Influence of Dose on Local Control

In many animal experiments, local tumor control increases sharply with increasing irradiation dose, and the shape of the curve closely follows the theoretical model.⁵ The animal data also show that the irradiation dose needed to control a certain percentage of tumors will increase as the tumor volume increases and, conversely, that the percentage of tumors that will be controlled at a certain dose level will decrease as the volume of the tumor increases. Although a given irradiation dose may be able to control a small tumor mass with high probability and acceptable morbidity, that same dose may be ineffective against larger volume tumors that contain a larger number of clonogenic cells.

Fletcher and colleagues⁶ performed an extensive evaluation of dose–response curves of human tumors emphasizing adenocarcinoma of the breast and squamous cell carcinomas (SCCs) of the head and neck. In breast cancer, the probability of controlling subclinical nodal or chest wall disease was 60% to 70% with a dose of 30 to 35 Gray (Gy), 85% with 40 Gy, and 95% with 45 to 50 Gy (the usual fractionation was 10 Gy per week in 2.0-Gy fractions). For locally advanced breast cancers, LC required much higher doses. For these large tumors, 70% LC was achieved with doses of 90 Gy (with protracted fraction) by Fletcher⁶ versus 35% LC with doses of 50 to 60 Gy in the series of Griscom and Wang.⁷

The most extensive information on LC versus dose exists for SCCs of the head and neck. These data have been summarized by Fletcher and Shukovsky⁶ and Tepper.⁸ For microscopic disease in lymph nodes, a dose of 30 to 40 Gy produces LC in 60% to 70% of patients, compared to greater than 90% control at doses of 50 Gy in 25 fractions over 5 weeks. For early-stage primary tumors of the head and neck, a strong dose–response curve has not been demonstrated, because of good control at virtually all doses commonly used. Data compiled by Tepper for higher stage tumors indicate that 20% LC results after a dose of 46 Gy, 50% control with 58.5 Gy, and 80% control only with a very high dose of 75.5 Gy. Thus, a marked improvement in LC results from the ability to increase the tumor dose significantly.

Local Tumor Control versus Complications

For patients with locally advanced abdominal or pelvic malignancies in whom all disease cannot be removed surgically with negative margins, EBRT (with or without chemotherapy) is often only palliative, because doses greater than 45 to 50 Gy in 25 to 28 fractions cannot be delivered safely. Gastrointestinal tolerance to fractionated EBRT is demonstrated in Table 16-1.⁹ If treated with tolerable doses, patients often have local persistence or relapse of disease with secondary complications that may require hospitalization and/or reoperation for small bowel obstruction, ureteral obstruction, bowel perforation, and so on.

If microscopic residual disease exists after gross total resection (R1 resection), EBRT doses necessary to accomplish LC are ≥60 Gy in 1.8- to 2.0-Gy fractions; dose requirements would be even higher if gross residual disease remains after maximal resection. With doses ≥60 Gy, the radiation tolerance of numerous organs and structures in the abdomen and pelvis would be exceeded. Therefore, whereas an aggressive EBRT philosophy may allow better local tumor control, it may also cause severe treatment-related complications that could require hospitalization and operative intervention. If small or large bowel problems result from excessive irradiation, complications such as fistulae, perforation, and so on can occur, which usually require a reoperation.

A preferred treatment alternative for patients with locally advanced malignancies is to give tolerable EBRT doses of 45 to 50 Gy preoperatively (1.8-Gy fractions) and deliver IORT as a supplement at the time of subsequent surgical exploration and maximal resection. Dose-limiting organs can be excluded by surgical mobilization or shielding. This approach allows an increase in LC (LC curve shift to the left) with a lower risk of complications than with an EBRT-only approach (complication curve shift to the right).

EBRT With IORT

In view of the dose limitations of EBRT, the IORT approaches mentioned (IOERT, HDR-IORT, and orthovoltage) have been employed in an attempt to improve the therapeutic ratio of LC versus complications. In Japanese IOERT trials instituted in the 1960s, as well as in early US trials, IOERT was the sole radiation modality, with single doses of 20 to 40 Gy using electron beams.

Massachusetts General Hospital (MGH) and Mayo Clinic investigators preferred to use IOERT as a boost dose in combination with conventional fractionated EBRT with or without chemotherapy and maximal surgical resection as indicated by site. This preference was based on several potential advantages that exist when a combined EBRT-IORT approach is used instead of IORT alone: (1) improvement in local-regional control (LRC) because of a decreased risk of marginal relapse (areas at risk are included in the EBRT fields) and the radiobiological advantages of fractionated irradiation; (2) less risk of normal tissue damage or necrosis. The excellent long-term results achieved with EBRT-plus-boost techniques for breast, gynecologic, and head and neck cancers support the concept of this combined approach, because good LC is achieved with relatively low morbidity to dose-limiting normal tissues. The only difference is the method of delivering the boost dose. Patients with head and neck and breast lesions require interstitial techniques or fractionated outpatient electrons; gynecologic lesions are treated with an intracavitary technique; IOERT or HDR-IORT are used for intra-abdominal, pelvic, or thoracic lesions.

The combination of IORT with EBRT has the potential to improve the therapeutic ratio of LC versus complications by allowing several benefits: (1) decreasing the volume of the irradiation boost field by direct tumor visualization and appositional treatment with IORT; (2) excluding all or part of dose limiting sensitive structures by operative mobilization or shielding or the use of appropriate electron energies; and (3) increasing the effective dose (both of the preceding benefits).

Shrinking Field Techniques

The rationale for shrinking field irradiation techniques, using EBRT alone or EBRT plus brachytherapy, has been in existence for many decades. The initial EBRT field is usually designed to include a 3- to 5-cm margin beyond the primary or recurrent tumor plus regional nodal areas that are at risk for metastatic spread. Initial fields are treated to an accepted subclinical dose level of 45 to 50.4 Gy in 1.8- to 2.0-Gy fractions. Subsequent boost techniques are used to bring gross disease to the level of 65 to 80 Gy with EBRT or brachytherapy techniques. The excellent long-term results achieved with EBRT plus boost techniques for breast, gynecologic, and head and neck cancers support the concept of this combined approach, because good LC is achieved with relatively low morbidity to dose-limiting normal tissues. Combining IORT with EBRT with or without resection for abdominal and pelvic malignancies is an extension of this philosophy.

Impact of Local Control on Distant Metastases

In the ASTRO Gold Medal paper of Dr. Herman Suit,¹⁰ the theme of distant metastases developing from a locally recurrent tumor was discussed as a component of the overall premise that LC benefits survival. Data were presented from several spontaneous tumor systems to suggest that the rate of distant metastases was related to both tumor size and disease presentation as primary versus locally recurrent disease. In both the spontaneous fibrosarcoma FSaII and SCC VII lines in the C3H/Sed mouse, Ramsey et al. reported increased rates of distant metastases with 6-mm versus 12-mm tumor size and primary versus recurrent tumors.¹¹ Ramsey’s work confirmed an earlier evaluation by Suit et al.¹² in which 12-mm isotransplants of C3H mouse mammary tumors were treated with single-dose irradiation and evaluated for disease control both locally and distantly. The rate of distant metastases increased with lack of LC. The incidence of distant metastases was 31% (16 of 52) in mice with LC, 50% (9 of 18) in those with local relapse who were salvaged with further resection, and 80% (12 of 15) in mice with local relapse in whom salvage was not attempted.

Human data were also quoted to support the thesis of metastases arising from the local relapse. For patients with squamous cell cancers of the cervix, prostate, and head and neck cancers, the metastatic frequency was higher in patients with local relapse than in those with LC.^13–16

Patient Selection Criterion

Appropriateness for IORT should be determined by the surgeon and radiation oncologist in the setting of a joint preoperative consultation whenever feasible. This allows input from both specialties with regard to studies that would be helpful for IORT and EBRT planning and whether IORT is appropriate. Informed consent can be obtained with regard to potential benefits and risks, and optimal sequencing of surgery and EBRT can be discussed and determined.

The following general criteria have guided the selection of appropriate patients for IORT at our institutions: (1) Surgery alone will not achieve acceptable LC (i.e., more than microscopic residual disease after maximal resection). By definition, there must be no medical contraindications for a surgical attempt at gross total resection. (2) EBRT doses needed for adequate LC following subtotal resection or no resection would exceed normal tissue tolerance (60 to 70 Gy in 1.8- to 2.0-Gy fractions for microscopic residual disease; 70 to 90 Gy for gross residual or unresected disease). (3) IORT will be performed at the time of a planned operative procedure. (4) The IORT-plus-EBRT technique would theoretically result in a more suitable therapeutic ratio between cure and complications by permitting direct irradiation of marginally resected or unresected tumor, with single or abutting fields, while surgically displacing or shielding dose-limiting structures or organs. (5) There is no evidence of distant metastases or peritoneal seeding (rare exceptions: resectable single organ metastasis, excellent chemotherapy options, slow progression of systemic disease).

Patient Evaluation

The pretreatment work-up should include a detailed evaluation of the extent of the locally advanced primary or recurrent lesion combined with studies to rule out hematogenous or peritoneal spread of disease. In addition to history and physical examination, routine evaluation includes complete blood count (CBC), liver and renal chemistries, chest film, and serum tumor markers (CEA, CA 19-9, CA-125). When palpable pelvic lesions are immobile or fixed on rectal or bimanual examination or symptoms suggest pelvic relapse following initial resection, computed tomography (CT) or magnetic resonance imaging (MRI) can confirm lack of free space between the malignancy and a structure that may be surgically unresectable for cure (e.g., presacrum, pelvic sidewall). In such patients, preoperative EBRT with or without concurrent chemotherapy should be given before an attempt at resection. Extrapelvic spread to para-aortic nodes or liver can also be determined. If hematuria is present or findings on CT or excretory urogram suggest bladder involvement, cystoscopy is done before or on the day of surgery.

Sequencing of Surgery, EBRT, and IORT

Optimal sequencing of surgery and EBRT for locally advanced cancers should be discussed and determined at the time of a joint multispecialty consultation involving a surgeon, radiation oncologist, and medical oncologist. This allows input from all specialists with regard to studies that would be helpful for IORT and EBRT treatment planning and whether IORT may be appropriate. Whenever feasible, total or gross total resection of disease is performed before or after EBRT. Resection is an almost uniform component of IORT-containing regimens with esophagogastric, colorectal, gynecologic, and renal cancers and abdominal-pelvic sarcomas, but is less feasible with biliary and pancreatic cancers.

For many patients with locally advanced lesions, pre-op EBRT of 45 to 50 Gy in 1.8- to 2.0-Gy fractions (with or without chemotherapy as indicated) followed by exploration and resection in 3 to 5 weeks offers theoretical advantages over a sequence of resection and IORT followed by EBRT. Theoretical advantages are as follows: (1) deletion of patients with metastases detected at the restaging work-up or laparotomy, thus, sparing the potential risks of aggressive surgical resection with or without IORT; (2) possible tumor shrinkage with an increased possibility of achieving a gross total resection; (3) potential alteration of implantability of cells that may be disseminated at the time of a marginal or partial surgical resection; (4) reduction of treatment interval between EBRT and IORT (if resection/IORT precede EBRT, postoperative complications could delay EBRT/chemotherapy excessively); and (5) intact vascular supply to tumor with better oxygenation.

Dose and Technique: EBRT

The method of EBRT has been fairly consistent in most US and European single-institution and group studies. EBRT doses of 45 to 54 Gy are delivered in 1.8-Gy fractions 5 days per week over 5 to 6 weeks in patients who have had no previous irradiation. For pelvic lesions, treatments are given with linear accelerators using ≥10 MV photons and three-dimensional (3D) conformal radiation therapy (3DCRT) or intensity-modulated irradiation (IMRT) techniques. With extrapelvic lesions, unresected or residual disease plus 3- to 5-cm margins of normal tissues are included to 40 to 45 Gy with 3DCRT or IMRT. Reduced fields with 2 to 3 cm margins are treated with 45 to 54 Gy.

With a variety of malignancies (gastrointestinal [GI], gynecologic, other), concurrent chemotherapy is often given during external irradiation with 5-FU or cisplatin-based regimens. In patients who have had no previous irradiation, doses of 45 to 54 Gy are delivered in 1.8-Gy fractions 5 days per week over 5 to 6 weeks. For previously irradiated patients, an attempt is made to reirradiate with low dose preoperative EBRT doses of 20 to 30 Gy in 1.8- to 2.0-Gy fractions, preferably with concurrent chemotherapy. The use of routine patient immobilization devices, CT-based treatment planning, positron emission tomography (PET)/CT fusion, IMRT, and image-guided irradiation (IGRT) with onboard imaging has been instituted in some institutions for patients with previous EBRT in attempts to improve patient tolerance and facilitate dose escalation of the EBRT component of treatment.

Technique and Dose: IORT

The technical aspects of both the surgical and irradiation components of IORT procedures have been discussed in detail in previous publications^1–3 and will not be reiterated in detail. A carefully constructed team including surgeons, radiation oncologists, anesthesiologists, operating room nursing staff, radiation physics and dosimetry staff, and radiation therapists must jointly oversee IORT procedures.

Following surgical exploration and maximal resection, the radiation oncologist joins the surgeon in the operating room to determine whether IORT is indicated and technically feasible, based on a review of surgical-pathologic findings. The site of the IORT treatment field is determined and marked with sutures or clips. If the IORT treatment machine is in the radiation oncology department, the patient will then be transferred to a stretcher for transport after temporary closure of incisions, and placed on the linear accelerator table in the radiation oncology department for IOERT treatment. If the institution has a mobile X-band accelerator (Mobetron, electron energies of 4 to 12 MeV) that can be brought to the operating room, the IOERT applicator is immobilized in position with a modified Buchwalter retractor after the applicator size and shape has been selected to encompass the tumor bed or unresected disease with a margin of ∼1 cm (Fig. 16-1A-F). The operating room table is then shifted adjacent to the IOERT machine and the gantry angle of the mobile accelerator is adjusted to provide alignment between the IOERT applicator and the accelerator head (Fig. 16-1G-I). The IORT team exits the room and IOERT is delivered while the patient and anesthesia equipment are monitored. The operating room table is then shifted back to the original location for surgical reconstruction and closure of incisions.

FIGURE 16-1 • IOERT applicator options, placement, and docking: A, Lucite applicators, flat and bevel ends; B, Mobetron metal applicators with flat and bevel ends; C, placement of IOERT applicator after resection of upper abdomen malignancy, Mayo Clinic Arizona Hospital; D, immobilization of portable IOERT Mobetron system metal applicator to operating room table with modified Buchwalter retractor; E, F, Checking accurate placement by viewing down the IOERT applicator with light source; G, Mobetron in position in the operating room; H, shift of operating room table adjacent to Mobetron; I, docking of IOERT applicator using Mobetron gantry angle rotation and laser light alignment. IOERT, Intraoperative electron radiation therapy.

The IOERT energy and dose are dependent on the amount of residual disease remaining after maximal resection and on the EBRT component that is feasible (Figs. 16-2 and 16-3). When an R0 or R1 resection has been accomplished, 6 or 9 MeV electrons would provide adequate depth dose, but for R2 resection or unresectable disease, 9- to 12-MeV electron energies or higher would be necessary to ensure adequate depth dose coverage (Fig. 16-2). If previously unirradiated patients have received preoperative doses of 45 to 54 Gy (1.8-Gy fractions 5 days per week), the IORT dose usually varies from 10 to 20 Gy: microscopic residual disease or less, 10 to 12.5 Gy; gross residual disease, 15 to 20 Gy. In previously irradiated patients, the IORT dose is usually 15 to 20 Gy if EBRT doses of 20 to 30 Gy can safely be given pre- or postoperatively. IORT doses of 25 to 30 Gy have been given to patients in whom no or limited EBRT is planned, but such doses have higher risks of nerve intolerance. The biologic effectiveness of single-dose IORT is considered equivalent to 1.5 to 2.5 times the same total dose of fractionated EBRT.¹⁷ The effective dose in the IOERT field, when added to 45 to 50 Gy given with EBRT, is 60 to 70 Gy for 10-Gy IOERT, 75 to 87.5 Gy with a 15-Gy boost, and 85 to 100 Gy with 20-Gy IOERT.

FIGURE 16-2 • Depth dose of 6, 9, and 12 MeV electrons with nonbevel applicator on the Mobetron mobile accelerator using film measurements.

FIGURE 16-3 • Depth dose and isodose distributions for a 10-cm circular and 8 × 15 cm flat and 20-degree beveled applicators using 9 MeV electrons on the Mobetron (the effect of applicator shape and bevel angle on dose distribution is demonstrated). A, Depth doses for 8 × 15 cm bevel 20, 8 × 15 cm bevel 0 and 10 cm bevel 0 applicators. B, Isodose distribution for 8 × 15 cm bevel 20. C, Isodose distribution for 8 × 15 cm bevel 0. With the beveled applicators, the isodose curve is more shallow at the heel-end versus the toe-end of the applicator.

IORT is given with IOERT, HDR-IORT, or orthovoltage machines, depending on institutional preference and available technology. Some institutions have both IOERT and HDR-IORT equipment and choose which to use according to anatomical constraints and amount of residual disease after maximal resection (i.e., HDR-IORT is not ideal if thickness of residual disease exceeds 0.5 cm).⁴ If both are technically feasible, IOERT is often chosen because of shorter set-up and treatment times, better depth dose, and more homogeneous dose distribution. Since IOERT is delivered with rigid Lucite or metal applicators, some locations may be anatomically challenging, and HDR-IORT with malleable flab applicators may be preferable, if available.

In IOERT only institutions that have a wide variety of applicators including 15° and 30° beveled ends (Fig. 16-1A,B), the combination of applicator choice and patient position can usually result in a successful treatment. Most abdominal sites are usually easily treated with IOERT approaches using either flat or 15° bevel applicators (Fig. 16-1C-F). For pelvic lesions, the availability of 30° bevel applicators usually allows successful approximation of the IOERT applicator to the tumor bed whether treated through the abdominal incision (Fig. 16-4) or the perineal incision after abdominal-perineal resection (Fig. 16-5).

FIGURE 16-4 • Anterior-inferior pelvic IOERT docking via the abdominal incision on fixed linear accelerator in the Mayo Clinic Rochester shielded IOERT operating room at Methodist Hospital: A, view down applicator; B, lateral view of applicator with ∼45° gantry angle; C, anterior view of applicator. IOERT, Intraoperative electron radiation therapy.

FIGURE 16-5 • Perineal IOERT docking for patients with T4 rectal cancers with adherence to the prostate.

A-C, Patient in prone position on a linear accelerator table in the MCR radiation oncology department: A, patient in prone position with hip flexion due to wedge placement under hips; B, prostate seen via the perineal incision; C, applicator placement/treatment. D-F, Patient in supine position on a fixed linear accelerator in the MCR shielded IOERT operating room; D, prostate seen within Lucite applicator; E, lateral view of applicator; F, note gantry angle beyond 90°. G-I, Patient in prone position for treatment with Mobetron mobile accelerator in Mayo Clinic Arizona operating room: G, patient in prone position with head and chest support. I, soft docking with laser light alignment, gantry angle of ∼45°. IOERT, Intraoperative electron radiation therapy; MCR, Mayo Clinic Rochester.

Summary

Many patients who are candidates for IOERT present with pain from recurrent tumors due to neurologic tumor compression or invasion. Although all patients receive informed consent about possible nerve-related side effects, they are aware that with uncontrolled tumor they will often have similar side effects. On the basis of both human and animal data, when a full component of EBRT options exist, (i.e., 45 to 54 Gy fractionated EBRT can be delivered), an IORT boost dose of 10 to 20 Gy should be used, depending on the amount of tumor remaining after maximal resection. If a marginal gross total resection can be accomplished after full dose pre-op EBRT, the IORT dose can be limited to 10 to 12.5 Gy, with an associated decreased risk of neuropathy. IORT doses more than 20 Gy to 25 Gy are used in our institutions only when EBRT doses must be limited because of previous EBRT.

EBRT Plus Chemotherapy

For unresectable lesions, the use of EBRT plus concurrent 5-FU or gemzar-based chemotherapy results in a doubling of median survival rate (SR) compared with surgical bypass or stents alone (median SR: 3 to 6 months vs 9 to 13 months) and an increase in 2-year SR from 0%-5% to 10%-20%.^35–39 However, 5-year SR is rare and LC is low. In a series from Thomas Jefferson University (TJUH) using EBRT doses of 60 to 70 Gy in 1.8- to 2.0-Gy fractions over 7 to 8 weeks, LC was achieved in less than 20% of patients treated with EBRT alone.^35–36 With EBRT plus chemotherapy, LC was achieved in ∼30% of patients.

IORT Alone or Plus EBRT

The combination of EBRT plus IOERT has resulted in an improvement in LC in IOERT series from MGH, Mayo, and TJUH^37,39–45 (Table 16-5). This has not, however, translated into major improvements in either median or 2-year survival. The delivery of EBRT plus concurrent chemotherapy before restaging and laparotomy plus IOERT or resection plus IOERT translates into improved patient selection and some improvement in median and 2-year survival.^41,45

EBRT Alone or Plus Chemotherapy

When EBRT with or without chemotherapy is utilized for patients with residual disease after resection or unresected lesions, most trials show an advantage to combined versus single modality treatment (EBRT plus chemotherapy versus EBRT or chemotherapy alone). Long-term survival is 10% to 15%.^47,48

IORT Alone or Plus EBRT

For partially resected gastric cancer, the use of IOERT alone or in conjunction with EBRT has yielded a 5-year SR of 15% to 20%.^47–58 Abe and Takahashi reported a Kyoto trial of surgery with or without IOERT in 211 patients in which subset analyses suggested SR advantages with IOERT for Japanese stages II to IV.^49–51 The 5-year SR for stage IV disease in 27 IOERT patients was 15% (versus 0% for 18 patients treated with surgery alone; three of four IOERT survivors had residual disease). Five-year results with stages II and III were 84% (versus 62% for patients treated with surgery alone) and 62% (versus 37%). In a Pamplona pilot study, EBRT with or without chemotherapy has been combined with IOERT in 48 patients (EBRT doses of 46 Gy in 1.8- to 2.0-Gy fractions; IOERT dose usually 15 Gy).⁵² In 13 patients with stage IV disease, in-field relapse occurred in only three patients. Two of eight patients with known residual disease after maximal resection were long-term disease-free survivors (>22 and >65 months).

Separate randomized trials have been reported from Beijing⁵³ and the NCI.⁵⁴ In the Beijing series, patients with stage III (serosal involvement or node positive tumors) or IV disease (unresectable metastases or adjacent organ involvement) were randomized to surgery with or without IOERT (25 to 40 Gy). In a report of 200 patients,³⁷ a SR advantage with IOERT was shown for stage III patients (5-year SR: 65% versus 30%; 8-year SR: 52% versus 22%; P < .01). At NCI, Sindelar et al. performed a small randomized trial of IOERT versus EBRT after complete resection, which demonstrated improved LC with IOERT but no SR benefit.⁵⁴

A series of 24 patients with esophageal or gastric cancer received IOERT as a component of treatment at MCR in conjunction with pre- or post-op EBRT and maximal resection.⁵⁸ Local and regional control of disease was excellent (85% at 5-year) but survival was less than optimal in view of the ∼80% rate of distant metastases.

MCR analyses demonstrated that even patients with local or regional relapse of gastric cancer may be candidates for salvage with aggressive approaches that includes IOERT as a component of treatment. For patients who received preoperative EBRT plus concurrent chemotherapy followed by maximal resection and IOERT, 4-year survival was ∼20%⁵⁷ and 5-year survival exceeded 10%.⁵⁸

EBRT Alone or Plus Chemotherapy/Resection

EBRT has been combined with resection and chemotherapy for locally advanced colorectal cancers. In separate series from Princess Margaret Hospital (PMH) and Mayo Clinic, using EBRT alone (PMH, Mayo) or combined with systemic therapy (Mayo), the local relapse rate was more than 90% in evaluable patients.⁵⁹Although a combination of EBRT (with or without 5-FU) with surgery for residual disease after subtotal resection or initially unresectable disease produces better LC than no resection, local relapse is too high at 30% to 50%. For locally recurrent rectal cancers, EBRT with or without chemotherapy results in excellent short-term palliation (6 to 12 months), but LC and long-term survival are infrequent (0% to 5%; 5 years).⁶⁰

EBRT Plus IORT: Primary Unresectable Cancers

In an attempt to decrease local recurrence and improve survival, institutions in the United States, Europe, Japan, and Scandinavia have combined an IORT boost with fractionated EBRT (45 to 50 Gy in 1.8-Gy fractions) and resection.^32,59–67 In US studies, the IOERT dose varies from 10 to 20 Gy, depending on the amount of residual disease after maximal resection (microscopic: 10 to 12.5 Gy; gross <2 cm: 15 Gy; gross ≥2 cm or unresectable: 17.5 to 20 Gy. The HDR-IORT dose at Memorial Sloan-Kettering Cancer Center (MSKCC) has been 12 or 15 Gy as calculated at a 0.5 cm distance from the Harrison-Anderson-Mick (HAM) applicator surface.^62,63