods of pulsed times are required.

Pulsed LDR brachytherapy has been made possible with the development of commercial devices modified from HDR intracavitary brachytherapy applications. A single high-activity source that can be programmed for a dwell time in each position at appropriate periods, to reflect the required differential loading of activity, and with a dose rate of 0.5 Gy/h, has been used at a few institutions. Using the linear-quadratic formula, Brenner and Hall³⁹ determined the pulse lengths and frequencies based on radiobiologic data that were equivalent to conventional continuous LDR irradiation. They determined that for a regimen of 30 Gy in 60 hours, a 1-hour period between 10-minute pulses might produce up to a 2% increase in late effects probability.

Visser and associates⁴⁰ described a radiobiologic model and equations to determine the PDR or HDR schedules equivalent to certain LDR schedules, similar to that proposed by Brenner and Hall,³⁹ by applying probable ranges for the values for alpha/beta ratio and repair time. They concluded that eight fractions of 1 to 1.5 Gy per 24 hours, up to 3 hours apart, would be equivalent to commonly used LDR treatment schedules. Hall pointed out that Visser and associates⁴⁰ showed that the more different the proposed regimen is from continuous LDR, the longer the overall treatment time needs to be extended to preserve the therapeutic ratio.

Erickson and Shadley,⁴¹ using in vitro irradiation experiments on rodent tumor cell lines, showed that there was a slight increase in cell killing with PDR relative to continuous LDR irradiation of hourly 5-, 10-, or 20-minute pulses, or a 20-minute pulse every 2 hours. In no case was the increased killing statistically significant, and the cells did appear to be clinically indistinguishable as determined by the Brenner and Hall criteria.

In an editorial, Hall and Brenner⁴² noted that although the linear-quadratic model has been widely used and accepted, it has not been tested in extreme cases and that the biologic data needed for the model calculations are not well known. Armour, White, and colleagues^43,44 at WBH developed a reproducible rat model for comparing late rectal toxicity from different brachytherapy techniques, that is, LDR, HDR, and PDR. Later, Armour and coworkers, using the same rat model, reported PDR results with a very strong dependence of late rat rectal injury on radiation pulse size.⁴⁵

PDR has a significant potential for paradigm shift in brachytherapy. Nonetheless, knowledge of tissue repair kinetics is paramount for adequate selection of dose per pulse and interpulse interval. Therapeutic ratio can be improved by adjusting interpulse intervals to the repair half-times for normal tissues. Likewise, superfractionated schedules with low dose per pulse can be explored in conditions of tumor hypoxia, thanks to the predicted hypersensitivity at low dose per fraction. The use of chemical agents (nicotinamide and others) concurrent with this superfractionated schedule is foreseen in controlled clinical trials.⁴⁶

Although PDR has prospered in Europe and Asia, unfortunately, in the United States it has floundered, because the U.S. Nuclear Regulatory Committee (NRC) requires that a physicist and/or radiation oncologist (or other suitably qualified person) be present throughout the treatment, which is almost impossible to accomplish in a long treatment schedule in a hospital setting.

Dosimetry

In the United States and most other countries, the brachytherapy dosimetric calculations are performed with the aid of computers. Orthogonal radiographs, stereo-shift, and/or computed tomography (CT)-based reconstruction are used. The greatest advantage of CT, magnetic resonance imaging (MRI), or ultrasound-based reconstruction is the ability to see the relationship of the tumor boundaries, surrounding normal tissues, and catheters and applicators. This allows the most critical assessment of implant quality parameters such as target volume coverage, dose homogeneity through the implant volume, dose to neighboring critical structures, and three-dimensional (3D) graphics for documentation of isodose distributions. For interstitial brachytherapy, the use of image-guided dosimetric analysis with CT, MRI, or ultrasound is strongly recommended.

It is extremely important in the use of brachytherapy to formulate and strictly observe radiation safety procedures at each institution in compliance with U.S. NRC regulations. The safety of personnel, patients, and visitors is based on three factors: (1) time of radiation exposure as short as possible, (2) distance as great as practically allowed between the radioactive sources and the operator, and (3) shielding to diminish radiation exposure to all concerned.

Careful quality control procedures should be followed in the prescription and calculation of doses; preparation, calibration, and handling of radioactive sources; and verification of treatment parameters. If promptly discovered, an error in brachytherapy can be corrected, but this is more difficult to do than in fractionated EBRT. The prescription is written on a form that is given to the brachytherapy medical physicist specifying the configuration of source strengths for intracavitary treatment or the array of active lengths and linear activity. Treatment duration is generally determined after conjointly reviewing the computer isodose rate distributions and is double-checked with hand calculations. The physicist documents the preparation of sources in a treatment logbook, on a source inventory sheet that is posted on the patient’s door, and on a magnetic source inventory in the radioactive source room. A well-type ion chamber is used to verify the source activity in accord with American Association of Physicists in Medicine (AAPM) recommendations.

When manual intracavitary afterloading is used, for the sake of prompt patient loading, the various cesium tubes are color-coded. The attending physician or resident (after verifying the source loading) and the dosimetrist/physicist load the applicator in the patient. The loading time is documented by the physician, and the physicist measures the radiation exposure levels around the patient and arranges lead shields appropriately. The nursing division is also actively involved in checking every 3 to 4 hours that applicators or sources do not become dislodged over the course of treatment. For further discussion of LDR brachytherapy quality assurance techniques and programs, the reader is referred to a review by Williamson⁴⁷ and published AAPM recommendations.

The physician’s order sheets contain the home telephone number and the beeper number of at least two physicians who can be contacted in case of an emergency if source removal is required. The attending physician or resident is responsible for the unloading of an implant. Afterward, the physician counts the sources removed and places them in a lead carrier. After removal of the sources, the patient is surveyed to ensure that no radioactivity remains in the patient or in the patient’s room. The time of unloading is documented, and all radiation warning signs are removed from the patient’s door. The source curator checks that all sources have been recovered and returns the sources to their designated storage area. The magnetic inventory board is revised to show that the sources have been returned to their storage area. Additionally, source recovery is documented in the source logbook.

Safety Regulations in the United States

The U.S. NRC and states that have negotiated agreements with the NRC regulate the use and safety of all reactor by-product materials (excluding naturally occurring radionuclides such as ²²⁶Ra and electronically generated radiation). Specific regulations for medical use of by-product materials are outlined in Title 10 Code of Federal Regulations, Part 35.

At the institutional level, a radiation safety committee and radiation safety officer are responsible for supervising the use of by-product materials and seeing that all NRC license requirements are in compliance. The NRC mandates an institutional quality management program (QMP) philosophy aimed to zero incidence of misadministration or recordable events. When misadministration occurs, the licensee is required to report to the NRC by telephone within 24 hours and in writing within 15 days; the patient and referring physician should be informed verbally within 24 hours and by written report within 15 days. If informing the patient would be medically harmful, a relative or friend of the patient must be selected to receive this information. A QMP review must be conducted at least annually to determine compliance and whether modifications are required. For HDR or PDR procedures, the NRC requires the presence of an authorized radiation oncologist and physicist at all times when a procedure is being performed. Imaging or techniques must be in place to verify source position and accuracy before a procedure is performed. A physicist must verify the accuracy of plan input date, dose calculation, and information transfer. Before treatment, the technologist verifies treatment site, isotope, total dose, dose per fraction and treatment modality, program sequence of source position, and dwell times, which must agree with the treatment plan calculation; the technologist also must verify that the HDR treatment channels are correctly connected to corresponding applicators. Before treatment, the attending physician must review the record and sign forms as required.

Radiation Safety in the Operating Room

If radioactive sources are prepared in the operating room (e.g., preloaded needles for prostatic implants), a workbench with shielding should be placed in one comer of the room so no one except the brachytherapy technician preparing the sources is exposed to radiation. The workbench is designed with a frontal working area with an L-shaped lead screen to protect the trunk, lower extremities, and medial aspect of the arms. In addition, a leaded-glass screen reduces exposure to the eyes. Behind the barrier there should be a lead well to store the remaining radioactive material while the individual needles or seeds are being prepared for insertion into the patient. The bench is covered with sterile drapes.

Exposure to the eyes and hands can be reduced only by distance and by dexterity gained through experience. All radioactive sources should be handled with long instruments. After insertion of the sources and removal of the patient, the remaining sources should be carefully inventoried and the operating room surveyed using a Geiger-Muller detector.

Removal of Implants

The carrier housing the interstitial implants (nylon catheter) can generally be removed in the brachytherapy suite and/or in the patient’s room. For patients with standard implants of the oropharynx or for less-than-cooperative patients, it is preferable, and sometimes essential, to remove the implant in the operating room, at times with the patient under general anesthesia; thus, adequate lighting, suction, and assistants are available. Bleeding at the time of catheter removal is infrequent, but when it occurs, it may cause the patient or the assisting staff to panic. Firm and steady pressure with a finger on a compress over the bleeding point for several minutes usually is adequate treatment; occasionally, a surgeon’s assistance is required for bleeding control.

For the sake of radiation protection, it is advisable, initially, to uncrimp the metallic buttons and carefully remove the radioactive sources, which are accounted for and immediately placed in a portable safe or shielded cart. After this is done, each individual tube is removed by freeing one end. For oral cavity or oropharynx implants, we prefer to cut the two ends of the tubing at the skin and pull it out through the oral cavity. A previously tied silk thread inside the cavity on the nylon tube loop is helpful in this maneuver.

Brain Implants

Brachytherapy may allow delivery of interstitial irradiation boosts to primary brain tumors after conventional EBRT or may be used to treat recurrent brain tumors. Patients with primary malignant brain tumors who received initial doses of more than 50 Gy of EBRT to the whole brain survived 20.5 weeks longer than did patients treated by surgery only. Walker and colleagues,⁴⁸ analyzing the Brain Tumor Study Group data, showed stepwise increments in survival in patients receiving 50, 55, or 60 Gy. At the same time, it is well known that higher irradiation doses may significantly increase the risk of brain necrosis.

At some institutions, permanent implants have been used; however, removable implants are more popular. The advantages of removable implants include (1) greater control of the irradiation dose because the source placement can be rearranged and differential activity can be used to improve dose distribution; (2) no possibility of migration of the radioactive sources; (3) easy removal of the sources if emergency decompressive surgery is required; and (4) provision of dose rates greater than 0.3 Gy/h, which may be necessary to treat fast-growing malignant brain tumors as suggested by some data.

Several techniques have been used for interstitial irradiation of the brain, some using multiple planar implants (with or without templates) and ¹⁹²Ir wires or seeds and others with a few higher-intensity ¹²⁵I sources. The same concept has been used in the treatment of patients with tumors of the base of the skull or spine, placing 0.5-mCi ¹²⁵I sources intraoperatively at the time of neurosurgical tumor resection. Doses of 50 to 200 Gy were delivered with permanently implanted sources.

Prados and coworkers⁴⁹ reported results in 56 patients with glioblastoma multiforme and 32 patients with anaplastic glioma treated with temporary ¹²⁵I interstitial implants. Patients received EBRT (median, 59.4 Gy), most with concomitant hydroxyurea, followed by interstitial implant. Eight patients (14%) survived 3 years or longer, and 16 (29%) survived 2 years or longer. A second operation was necessary in 50% of patients to remove symptomatic necrosis produced by the implant. Prolonged steroid use was necessary in many patients.

Another technique described was developed at Washington University using radioactive sources placed in Teflon catheters inserted into the brain under direct CT monitoring.⁵⁰ Multiple burr holes are made in the brain at 1-cm intervals (with the patient under local anesthesia). The locations of the burr holes are determined using a template, which is attached to a stereotactic frame and to the patient’s head. The template used is a thick acrylic block containing a 7- × 7-cm array of 49 holes spaced at 1-cm intervals. The holes along the diagonal axis of the template have slightly larger diameters to provide a method of orientation for each CT slice. The tumor is outlined on the CT screen with the aid of intravenously administered contrast material. The template is placed against the scalp at the site allowing best access to the tumor, usually a lateral surface. Intravenous contrast material is administered and scanning is performed with the scan plane parallel to the rows of the template. The target volume for the implant is the contrast-enhancing ring seen on CT scans, with a 1-cm margin. The number of catheters required to encompass the target at each level is determined at the CT console. Seventeen-gauge catheters, 15 cm long spaced at 1-cm intervals, are then placed through the template into the brain to the desired depths with CT monitoring. Following the grid pattern, under CT observation, the Teflon angiocatheters with a metallic stylet are inserted through the burr holes into the brain substance to ensure straight and parallel insertion. After the tumor volume is implanted, the length of the radioactive sources is determined, and films, with the distribution of the catheters, are obtained for dosimetry calculations. Dummy seeds and ribbons are loaded in each of the catheters. Once the catheters are secured, the patient is transferred to the intensive care unit, where the dummy sources are replaced by ribbons of active ¹⁹²Ir seed with a specific activity of about 0.6 mCi per seed. Metal buttons are attached to the catheters to fasten them to the scalp.

Careful records are maintained of the position and length of all the catheters. Computer-generated isodose calculations are used to determine the dose and distribution in the implant volume. The dose rate ranges from 0.5 to 0.8 Gy/h at 0.5 to 1 cm. In general, the implant duration is 70 to 100 hours to deliver a 60- to 70-Gy total dose to the entire tumor. Verification dosimetry with thermoluminescent dosimeters placed in catheters disclosed an agreement of ± 5% to 10% between the computer calculations and the actual doses at any point within the irradiated volume. This method has been used in more than 70 patients at Washington University, most of them with glioblastoma multiforme, sometimes recurrent after EBRT, and in a few patients with solitary brain metastasis.⁵⁰ Fatal intracranial bleeding has been rare (<5%), and edema is not severe enough to represent a significant management problem. Brain necrosis has been observed in about 25% of patients.

Ocular Implants

Maxillary Sinus Therapy

Rosenblatt and colleagues⁶² described the use of a surgical obturator made of vinyl polysiloxane as a carrier for after-loading ¹⁹²Ir seed ribbons to treat patients with maxillary antrum tumors after partial or total maxillectomy. Two weeks after the surgical procedure, an impression was made of the maxillary cavity, and the obturator mold was built. Multiple nylon catheters were inserted, depending on the geometry and dosimetry of the implant. Prescribed doses were 45 to 70 Gy at 0.5 cm from the outermost source plane. The obturator mold previously loaded with ¹⁹²Ir was carefully coated with acylmethacrylate resin to secure it in place and prevent disturbance of the dosimetry once inserted in the surgical cavity.

Nasal Vestibule Implants

Small lesions of the nasal vestibule can be adequately treated with either external or interstitial irradiation, whereas more advanced lesions require a combination of both modalities. Irradiation is an excellent alternative to surgery in the treatment of these tumors because tumor control can be very good and cosmetic results are better than with surgery.^63,64

These tumors are implanted with single- or double-plane techniques using rigid radium or cesium needles or ¹⁹²Ir nylon tubing techniques. According to Mendenhall and associates, the distal vertical needles (perpendicular to the dorsum of the nose) in each plane may be mounted in a nylon bar in order to stabilize them.^63,64

For small or large primaries, at WBH we always recommend the use of a cast and/or template to improve the geometric coverage of the implant. Both afterloading, LDR, and HDR treatment techniques can be used. It is important to pack all empty spaces to minimize the cavities. Figure 14-1 illustrates a patient treatment with the cast technique.

Figure 14-1 Application of a thermoplastic cast. A, Standard nasal splint is measured and marked for catheter placement. B, The cast in place. The volume below the nares will be packed with wet gauze to provide full scatter (not shown for clarity).

Skin and Lip Implants

Interstitial single- or double-plane implants could be performed to encompass the tumor with a safe margin. Doses of 50 to 70 Gy are delivered in 5 to 7 days. Carcinoma of the skin has been treated with surface molds or interstitial brachytherapy.⁶⁵ Jorgensen and coworkers⁶⁶ reported on 869 patients with squamous cell carcinoma of the lip for whom irradiation was the initial form of treatment in all but 25. Radium implants were used in 766 patients, with local tumor control rates of 93% in T1, 87% in T2, and 75% in T3 tumors. Brachytherapy is recommended over surgery in lesions at or close to the commissure. Functional results are superior to surgery without the postsurgical drooling of saliva.

Nasopharyngeal Implants

Some investigators have used interstitial techniques, which are more difficult to perform because of difficulty in positioning the needles/seeds in the tumor area and limitation of effective depth dose. Palatal fenestration may be required in patients with lesions in the superior and high posterior nasopharyngeal walls, which are more difficult to reach through the nasal or oral cavities.67,68 The use of ¹⁰³Pd seeds for permanent implant of nasopharyngeal tumors has been described by Porrazzo and associates.⁶⁹

Wang⁷⁰ described the use of intracavitary brachytherapy alone or combined with EBRT to boost the dose to the nasopharynx. Two pediatric endotracheal tubes with inner and outer diameters of 5 mm and 6.9 mm, respectively, each loaded with two 20-mg RaEq ¹³⁷Cs sources, are used. Local anesthesia of the nasal cavity is achieved using cocaine. The endotracheal tubes are introduced through the nares into the nasopharynx with the head hyperextended. Under fluoroscopic control on the simulator, the tips of the cesium sources are placed at the free edge of the soft palate posteriorly and behind the posterior wall of the maxillary sinus anteriorly. A 5-mL balloon attached to the distal end of the endotracheal tube is inflated for anchoring purposes. The dose reference point is 0.5 cm below the mucosa of the nasopharyngeal vault; the dose rate is approximately 1.2 Gy/h.

Levendag and colleagues described a nasopharyngeal applicator for HDR brachytherapy, currently commercially available (Nucletron™, Venendaal, The Netherlands), used as a boost.^71,72 The Dutch investigators evaluated different high-dose, high-precision techniques as a boost in T1 to T4 nasopharyngeal cancers treated with EBRT.⁷³ HDR brachytherapy was found to offer optimal sparing of organs at excellent target coverage for T1 to T2b tumors, whereas IMRT with stereotactic radiosurgery boost was the preferred technique for T3 to T4 lesions.

A recent publication from the MSKCC showed that re-irradiation of locally recurrent nasopharyngeal cancer resulted in significantly fewer grade 3 or higher events when an intracavitary brachytherapy boost was employed in conjunction with IMRT compared with IMRT alone (8% vs. 73%; p <.005), with the same local control and OS rates.⁷⁴

For all interstitial implants in the head and neck area, CT or MRI reconstruction is strongly recommended. Standard orthogonal films and/or stereo-shift techniques are suboptimal.

Oral Cavity Implants

For implants of the oral cavity, it is desirable to outline the tumor with gentian violet, Castellani’s paint, or a surgical marker before starting the implantation of sources. For small lesions, the intraoral approach is preferable. For larger lesions, the submental approach is usually recommended.

The anterolateral needles of an implant of the oral cavity should be kept away from the thin mucous membrane that covers the bone in the upper and lower gum, as well as from the periosteum, teeth, and bone. To increase and maintain the distance, a regular fluoride carrier is thickened on the inside by one to four layers (one layer = 2 mm) of lead to increase the distance and shield part of the dose to the mandible.

Implants at the Base of the Tongue

Because of the possibility of airway obstruction, it is imperative to perform an elective temporary tracheostomy before the implant procedure is initiated. Implantation of the base of the tongue (and sometimes the posterolateral border of the oral tongue) is best accomplished by using long metallic needles inserted through the submaxillary/subdigastric region, with the index finger of the other hand in the oropharynx to verify the position of the guide at the exit point, the base of the tongue. As described earlier, the nylon thread is inserted through the tubing into the oropharynx, looped around, and brought out through the opposite guide, thus providing the equivalent of a crossing needle in the cephalad end of the implant. The metallic guides are withdrawn from the submental region and the nylon tubes are secured externally with metallic buttons as described earlier. As in lesions of the oral tongue, a single row of needles with a gold button without a loop could be used. Double-plane or volume implants can be easily performed. After implant localization, x-ray films (CT- or MRI-based) are taken, afterloading ¹⁹²Ir wire or seeds or ¹²⁵I seeds in nylon threads are inserted into the nylon tubing or metallic guides, and isodose distributions are obtained. Most patients are treated with EBRT followed by a brachytherapy boost (LDR or HDR) to increase local control and decrease complications related to the temporomandibular joint and middle ear.

Implants of the Tonsillar Region, Including the Faucial Arch

Iridium 192 hairpin or plastic tube techniques have been used by Mazeron and coworkers.⁷⁶ The nylon tube technique also may be used to implant the soft palate.⁷⁷ The iridium hairpin technique is used with one gutter guide placed in the soft palate in the transverse plane and additional gutter guides placed vertically into the anterior tonsillar pillars, depending on the extent of the lesion. Iridium hairpins are afterloaded into the gutter guides, which are removed as described earlier.

Mendenhall and associates⁷⁸ reviewed the techniques for implantation of the anterior tonsillar pillars, soft palate, or tonsillar region using two nylon bars, each containing three full-intensity, 2- to 3-cm active-length radium or cesium needles implanted into the anterior tonsillar pillar and the other 1 cm medial to the tonsillar pillar bar, in the base of the tongue. A crossing needle is sometimes included in the anterior pillar bar to ensure adequate mucosal dose. Goffinet and associates⁷⁹ developed a method for intraoral tonsillopalatine implants.

Breast Implants as a Boost

Interstitial irradiation of the breast has been used as a boost in conjunction with conservation surgery after the whole organ is given EBRT (45 to 50 Gy). Bartelink and Borger in Europe⁸⁰ and Martinez and Goffinet in the United States⁸¹ pioneered this technique. Selection of patients for this technique is limited to those with an adequate breast volume and lesions less than 5 cm in diameter.

The procedure can be performed with the patient under general anesthesia, although at some institutions, it is performed with local anesthetic. Implantation is also performed in conjunction with resection of the primary tumor (and, when indicated, the axillary dissection) or as a separate operating room procedure. The former approach has the advantages of eliminating one round of anesthesia, reducing the cost of treatment, and allowing the surgeon and radiation oncologist to interact closely in determining the extent and location of the tumor bed and in better planning the placement of the needles.

After the volume to be implanted is determined, lines are drawn on the surface of the breast to determine the position of the planes of the implant (this is also done for free-hand implants). The implant planes are drawn with 1.5-cm separation, and the placement of the metallic or plastic guides is set at 1.2 to 1.5 cm from each other. Depending on the configuration of the breast and the location of the tumor, the needles may be inserted on a coronal or a transverse plane. For template-guided implants, which we strongly recommend, the comers of the template are drawn on the patient’s skin. The needles are then placed based on the predrilled hole pattern of the template.

Rigid metallic guides or Teflon catheters with metallic guides are inserted into the breast, passing through the tumor excision site until the end of the guide reaches the opposite portion of the breast. In general, for multiple-plane implants, the guides for the deep plane are inserted first, followed by those for the superficial planes. For closed cavity implants, percutaneous ultrasound is recommended for needle guidance and good deep plane coverage. Next, the nylon tubing for afterloading insertion of the ¹⁹²Ir seed nylon thread is inserted through the metallic guides, which are withdrawn progressively. The distal end of the nylon tubing is secured by crimping metallic buttons at the level of the skin surface. The length of the ¹⁹²Ir seed nylon thread is determined by inserting dummy sources and measuring the bed cavity, which should be 0.5 to 1.5 cm from the skin surface at both ends to prevent excessive skin dose. Radiopaque dummy sources are inserted into the nylon tubing with appropriate (colored) identification tags. The proximal end of the tubing is left open for future removal of the dummy sources and insertion of the radioactive seeds. Radiographic films (anteroposterior and lateral) of the breast are obtained after the patient is recovered from the anesthesia. However, CT-based reconstruction for dosimetric analysis and implant quality is recommended.

The patient is then taken to her hospital room, and the radioactive sources of appropriate length and strength are inserted into the plastic tubing, which is cut about 2 cm from the skin surface. Metallic buttons are crimped at the level of the skin to secure the plastic tubes in place.

The minimal desired dose rate is 0.5 to 0.6 Gy/h. In general, doses of 10 to 20 Gy are delivered to the volume of interest. Optimally, the maximum dose distribution throughout the implant volume should be within 10% to 15% of the minimum tumor dose.

Mansfield and associates⁸² described an intraoperative technique at the time of the breast tumor excision. The plastic tubes were loaded with the active sources within 6 hours of surgery. The dose rate was 0.3 to 0.5 Gy/h; the usual dose was 20 Gy delivered in 50 to 60 hours. Ten days later breast irradiation was begun with tangential fields, 6-MV photons, to deliver 45 Gy at 1.8 Gy per day. The 10-year local tumor control rates for stage T1 and T2 tumors were 93% and 87%, respectively, and the 10-year DFS rates were 82% and 75%, respectively.

Mazeron and associates⁸³ used a technique for interstitial brachytherapy of the breast with rigid metallic needles inserted through a template in single or double planes. After EBRT (45 Gy in 25 fractions), a boost of 37 Gy to the primary tumor was prescribed at the 85% basal dose rate (Paris system). Implanted volume was adapted to tumor extent by varying the number of sources and active length according to the Paris system rules. Fifty-eight patients were treated with single-plane and 340 with two-plane implants. Local recurrence rates were 10% for T1 (2 of 20), 15% for T2a (21 of 138), 23% for T2b (30 of 129), and 25% for T3 (13 of 53). The local tumor control rates at 15 years were 76% for T1 and T2a lesions and 70% for T2b and T3 lesions. Mean dose rates were 0.53 Gy/h for patients with local recurrence and 0.56 Gy/h for recurrence-free patients (p <.01). Local tumor control correlations with dose rate and tumor size were shown.

Accelerated Partial Breast Irradiation

Accelerated partial breast irradiation (APBI) is the delivery of a shortened course of adjuvant radiation to the planning target volume (PTV) (lumpectomy cavity plus a 1- to 2-cm margin) after breast-conserving surgery. The treatment is completed in 4 to 5 days; thus the term “accelerated treatment.”

In an effort to improve the accessibility, convenience, and logistics of breast-conserving therapy at WBH, we initiated pilot trials to test the technical feasibility and acute toxicity of interstitial brachytherapy directed only to the tumor bed after lumpectomy in selected patients with early-stage breast cancer treated with breast-conserving therapy.⁸⁴ An LDR APBI trial was initiated in 1991; in 1995 we switched to HDR interstitial breast brachytherapy and started an HDR APBI trial. Figure 14-2 demonstrates the application and use of one particular template system.

Figure 14-2 Breast template technique. A, Accurate application is often aided with intraoperative ultrasonography. B, Template in place for fractionated outpatient treatment. Sterile dressings and a support bra will complete the application.

The interim findings of our in-house protocol treating the tumor bed alone after lumpectomy with LDR interstitial brachytherapy in selected patients with early-stage breast cancer treated with breast-conserving therapy were published by Vicini and associates.⁸⁵ From March 1, 1993, through January 1, 1995, 50 women with early-stage breast cancer were entered into a protocol of tumor bed irradiation alone using an interstitial LDR implant. Patients were eligible if their tumor was an infiltrating ductal carcinoma 3 cm or smaller in diameter, surgical margins were clear by at least 2 mm, the tumor did not contain an extensive intraductal component, the axilla was surgically staged with three or fewer nodes involved with cancer, and a postoperative mammogram was performed. Implants were positioned using a template guide delivering 50 Gy over 96 hours to the lumpectomy bed plus a 1- to 2-cm margin. With a relatively short follow-up time, rates of local control, cosmetic outcome, and complications were encouraging

Patients ranged in age from 40 to 84 years (median, 65 years). The median tumor size was 10 mm (range, 1 to 25 mm). Seventeen (34%) of 50 patients had well-differentiated tumors, 22 (44%) had moderately differentiated tumors, and in 11 (22%) the tumor was poorly differentiated. Forty-five patients (90%) were node negative, whereas five (10%) had one to three positive nodes. A total of 23 (46%) patients were placed on tamoxifen, and 3 (6%) received adjuvant systemic chemotherapy. No patient was lost to follow-up. The median follow-up time for surviving patients is 47 months (range, 37 to 59 months). No patient has experienced a local, regional, or distant failure. Three patients have died at 19, 33, and 39 months after treatment. All were without clinical evidence of recurrent disease and all deaths were unrelated to treatment.

(see web-only expanded discussion, available on the Expert Consult website). Good-to-excellent cosmetic results have been observed in 49 (98%) of 50 patients (the median cosmetic follow-up time was 44 months, with a range of 19 to 59 months). No patient has experienced significant sequelae related to the implant.

Vicini and associates⁸⁶ published results in 199 breast cancer patients treated with APBI interstitial brachytherapy at WBH using either LDR or HDR treatment. At 5 years, the results (local control, cosmesis) are as good as those obtained with the more standard 6 weeks of whole breast EBRT. Chen and colleagues⁸⁷ updated the toxicity analysis in these 199 patients with a mean follow-up of 5.4 years. The long-term rate of toxicity was as low as that for conventional 6-week treatment. Benitez and colleagues⁸⁸ reported on the acute and long-term surgical complications of APBI with interstitial brachytherapy and found no increase in intraoperative, perioperative, or postoperative complications.

Results in various series using APBI with either HDR or LDR techniques are shown in Tables 14-1 and 14-2. Table 14-1 summarizes the phase I/II APBI using interstitial HDR breast brachytherapy, and Table 14-2 describes the phase I/II APBI using interstitial LDR breast brachytherapy.

In the only randomized trial completed to date, comparing whole breast irradiation (WBRT) to APBI with HDR multicatheter brachytherapy in 258 patients, there was no difference in 5-year rates of OS, DFS, or cancer-specific survival (CSS) between the two treatment modalities. However, there was a significantly better cosmesis achieved with HDR brachytherapy (APBI) as opposed to WBRT (excellent and good scores, 87% vs. 63%, respectively; p = .009).⁸⁹

A single-institution matched-pair analysis was recently published by our group, examining the patterns of failure in patients treated with APBI versus WBRT with 10 years of follow-up.⁹⁰ The rates of ipsilateral breast tumor recurrence were 4% in the WBRT group versus 5% in the APBI group (p = .48), and, therefore, WBRT would not confer an advantage in terms of ipsilateral breast tumor recurrence over APBI in well-selected patients.

Polgar and colleagues⁹¹ recently published data on the 12-year clinical outcome of one of the earliest experiences with interstitial HDR brachytherapy for suitable breast cancer patients (N = 45). Four (8.9%) ipsilateral breast tumor recurrences were observed, for a 5-, 10-, and 12-year actuarial rate of 4.4%, 9.3%, and 9.3%, respectively. A total of two regional nodal failures were observed for a 12-year actuarial rate of 4.4%. The 12-year rates of DFS, CSS, and OS were 75.3%, 91.1%, and 88.9%, respectively. Grade 3 fibrosis was observed in one patient (2.2%). No patient developed grade 3 telangiectasia. Fat necrosis requiring surgical intervention occurred in one woman (2.2%). Cosmetic results were rated as excellent or good in 35 patients (77.8%).

The Beaumont group confirmed the excellent cosmesis obtained with multicatheter HDR APBI, with over 95% of patients having excellent or good cosmesis with long follow-up. Most importantly, it was noted that cosmetic results stabilized at 2 years with a mild improvement thereafter.⁹²

A new applicator, the single-lumen MammoSite balloon, was introduced as an alternative to the multiple-catheter brachytherapy technique. Edmundson and associates⁹³ reported the dosimetry and excellent conformality in dose distribution. Keish and colleagues⁹⁴ published the preliminary results using the MammoSite balloon technique.

Given the relatively simple insertion, excellent target conformality, and patient comfort, balloon brachytherapy evolved from single-lumen devices to multiple-lumen balloons (MammoSite from Hologic, Inc., and Contura from SenoRx/Bard), enabling better skin and chest wall sparing along with improved dose conformity. Other partial breast devices entered the market in the last years, including the Xoft, Inc. balloon catheter (Sunnyvale, California), Savvy (Cianna Medical, Aliso Viejo, California), and others; however, a detailed discussion of their specific advantages and disadvantages in APBI is beyond the scope of this chapter.

In the summer of 2005, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and Radiation Therapy Oncology Group (RTOG) opened a randomized clinical trial testing the long-term effectiveness of APBI compared with the more standard 6 weeks of WBRT. The accrual objective is 4300 women. Alternate acceptable methods of APBI allowed in the trial include multiple-catheter interstitial brachytherapy techniques (LDR or HDR), the MammoSite balloon technique, or EBRT.

Lung and Mediastinum Implants

Intrabronchial Site Implants

Intrabronchial insertion of LDR or HDR radioactive sources has gained popularity for treatment of patients with symptoms related to malignant airway obstruction. Figure 14-3 illustrates the use of a bronchoscopically placed endobronchial catheter.

Figure 14-3 Bronchoscope-guided brachytherapy. A, Treatment catheter is passed through the biopsy channel of the bronchoscope under direct visualization. B, Catheter is taped in position at the nares for treatment.

Lo and colleagues⁹⁸ described results in 110 patients (group 1) treated with LDR brachytherapy (133 procedures) and 59 patients (group 2) treated with HDR brachytherapy (161 procedures). In group 1, patients were treated with one or two sessions of 30 to 60 Gy each, calculated at a 1-cm radius. In patients in group 2, three weekly sessions of 7 Gy each, calculated at a 1-cm radius, were used. EBRT had previously been given to 88% of patients in group 1 and to 85% of patients in group 2. Laser bronchoscopy was performed in 36% of patients in group 1 and in 24% of patients in group 2 before brachytherapy. Clinical or bronchoscopic improvement was noted in 72% of patients in group 1 and in 85% of patients in group 2 (p >.05). Complication rates were low and equivalent in both groups. Survival rates were similar in both groups (median, <6 months).

Esophageal Implants

Irradiation, both EBRT and intracavitary, has been used in the curative and palliative treatment of patients with esophageal cancer, either alone or combined with surgery. LDR intracavitary insertions have been performed using ²²⁶Ra, ⁶⁰Co, ¹³⁷Cs, or ¹⁹²Ir sources.

Flores and coworkers⁹⁹ outlined the advantages of intracavitary brachytherapy. Radiation sources can be easily placed at the desired tumor site and subsequently removed. Normal anatomy is preserved. Radiation dose to the tumor is higher than to the adjacent tissues. With remote afterloading, radiation exposure to the staff can be eliminated. The insertion technique can be performed as an outpatient procedure under mild sedation. A soft rubber bougie or French catheter (No. 24 to 26) is inserted, preferably through the nose. The cut-end feeding tube is removed, and the esophageal stricture is dilated to 32-French by a balloon dilator (2 minutes required). The esophageal bougie containing dummy markers for intracavitary treatment is placed and secured in the desired position using fluoroscopy. After the position of the dummy sources is verified on radiograph, the patient is taken to the treatment room where the remote-controlled afterloading device is connected for treatment. If LDR sources are used, the usual dose rate is 0.4 Gy/h at 0.5 to 1 cm. Depending on the EBRT dose given, the total intracavitary dose is prescribed to complete 65 to 70 Gy to the tumor volume. With higher dose rates, corresponding lower treatment times and total doses are used.

Syed and colleagues¹⁰⁰ described a comparable technique used in 47 patients with carcinoma of the esophagus (37 with primary and 10 with recurrent lesions). After completion of EBRT, patients received intraluminal brachytherapy to deliver 30 to 40 Gy at 0.5 cm from the surface of the applicator in two applications, 2 weeks apart. In patients with minimum residual tumor, only one application was used to deliver a 20- to 25-Gy minimal tumor dose. Most patients also received concomitant 5-fluorouracil infusion. Intraluminal application was performed with a Syed-Puthawala-Hedger esophageal applicator. The total length of the applicator is 65 cm. Marked rings are present at 10-cm intervals from the tip of the applicator for identification on localization films. The central nasogastric tube can be used for both feeding and suction. The procedure is performed under either general anesthesia or deep sedation and local anesthesia. Extent of the tumor, stricture, ulceration, and impending tracheoesophageal fistula are evaluated by endoscopy. Determination is made of the proximal and distal end of the tumor from the level of the incisor teeth, on endoscopy, and on review of the initial barium swallow x-ray films. Orthogonal anteroposterior and lateral x-ray films of the chest are obtained after inactive dummy sources have been inserted into the afterloading catheters in the applicator. The location of the tumor is marked on the x-ray films, and appropriate margins are determined to perform the dose calculations. Radioactive sources are spaced 0.5 to 1 cm apart, and margins of 3 cm above and below the tumor are allowed.

The main indication for brachytherapy in esophageal cancers is palliation of dysphagia in locally advanced or recurrent disease. A Dutch randomized trial comparing single-dose brachytherapy versus self-expanding metal stents used for palliation of esophageal obstruction due to inoperable cancer recruited 209 patients in nine institutions.¹⁰¹ Primary outcome was relief of dysphagia during follow-up, and secondary outcomes were complications, treatment for persistent or recurrent dysphagia, health-related quality of life, and costs. Dysphagia improved more rapidly after stent placement than after brachytherapy, but long-term relief of dysphagia was better after brachytherapy. Stent placement had more complications than brachytherapy (33% vs. 21%; p = .02), which was mainly due to an increased incidence of late hemorrhage (13% vs. 5%; p = .05). Groups did not differ for persistent or recurrent dysphagia (p = .81), or for median survival (p = .23). Quality-of-life scores were in favor of brachytherapy compared with stent placement. and total medical costs were the same.

Pancreatic Implants

Interstitial irradiation, most frequently using ¹²⁵I permanent implants, has been used in patients with locally advanced unresectable carcinoma of the pancreas. With the patient under general anesthesia, after the tumor is exposed by the surgeon, tumor volume is evaluated and biliary and/or gastric bypasses are performed as required. Multiple seeds are implanted in the pancreas with ¹²⁵I implantation techniques (with a device such as the Mick applicator). The posterior wall of the stomach can be displaced away from the implant with an omental pedicle flap. After localization, x-ray films are obtained by the stereo-shift or orthogonal technique and computer dose calculations are obtained to determine the minimal peripheral dose.

In 98 patients described by Peretz and associates,¹⁰² the mean matched peripheral dose was 136.6 Gy. The mean activity of the implant was 35 mCi, and the mean volume was 53 cm³. Ten patients (10%) survived more than 18 months, and three patients are long-term survivors. Twenty-eight of 68 patients (45%) who had one or more follow-up radiographic studies to assess tumor response showed 30% or more reduction in tumor size. Significant pain relief was observed in 37 (65%) of 57 patients. Nineteen patients (20%) experienced postoperative complications; one patient died with a pancreatic fistula and generalized sepsis, and eight patients (8%) experienced major complications that included fistula formation, gastrointestinal bleeding, gastrointestinal obstruction, and intra-abdominal abscess. Similar survival results have been reported from other institutions. Because of potential biologic disadvantages of ¹²⁵I (long half-life and LDR), Peretz and associates introduced ¹⁰³Pd (half-life of 17 days and 20 to 23 KeV) as a new isotope for pancreatic implants.¹⁰²

Biliary Tree Implants

An increasingly popular technique is the insertion of radioactive sources via Teflon catheters in the biliary tree under fluoroscopic conditions. The main objective is to drain bile and palliate obstructive jaundice. Intracatheter irradiation is best delivered as a boost supplement to EBRT, which is delivered to a larger target volume, including nodal drainage.¹⁰³

A transhepatic cholangiogram is initially performed, usually percutaneously. After the site of obstruction is identified, flexible catheters are inserted into the biliary tree to appropriate lengths, under fluoroscopic control. A dual-lumen catheter or two separate catheters should be inserted, one for lodging the radioactive sources and the other for bile drainage. The patency of the biliary tree is monitored with injection of radiopaque material under fluoroscopic control. Special care must be taken to maintain biliary drainage. The catheter is sutured to the skin. Radiographs are obtained to determine the length of active radioactive sources to be inserted and the exact position of the catheter for dosimetric purposes.

An alternative method of insertion for the radioactive sources is via an endoscopic approach under fluoroscopic control. This has become the preferred technique in institutions at which liver transplant is considered after planned preoperative chemoradiation, because it prevents potential tumor implantation in the catheter tract that transgresses the chest or abdominal wall (see Chapter 47).

Doses of 20 to 30 Gy are delivered at a 1-cm radius (2-cm diameter) from the catheter when combined with EBRT (45 to 50 Gy in 1.8- to 2-Gy fractions, preferably) plus concomitant 5-fluorouracil. If only intracavitary irradiation is prescribed, the doses with this modality are 60 to 65 Gy at a 1-cm radius. HDR brachytherapy with 40 Gy in 10 fractions of 4 Gy in a twice-daily fractionation regimen is also an alternative.

Meerwaldt and associates¹⁰⁴ reported on 42 patients with bile duct tumors treated with one or two brachytherapy sessions plus EBRT, alone or combined with palliative resection. A dose of 15 Gy was delivered at each of two sessions or 25 Gy in one session, calculated at 2 cm from the wire, combined with EBRT (40 Gy in 16 fractions). Fourteen percent of the 42 patients survived for 2 years or more. Median and long-term survival rates were best in the 11 patients who had a noncurative resection in addition to irradiation (median survival of 15 months versus 8 months; 3-year OS rate of 36% vs. 6%; p = .06). Fever occurred shortly after insertion of the ¹⁹²Ir wire in 6 of 38 brachytherapy sessions; it was usually controlled with antibiotics.

Fritz and colleagues¹⁰⁵ reported on 18 patients with carcinoma of the hepatic duct bifurcation and 12 patients with carcinoma of the common duct or the common hepatic duct treated with EBRT and intraluminal HDR brachytherapy alone or combined with noncurative resection. Nine patients received radiation therapy after palliative tumor resection, and 21 patients were primarily irradiated. Twenty-five patients completed the full course of radiation therapy. EBRT dose varied from 30 to 45 Gy and brachytherapy doses from 20 to 45 Gy. Biliary drainage after irradiation was achieved using percutaneous catheters, endoprostheses, or stents. The median survival time for the entire group was 10 months. The actuarial survival rate was 34% after 1 year, 18% after 2 and 3 years, and 8% after 5 years. Three patients were still living without evidence of disease at 35 to 69 months. Major complications such as bacterial cholangitis could be lowered from 37% to 28% through exchange of percutaneous transhepatic catheters to endoprosthesis or stents. The longest lasting drainage was achieved using stents. The incidence of radiogenic ulcers was lowered from 23% to 7.6% after the total dose of HDR afterloading boost was reduced to 20 Gy.

Mayo Clinic investigators published results in a series of 24 patients with unresectable bile duct cancers treated with EBRT plus ¹⁹²Ir alone or with concomitant 5-fluorouracil during EBRT.¹⁰⁶ EBRT was delivered at a dose of 45 to 54 Gy in 25 to 30 fractions over 5.5 to 6 weeks, and the brachytherapy dose was 20 to 30 Gy at a 1-cm radius. Three of the 24 patients were 5-year survivors; results appeared best in the nine patients who received concomitant 5-fluorouracil during EBRT (5-year OS of 22% vs. 8%).

Soft Tissue Sarcomas

In treatment of soft tissue sarcomas, EBRT combined with limb-preservation surgery has been successful in achieving the same results as those obtained with radical surgical resection. Interstitial brachytherapy can be successfully combined with EBRT in patients who have a marginal gross total resection with narrow margins or microscopic residual disease. The theoretical advantages of such a combination include (1) less extensive surgery; (2) synchronous brachytherapy, which allows aggressive treatment of microscopic residual malignant cells at a time when these cells are still oxygenated and before they are embedded in scar tissue; (3) placing of the implant plane(s) on the tumor bed, which ensures that this site will receive the highest irradiation dose; and (4) short treatment (4 to 5 days as primary treatment; 2 days if combined with EBRT) completed before discharge of the patient from the hospital, which presents considerable medical, psychological, and economic advantages. Brachytherapy alone (no EBRT) can be either combined with surgery in the primary treatment of high-grade sarcomas or used as a potentially curative salvage procedure for locally recurrent sarcomas when surgery and EBRT have failed to prevent relapse.

Usually, a single-plane implant is satisfactory. A margin of 2 to 5 cm beyond the boundaries of gross or suspected tumor must be added; the extent of the margin is normally larger along muscles, nerves, and vessels that transverse to those structures. The dimensions of the area to be implanted are measured and recorded. The number of afterloading tubes to be placed at intervals of 1 to 1.5 cm in the target area to deliver 10 Gy/day is determined using the planar implant nomogram of the MSKCC or comparable dosimetry system. To ensure a proper implant, the points of needle insertion are marked on the skin with a sterile pen. The tubes are inserted through normal skin after surgical resection but before completion of any reconstruction and wound closure. At the MSKCC, the tubes are placed parallel to the surgical incision, but at the Mayo Clinic and other institutions, physicians usually prefer placement of the tubes vertical or perpendicular to the incision plane.

With the perpendicular or vertical placement, parallel stainless-steel needles are spaced uniformly and embedded in the depth of the operative field. The closed end of each afterloading nylon tube (in the sealed-end technique) is threaded through the needle until it emerges from the opposite end of the needle. The needle is withdrawn while the plastic tube is held in place until the needle is out of the skin. This process is repeated for the total planned number of afterloading tubes. Each tube is secured in proper position in the tumor bed either by anchoring the needle (and subsequently the tube) in the fascia or muscle, or by securing the nylon tube with No. 2 or 3 absorbable suture material. Metallic clips are placed near each blind end of the nylon tube for later identification of this end on the localization radiographs. The afterloading tubes are individually secured to the skin by means of a stainless-steel button that is threaded over the tube, fixed to it by crimping, and anchored to the underlying skin by silk sutures. A plastic hemispheric bead cushions the button on the skin, protecting it from undue pressure.

Because of the use of irradiation, wound closure requires extra planning and care to avoid undue tension predisposing to wound breakdown. To further diminish wound complications, the loading of the ¹⁹²Ir ribbon or ¹²⁵I seeds is delayed until 3 or 5 days after surgery (3 days is adequate if there is no wound tension).¹⁰⁷ Before loading, anteroposterior and lateral radiographs with radiopaque dummy sources in the plastic tubes provide the information necessary for computerized dosimetry calculations and dose-rate determination. CT planned dosimetry is recommended.

The LDR dose for tumor bed implants is 45 to 50 Gy in 4 to 5 days if used as the sole therapy for high-grade sarcomas. For HDR implants the dose is 4 Gy × 10¹ in a twice-daily schedule or 15 to 20 Gy if used as a supplement to EBRT doses of 45 to 50 Gy and a marginal gross total resection. At the MSKCC, EBRT is now combined with brachytherapy for high-grade sarcomas with positive margins of resection and for all low-grade lesions. In such cases the implant boost dose is 15 to 30 Gy, supplemented by 45 to 50 Gy of EBRT (15 to 20 Gy for narrow or microscopic positive margins, 30 Gy for grossly positive margins). For additional technical details, the reader is referred to the textbook by Hilaris and colleagues.¹⁰⁸

Pisters and coworkers¹⁰⁹ reported on 164 patients with soft tissue sarcomas randomized to receive or not receive brachytherapy as the sole method of irradiation after complete wide local tumor resection at the MSKCC (78 and 86 patients in either group, respectively). A target region in the tumor bed was identified by adding 2 cm to the superior and inferior dimensions and 1.5 to 2 cm in the medial and lateral directions. Afterloading catheters were placed approximately 1 cm apart and were fixed in treatment position with absorbable sutures, secured to the skin at the catheter exit site with buttons and nonabsorbable sutures. Implant dose was 42 to 50 Gy over 4 to 6 days using ¹⁹²Ir. Sources were loaded on the fifth or sixth postoperative day to decrease interference with wound healing. There were 13 local recurrences in 78 patients (16%) who received brachytherapy and 25 (29%) in 86 patients treated with surgery only. Actuarial estimates of local recurrence at 60 months were 18% in the brachytherapy group and 31% in the no-irradiation group. It is highly likely that the prescribed dose of irradiation was not adequate to eliminate microscopic disease, and higher doses (55 to 60 Gy) would have been more effective. Subsequent evaluations of the MSKCC data show inadequate local control of low-grade sarcomas using brachytherapy alone and of high-grade lesions with positive margins of resection. Such patients are now treated with combined EBRT and brachytherapy.

Potter and colleagues¹¹⁰ reported on 12 patients with soft tissue sarcomas treated with HDR or PDR brachytherapy. Brachytherapy was part of the recurrence treatment regimen in eight patients and part of the primary treatment alone or combined with EBRT in four patients.

In HDR treatment, a dose of 15 to 43 Gy was delivered in 3 to 16 fractions, and in PDR treatment 13 to 36 Gy in fractions of 1 Gy/h were used. With a median follow-up time of 14 months, 7 of the patients showed no evidence of disease, 9 of 12 patients had local control, and 3 patients progressed locoregionally In six patients with Ewing’s sarcoma, brachytherapy was performed intraoperatively as a boost treatment after EBRT (50 to 55 Gy), if no wide resection could be achieved. A dose of 10 to 12 Gy was applied in one fraction to a limited volume (20 to 50 cm³) at the time of surgery. Follow-up is 13 to 26 months (median, 21 months).

All patients are disease free, and perioperative and subacute morbidity were not increased (see web-only expanded discussion, available on the Expert Consult website).

Brachytherapy (15 to 20 Gy with LDR) was combined with EBRT (45 to 50 Gy) either preoperatively or postoperatively by Schray and associates at the Mayo Clinic.¹¹¹ Three-dimensional reconstruction of the tumor or tumor bed was accomplished by CT scan or MRI. Margins beyond the tumor were 5 to 10 cm axially or along tissue planes and 2 to 4 cm radially or perpendicular to tissue planes for the EBRT component of treatment. Brachytherapy was performed with standard nylon afterloading tubes positioned to encompass the boost volume with a 2- to 4-cm margin (Fig. 14-4). The boost volume was considered to be the tumor bed after preoperative irradiation and the surgical bed and incision if no previous irradiation had been given. With rare exceptions (distal extremities, groin), needles were placed transversely to the incision (and axis of the extremity) under direct visualization of the tumor bed and with entry and exit points outside the tumor and surgical bed. Nylon tubes were commonly placed in contact with bone and neurovascular structures and were maintained in place by skin fascia and muscle, sutures being rarely used. After the implant was in place, the skin was closed with sutures. Implants were loaded 72 to 96 hours postoperatively with ¹⁹²Ir; the sources were placed 1 cm deep to the skin surface along the tube axis. Average implant activity was 107 mCi, and a portion of the implants used two or more planes. The average dose rate was 48.6 cGy/h, average time was 44.2 hours, and average dose was 20.52 Gy. In 63 patients, 65 brachytherapy procedures were performed. With median follow-up of 20 months, there were two local failures in 56 patients (4%) treated initially and in 3 of 9 patients treated for recurrent tumors. Only one of the five local recurrences was within the implanted volume. Two of 40 implants (5%) performed at initial resection followed by postoperative EBRT led to wound complications, in contrast to 4 of 16 implants (25%) performed at resection after preoperative EBRT.

Figure 14-4 Artist’s idealized depiction of surgical technique of wide excision of extremity sarcoma with placement of afterloading tubes for brachytherapy (LDR or HDR). A, Elliptical incision of biopsy site for wide excision of soft tissue sarcoma involving the vastus lateralis. B, Anterior and posterior flaps are raised. Dissection is carried down through the muscle, with care taken to maintain a 1- to 2-cm margin of soft tissue around the tumor. C, Hollow needles are placed to cover the surgical bed at 1- to 1.5-cm intervals. D, Plastic hollow catheters are threaded through the needles and anchored with barium buttons for afterloading with ¹⁹²Ir (LDR brachytherapy) or HDR source.

One of the largest series of patients with high-grade soft tissue sarcomas of the extremities treated with surgery and immediate adjuvant HDR brachytherapy followed by EBRT was reported from the University of Florence, in Italy.¹¹² One hundred twelve patients were enrolled, and the median follow-up time was 75 months (minimum, 11 months). The OS was 77.5% and 71.1% at 5 and 7 years, respectively, and the DFS was 63.3% and 58.4% at 5 and 10 years, respectively. Local control was achieved in 91.5% and 87% at 5 and 10 years, respectively. Fourteen patients (12.5%) had local complications attributed to radiotherapy. Eleven patients developed wound healing problems that needed further surgery.

The addition of brachytherapy after surgery for primary or recurrent sarcomas of the extremities yields good results with local control in excess of 88% and a relatively low rate of complications (below 15%).113,114,115,116,117

Uterine Cervical Implants

Intracavitary insertions in carcinoma of the cervix are performed under general, spinal, or local (block) anesthesia. The patient is placed in the lithotomy position, and a complete bimanual pelvic and rectal examination is performed. After adequate preparation, the cervix is grasped with a tenaculum, and the uterus is sounded carefully to prevent a perforation. If the cervical os/canal is not identified, a small metallic probe may be used. Bimanual pelvic examination may be extremely helpful in determining the position of the uterus and the probe or sound. In most patients, dilation and curettage is performed at the time of the first intracavitary insertion (if not performed at the initial workup). Radiopaque markers (lead shots or metallic clips) are placed in the anterior and posterior lips of the cervix. The tandem is inserted in the uterus to the appropriate depth (as determined by a stopper), and, subsequently, each ovoid is gently inserted to prevent injury to the vaginal mucosa.

If ideally inserted in the patient, the tandem should be in the midline or as nearly as possible equidistant from the lateral pelvic wall, and the vaginal colpostats should be symmetrically positioned against the cervix in relation to the tandem. The tandem should be kept along the sagittal axis of the pelvis, equidistant from the pubis, sacral promontory, and lateral pelvic wall, as allowed by the geometry of the patient and the tumor to avoid overdosage to the bladder, rectosigmoid, or either ureter. Corn and colleagues,¹¹⁸ in a retrospective evaluation of the technical quality of brachytherapy procedures with respect to ovoid and tandem placement, demonstrated a significantly worse outcome for patients whose implants were judged to be unacceptable.

After the tandem and colpostat positions are judged to be correct, careful packing of the vagina should be performed. A small amount of packing in front of and behind the colpostats (making sure overpacking does not separate the cervix from the colpostats) decreases the dose to the bladder base and the anterior rectal wall.

An indwelling Foley catheter should be inserted in the bladder; 7 mL of radiopaque contrast material in the Foley balloon will aid in determining a point dose to the bladder neck. For difficult insertions, intraoperative x-rays with C-ARM are recommended. After the patient recovers from anesthesia, anteroposterior and lateral x-ray films of the pelvis are obtained to document the position of the applicator, and isodose curves are generated.

Endometrial Implants

Carcinoma of the endometrium may grow irregularly into the uterine cavity and produce deformity of the lumen. It is important to determine the size and shape of the uterine cavity as well as the thickness of the uterine wall. This is accomplished by rotating the uterine sound and measuring the width and depth of the uterine cavity as well as by bimanual palpation or hysterography. Special care should be taken to avoid a perforation; if this occurs, packing with Heyman capsules should not be performed at that time. However, a carefully inserted tandem may be used, avoiding the site of perforation. Ultrasound may help in ascertaining the exact position of the tandem. Rupture (splitting) of the cervix, which may be caused by excessive careless dilation, should be avoided. Assessment of uterine wall thickness is done by MRI, CT, or ultrasound. This is important in determining the dose prescription point.

Uterine packing with capsules was originally described by Heyman in 1934. The practice of introducing as many capsules as possible to stretch the wall of the uterus has several advantages: A bulky tumor can be flattened out, allowing the base of the lesion to be more effectively irradiated; stretching of the uterine wall to make it thinner permits higher doses to be delivered to the serosa of the organ; and a more uniform distribution of the radiation is delivered to the entire myometrium. Afterloading Heyman-Simon capsules are available in 6-, 8-, and 10-mm diameters and 2- to 3-cm lengths.

When capsules are used, it is convenient to insert an afterloading tandem to cover the lower uterine segment because this permits more flexibility in the loading, to obtain improved coverage of this portion of the uterus and the cervical canal. Afterloading colpostats should be routinely used to irradiate the vaginal cuff. A technical problem with the afterloading Heyman-Simon capsules is the relatively large thickness of the sterns, which requires continued dilation of the cervical canal (Hegar dilators) after a few capsules have been inserted. It is critical to record the order of insertion of the capsules (by numbers that are printed on each capsule), so that removal is performed in the reverse order of insertion. Otherwise, the capsules may become jammed, making removal more difficult. Ideally, a minimum of four capsules should be inserted. If fewer are allowed by the size of the endometrial cavity, it may be better to insert an afterloading tandem.

The dose of irradiation delivered with this system is somewhat empirically derived. In general, in preoperative insertions we use 3500 mg/h in the uterine cavity; however, cavities larger than 8 cm receive doses of approximately 4000 mg/h. Doses of about 65 Gy to the mucosal surface of the vagina are delivered (1900 to 2000 mg/h) with 2-cm-diameter vaginal ovoids. Grigsby and colleagues¹⁴⁶ reported higher survival rates and fewer pelvic recurrences and distant metastases in patients with stage I poorly differentiated endometrial carcinoma when doses higher than 3500 mg/h were delivered in the uterus. A lesser beneficial impact was noted in moderately differentiated tumors.

In patients treated with radiation therapy alone, higher intracavitary doses (in the range of 8000 mg/h) are given in two or three insertions. This is combined with EBRT of 20 Gy to the whole pelvis and an additional 30 Gy to the parametria with midline shielding.

For postoperative irradiation in endometrial carcinoma, if no preoperative irradiation was delivered, we use afterloading colpostats to deliver 55 to 65 Gy to the vaginal mucosa with LDR brachytherapy in patients with poorly differentiated tumors even in the absence of deep myometrial invasion. When there is deep myometrial invasion (>50%), regardless of the histologic features, the intracavitary therapy is combined with EBRT (20 Gy to the whole pelvis and an additional 30 Gy to the parametria with midline shielding).

Chao and colleagues¹⁴⁷ described the medical complications associated with 150 intracavitary implants performed in 96 patients treated with irradiation alone for inoperable carcinoma of the endometrium. General anesthesia was used in 98 implants, spinal anesthesia in 26 implants, local anesthesia in 25 implants, and epidural anesthesia in 1 implant. Preventive measures included low-dose cutaneous heparin in 55 patients and intermittent pneumatic compression boots in 29. Four patients (4.2%) developed life-threatening complications (myocardial infarction in two patients, congestive heart failure in one patient, and pulmonary embolism in one patient). Two patients died (of myocardial infarction and pulmonary embolism).

Rotte¹⁴⁸ reported an incidence of 7.5% thromboembolic complications in 106 patients with carcinoma of the endometrium undergoing LDR implants. In contrast, none of the patients treated at the institution with HDR devices had thromboembolic phenomena. It is important to identify patients at high risk for thromboembolic complications, such as those with trauma to the lower extremities or pelvis, obesity, advanced age, and a history of prior thromboembolism. For these patients, outpatient HDR brachytherapy is the recommended intracavitary treatment.

Implants of the Vagina, Vulva, and Female Urethra

Indications for and techniques of interstitial therapy for carcinoma of the vagina, vulva, and urethra have been described.32,137,149 These areas are potentially vulnerable to severe complications because of the reported lower tolerance of the surrounding tissues to irradiation and because these areas are exposed to the constant irritation of perspiration, urine, and, occasionally, feces; therefore, it is important to minimize irradiation to the surrounding normal areas.

Use of interstitial implants ideally should be limited to a volume encompassing 75% or less of the circumference of the vagina, particularly when the lesion involves the posterior wall and rectovaginal septum. The remaining normal tissues should be kept away from the implanted area as much as possible, with the judicious use of gauze packing, cylinders, or templates. The use of abductor pillows helps by separating the inner thighs from the sources in or at the perineum.

Afterloading vaginal cylinders have a central, hollow, tandem cylinder, in which the sources are placed, and plastic rings 2.5 cm in length and of varying diameters are inserted over the tandem. Domed cylinders are used to irradiate the vaginal cuff homogeneously, when indicated.

An intracavitary application with a vaginal cylinder or similar applicator (e.g., Bloedorn, Burnett, Delclos, MIRAv) delivering about 65 to 75 Gy to the mucosa is adequate to control carcinoma in situ. Because of the multicentric nature of this tumor, the entire vaginal mucosa must be treated. When HDR vaginal cylinders are used, 3.6 to 4 Gy in 8 to 10 fractions delivered to the mucosal surface is recommended.

The most superficial tumors are treated with an intracavitary insertion alone, with the largest cylinder covering the entire vagina. If the lesion is thicker, a single-plane needle implant is used in addition to the intracavitary cylinder. This has the advantage of increasing the tumor depth dose without delivering excessive irradiation to the uninvolved vaginal mucosa, which receives 60 to 65 Gy. The gross tumor is treated with 65 to 75 Gy calculated to 0.5 cm beyond the plane of the implant; the vaginal mucosa in this area receives an estimated 80 to 100 Gy, depending on the size of the lesion and tumor dose prescribed. More extensive tumors are treated with intracavitary and interstitial therapy supplemented with EBRT. When EBRT is used, the brachytherapy dose is adjusted downward; it is added to the whole pelvis dose to achieve the prescribed total vaginal tumor dose.

Patients with more advanced paravaginal tumors without extensive parametrial infiltration (stage II lesions) are always treated with a greater EBRT dose of 40 Gy to the whole pelvis and an additional parametrial dose with midline block, to deliver a total of 50 to 60 Gy to the lateral pelvic wall. In these patients, interstitial therapy should also be used, delivering 30 Gy to the tumor to administer about 70 Gy to a volume 0.5 to 1 cm around the palpable tumor (dose includes whole pelvis EBRT contribution). Because of the more extensive tumor, double-plane or volume implants are necessary.

Anal Canal and Rectum Implants

Interstitial and intracavitary techniques have been used for many years for the treatment of anorectal carcinoma. Ideally, implants should be restricted to lesions that require implantation of no more than half the circumference of the anal canal for preservation of sphincter function. Single-plane, double-plane, or volume implants may be necessary, depending on the extent of the tumor. Because of the excellent response to chemoradiation in anal canal carcinoma, brachytherapy is now seldom used.

The catheters are inserted through the perianal area in the central plane 0.5 cm from the anal or rectal mucosa with one finger (double-gloved) in the rectum to verify appropriate placement. Peripheral planes are placed at 1- to 1.5-cm spacing. The anal canal is kept distended with a custom-designed rectal plug, which reduces the dose to the opposite side of the canal to less than 15% of the minimum tumor dose at the implanted area. Perineal templates are strongly recommended.

Papillon and coworkers¹⁵¹ reported on 221 patients with epidermoid carcinoma of the anal canal treated with EBRT ⁷ combined with 5-fluorouracil and mitomycin C, followed by a ¹⁹²Ir implant 2 months later. The implants were performed with either a plastic template or a steel fork, using four to eight wires, 5 to 7 cm long, adapted to the tumor extent covering the quadrants of the anal circumference involved by the tumor. A minimum dose of 15 to 20 Gy was delivered in 15 to 28 hours. Of 179 patients followed for 5 years, 118 (65.9%) were alive and well and 110 (61.4%) had anal preservation. Thirty-three patients (18.4%) died of cancer. Of patients with tumors measuring less than 4 cm, 50 (75.7%) of 66 were alive with anal preservation at the time of the report, and only 5 (7.5%) died of cancer.

Papillon and colleagues¹⁵¹ also reported on 90 patients with T1 or T2 rectal carcinoma treated with contact x-ray endocavitary therapy followed by a ¹⁹²Ir implant with an iridium fork. Doses were similar to those administered to the patients with anal carcinoma. The 5-year OS was 77.8%; 67 (74%) were alive with anal preservation, and only 10 (11.1%) died of cancer. They also reported on a third group of patients with more advanced, moderately infiltrating, low-lying T2 or T3 tumors, who would have been treated by abdominoperineal resection but because of age or poor operative risk were treated with radiation therapy, including interstitial implants. At 4 years, 37 (59.6%) of 62 patients were alive, and 36 (58%) had anal preservation. Only nine patients (14.5%) died of cancer; three had unresectable lesions and one died after major surgery.

Puthawala and colleagues¹⁵² reported on 40 patients with anorectal cancer who were treated with EBRT (40 to 50 Gy in 25 to 30 fractions) followed by two ¹⁹²Ir implants using the Syed template to deliver a total tumor dose of 65 to 75 Gy. Local tumor control was achieved in 70% of tumors, with 20% major morbidity.

A nonrandomized comparison between EBRT boost versus brachytherapy was done in a cohort of 162 patients with invasive nonmetastatic anal squamous cell carcinoma treated with a split course of EBRT to 45.1 Gy followed by either an EBRT boost or brachytherapy to a mean dose of 17.9 Gy. Boost modality and overall treatment time were the only significant prognostic variables in multivariate analysis.¹⁵³ In the subgroup of patients with an overall treatment time of less than 80 days, the 5-year cumulative rate of local recurrence was significantly decreased with the brachytherapy boost (brachytherapy versus EBRT, 9% vs. 28%; p = .03). In the case of an overall treatment time of 80 days or more, the 5-year rate of local recurrence was not affected by the boost technique (brachytherapy vs. EBRT, 29% vs. 38%; p = .21).

Interstitial implants with 10- to 15-cm nylon catheters for ¹⁹²Ir ribbons are used to treat patients with recurrent carcinoma of the rectum in the perineal and presacral fossa after abdominoperineal resection. Care should be exercised to direct the metallic guides initially inserted or the catheters with a posterior orientation (5 to 10 degrees from the horizontal plane). In many instances, the needles find resistance from the sacrum; occasionally, the sources are inadvertently placed in the bladder. Occasionally, we have placed intraoperative implants at the time of resection of the recurrent tumor, which allows for better identification of the volume to be treated and placement of the catheters.

Bladder Implants

Van der Werf-Messing¹⁵⁴ popularized bladder implants with radium or cesium needles. Apart from surgery and general anesthesia, disadvantages of this technique were radiation safety, impaired wound healing because of acute side effects, and, sometimes, difficulties in removing the radioactive sources. In a series of 160 patients, the mean hospitalization time was 36 days after the operation. In 10% of the patients, the abdomen had to be reopened to remove one or more needles. Van der Werf-Messing and associates used radium implants in 328 patients with T2 tumors and 63 patients with T3 tumors after a small dose of preoperative irradiation (3.5 Gy for three fractions). The recurrence rates were 16% for the T2 tumors and 28% for the T3 tumors. The DFS was 75% and 62%, respectively. Battermann and Tierie,¹⁵⁵ using a similar technique, obtained local tumor control in 69 (81%) of 85 patients with T2 tumors, and a 10-year DFS of 56%. Subsequently, van der Werf-Messing and van Putten¹⁵⁶ used 40-Gy EBRT followed by ¹³⁷Cs implants in 48 patients with T2 bladder tumors and 42 patients with T3 tumors. The 5-year DFS was 70%.

A different method using iridium wires was designed in France and subsequently modified by Battermann and Boon¹⁵⁷ to overcome most of the disadvantages of the rigid needle technique. After a lower abdominal incision, the bladder is opened to visualize the tumor area. Plastic carriers consisting of a hollow part and a thinner leading end are inserted 1.5 cm apart. The tubes penetrate the abdominal wall, are tunneled in the bladder muscle through the tumor and out of the bladder, and penetrate the abdominal wall again. The catheters should be placed in such a way that removal is feasible without a second laparotomy, although in more complex cases this may be necessary. Dummy sources are introduced in the carriers to visualize the length of the source to be used while the bladder is still open. After the position of the sources is checked, the bladder is closed, and subsequently the abdomen is closed. A Foley catheter is placed for drainage. After film localization, the dose distribution is determined. The carriers are connected to the MicroSelectron (LDR or HDR), and the radioactive phase of the procedure is started. The tubes are well tolerated and, after completion of irradiation, can be removed easily. All patients receive preoperative EBRT to prevent tumor seeding during operation (30 Gy). A dose of 40 Gy is given by brachytherapy at a dose rate of 0.3 to 0.5 Gy/h.

Although EBRT combined with chemotherapy is a well-established alternative to surgery in selected bladder cancer patients in an effort to preserve the organ or in inoperable cases, the combination of EBRT and brachytherapy was studied less in this setting. A multi-institutional Dutch retrospective case-control study comparing the outcome of surgery and brachytherapy-based radiotherapy in patients with solitary T1G3 to T2 bladder tumors with a diameter of up to 5 cm was recently published.¹⁵⁸ Eighty-nine patients (mean age, 68.4 years) underwent transurethral tumor resection (TURT) followed by a course of EBRT and interstitial brachytherapy, and 179 patients underwent TURT followed by cystectomy. Their technique was previously described and consisted of placing needles at the time of cystectomy and using ¹³⁷Cs, and after 1996, afterloading catheters using ¹⁹²Ir.¹⁵⁹ The dose delivered with brachytherapy was either 55 Gy in combination with pelvic EBRT of 304 fractions of 3.5 Gy or 30 Gy with brachytherapy followed by 20 Gy of EBRT in 10 fractions. With a median follow-up of over 5 years, there was no difference in disease-specific survival rates between the groups (5- and 10-year rates of 71% and 66% in the brachytherapy group and 60% and 57% in the cystectomy group, respectively). Five-year OS were 57% in the brachytherapy group and 52% in the cystectomy group; however, the 10-year OS was better in the cystectomy group than in the brachytherapy group (42% and 33%, respectively). This is caused by the significant age difference in favor of the cystectomy group. The cystectomy-free survival rate in the brachytherapy group was 70%. These results, obtained in a multi-institutional setting, suggest that in a selected patient population a bladder-sparing treatment including brachytherapy (i.e., a combination of TURT, EBRT, and interstitial brachytherapy) can be applied successfully.

Implants of the Penis

The treatment of penile squamous cell carcinoma is generally surgical. In selected cases (T1 to T2 tumors <4 cm, no penile shaft invasion), brachytherapy yields excellent results with good erectile function preservation (see Chapter 55).^{160,161,162,163–165}

The most common technique uses a pair of Plexiglas templates and rigid needles.160,165 Iridium 192 wires are manually loaded. A dose of 60 Gy is delivered over 4 to 5 days. Pulse-dose-rate therapy is an alternative to ¹⁹²Ir wires, with the added benefit of radioprotection. Pretreatment circumcision is essential for good cosmesis and adequate follow-up.

The 5-year penile preservation rates are 70% to 88%, and at 10 years, 67% to 72%. In one of the largest published series from France, the 10-year painful ulceration and stenosis risk rates were 26% and 29%, respectively.¹⁶¹ The 10-year CSS was 92%.

Prostate Implants

Transperineal Implants: Ultrasound Guided

Implants are performed on an outpatient basis under spinal anesthesia. With the patient in an exaggerated pelvic tilt lithotomy position, the 7.5-MHz biplanar ultrasound probe is inserted in the rectum to guide the physician in the positioning of the needle insertion. Transverse images are recorded at 5-mm increments from the base of the prostatic apex. The optimal seed distribution is determined by superimposing the computer-generated isodose distribution over the target volume. Disposable guides preloaded with sources and absorbable spacers and/or seeds in a strand of absorbable suture are introduced through the appropriate template holes as indicated in the plan. Alternatively, the Mick applicator (Mick Radio-Nuclear Instruments, Inc., Bronx, New York) may be used. Each needle is guided to its predetermined position within the prostate under direct ultrasound visualization. Figure 14-5 demonstrates the use of ultrasound volume studies in treatment planning for prostate implants. The onscreen template coordinates of the ultrasound unit allow accurate visualization of the needle position in the prostate. Some institutions have used CT-based fluoroscopic methods for monitoring needle insertion. CT-based dosimetry is performed on every patient.

Figure 14-5 Ultrasound-guided permanent implant planning. A, Volume study with prostate and urethra identified. Note the eccentric positioning of the urethra. B, Isodose distribution of the same patient. Red color wash is 100%; blue line indicates 75%.

The recommendation for use of permanent implants is based on both patient and disease factors. These include prostate volume less than 60 cm³, no severe pubic arch interference, no severe urinary obstructive symptoms, and clinically intracapsular disease; prior transurethral resection of the prostate is discouraged. The Gleason score should be 6 or less and the PSA level 10 or less; the patient should be stage T1 or T2a. In addition, one can use either ¹²⁵I or ¹⁰³Pd, alone or as a boost, after EBRT. Use of ¹²⁵I and/or ¹⁰³Pd seeds embedded in a stiffened Vicryl carrier has decreased the possibility of seeds migrating and causing lung embolization. Indeed, in a small randomized study of 64 patients comparing loose seeds with stranded seeds, more of the patients with loose seeds experienced seed loss (47%) than those with stranded seeds (23%).¹⁷⁰

Because tissue tolerance is a function of total dose as well as dose rate, some adjustment of target dose must be made when considering ¹⁰³Pd rather than ¹²⁵I for implantation. Clinical observations of the normal tissue effects of permanent implants have been mathematically quantified into biologic dosimetry in terms of time-dose factors.

A typical ¹²⁵I prostate implant (MPD of 160 Gy) yields an initial dose rate of 0.08 to 0.1 Gy/h. The substantially larger amount of total activity of ¹⁰³Pd implants (typically, 110 to 130 mCi vs. 30 to 35 mCi for ¹²⁵I) result in an initial dose rate two or three times greater (0.18 to 0.2 Gy/h) than that of ¹²⁵I. However, because of the half-life difference, the dose rate of ¹⁰³Pd decreases more rapidly with time than that of ¹²⁵I. At 5 weeks after implantation, the dose rates of the two radionuclides will be approximately equal, but thereafter ¹²⁵I will deliver a somewhat higher dose rate to full decay. At 5 weeks, the ¹⁰³Pd will have delivered approximately 76% of a 115-Gy dose, and the ¹²⁵I implant will have delivered only 33% of a 160-Gy dose.

Wallner and associates,¹⁷¹ in a review of 65 patients treated with a transperineal ¹²⁵I implant for T1 and T2 prostatic carcinoma, noted that a greater incidence of urinary grades 2 and 3 morbidity was associated with the maximum central urethral dose, length of urethra that received more than 300 Gy, and large prostate volume. Rectal ulceration was associated with irradiation of the rectal wall to doses greater than 100 Gy. Efforts should be made to keep the central urethral dose below 400 Gy and rectal surface dose below 100 Gy to decrease toxicity.

Long-term outcome with permanent seed implants for localized prostate cancer were published on both sides of the Atlantic. One of the largest series based on a multi-institutional pooled analysis was reported by Zelefski and colleagues.¹⁷² The study population included 2,693 patients treated in 11 U.S. institutions with permanent interstitial brachytherapy monotherapy for T1 to T2 prostate cancer between 1988 and 1998, with a minimum follow-up of 5 years. The PSA relapse-free survival rate at 8 years was 92% for patients achieving a nadir PSA level of less than 0.5 ng/mL and 67% if the nadir PSA level was more than 2 ng/mL. Once again, the implant quality reflected by the dose delivered to 90% of the prostate (D90) emerged as a significant predictor of biochemical outcome, along with tumor stage, Gleason score, and pretreatment PSA level. Notably, patients treated with ¹²⁵I with a D90 of 130 Gy or more had an 8-year PSA relapse-free survival rate of 93% compared with 76% for those with a D90 of less than 130 Gy.

A large European, single-institution series of brachytherapy monotherapy using ¹²⁵I was reported in 921 prostate cancer patients treated between 1989 and 2004 with a T stage of T2c or less.¹⁷³ Only 232 patients were classified as low risk, 369 patients as intermediate risk, and the remaining 320 patients as high risk. The median follow-up was close to 6 years. Average 5- and 10-year rates of biochemical no evidence of disease (bNED) were 79% and 57%, respectively. Average 10-year rates of bNED by risk group were 88% for low-risk disease, 61% for intermediate-risk disease, and 30% for high-risk disease. The average 10-year OS and disease-specific survival (DSS) rates were 59% and 82%, respectively. Ten-year rates of OS and DSS by risk group were, respectively, 68% and 96% for low-risk disease, 64% and 87% for intermediate-risk disease, and 49% and 69% for high-risk disease. In multivariate Cox regression analysis, both risk group and treatment era were independent predictors of bNED and survival.

A matter of controversy is the question of whether or not to add EBRT to patients classified as having intermediate-risk or high-risk disease. The Seattle group reported 15-year biochemical relapse-free survival (bRFS) data on 223 patients treated with ¹²⁵I or ¹⁰³Pd brachytherapy after 45-Gy neoadjuvant EBRT. The 15-year PRFS for the entire treatment group was 74%. Grouping by the risk classification described by D’Amico, the PRFS was 85.8% for the low-risk group, 80.3% for the intermediate-risk group, and 67.8% for the high-risk group (p = .002).

Similar results were reported by Dattoli and coworkers in 282 prostate cancer patients with intermediate-risk and high-risk disease.¹⁷⁴ With a median follow-up of 9.5years, the 14-year PRFS was 87% for the intermediate-risk group and 72% for the high-risk group.

Lee and colleagues reported the preliminary results of the RTOG 0019 phase II study examining the rate of biochemical recurrence and late grade 3 or higher genitourinary and gastrointestinal toxicity after treatment with EBRT and brachytherapy in a multi-institutional, cooperative group setting; 138 patients were enrolled, and 130 were eligible for the analysis.¹⁷⁵ The median follow-up for surviving patients was 49 months (range, 20 to 60 months). The 48-month estimate of late grade 3 or higher genitourinary or gastrointestinal toxicity was 15% and the 48-month estimate of biochemical recurrence was 14% according to the Phoenix definition (nadir + 2 ng/mL).

A phase III randomized trial, RTOG 0232, is currently under way, comparing permanent seeds implants alone or in combination with EBRT. The trial was designed to determine whether EBRT added to brachytherapy results in better freedom from progression at 5 years in patients with intermediate-risk prostate cancer.

Image-Guided Intensity-Modulated High-Dose-Rate Prostate Brachytherapy

Image-guided intensity-modulated prostate brachytherapy began in 1988 at Kiel University in Germany and soon after, in 1991, at the WBH in Royal Oak, Michigan, and the Seattle Tumor Institute.¹⁷⁹ This section will be subdivided between intensity-modulated HDR prostate brachytherapy (IMBT) as a boost and as monotherapy.

Intensity-Modulated HDR Brachytherapy Boost

To improve treatment results in prostatic adenocarcinoma, studies were designed to optimize treatment planning toward more conformal radiotherapy delivery. Three major drawbacks of external beam conformal radiotherapy are variations in internal organ motion/deformation, daily setup inaccuracies, and exclusion of several patients for conformal radiotherapy based on poor geometric relationships as identified by 3D treatment planning. To overcome these problems, we began the first prospective, phase I/II dose-escalating clinical trial of conformal IMBT combined with fractionated EBRT. As stated before, the modulation on energy deposition from HDR is related to the computer-controlled spatial distribution of dwell positions and dwell times.

With ultrasound guidance and the interactive online dosimetry system, organ motion and setup inaccuracies (as compared with EBRT) are insignificant because they can be corrected during the procedure without increasing target volume margins. Common pitfalls of brachytherapy, including operator dependence and difficulty with reproducibility, have been eliminated with the intraoperative online planning system^180,181 (Fig. 14-6).

Figure 14-6 HDR planning for prostate. A, Prostate is contoured at its maximum extent. Blue arrows denote needle positions proposed by the computer. B, Same plan, showing isodose distribution and urethral and rectal doses.

PSA levels have been used as a surrogate to judge disease control of prostate cancer. Several published data sets now attest to the greater ability of IMBT using HDR to control disease compared with conventional irradiation.

From November 1991 through November 1995, 58 patients received 45.6-Gy pelvic EBRT and three HDR ¹⁹²Ir boost implants of 5.5 to 6.5 Gy each.¹⁸² They were compared with 278 similarly staged patients treated from January 1987 through December 1991 with EBRT to prostate-only fields (median dose, 66.6 Gy).¹⁸³ No patient received androgen deprivation. Patient outcome was analyzed for biochemical control. Biochemical failure was defined as a PSA level higher than 1.5 ng/mL and rising on two consecutive values. If serial posttreatment PSA levels were showing a continuous downward trend, failure was not scored. Median follow-up was 43 months for the conventionally treated group and 26 months for the IMBT boost group. The median pretreatment PSA level was 14.3 ng/mL for the EBRT-alone group and 14 ng/mL for the IMBT boost group. The median Gleason scores were 6 and 7, respectively, for the two groups. The biochemical control rate was significantly higher in the IMBT boost treatment group. Three-year actuarial biochemical control rates were 85% and 52% for the conformal IMBT boost patients and conventionally treated patients, respectively. In a multivariate analysis, the use of IMBT boost and the pretreatment PSA level were significant prognostic determinants of biochemical control. The 3-year actuarial rates of biochemical control for conformal IMBT boost versus conventionally treated patients, respectively, were 83% and 72% for a pretreatment PSA level of 4.1 to 10 ng/mL, 85% and 47% for a PSA level of 10.1 to 20 ng/mL, and 89% and 29% for a PSA level higher than 10 ng/mL. When the analysis was limited to patients in both groups with a minimum 12-month follow-up, the IMBT boost group continued to show a higher biochemical control rate than the conventional radiation group (3-year actuarial rates of 86% vs. 53%).¹⁸³

Martinez and associates¹⁸⁴ updated the series with an analysis of 207 patients treated on the dose-escalation IMBT-HDR prostate brachytherapy trial. It was demonstrated to be a precise and accurate dose delivery system and a very effective treatment for patients with unfavorable prostate cancer. The improved outcomes coupled with the low risk of complications and the advantages over permanent seed of not being radioactive after implantation, define a new standard for treatment. Using the same database, Brenner, Martinez, and associates¹⁸⁵ reported a low α/β ratio of 1.2 showing high sensitivity to fractionation similar to the late-responding tissues.

With longer follow-up and a larger number of patients, Martinez and associates published the long-term results of the WBH prostate HDR dose-escalation trial.¹⁸⁶ Data demonstrated that a conformal IMBT HDR brachytherapy boost improves biochemical control and CSS in patients with prostate cancer and poor prognostic factors. At the 2005 ASTRO annual meeting, Vargas and colleagues¹⁸⁷ from WBH reported the final analysis of the HDR boost dose-escalation trial. For the first time, an improvement in biochemical control led to a decrease in metastatic rate and improved OS.

Galalee and colleagues¹⁷⁹ reported on the collaborative trial between Kiel University in Germany, the Seattle Tumor Institute, and the WBH on long-term outcomes by risk factor using a conformal HDR brachytherapy boost for patients with localized prostate cancer during the PSA era. Similar results were found at the three institutions in 611 patients with prostate cancer harboring intermediate-risk and high-risk factors. With a mean follow-up of 5 years, the 5- and 10-year biochemical control rate was 77% and 73%, the DFS was 67% and 49%, and the CSS was 96% and 92%, respectively. The similarity in results at the three institutions gives credence to the reproducibility of the brachytherapy boost treatment. Dose escalation greater than 95 Gy resulted in better 5-year biochemical control for conformal HDR boost (59% vs. 85%; p <.001) for the entire cohort of hormonal-naïve men. Discriminating by risk factors, a striking dose-escalation effect was seen in the group of patients with two or three poor prognostic factors (p = .02 and p <.001). This unfavorable group has a remarkable 5-year biochemical control rate of 85%.

These excellent results were confirmed by others, showing that HDR prostate brachytherapy is a robust, safe, and reproducible treatment method.188,189,190,191

Two randomized trials demonstrated the superiority of adding HDR boost to EBRT compared with EBRT.

In a study by Sathya and coworkers, 104 patients with T2 and T3 prostate cancer with no evidence of metastatic disease were randomly assigned to EBRT of 66 Gy in 33 fractions during 6.5 weeks or to HDR boost of 35 Gy delivered to the prostate during 48 hours plus EBRT of 40 Gy in 20 fractions during 4 weeks.¹⁹² The median follow-up was 8.2 years. In the HDR boost plus EBRT arm, 17 patients (29%) experienced biochemical failure (BCF) compared with 33 patients (61%) in the EBRT arm (p = .0024). Eighty-seven patients (84%) had a postradiation biopsy; 10 (24%) of 42 in the HDR boost plus EBRT arm had biopsy positivity compared with 23 (51%) of 45 in the EBRT arm (odds ratio, 0.30; p = .015). The OS was over 90% for both treatment regimens.

Hoskin and colleagues randomized 220 patients with prostate cancer and PSA levels less than 50 ng/mL to receive either standard EBRT with 55 Gy in 20 fractions over 4 weeks or a combined schedule of EBRT with 35.75 Gy in 13 fractions over 2.5 weeks followed by a temporary HDR afterloading implant delivering 17 Gy in 2 fractions over 24 hours.¹⁹³ With a median follow-up of 30 months, a significant improvement in actuarial bRFS was seen in favor of the combined EBRT/brachytherapy schedule (p = .03). A lower incidence of acute rectal discharge was seen in the EBRT/brachytherapy group (p = .025), and other acute and late toxicities were equivalent. Patients randomized to brachytherapy had a significantly better Functional Assessment of Cancer Therapy–Prostate (FACT-P) score at 12 weeks (p = .02).

Martinez and associates¹⁹⁴ looked at the question of effects on long-term survival with a short course (≤6 months) of adjuvant androgen deprivation when a very high radiation dose was delivered to 934 patients treated with an IMBT-HDR brachytherapy boost in a hypofractionated regimen. At 8 years, the addition of a course of 6 months or less of androgen-deprivation therapy (ADT) to a very high hypofractionated radiation dose had not conferred a therapeutic advantage but added side effects and cost. Furthermore, for the most unfavorable group of patients harboring all three poor risk factors, there was a higher rate of distant metastasis and more prostate cancer-related deaths. This result questions the value of a short course of ADT and the impact on delaying curative treatment.

Intensity-Modulated HDR Brachytherapy as Monotherapy

The twice-per-day accelerated hypofractionated regime was selected based on HDR favorable radiobiologic considerations and physical dose delivery advantages of transrectal ultrasound (TRUS) guidance,¹⁹⁵ with conformal intensity-modulated real-time dosimetry of prostate HDR brachytherapy. The Beaumont HDR dose schedule is 38 Gy in four fractions of 9.5 Gy delivered twice-daily via a single implant. This is biologically equivalent to 74 Gy in daily fractions of 2 Gy of EBRT. At the California Endocuritherapy (CET) Cancer Center, the HDR dose schedule is 42 Gy in six fractions twice daily in two separate implants 1 week apart. The biologic equivalence is 76 Gy in 2-Gy daily fractions of EBRT.

Patients with clinical stage II (T1c to T2a) disease, a Gleason score of less than 7 (unilobar, 3 + 4, no perineural invasion) and pretreatment PSA levels of less than 12 ng/mL were treated with monotherapy. The majority of patients presented with what would be considered low-risk or favorable prostate cancer. Patients were offered either HDR or LDR brachytherapy as treatment options, and then the patient selected the brachytherapy modality. A short course of neoadjuvant androgen deprivation (<6 months) was used for downsizing the gland volume in 31% of WBH patients, in equal proportions between permanent seeds and HDR and in 30% of the CET Cancer Center patients.¹⁹⁶ All procedures were done under spinal anesthesia. Figure 14-7 depicts an HDR intraoperative implant using the Nucletron SWIFT guidance system.

Figure 14-7 HDR intraoperative implant using the Nucletron SWIFT guidance system. A, The 3D reconstruction of the prostate gland, urethral trajectory, and needle orientation. B, Anatomic relationship of the prostate, the urethra, and the needles with the selected dwell positions on each needle. C, Final TRUS-based intraoperative dosimetry and coverage of the PTV. D, Dosimetric rendition of the prostate coverage by the 100% isodose cloud in red with urethral sparing from modulating the dwell times and dwell positions.

Between January 1996 and December 2002, 378 consecutive patients with clinically localized prostate cancer were treated with accelerated hypofractionated brachytherapy as the sole treatment modality. Of the patients, 172 were treated with HDR brachytherapy alone using ¹⁹²Ir, and 206 patients were treated with LDR brachytherapy alone using ¹⁰³Pd.

For the implant procedure and for pain control during the entire treatment time, spinal anesthesia was administered following placement of an epidural catheter for analgesia. Dosimetry was continuously updated in real time based on the actual location of needles to compensate for organ distortion and motion and to ensure conformal coverage of the gland.^180,181 Gold seed markers were then placed under TRUS guidance at the base and at the apex of the prostate to assess and measure possible interfraction needle displacement. Before delivery of the radiation, the entire prostate was imaged again, with final needle and urethral positions captured by TRUS, and a final treatment plan was created.

At CET, after recovery the patient underwent a dual method of simulation radiography consisting of plain film localization for applicator adjustment and quality control, and a CT scan was performed. The images were downloaded to the “treatment planning” computer and a 3D reconstruction was carried out. A dose-volume histogram (DVH) and virtual images of the anatomy, clinical target volume (CTV), and planning target volume (PTV) were obtained.

The toxicity profile of IMBT-HDR monotherapy was first described by Grills and colleagues¹⁹⁷ from WBH, demonstrating less acute and chronic toxicity with HDR when compared with permanent seeds with ¹⁰³Pd. Also, the impotency rate was decreased in the HDR group of treated patients by half compared with the rate with permanent seeds. The following toxicity analysis is an updated report from the combined experience from WBH and CET.¹⁹⁸ The median follow-up for all patients was 4.1 years (range, 0.8 to 12.3 years).

Acute Toxicity

HDR brachytherapy alone was associated with statistically significant reductions in the acute rates of dysuria (65% with ¹⁰³Pd seeds vs. 38% with HDR monotherapy; p <.001), as well as urinary frequency and/or urgency (94% for ¹⁰³Pd vs. 53% for HDR; p <.001) and urinary retention (43% for ¹⁰³Pd vs. 29% for HDR; p = .012). In addition to reduced acute genitourinary symptoms, HDR was also associated with lower rates of rectal pain (18% with LDR vs. 7% with HDR; p = .025). The majority of acute toxicities in both groups were grade 1. Hormonal androgen ablation for gland downsizing was given to 31% of patients in both groups.

Chronic Toxicity

HDR brachytherapy alone was again associated with reduced urinary frequency and urgency (54% with ¹⁰³Pd vs. 32% with HDR; p <.001). The majority of toxicities were grade 1. There were no differences in the remaining chronic toxicity rates of urinary incontinence or retention, hematuria, diarrhea, rectal pain, or rectal bleeding between the two treatment groups. The rate of urethral stricture requiring dilation was 3% with HDR compared with 1% with ¹⁰³Pd (p = .3). The median time to development of urethral stricture was 17 months, with a range of 4 to 37 months. The cumulative proportion of chronic grade 3 toxicity by treatment modality did not differ between the two treatment types.

Potency

Regardless of the use of adjuvant hormonal therapy, all cases were included for which complete pretreatment and post-treatment information was available. This included 61 patients treated with HDR brachytherapy alone and 81 patients treated with permanent ¹⁰³Pd. The 5-year probability of impotency was 38% for all patients with available data. As shown in Figure 14-8, the probability was 49% for LDR patients and 21% for HDR patients (p = .006). The mean times to impotency for the HDR and LDR treatments were 3.9 and 3.2 years, respectively.

Figure 14-8 Probability of sexual impotence by treatment method.

Survival Outcomes

The 5-year actuarial outcomes for monotherapy showed no difference in terms of ASTRO definitions for biochemical failure, cancer mortality, or overall survival between HDR alone versus permanent seeds. In Figure 14-9, the actuarial 5-year biochemical control curves for HDR and LDR are depicted. No difference in biochemical control ASTRO definition can be seen by treatment modality.

Figure 14-9 Actuarial analysis of biochemical control, ASTRO definition.

Updated Analyses

An update of the largest prostate HDR monotherapy series of 248 patients from WBH and CET was published in 2009, with a median follow-up of 5 years.¹⁹⁸ The 5-year Phoenix definition for biochemical control was 91%. In a comparable cohort of patients treated with permanent seed implants (Pd¹⁰³), the biochemical control was similar; nonetheless, the HDR patients experienced significantly less acute and chronic genitourinary and gastrointestinal toxicities.

The Beaumont group started a hypofractionated HDR monotherapy trial for low-risk prostate patients in which the total dose was 24 Gy for the first 50 patients, delivered in a single implant and in two fractions, 6 hours apart. The subsequent 50 patients received 27 Gy in two fractions in 1 day. There were no differences in acute or chronic toxicities between the two regimens with a median follow-up of 1.4 years. The maximum chronic genitourinary and gastrointestinal toxicities of grade 2 or higher were 5% or lower, with only urinary frequency/urgency being 16%. However, after 6 months this issue resolved in almost all patients (0% for the 24-Gy group and 4.8% for the 27-Gy group). Encouraged by this excellent tolerance and toxicity profile, we activated a new protocol in which HDR monotherapy is delivered in one single fraction of 19 Gy.

Animal Studies

Animal experiments in pigs^199,200 using coronary endovascular brachytherapy with ¹⁹²Ir at doses ranging from 7 to 25 Gy have shown a significant reduction in the incidence and degree of restenosis after injury of the swine coronary vessels with a stretching balloon. Most of the studies have been done at 1 month after the procedure and irradiation. Wiedermann and colleagues²⁰¹ with 20 Gy at 1.5 mm, observed a 70% reduction in restenosis. Waksman and coworkers,²⁰² with doses of 7 or 14 Gy at 2 mm, noted a reduction of 30% and 67%, respectively, in restenosis at 6 months, and Raizner²⁰⁰ observed not only a dose effect but a dose-rate effect as well with regard to restenosis.

Biologic and pathophysiologic observations from in vitro and in vivo experiments on radiation effects have shown that, in addition to clonogenic cell death (postmitotic), a significant portion of irradiated endothelial cells succumbs to apoptosis. Studies have also demonstrated that basic fibroblast growth factor, a known mitogen for endothelial cells, protected them against radiation-induced apoptosis but not against clonogenic cell kill. Immunohistochemical studies showed that basic fibroblast growth factor is present in large arteries and veins, whereas there are very small amounts in the vasa vasorum and small capillaries. Therefore small capillaries undergo apoptosis because of this fibroblast growth factor deficiency, whereas larger vessels are immune to apoptosis.

In addition to endothelial proliferation, there is smooth muscle degeneration and hyperplasia, which contribute to restenosis after angioplasty and stenting. Waksman and colleagues^134,135 have shown experimentally that intravascular irradiation modifies this response, inhibiting early adventitial cell proliferation and modifying the production of α-actinin by the adventitia myofibroblasts at later times after injury. Intravascular irradiation may be expected to reduce the growth of the restenosis lesion and has the potential to positively affect vascular remodeling.

Human Studies

Schopohl and colleagues²⁰³ used a Nucletron MicroSelectron HDR device, a 5-French catheter, and a 9-French ReKa catheter to deliver 12 Gy at 3 mm from the ¹⁹²Ir source. With a follow-up of 8 to 69 months, of 29 patients treated after repair (stent) of femoral restenosis, 21 remained without restenosis, 4 had reocclusion, 1 died at 36 months of ovarian cancer, and 2 had no follow-up because they had moved and had no forwarding address.

Condado and coworkers²⁰⁴ treated 21 patients using HDR ¹⁹²Ir to deliver 20 to 25 Gy. Three of 11 patients treated with 20 Gy developed restenosis in contrast with no restenosis in 10 patients treated with 25 Gy. One patient developed a coronary aneurysm. Initially, the dose was prescribed at 25 Gy, but review of the dosimetry showed that the actual dose delivered was 54 Gy.

Scripps Clinic investigators conducted a randomized study comparing sham radiation with coronary intravascular irradiation with LDR.^205,206,207 Eligibility for the study included patients with stenosed vessels who had previous successful stenting or angioplasty in lesions in coronary vessels larger than 3 mm. The iridium source had a strength of 100 mCi, and the mean treatment time was approximately 35 minutes. Maximum vessel and the minimum dose in the adventitia was 80 Gy (average). One patient died, and one required restenting. Results were reported in 26 patients assigned to ¹⁹²Ir and 29 assigned to a placebo. Angiographically identified restenosis (>50% of luminal diameter) was noted in 17% of the ¹⁹²Ir group and 54% of patients not irradiated (p = .01). The mean luminal diameter was larger with irradiation (2.43 mm) than with placebo (1.85 mm). Updated 3-year angiographic restenosis rates favored irradiated patients (64% with placebo vs. 33% with irradiation, p <.05), and the target lesion revascularization (TLR) rate at 5-year follow-up was significantly lower in irradiated patients (48% vs. 23%, p = .05).

Subsequently, three multi-institutional phase III trials were performed that demonstrated the advantage of endovascular radiation versus placebo (GAMMA I, START, and INHIBIT).^208–211 The GAMMA I trial²⁰⁸ was a multi-institutional phase III trial of 252 patients (12 institutions) testing the value of ¹⁹²Ir (gamma radiation) in preventing coronary in-stent restenosis. At 6-month follow-up, the rate of angiographic restenosis was reduced from 50.5% to 21.5% in favor of irradiated patients, and the TLR rate at 9 months was reduced from 45% to 24% (p = .03). The START trial²⁰⁹ was a multi-institutional phase III trial, involving 476 patients (50 centers) with in-stent restenosis, which tested ⁹⁰Sr/Y (beta radiation). At 8-month follow-up, the angiographic in-stent restenosis rate was significantly decreased from 41% with placebo to 14% with irradiation, and the TLR rate was decreased from 22% to 13% (p <.008). The INHIBIT trial^210,211 randomized 332 patients (27 institutions) with in-stent restenosis to placebo versus irradiation with ³²P (beta radiation). The in-stent angiographic restenosis rate at 9 months was decreased from 49% with placebo to 16% with irradiation (p <.0001), and the rate of major adverse cardiac events was decreased from 31% to 15% (p = .0006).

Although the above reported trials demonstrated a favorable response to endovascular irradiation, the complex interactions of two specialties (cardiology, radiation oncology) coupled with a difficult delivery system led the cardiologist to seek other treatment alternatives. Drug-eluting stents were developed and tested. The results of the drug-eluting stent trials demonstrated equal effectiveness in preventing restenosis with a much simpler cardiology approach.²¹²

Current Indications

The indications for and utilization of endovascular coronary brachytherapy have changed markedly over the past 5 to 10 years. This is primarily due to the availability and success of drug-eluting stents that dramatically decreased, or in some instances virtually eliminated, in-stent restenosis, thereby eliminating the need for routine endovascular brachytherapy. Most U.S. institutions are no longer using coronary brachytherapy in view of the drug-eluting stent success.

In those institutions that still use coronary brachytherapy, both indication and system availability have changed dramatically. The main indication for endovascular brachytherapy is “drug-resistant in-stent restenosis” after the deployment of a drug-eluting stent, either rapamycin- or Taxol-coated stents. The only endovascular brachytherapy system available is the Beta-Cath system (Novoste Corporation, Norcross, Georgia) using ⁹⁰Sr.