Herman D. Suit

Advanced prostate cancer: The results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone☆

PURPOSE Following a thorough Phase I/II study, we evaluated by a Phase III trial high versus conventional dose external beam irradiation as mono-therapy for patients with Stage T3-T4 prostate cancer. Patient outcome following standard dose radiotherapy or following a 12.5% increase in total dose to 75.6 Cobalt Gray Equivalent (CGE) using a conformal perineal proton boost was compared for local tumor control, disease-free survival, and overall survival. METHODS AND MATERIALS Stage T3-T4, Nx, N0-2, M0 patients received 50.4 Gy by four-field photons and were randomized to receive either an additional 25.2 CGE by conformal protons (arm 1--the high dose arm, 103 patients, total dose 75.6 CGE) or an additional 16.8 Gy by photons (arm 2--the conventional dose arm, 99 patients, total dose 67.2 Gy). Actuarial overall survival (OS), disease-specific survival (DSS), total recurrence-free survival (TRFS), (clinically free, prostate specific antigen (PSA) less than 4ng/ml and a negative prostate rebiopsy, done in 38 patients without evidence of disease) and local control (digital rectal exam and rebiopsy negative) were evaluated. RESULTS The protocol completion rate was 90% for arm 1 and 97% for arm 2. With a median follow-up of 61 months (range 3 to 139 months) 135 patients are alive and 67 have died, 20 from causes other than prostate cancer. We found no significant differences in OS, DSS, TRFS or local control between the two arms. Among those completing randomized treatment (93 in arm 1 and 96 in arm 2), the local control at 5 and 8 years for arm 1 is 92% and 77%, respectively and is 80% and 60%, respectively for arm 2 (p = .089) and there are no significant differences in OS, DSS, and TRFS. The local control for the 57 patients with poorly differentiated (Gleason 4 or 5 of 5) tumors at 5 and 8 years for arm 1 is 94% and 84% and is 64% and 19% on arm 2 (p = 0.0014). In patients whose digital rectal exam had normalized following treatment and underwent prostate rebiopsy there was a lower positive rebiopsy rate for arm 1 versus arm 2 patients (28 vs. 45%) and also for those with well and moderately differentiated tumors versus poorly differentiated tumors (32 and 50%). These differences were not statistically significant. Grade 1 and 2 rectal bleeding is higher (32 vs. 12%, p = 0.002) as may be urethral stricture (19 vs. 8%, p = 0.07) in the arm 1 versus arm 2. CONCLUSIONS An increase in prostate tumor dose by external beam of 12.5% to 75.6 CGE by a conformal proton boost compared to a conventional dose of 67.2 Gy by a photon boost significantly improved local control only in patients with poorly differentiated tumors. It has increased late radiation sequelae, and as yet, has not increased overall survival, disease-specific survival, or total recurrence-free survival in any subgroup. These results have led us to test by a subsequent Phase III trial the potential beneficial effect on local control and disease-specific survival of a 12.5% increase in total dose relative to conventional dose in patients with T1, T2a, and T2b tumors.

Clinical and pathologic review of 48 cases of chordoma

The results of treatment of 48 patients with the diagnosis of chordoma during the period 1931 to 1981 at the Massachusetts General Hospital were reviewed. Fourteen patients were treated with surgery alone: eight patients with primary tumors in the sacrococcygeal region were treated with radical surgery and four are alive with no evidence of disease (NED) with follow‐up of 8 to 20 years. Recurrent tumors in six patients were treated with surgery alone resulting in long palliation (3–25 years). The actuarial survival rate at 5 years for all patients treated with surgery was 76%. Radiation therapy was used in patients after either a biopsy (15), partial excision (17), or before radical excision in 2 patients. To achieve a worthwhile level of palliation, doses greater than 4000 cGy were required. High‐dose levels (>6500 cGy) were achieved in nine cases by a combination of photon and 160 MeV proton beams. The results to date of this approach for lesions of the base of skull and cervical vertebral body are encouraging: high local control and low morbidity. The 5‐year actuarial survival rate of all patients treated with radiation was 50%.

Preoperative, intraoperative, and postoperative radiation in the treatment of primary soft tissue sarcoma.

The rationale for combining radiation with conservative surgery in the treatment of sarcoma of soft tissue is discussed, as well as the advantages for performing the radiation preoperatively on the one hand and postoperatively on the other. The results of treatment of soft tissue sarcoma by radical resectional surgery or amputation in 464 patients at four centers and by conservative surgery, and postoperative radiation in 416 patients at three centers, have been reviewed. The local failure rates were 18.1% and 18.3%, respectively. The results obtained by radiation administered postoperatively (110 patients) or preoperatively (60 patients) at the Massachusetts General Hospital during the period September 1971 to August 1982 are analyzed and discussed with reference to 5‐year actuarial local control and survival results as well as causes of failure with respect to AJC stage, histologic type, anatomic site, and size of tumor. The results which have been obtained by the preoperative approach are judged to be superior, particularly for the larger lesions and higher grades that predominated in that group. Of a total of 170 patients, there were 19 local failures; 13 of these were diagnosed at the time when metastatic disease was not evident. Of those 13, 12 have been subjected to salvage surgery and 7 remain with no evidence of disease at 1 to 3.5 years after the salvage procedure. A major problem in the management of these patients remains the occult metastatic disease.

Sarcoma of soft tissue: Clinical and histopathologic parameters and response to treatment

Radical dose radiation therapy alone or combined with limited surgery has been employed in the management of 100 patients with primary (71) and recurrent (29) sarcoma of soft tissue. Results of this experience show that a combination of conservative surgery and radiation therapy, based upon radical dose levels and sophisticated techniques, is effective: only 13 of 100 patients showed local regrowth during a followup of 2–12 years. This may be compared with an expected ⩽25 recurrences had treatment been radical surgery (wide resection or amputation). For lesions located on the distal extremities (elbow‐hand, knee‐foot) there were local failures in only 3 of 59 (5%). Further, 75% of patients treated by the improved techniques utilized in the recent 8 years retained a useful limb which is free of pain or edema. Histopathologic grade is demonstrated to be an important indicator of prognosis of local recurrence and of disease‐free survival. Local recurrence rates were 0/23, 9/53, and 4/24 for Grades 1, 2, and 3. Disease‐free survival rates were 19/23 (86%), 27/53 (51%), and 4/24 (17%) for Grades 1, 2, and 3, respectively. Invasion of skin appeared to be a sign of poor prognosis; 8 of 9 such patients developed distant metastases.

Carcinoma of the pancreas: Review of MGH experience from 1963 to 1973—Analysis of surgical failure and implications for radiation therapy

A retrospective study was done of all patients who were seen for definitive treatment of adenocarcinoma of the pancreas at the Massachusetts General Hospital from 1963 to 1973. There were a total of 145 patients. Thirty‐one patients were treated with radical surgery, with a 16% operative mortality, a 5‐year crude survival rate of 15%, and a local recurrence rate of 50%. Sixty‐two patients were treated with a palliative procedure with a 5‐year crude survival of 5%. Fifty‐two patients were treated with biopsy alone, with no 5‐year survivors. In addition, there were 35 patients who did not have a radical surgical procedure performed only because of the extent of the local disease. It is proposed that postoperative irradiation may reduce the incidence of local failure after radical surgery, and that preoperative radiation therapy or radiation therapy alone would be an appropriate treatment of those patients in whom the local extent of disease is initially too far advanced to perform radical surgery.

Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas

PURPOSE Treatment of extremity soft-tissue sarcomas yields excellent local control, but distant failure is common with large, high-grade tumors. A regimen of preoperative chemotherapy consisting of mesna, adriamycin, ifosfamide, and dacarbazine (MAID) interdigitated with radiotherapy followed by resection and postoperative chemotherapy with or without radiotherapy was designed to improve treatment outcome. We report the mature outcome data on 48 treated patients and compare them with the data of an historical matched control patient population. METHODS AND MATERIALS Adult patients with high-grade extremity soft-tissue sarcomas >or=8 cm were treated with three cycles of preoperative chemotherapy combined with 44 Gy of radiotherapy followed by surgery. Three cycles of postoperative MAID were planned. For patients with positive surgical margins, 16 Gy was delivered postoperatively. RESULTS All 48 patients (M0) received the MAID protocol treatment, and their outcome was superior to that of the historical control patients. The 5-year actuarial local control, freedom from distant metastasis, disease-free survival, and overall survival rate was 92% and 86% (p = 0.1155), 75% and 44% (p = 0.0016), 70% and 42% (p = 0.0002), and 87% and 58% (p = 0.0003) for the MAID and control patient groups, respectively. Acute hematologic toxicity in the MAID group included febrile neutropenia in 12 patients (25%). Wound healing complications occurred in 14 (29%) of 48 MAID patients. One MAID patient developed late fatal myelodysplasia. CONCLUSION After aggressive chemoradiation and surgery, these patients showed a significant reduction in distant metastases, with a highly significant gain in disease-free and overall survival compared with a historical control group. On the basis of this experience, the Radiation Therapy Oncology Group conducted a multi-institutional trial.

INDIVIDUALIZING MANAGEMENT OF AGGRESSIVE FIBROMATOSES

PURPOSE To examine prognostic indicators in aggressive fibromatoses that may be used to optimize case-specific management strategy. METHODS AND MATERIALS One hundred and seven fibromatoses presenting between 1971 and 1992 were analyzed. The following treatment modalities were utilized: (a) surgery alone for 51 tumors; (b) radiation alone for 15 tumors; and (c) radiation and surgery (combined modality) for 41 tumors. Outcome analysis was based on 5-year actuarial local control rates. RESULTS Control rates among surgery, radiation therapy, and combined modality groups were 69%, 93%, and 72%. Multivariate analysis identified age < 18 years, recurrent disease, positive surgical margins, and treatment with surgery alone as predictors for failure. Patients treated with surgery alone had control rates of 50% (3 of 6) for gross residual, 56% for microscopically positive margins, and 77% for negative margins. Radiation and surgery resulted in rates of 59% for gross residual, 78% for microscopically positive margins, and 100% (6 of 6) for negative margins. For recurrent vs. primary tumors, control was achieved in 48% vs. 77%, 90% vs. 100% (5 of 5), and 67% vs. 79% in the Surgery, Radiation, and Combined modality Groups, respectively. Patients presenting with multiple disease sites tended to have aggressive disease. A radiation dose-control relation to > 60 Gy was seen in patients with unresected or gross residual disease. Of the patients, 23 with disease involving the plantar region had a control rate of 62%, with significantly worse outcomes in children. CONCLUSIONS These results are consistent with those found in the relevant literature. They support primary resection with negative margins when feasible. Radiation is a highly effective alternative in situations where surgery would result in major functional or cosmetic defects. When negative surgical margins are not achieved in recurrent tumors, radiation is recommended. Perioperative radiation should be considered in other high-risk groups (recurrent disease, positive margins, and plantar tumors in young patients). Doses of 60-65 Gy for gross disease and 50-60 Gy for microscopic residual are recommended. Observation may be considered for primary tumors with disease remaining in situ when they are located such that progression would not cause significant morbidity. Although plantar lesions in children may represent a group at high risk for recurrence or aggressive behavior, the greater potential for radiation-induced morbidity in this group must also temper its use. Given the inconsistent nature and treatment response of this tumor, it is fundamental that treatment recommendations should be made based on the risk:benefit analysis for the individual patient, dependent on tumor characteristics and location, as well as patient characteristics and preferences.

Treatment of the patient with stage M0 soft tissue sarcoma.

During the period 1971 to 1985, 220 patients with soft tissue sarcoma of the extremities, torso, and head-neck region were managed by radiation and resectional surgery at the Massachusetts General Hospital (MGH). Actuarial 5-year local control and disease-free survival rates were 86% and 70%, respectively. The success rate improved during this time period. Namely, the local control rates for 1971 to 1975, 1976 to 1980, and 1981 to 1985 were 81%, 81%, and 94%, respectively. For the same time periods, the 5-year disease-free survival rates were 64%, 70%, and 76%. One hundred thirty-one patients were treated with postoperative radiation, and 89 with preoperative radiation. In the most recent 5-year period, the local control rates were 91% and 97% for the two groups (number of patients being 50 and 57 in the post- and preoperative groups, respectively). Treatment by preoperative radiation appears to have a major advantage for patients with very large sarcomas, ie, greater than 15 cm in maximum dimension. None of our patients with local control of grade 1 sarcoma have developed distant metastasis (DM). In contrast, among patients with grade 2 or 3 sarcomas, there is a relentless and progressive increase in the frequency of DM with size of the primary lesion, namely, 6% at less than or equal to 2.5 cm, congruent to 60% at 15 to 20 cm, and congruent to 80% at greater than 20 cm.

Radiation therapy in the treatment of aggressive fibromatoses (desmoid tumors).

Twenty‐five patients with aggressive fibromatoses (desmoid tumors) have been treated or followed in the Department of Radiation Medicine at the Massachusetts General Hospital between 1972 and 1982. Seventeen patients were treated by radiation, 4 for primary and 13 for recurrent disease. Seven patients were treated in conjunction with surgery. Partial or complete regression was achieved in 76%, and 59% are without evidence of disease (NED) at 9 to 94 months follow‐up. Eight of ten patients treated primarily with radiation have achieved complete response without an attempt at resection (five) or have achieved stabilization (three) of their disease after some regression. Consistent complete control was seen with doses above 60 Gy. Periods to 27 months were required to observe complete responses. Only three failures within the radiation field were observed, two after low doses (22 and 24 Gy, respectively). Eight patients were seen after resection but with uncertain or histologically minimum positive margins, and were followed regularly and not treated. One patient has failed to date and is NED after resection. Radiation therapy is recommended in those situations where wide‐field resection without significant morbidity is not possible for gross local disease. If minimally positive margins exist after resection in a patient who may be followed carefully, frequent follow‐up and prompt treatment at recurrence may be an effective alternative to immediate radiation therapy.

Radiation dose-response of human tumors

PURPOSE The dose of radiation that locally controls human tumors treated electively or for gross disease is rarely well defined. These doses can be useful in understanding the dose requirements of novel therapies featuring inhomogeneous dosimetry and in an adjuvant setting. The goal of this study was to compute the dose of radiation that locally controls 50% (TCD50) of tumors in human subjects. METHODS AND MATERIALS Logit regression was used with data collected from single institutions or from combinations of local control data accumulated from several institutions treating the same disease. RESULTS 90 dose response curves were calculated; 62 of macroscopic tumor therapy, 28 of elective therapy with surgery for primary control. The mean and median TCD50 for gross disease were 50.0 and 51.9 Gy, respectively. The mean and median TCD50 for microscopic disease control were 39.3 and 37.9 Gy, respectively. At the TCD50, an additional dose of 1 Gy controlled an additional 2.5% (median) additional patients with macroscopic disease and 4.2% (median) additional patients with microscopic disease. For both macro- and microscopic disease, an increase of 1% of dose at the TCD50 increased control rates approximately 1% (median) or 2-3% (mean). A predominance of dose response curves had shallow slopes accounting for the discrepancy between mean and median values. CONCLUSION Doses to control microscopic disease are approximately 12 Gy less than that required to control macroscopic disease, and are about 79% of the dose required to control macroscopic disease. The percentage increase in cures expected for a 1% increase in dose is similar for macroscopic microscopic disease, with a median value of approximately 1%/% and a mean of approximately 2.7%/%.