High-dose-rate intraoperative radiation therapy (HDR-IORT) for retroperitoneal sarcomas

PURPOSE: Retroperitoneal sarcomas represent a formidable challenge to the treating oncologist due to their location, large size, and poor prognosis. The purpose of this study was to determine if the addition of high-dose-rate intraoperative radiation therapy (HDR-IORT) to surgery and external beam radiotherapy (EBRT) would improve the outcome in these patients. METHODS AND MATERIALS: Thirty-two patients with retroperitoneal soft tissue sarcoma were prospectively treated according to a protocol that included maximal tumor resection, HDR-IORT, and postoperative EBRT when feasible. Twelve patients presented with primary and 20 with locally recurrent disease. The tumors were high-grade in 20 patients and low-grade in 12 patients. Complete gross resection was achieved in 30 patients. HDR-IORT was given to a dose of 12-15 Gy. Additional EBRT was given to 78% of patients to a dose of 45-50.4 Gy. The two patients with gross residual disease received an additional I-125 permanent implant to a median peripheral dose of 140-160 Gy. The median follow-up was 33 months (range 1-77 mo). RESULTS: The 5-year actuarial local control rate for the whole group was 62%. For patients with primary disease, the local control rate was 74% compared to 54% in patients with recurrent disease (p = 0.4). The overall 5-year distant metastasis-free survival rate was 82%. In patients with high-grade tumors the rate was 70% vs. 100% in those with low-grade tumors. This difference was statistically significant, p = 0.05. The 5-year disease-free and overall survival rates were 55% and 45%, respectively. The most common type of post-treatment complication was gastrointestinal obstruction (18%) followed by fistula formation (9%), peripheral neuropathy (6%), hydronephrosis (3%), and wound complication (3%). CONCLUSIONS: We are encouraged by the favorable local control rate and the acceptable morbidity with this new technique applied to a challenging patient population.     

The influence of surgical margins on advanced cancer treated with intraoperative radiation therapy (IORT) and surgical resection

Intraoperative radiation therapy (IORT) has been used successfully in the treatment of malignancies, alone and as an adjunct to surgical resection. This study examined a single institution's experience with combined IORT and surgical resection in the treatment of advanced cancer. The records of 41 consecutive patients undergoing intraoperative radiation therapy (IORT) at the Fox Chase Cancer Center, from My 1987 through March 1990, were retrospectively reviewed. All patients had locally advanced disease, of whom 73% had failed previous multimodality therapy and 44% had undergone prior radiation therapy (XRT). The 2-year actuarial survival for the entire cohort was 72%. Disease-free survival was 47% at 1 year and 5% at 2 years. The only important prognostic factor predicting outcome was status of the surgical margin. Positive surgical margins decreased the 2-year actuarial survival from 100% to 59%, and increased the local failure rate from 21% to 52%. Margin status had no effect on the later development of metastatic diseae. Higher IORT doses, field sizes >7 cm, and multiple IORT fields were used for larger tumors and larger amounts of residual disease. These parameters alone did not correlate with improved local control. This analysis suggests the usefulness of aggressive surgical resection with IORT in extending survival for locally advanced or recurrent cancer. Negative margin status is the best predictor of a favorable outcome and should be used to select patients who may benefit from IORT. The use of radiation sensitizing agents should be explored in patients with positive margins, since in-field failure continues to be the major pattern of failure. IORT in conjunction with aggressive surgical resection should continue to be studied in prospective randomized clinical trials. © 1993 Wiley-Liss, Inc.     

High dose rate intraoperative radiation therapy (HDR-IORT) as part of the management strategy for locally advanced primary and recurrent rectal cancer

Purpose: Primary unresectable and locally advanced recurrent rectal cancer presents a significant clinical challenge. Local failure rates are high in both situations. Under such circumstances, there is a significant need to safely deliver tumoricidal doses of radiation in an attempt to improve local control. For this reason, we have incorporated a new approach utilizing high dose rate intraoperative radiation therapy (HDR-IORT).Methods and Materials: Between 11/92–12/96, a total of 112 patients were explored, of which 68 patients were treated with HDR-IORT, and 66 are evaluable. The majority of the 44 patients were excluded for unresectable disease or for distant metastases which eluded preoperative imaging. There were 22 patients with primary unresectable disease, and 46 patients who presented with recurrent disease. The histology was adenocarcinoma in 64 patients, and squamous cell carcinoma in four patients. In general, the patients with primary unresectable disease received preoperative chemotherapy with 5-fluorouracil (5-FU) and leucovorin, and external beam irradiation to 4500–5040 cGy, followed by surgical resection and HDR-IORT (1000–2000 cGy). In general , the patients with recurrent disease were treated with surgical resection and HDR-IORT (1000–2000 cGy) alone. All surgical procedures were done in a dedicated operating room in the brachytherapy suite, so that HDR-IORT could be delivered using the Harrison-Anderson-Mick (HAM) applicator. The median follow-up is 17.5 months (1–48 mo).Results: In primary cases, the actuarial 2-year local control is 81%. For patients with negative margins, the local control was 92% vs. 38% for those with positive margins (p = 0.002). The 2-year actuarial disease-free survival was 69%; 77% for patients with negative margins vs. 38% for patients with positive margins (p = 0.03). For patients with recurrent disease, the 2-year actuarial local control rate was 63%. For patients with negative margins, it was 82%, while it was 19% for those with positive margins (p = 0.02). The disease-free survival was 47% (71% for negative margins and 0% for positive margins) (p = 0.04). Prospective data gathering indicated that significant complications occurred in approximately 38% of patients and were multifactorial in nature, and manageable to complete recovery.Conclusion: HDR-IORT using our technique is versatile, safe, and effective. The local control rates for primary disease compare quite well with other published series, especially for patients with negative margins. For patients with recurrent disease, locoregional control and survival are especially encouraging in patients with negative resection margins. Further follow-up is needed to see whether these encouraging data will continue.     

Treatment of locally advanced rectal cancer with external beam radiation, surgical resection, and intraoperative radiation therapy

To try to improve the local control and survival of patients with locally advanced rectal cancer we have used a combination of high-dose pre-operative radiation therapy to 5,040 cGy followed by surgical resection and intraoperative electron beam radiation therapy (IORT) when there was visible or palpable residual disease, microscopically positive surgical margins, or persisting tumor adherence. A total of 75 patients were taken to surgery for resection +/- IORT who did not have distant metastases. Of the 49 patients with primary tumors, 11 did not have IORT as the tumor was thought to be completely resected. Of these 11, there were two local recurrences and a 3-year survival of 71%. Thirty-six patients with primary tumors had resection (20 complete, 16 partial) plus IORT, with a 3-year survival of 58% and three local failures. Twenty-six additional patients were treated for locally advanced recurrence of whom four could not receive IORT because of pelvic size or the extent of tumor. Of the 22 who received IORT, 7/9 with complete resection, 2/8 with partial resection, and 1/5 with no resection had local control with an overall 3-year actuarial survival of 32%. The local control and survival results in the primary tumors appear favorable compared to other series in the literature and suggest benefit to the use of IORT. For patients treated for local recurrence, local control and long-term survival can be obtained, but the results are not as encouraging as for the primary tumors.     

Survival after attempted surgical resection and intraoperative radiation therapy for pancreatic and periampullary adenocarcinoma

PURPOSE: To evaluate a single institution's experience with intraoperative radiation therapy (IORT) in combination with attempted surgical resection for pancreatic and periampullary adenocarcinoma. METHODS AND MATERIALS: From May 1986 until June 2001, 77 patients at LDS Hospital underwent attempted surgical resection and IORT for pancreatic or periampullary adenocarcinoma. A potentially curative resection was defined as surgery with negative or microscopic positive margins. No patients had metastatic disease at the time of surgery and IORT. Forty-four patients with tumors located in the pancreas and 9 patients with periampullary tumors underwent potentially curative surgical resection and IORT. Twenty-four patients had pancreatic tumors deemed unresectable and underwent surgical bypass and IORT. Actuarial survival was calculated from the date of IORT until last follow-up or death by use of the Kaplan-Meier method. RESULTS: Patients undergoing a potentially curative resection and IORT for periampullary adenocarcinoma had a median survival of 167 months and a 56% 5-year actuarial survival, compared with a median survival of 16 months and a 19% 5-year actuarial survival for patients undergoing the same treatment for pancreatic adenocarcinoma (p = 0.03). Patients with unresectable disease who underwent bypass and IORT had a median survival of 11 months and a 0% 3-year survival, significantly worse than patients able to undergo surgical resection and IORT (p = 0.0002). The operative mortality for all patients undergoing potentially curative resection and IORT was 3.7%. CONCLUSIONS: Intraoperative radiation therapy is well tolerated and does not increase the morbidity or mortality of potentially curative surgical resection for pancreatic or periampullary adenocarcinoma. Patients with periampullary adenocarcinoma have a better prognosis than those with pancreatic adenocarcinoma, and patients with unresectable pancreatic disease fared worse.     

Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma.

PURPOSE: The primary objective of this phase I trial was to define the maximum-tolerated dose of external-beam radiation with concurrent fixed-dose continuous-infusion doxorubicin followed by surgical resection and electron-beam intraoperative radiation therapy (EB-IORT) for patients with localized, potentially resectable retroperitoneal sarcomas (RPS). PATIENTS AND METHODS: Thirty-five patients with radiographically resectable primary or recurrent intermediate- or high-grade RPS were treated. Doxorubicin was administered each week for 4 or 5 weeks as an initial bolus (4 mg/m2) followed by a 4-day continuous infusion (4 mg/m2/d). Concurrent radiation therapy was administered in escalating doses of 18.0, 30.6, 36.0, 41.4, 46.8, or 50.4 Gy in 1.8-Gy fractions. Radiographic restaging was performed 4 to 8 weeks after chemoradiation, and patients with localized disease underwent surgical resection with EB-IORT (15 Gy). RESULTS: Chemoradiation was completed as outpatient therapy in 31 patients (89%); four patients required hospital admission during chemoradiation or in the postchemoradiation preoperative period. At the highest radiation dose of 50.4 Gy, two (18%) of 11 patients had grade 3 or 4 nausea. Twenty-nine patients (83%) underwent laparotomy; six patients had interval disease progression and did not undergo surgery. Grossly complete resection (R0 or R1) was performed in 26 (90%) of 29 patients who had surgery. EB-IORT was feasible and successfully administered to 22 patients who had R0 or R1 resections. CONCLUSION: Preoperative chemoradiation, surgical resection, and EB-IORT are feasible for patients with RPS. Preoperative external-beam radiation can be administered to a total dose of 50.4 Gy with continuous-infusion doxorubicin.     

The role of intraoperative radiation therapy (IORT) in the treatment of locally advanced gynecologic malignancies

The prognosis in women with locally advanced primary or recurrent gynecologic malignancies is rather poor. Doses of external beam radiation necessary to treat gross or microscopic recurrence among patients surgically treated or previously irradiated exceed what is tolerated by normal structures. In this group of patients, intraoperative radiation therapy (IORT) can be utilized to maximize local tumor control, minimizing the radiation exposure of dose-limiting surrounding structures. Review of the available literature indicates that IORT may improve long-term local control and overall survival in women with pelvic sidewall and/or para-aortic nodal recurrence. The most encouraging results have been reported in the cases of microscopic residual disease, following surgical debulking.     

Stereotactic body radiation therapy for the treatment of locally recurrent pancreatic cancer after surgical resection

BackgroundTo report on a cohort of radiation-naïve patients with pancreatic cancer who developed isolated local recurrence following surgical resection and were subsequently treated with stereotactic body radiation therapy (SBRT).MethodsPatients with pancreatic cancer who were treated with SBRT for isolated local recurrence after surgical resection were retrospectively reviewed. Clinical outcomes were calculated from completion of SBRT and included overall survival (OS), local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS). Univariate (UVA) analysis was performed to identify variables associated with clinical outcomes. Kaplan-Meier method was used for survival outcomes. Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0.ResultsFrom September 2012 to November 2018, a total of 19 patients with localized pancreatic cancer were treated with SBRT for isolated local recurrence after initial surgical resection. No patients had prior radiation. The median biologically effective dose (BED₁₀) was 54.8 Gy (range, 37.5–54.8 Gy). Median OS was 17.1 months, with 6-month and 1-year OS rates of 94.4% and 69.6%, respectively. Nine patients (47.4%) developed local failure after SBRT. Pattern of first failure after SBRT was distant in 7 patients (46.7%), local in 5 patients (33.3%), and synchronous distant and local in 3 patients (20.0%). One patient developed local failure after developing distant disease first. Of the 9 local failures, 3 (33.3%) were out-of-field. Median LPFS was 22.2 months, with 6-month and 1-year LPFS rates of 86.9% and 63.2%, respectively. A BED₁₀ <54.8 Gy was associated with inferior LPFS (1-year, 25.0% vs. 80.2%, P<0.009). Median DMFS and PFS were 15.6 months. There was 1 case (5.3 %) of grade 3 gastric perforation. There were no cases of grade 4–5 toxicity events.ConclusionsSBRT for locally recurrent pancreatic cancer after initial curative resection is safe and feasible. A BED₁₀ <54.8 Gy was significantly associated with inferior local control. Further studies investigating dose escalation and optimal treatment volumes in the locally recurrent setting are warranted.     

Phase II trial of induction high-dose chemotherapy followed by surgical resection and radiation therapy for patients with marginally resectable non-small cell carcinoma of the lung

The combination of carboplatin and paclitaxel is an active regimen in non-small cell lung cancer (NSCLC). Historically, patients with stage III disease have manifested higher response rates than patients with metastatic disease, and patients achieving a pathologic complete response to induction chemoradiation therapy prior to surgery have shown better long-term outcome. Based upon our pilot data using high-dose carboplatin and paclitaxel, we designed a phase II trial in patients with marginally resectable stage IIIA NSCLC. Ten patients, with bulky nodal stage IIIA disease, initially received etoposide (2 g/m2) and granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells (PBSC). Two cycles, 28 days apart, of carboplatin (AUC 12 in seven patients; AUC 16 in three patients) and paclitaxel (250 mg/m2) were administered with filgrastim (5 microg/kg) and PBSC support. After re-evaluation, patients underwent a thoracotomy followed by radiotherapy (44-60 Gy) if deemed resectable, or radiotherapy alone (60 Gy) if not resectable. The median age was 58.5 years (48-66) with a median ECOG performance status of 0 (0-1). Histology was adenocarcinoma in seven patients; the remainder had either squamous cell, large cell or bronchoalveolar carcinoma. Based on CT radiography, the overall response rate was 40%. Eight of ten patients underwent resection with four right pneumonectomies, three right upper lobectomies and one wedge resection of the right upper lobe. Six patients had a complete resection. Of eight patients resected, four were downstaged by induction therapy, three remained unchanged and one was found to have more extensive disease. The remaining two patients developed metastatic disease while receiving chemotherapy. The median dose of postoperative radiotherapy was 54 Gy (35-66 Gy). Actual median follow-up for all patients was 89 weeks (25 to 136+). The actuarial median overall survival was 124 weeks (25 to 136+) and time to progression was 57 weeks (17 to 136+). The median dose of carboplatin delivered expressed as mg/m2 was 779 (615-1540). Neutropenic fever occurred in two patients during the initial mobilization cycle only. The median number of units of RBC and/or platelets transfused was 0 (0-2 and 0-6, respectively). There were no significant non-hematologic toxicities. High-dose induction chemotherapy with stem cell rescue is feasible and safe with an acceptable response rate. Thoracotomy, including pneumonectomy and postoperative radiotherapy, were well tolerated by patients after undergoing high-dose induction chemotherapy with no apparent increase in peri-operative morbidity. The pathologic complete response rate was low--one out of ten patients. These results indicate that dose escalation of induction chemotherapy does not improve response rates even in this highly selected patient population. Accordingly, the complexity and potential toxicity of high-dose chemotherapy, as delivered in this trial as neoadjuvant treatment of non-small cell lung cancer, is not warranted.     

Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome

BACKGROUND: Rectal carcinoma patients with local recurrence are reported to have a dismal prognosis. The purpose of this study was to evaluate the effect of combined modality therapy on clinical outcome and to determine the prognostic impact of a "presurgical" staging system. METHODS: Between September 1989 and June 1997, 47 patients (with a median follow-up of 80 months) with locally recurrent, nonmetastatic rectal carcinoma were classified according to the extent of pelvic sidewall involvement as determined by pretreatment computed tomography (CT) scan. They received preoperative external beam radiation (45-47 grays [Gy] in 34 patients; 23.4 Gy in 13 preirradiated patients) plus concomitant 5-fluorouracil (1000 mg/m(2)/day as a 96-hour continuous infusion on Days 1-4 + 29-32) and mitomycin C (10 mg/m(2) as a bolus intravenously on Day 1 + 29). After 4-6 weeks, the patients were evaluated for surgical resection and intraoperative radiation therapy (IORT) procedure (10-15 Gy) or, in unresectable patients, a boost dose was planned by chemoradiation (23.4 Gy) or brachytherapy. Thereafter, adjuvant chemotherapy (5-fluorouracil and leucovorin for a total of six to nine courses) was prescribed. RESULTS: During chemoradiation, 2 patients (4.3%) developed Radiation Therapy Oncology Group Grade 3-4 acute toxicity. Twenty-five patients (53. 2%) had an objective response after chemoradiation. Twenty-one patients (45%) underwent radical surgical resection. The overall 5-year survival and local control rates were 22% and 32%, respectively. The classification system significantly predicted survival (P = 0.008). Radically resected patients had better local control and survival (P < 0.0001); in patients treated with IORT, the 5-year local control and survival rates were 79% and 41%, respectively. CONCLUSIONS: The data from the current study suggest that combined modality therapy was well tolerated and improved resectability, local control, and survival. The classification system appears to be a reliable tool with which to predict clinical outcome in patients with locally recurrent rectal carcinoma.     

Peripheral neuropathies following experimental intraoperative radiation therapy (IORT)

Injury to peripheral nerves in the lumbar para-aortic region was evaluated in beagle dogs 2 years following fractionated irradiation (EBRT), intraoperative irradiation (IORT), or a combination of IORT and EBRT. Time to onset of peripheral neuropathy was determined by means of serially completed neurological and electrophysiological examinations. Peripheral neuropathies were seen beginning as early as 6 months following 35 Gy (or greater) IORT only and 35 Gy plus 50 Gy EBRT. The incidence of peripheral neuropathies increased with increasing IORT doses beginning at 15 Gy. Onsets of peripheral neuropathies following IORT alone were clustered between 6 and 18 months, with onset in some dogs occurring as late as 24 months. The combination of IORT and EBRT resulted in an incidence and latency to onset of neuropathies similar to that seen with IORT alone. Neuropathies were not seen with EBRT alone at doses from 50 Gy to 80 Gy. Recovery of nerve function did not occur in affected dogs. Histological studies of nerves 2 years following irradiation demonstrated loss of axons and myelin, with a corresponding increase in endoneurial, perineurial, and epineurial connective tissue. Percentage of axon and myelin decreased to about 60% of normal at 15 Gy IORT, and additionally at higher doses. An insignificant decrease in percentage of axon and myelin was seen following EBRT alone. A significant lesion occurring in and around nerves at most IORT doses was necrosis and hyalinization of the media of small arteries and arterioles. The dose for a 50% probability for causing severe vessel lesions in the 2-year study was 19.5 Gy IORT only and 18.7 Gy when IORT was combined with EBRT. These lesions were not seen with any EBRT only dose. These studies suggest that peripheral nerve is a dose limiting normal tissue in IORT. Neuropathies appear to result from direct effects of irradiation on nerve and secondary effects to nerve resulting from damage to regional vasculature.     

Role of image guided radiation therapy in obese patients with gynecologic malignancies

PurposeWe investigated the effect of body mass index on setup errors by analyzing daily shifts required in treating patients undergoing image guided radiation therapy (IGRT) for gynecologic malignancies.Methods and MaterialsForty successive patients treated with daily kV-based IGRT for gynecologic malignancies between April 2009 and June 2012 were identified. Directional setup corrections were analyzed according to patient body mass index. Random and systematic setup errors were calculated. Image acquisition dose was estimated by performing ionization chamber measurements in a phantom.ResultsObese patients had larger random setup errors, particularly in the right-left (R-L) direction, with a setup error of 7.6 mm, versus 3.9 mm for nonobese patients. The range of individual patient random errors in the R-L direction was 1.5 to 7.6 mm among nonobese patients versus 2.0 to 17.0 mm among obese patients (P = .03, F-test). For obese patients, daily IGRT prevented treating outside the planning target volume in 33% of fractions, versus 16% in the nonobese group (P = .001). The mean total image acquisition dose from daily kV-IGRT was approximately 3 cGy, versus 150 cGy if daily megavoltage portal imaging were used to correct for erratic setup errors.ConclusionsDaily kV-based IGRT in obese patients allows for correction of erratic setup error and minimizes excess dose from portal imaging.     

Radical surgical procedure improves survival time in patients with recurrent ovarian cancer.

BACKGROUND. There is plenty of evidence that survival time associated with advanced ovarian cancer is predominantly related to the amount of residual tumor after primary operation. However, there are only few and inconclusive reports concerning the effect of second debulking procedures on survival time after relapse. METHODS. To evaluate the effect of radical second operation, 30 patients with clinically diagnosed relapses had second operations after a median recurrence-free interval of 16 months. Considerable efforts were made to resect all tumor tissue. Complete resection was achieved in 14 of 39 (47%) patients, and residual tumors smaller than 2 cm remained in 12 (40%) patients. In 19 (63%) patients, intestinal resections were necessary. Operation time, blood units needed, hospital stay, and complication rates were comparable to those associated with primary debulking procedures. RESULTS. Survival time after second operation was closely correlated with the residual tumor remaining after second surgical procedure and also with the length of the recurrence-free interval. Patients with complete resections had significantly longer survival times than those with residual tumors of less than 2 cm (median, 29 months versus 9 months; P = 0.004). Patients with a recurrence-free interval of more than 12 months had a longer survival time than those with a shorter disease-free time (median, 29 months versus 8 months; P = 0.002). Postoperative treatment also was shown to influence survival time, whereas grade of the tumor (P = 0.74), age of the patient (P = 0.87), and initial FIGO stage (P = 0.58) had no influence on survival time after second operation. Multivariate analysis (Cox regression) revealed that residual tumor after second surgical procedure (relative risk, 4.7) was the most important independent variable predicting survival time after second surgical procedure. Recurrence-free interval (relative risk, 2.7) and postoperative (second-line) treatment (relative risk, 3.0) were equally potent variables. Residual tumor after primary operation, was almost significant (P = 0.06) in the univariate analysis, but was canceled in the multivariate setting by the recurrence-free interval. Again, FIGO stage, grade of the tumor, and patient age had no predictive value. CONCLUSIONS. The authors conclude that radical surgical procedure can prolong survival times in patients with recurrent ovarian cancer. Patients who had a complete resection of cancer tissue in the primary operation or those who experienced a disease-free interval of more than 12 months after primary operation are most likely to benefit from second operation in recurrent ovarian cancer. Radical surgical procedure should be offered to these patients to enhance efficacy of second-line chemotherapy, which is of limited value in bulky recurrent disease.     

Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma

The efficacy of high-dose chemotherapy (HDC) or standard salvage therapy was evaluated in patients with recurrent medulloblastoma (MBL) using retrospective chart review of all patients with recurrent MBL treated at Duke University Medical Center between 1995 and 2005 and who had undergone HDC with or without radiotherapy (RT) or standard salvage therapy after relapse. A total of 30 patients were diagnosed with recurrent MBL after standard RT alone or chemotherapy with RT. Nineteen patients (7 who received no RT before recurrence [group A] and 12 who received definitive RT before recurrence [group B]) underwent surgery and/or induction chemotherapy followed by HDC plus autologous stem-cell rescue. Eleven patients (group C) underwent standard salvage therapy. Six of seven group A patients also received standard RT just before or after recovery from HDC, and 5 of 12 group B patients received adjuvant palliative focal RT post-HDC. At a median follow-up of 28 months, three of seven patients in group A are alive and disease-free at >or=34, >or=110, and >or=116 months, respectively, post-HDC. All patients in groups B and C have died of tumor, at a median of 35 months and 26 months from HDC and standard salvage therapy, respectively. HDC or standard salvage therapy was ineffective in our patients with recurrent MBL who had received standard RT before recurrence. The favorable impact of HDC on disease control in the two long-term survivors cannot be clearly established due to the cofounding effect of definitive RT postrecurrence.