Adjuvant postoperative radiation therapy for colonic carcinoma.

One hundred thirty-three patients with Stage B2, B3, and C colonic carcinoma had resection for curative intent followed by adjuvant postoperative radiotherapy to the tumor bed. The 5-year actuarial local control and disease-free survival rates for these 133 patients were 82% and 61%, respectively. Stage for stage, the development of local regional failure was reduced for patients receiving postoperative radiotherapy compared with a historic control series. Local recurrence occurred in 8%, 21%, and 31% of patients with Stage B3, C2, and C3 tumors who had radiation therapy, respectively, whereas the local failure rates were 31%, 36%, and 53% in patients treated with surgery alone. There was a 13% and 12% improvement in the 5-year disease-free survival rate in the patients with Stage B3 and C3 lesions who had radiotherapy compared with the historic controls. For patients with Stage C disease, local control and disease-free survival rates decreased progressively with increasing nodal involvement; however, local control and disease-free survival rates were higher in the patients who had radiotherapy than in those who had surgery alone. Failure patterns in the patients who had radiotherapy did not show any notable changes compared with those for patients who had surgery alone. Postoperative radiation therapy for Stage B3, C2, and C3 colonic carcinoma is a promising treatment approach that deserves further investigation.

The role of misonidazole combined with intraoperative radiation therapy in the treatment of pancreatic carcinoma.

We tested the efficacy of the hypoxic cell sensitizer misonidazole in conjunction with intraoperative electron beam radiation therapy (IORT) and external beam irradiation in patients with locally advanced, nonmetastatic adenocarcinoma of the pancreas. Misonidazole was delivered intravenously (IV) at a dose of 3.5 g/m2 in conjunction with IORT of 1,500 to 2,000 cGy to the pancreas. Additional external beam radiation as administered to 4,960 cGy. The study was based on the premise that the effect of misonidazole would be maximized when a high dose of the drug was administered and, thus, high hypoxic cell sensitization could be obtained when using a high single dose of radiation where the hypoxic fraction would be expected to dominate in the survivors. In a nonrandomized study of 41 patients treated with misonidazole and 22 without, the 1-year local control was 67% and 55%, and 1-year survival was 50% and 77%, respectively. Although there was a bias towards larger tumors in the patients treated with the sensitizer, we were unable to demonstrate an advantage to misonidazole in this clinical situation.

Results of treatment of stage IA and IIA Hodgkin's disease.

This study analyzed the 5 year actuarial survival and disease-free survival of 122 patients with Stage IA and IIA Hodgkin's disease, (108 patients laparotomy staged) treated with mantle and paraaortic irradiation from 1975 to 1981. Prognostic subgroups and patterns of treatment failure were investigated. The 5 year actuarial survival and disease-free survival was 91% and 75% respectively for the entire group. For Stage IA patients, the 5 year survival and disease-free survival was 92% and 86% respectively, whereas for those in Stage IIA the respective figures were 86% and 65%. Individuals with greater than four sites of involvement at initial presentation; extensive mediastinal adenopathy; hilar or extramediastinal extension to lung, pleura or pericardium, had a poorer 5 year actuarial disease-free survival (43%-60%) than those without these factors (70%-85%). Of the 122 patients, there were 26 relapses: nine infield failures; two concurrent infield and systemic failures; nine marginal recurrences, and three relapses occurring systemically and three in nodal groups not irradiated. Following relapse, 17 patients were salvaged with chemotherapy. Two patients are alive with disease and seven patients died of Hodgkin's disease. Patients with less extensive mediastinal adenopathy and supradiaphragmatic nonmediastinal presentations can be satisfactorily treated with mantle and paraaortic irradiation, whereas patients with extensive mediastinal adenopathy receive six cycles of multiagent chemotherapy before irradiation.

Postoperative radiation therapy of rectal cancer.

Beginning in December 1975, at the Massachusetts General Hospital (MGH) patients with rectal carcinomas thought to be at high risk of local recurrence after potentially curative surgical resection, were entered on a treatment protocol of high dose postoperative radiation therapy. Treatment was given with X rays of 10 MeV, generally using a four-field box technique to a dose of 4500 cGy with a boost to 5040 cGy or higher when the small bowel could be excluded from the reduced field. One-hundred sixty-five patients who began their radiation therapy between December 1975 and December 1982 were entered into the study. The median age was 65 years. The median follow-up in the survivors was 56 months, with a minimum follow-up of 17 months. All but 10 patients were followed for more than 2 years. Of the entire group, the actuarial 5-year survival was 53%, with survival of 71% in patients with Stage B-2, 39% in Stage C-2, and 17% in Stage C-3. Local failure was seen in 5/53 patients with Stage B-2 disease and 0/7 of patients with Stage B-3 disease. In patients with positive lymph nodes, local failure occurred in 2/10 (20%) of patients with Stage C-1, 16/77 (21%) of Stage C-2, and 8/15 (53%) of patients with Stage C-3 disease. Compared to previous series of surgery alone, the local failure rate has been decreased by more than one-half in all patients, except those with Stage C-3. Efforts to maximize the radiation doses in all stages should be made to minimize local failure. For Stage C-3, newer strategies such as intraoperative radiation therapy should be employed to decrease the continuing high incidence of failures.

Results of treatment of stage 3A Hodgkin's disease.

From 1975 to 1981, 38 patients with Stage 3A Hodgkin's disease (35 patients pathologically staged) underwent mantle and para-aortic irradiation, and in 36 patients this was preceded or followed by at least six cycles of multiagent chemotherapy. Both the 5-year actuarial survival and disease-free survival for all 38 patients were 83%. There have been six treatment failures: two patients have relapsed within irradiated nodal groups, one patient in apical pericardial lymph nodes as a marginal recurrence, one patient concurrently infield and in unirradiated nodal groups, and two patients systemically (concurrently in unirradiated nodal groups). Of these six relapses, three patients have died of Hodgkin's disease, one patient has been salvaged, and two patients currently are under treatment for salvage. One patient has developed acute nonlymphocytic leukemia and died of this disease. Extensive disease, as estimated by the number of sites of involvement at presentation, degree of splenic involvement, extent of intra-abdominal disease or mediastinal involvement, did not reveal statistically significant prognostic subgroups for relapse. It is currently recommended that patients with Stage 3A Hodgkin's disease receive six cycles of multiagent chemotherapy and mantle and para-aortic irradiation.

Radiation therapy alone or in combination with surgery in the treatment of carcinoma of the esophagus.

The role of radiation in the treatment of squamous cell carcinoma of the esophagus was examined in a review of 74 patients treated with curative intent between 1974 and 1981. Aspects studied included the pattern of failure, the use of radiation as a surgical adjuvant, achievement of palliation, and the presence of technical or clinical factors predicting for a better outcome. The group was divided into 9 patients irradiated after esophageal resection, 14 patients irradiated before resection, and 51 patients treated with radiation and no resection. Median and 2-year survival rates among 51 patients treated by radiation without esophagectomy were 8.8 months and 11%, whereas they were 9.7 months and 0% in patients treated by radiation followed by resection, and 9.5 months and 28% in patients undergoing resection followed by radiation. Local failures were suffered in 28/51 patients treated without esophagectomy with rates of 2/4, 7/10, 7/15, and 5/10 after 50-55 Gy, 55-60 Gy, 60-65 Gy, and 65-69 Gy, respectively. Although prognosis for patients presenting with unresectable disease remains poor, a somewhat better outcome may be expected in patients treated with postoperative radiation after potentially unfavorable resections. Other predictors include sex and disease stage.

Renal complications secondary to radiation treatment of upper abdominal malignancies.

A retrospective review of all patients undergoing radiotherapy for carcinoma of the colon, pancreas, stomach, small bowel and bile ducts, lymphomas of the stomach, and other GI sites and retroperitoneal sarcomas was completed to assess the effects of secondary irradiation on the kidney. Eighty-six adult patients were identified who were treated with curative intent, received greater than 50% unilateral kidney irradiation to doses of at least 2600 cGy and survived for 1 year or more. Following treatment, the clinical course, blood pressure, addition of anti-hypertensive medications, serum creatinine and creatinine clearance were determined. Creatinine clearance was calculated by the formula: creatinine clearance equals [(140-age) X (weight in kilograms)] divided by (72 X serum creatinine) which has a close correlation to creatinine clearances measured by 24 hr. urine measurements. The percent change in creatinine clearance from pre-treatment values was analyzed. Of the thirteen patients with pre-radiotherapy hypertension, four required an increase in the number of medications for control and nine required no change in medication. Two patients developed hypertension in follow-up, one controlled with medication and the other malignant hypertension. Acute or chronic renal failure was not observed in any patient. The serum creatinine for all 86 patients prior to radiation therapy was below 2 mg/100 ml; in follow-up it rose to between 2.2-2.9 mg/100 ml. in five patients. The mean creatinine clearance for all 86 patients prior to radiotherapy was 77 ml/minute and for 16 patients with at least 5 years of follow-up it was 62 ml/minute. The mean percent decrease in creatinine clearance appeared to correspond to the percentage of kidney irradiated: for 38 patients with only 50% of the kidney irradiated the mean percent decrease was 10%, whereas for 31 patients having 90 to 100% of the kidney treated the decrease was 24%. Although physiologic changes were seen in patients receiving 50% or more unilateral kidney irradiation, the development of significant clinical sequelae was limited to one patient.

Prognostic variables in the treatment of squamous cell carcinoma of the vulva.

Records of 98 patients undergoing surgery for squamous cell carcinoma of the vulva between 1960 and 1982 were analyzed to evaluate and develop treatment policy. There were 32, 34, 26, and 6 patients in FIGO stages I-IV, respectively. Eighty-six patients underwent radical vulvectomy, 8 patients underwent less extensive procedures, and 4 underwent more extensive procedures. Eighty-seven patients underwent inguinal node dissection, and 40 underwent pelvic node dissection as well. Eight patients received external beam irradiation. Actuarial 5-year survival was 57%. Age, tumor size, FIGO (clinical) stage, surgically determined T and N stages, tumor differentiation, lymph vessel invasion, extent of surgical procedure, and adjuvant irradiation were analyzed to determine their effects on local control, freedom from distant metastases, and survival, using single variable and multivariate analysis. Local control was significantly related to FIGO stage; freedom from distant metastasis was significantly related to surgical N stage, tumor size, and surgical T stage; survival was significantly related to surgical N stage, tumor size, surgical T stage, age, and lymph vessel invasion. Metastatic involvement of inguinal lymph nodes was significantly correlated with tumor size and differentiation. Of 87 evaluable patients, 33 had inguinal node involvement, and of these, 17 developed recurrent disease. All 7 patients with pelvic node metastases had positive inguinal nodes, and all died; the cause of death could be determined in 5, of whom 4 manifested distant metastases. Pelvic lymphadenectomy conferred no survival benefit in this series, even in the presence of positive inguinal nodes. Local vulvar recurrence is a significant problem in patients with positive inguinal nodes, and postoperative irradiation should be directed to this area in these patients. Patients with vulvar recurrences, especially those occurring at least 2 years after surgery, can be successfully salvaged, and should therefore be treated aggressively.

Intraoperative electron beam radiotherapy in the treatment of unresectable rectal cancer.

We treated 29 patients who had primarily unresectable rectal cancer with an aggressive combined surgical and radiotherapeutic approach. Each patient received 5,040 rad of preoperative external beam radiation therapy. Eighteen patients responded adequately to allow resection of all macroscopic tumor; 11 patients underwent resection but had residual cancer in the pelvis. A single bolus of 1,000 to 2,000 rad of intraoperative electron beam radiation was given. Follow-up time ranged from three to 66 months, with a median of 43 months for living patients. The actuarial local control rate at 36 months for the entire group was 87%. In the group of 18 patients who underwent resection, the local control rate was 92%, with a three-year survival rate of 70%. Our results are considerably improved over our prior experience without intraoperative radiation therapy--a 57% local control rate and a 30% three-year survival rate.

Obstructive and perforative colonic carcinoma: patterns of failure.

Carcinoma of the colon complicated by obstruction or perforation has been recognized as having a poorer prognosis than tumors without obstruction or perforation. To clarify the natural history, failure patterns, and implications for adjuvant treatment after resection with curative intent, a review of the recent Massachusetts General Hospital (MGH) experience was undertaken. From 1970 to 1977, 77 patients with obstructive colonic carcinoma and 34 patients with localized perforation at the tumor site were identified and compared with a control group of 400 patients without obstruction or perforation undergoing curative resection. All patients were observed for a minimum of five years or until the patient's death. The actuarial five-year survival and disease-free survival rates in patients with obstruction was 31% and 44%, respectively, in contrast to 59% and 75% in control patients. For patients with localized perforation, the five-year actuarial survival and disease-free survival rates were 44% and 35%, respectively. Of the 77 patients with obstructing tumors, 32 patients (42%) developed local failure--nine with local failure only and 23 patients with local failure and distant metastases. Thirty-four patients (44%) developed distant metastases. Fifteen (44%) patients of 34 with perforative colonic carcinoma had local failure. Distant metastases occurred in 15 patients (44%). The incidence of local failure and distant metastases in the control group was 14% and 21%, respectively. The rate of local failure and distant metastases increased with stage and was generally higher stage for stage than in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure patterns following curative resection of colonic carcinoma.

To identify patterns of failure following curative resection of colonic (nonrectal) carcinoma, the medical records of 533 patients undergoing resection with curative intent were reviewed. The overall local failure rate was 19% (102/533 patients) with 32 patients having local failure alone and 70 patients having concurrent local failure and distant metastases. The incidence of local failure rose with advancing stage of disease. Tumors staged B3, C2, and C3 had local failure rates in excess of 30%. Local failures occurred predominantly in tumor bed and adjoining structures (82%) and not by regional nodal failure (18%). One hundred thirty-one patients (25%) developed distant metastases. One hundred ten patients (84%) failed in the abdomen-liver, peritoneal seeding, para-aortic, or portahepatic lymph nodes. Patients with Stage B3, C2, and C3 tumors were found to have abdominal failure rates (excluding local failure) of greater than 20%. The highest failure rates in the liver were in Stage C2 and C3 patients in which the subsequent development of liver metastases was 29% and 31%, respectively. In Stage C3, peritoneal seeding and abdominal lymph node failure occurred in 18% and 14% of the patients, respectively.

Sarcomas of the uterine corpus: prognostic factors and treatment.

Twenty-eight patients with sarcomas of the uterine corpus were followed at least 22 months or until death. All underwent laparotomy, eleven had radiation therapy, and six had chemotherapy. Three year actuarial survival was 24%, and three year actuarial local control was 36%. Multivariate analysis demonstrated that, as with sarcomas at other sites, the most important factors influencing survival were grade (P = 0.020) and stage (P = 0.022). For local control, multivariate analysis indicated the most important factors to be stage (P = 0.001) and radiation TDF (P = 0.01). Of 21 failures, 16 involved the pelvis, seven involved the upper abdomen, and 11 involved distant sites. The importance of both local and distant disease control is emphasized.

Complications of intraoperative radiation therapy.

The ability to demonstrate an improvement in therapeutic ratio is critical in assessing new treatment modalities; an evaluation of treatment complications is essential for this purpose. We have studied the severe complications occurring after treatment with intraoperative radiation therapy (IORT) in patients with locally advanced carcinoma of the rectum. Four groups of patients were compared: Group 1 (80 patients) had treatment with surgery alone for mobile and resectable tumors; Group 2 (23 patients) had treatment with high dose preoperative irradiation followed by surgical resection for tumors which were fixed to adjacent structures and initially unresectable for cure; Group 3 (24 patients, primary disease) and Group 4 (17 patients, locally recurrent disease) had locally advanced tumors as in Group 2 but were treated with IORT after preoperative irradiation and attempted surgical resection. All but 3 complications occurred within one year of therapy. Severe complications were seen in 16% of patients in Group 1, 35% in Group 2, 21% in Group 3 and 47% in Group 4 (32% in Groups 3 and 4 combined). There was a statistically insignificant increase (p = .10) in the complication rate in all irradiated patients (locally advanced tumors) compared to surgery alone (clinically mobile tumors). These data indicate no increase in severe complications with the use of IORT. If the ongoing studies continue to show improved local control with the use of IORT, expanded use of this modality may be warranted.

Intraoperative electron beam irradiation for patients with unresectable pancreatic carcinoma.

Since 1978 we have used electron beam intraoperative radiation therapy (IORT) to deliver higher radiation doses to pancreatic tumors than are possible with external beam techniques while minimizing the dose to the surrounding normal tissues. Twenty-nine patients with localized, unresectable, pancreatic carcinoma were treated by electron beam IORT in combination with conventional external radiation therapy (XRT). The primary tumor was located in the head of the pancreas in 20 patients, in the head and body in six patients, and in the body and tail in three. Adjuvant chemotherapy was given in 23 of the 29 patients. The last 13 patients have received misonidazole (3.5 mg/M2) just prior to IORT (20 Gy). At present 14 patients are alive and 11 are without evidence of disease from 3 to 41 months after IORT. The median survival is 16.5 months. Eight patients have failed locally in the IORT field and two others failed regionally. Twelve patients have developed distant metastases, including five who failed locally or regionally. We have seen no local recurrences in the 12 patients who have been treated with misonidazole and have completed IORT and XRT while 10 of 15 patients treated without misonidazole have recurred locally. Because of the shorter follow-up in the misonidazole group, this apparent improvement is not statistically significant. Fifteen patients (52%) have not had pain following treatment and 22 (76%) have had no upper gastrointestinal or biliary obstruction subsequent to their initial surgical bypasses and radiation treatments. Based on the good palliation generally obtained, the 16.5-month median survival, and the possible added benefit from misonidazole, we are encouraged to continue this approach.

Local failure following curative resection of colonic adenocarcinoma.

A retrospective review of the medical records of 533 patients undergoing resection with curative intent of large bowel above the peritoneal reflection was undertaken to identify subsets of patients at high risk for local failure. The overall local failure rate was 102/533 (19%) with 32/102 patients having local failure only and 70/102 patients having concurrent local failure and distant metastases. Pathological confirmation of local failure was obtained in 79% of the cases and by surgical exploration in 75%. Overall local failure rates increased with advancing stage of disease. Tumors staged B3, C2 and C3 all had local failure rates in excess of 30%, whereas for Stage A, B1, B2 and C1 lesions, the incidence of local failure was less than 4%. Stage B2 tumors arising in high and low sigmoid and splenic and hepatic flexure had a moderate incidence of local failure (21%) compared to low incidence (5%) at all other sites. The majority of local and regional failures 84/102 (82%) occurred in tumor bed and adjacent soft tissues whereas only 18/102 (18%) local failures occurred in regional nodal groups. The overall local failure rate increased from 27% with one lymph node involved to 50% with greater than 5 lymph nodes involved. Patients with Stage B3, C2 and C3 colon tumors at all sites and selected B2 tumors have a high rate of local failure after surgical resection. The value of postoperative radiotherapy should be formally studied in these patients.

Treatment of advanced Hodgkin's disease: 10-year experience in the Eastern Cooperative Oncology group.

Between 1972 and 1981, the Eastern Cooperative Oncology Group completed two major studies of advanced Hodgkin's disease. The first trial EST 2472, demonstrated that the five-drug combination of carmustine (BCNU), cyclophosphamide, vinblastine, procarbazine, and prednisone (BCVPP) is an effective alternative to mechlorethamine, vincristine, prednisone, and procarbazine (MOPP) chemotherapy. Although the complete remission (CR) rate for BCVPP (77%) was similar to that for MOPP (73%) in this randomized trial, the choice of induction chemotherapy significantly influenced CR duration. Patients achieving CR with BCVPP had a significantly greater disease-free survival than those who achieved CR with MOPP (65% vs 50%, respectively, at 5 years, P = 0.02). Overall survival is not different at this time between patients who received BCVPP and those who received MOPP. BCVPP produced significantly less gastrointestinal toxicity and neurotoxicity than MOPP. There was no influence on CR duration or survival with maintenance chemotherapy or BCG immunotherapy when compared to no further treatment. In the second trial, EST 1476, there was only a 58% CR rate with six cycles of low-dose bleomycin-MOPP induction chemotherapy. Complete responders and continuing partial responders were then randomized to receive either non-cross-resistant chemotherapy with doxorubicin, bleomycin, vinblastine, and DTIC (dacarbazine) (ABVD) or low-dose radiotherapy to all sites of pretreatment involvement except bone marrow. Fifty percent of the partial responses were converted to CR with either ABVD or radiotherapy consolidation. The overall CR rate at the end of consolidation was 68%. At the present time, there is no significant difference in disease-free or overall survival between ABVD and radiotherapy.

Nodular mixed lymphoma: results of a randomized trial failing to confirm prolonged disease-free survival with COPP chemotherapy.

Fifty-two patients with stage III or IV nodular mixed lymphocytic-histiocytic lymphoma (NM) were entered on a prospective randomized trial comparing cyclophosphamide-prednisone (CP) to either COPP (cyclophosphamide, vincristine, procarbazine, prednisone) or BCVP (BCNU, cyclophosphamide, vincristine, prednisone). The COPP regimen utilized in this Eastern Cooperative Oncology Group (ECOG) trial was similar to the four-drug regimen C-MOPP reported by the National Cancer Institute to achieve prolonged relapse-free survival in this histology. No significant differences in complete response rates, response duration, or overall survival were noted among the three regimens. A pattern of continuous late relapse was observed for all three chemotherapy programs. Although 11 of the 18 (61%) COPP patients achieved a complete response, only 3/11 (27%) remain disease-free with a median follow-up of over 3 yr. However, two of these three long-term complete responders have died with no clinical evidence of recurrent disease. The COPP patients received 84% of the calculated ideal doses of cyclophosphamide and 78% of the ideal dosage of procarbazine. Grade 3-4 hematologic toxicity was noted in 22% of the COPP group, 36% with BCVP, and 0% for the CP patients. We were unable to confirm the ability of COPP to achieve durable complete remissions in NM lymphoma. The cyclophosphamide-prednisone combination was equally effective when compared with COPP and BCVP, but produced minimal toxicity.