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