Alon J. Dembo

SEMINOMA OF THE TESTIS: RESULTS OF TREATMENT AND PATTERNS OF FAILURE AFTER RADIATION THERAPY

Four hundred and forty-four patients with the histological diagnosis of pure seminoma were treated at The Princess Margaret Hospital between 1958 and 1976. Using the Walter Reed Hospital staging classification, 338 patients (76.1%) were Stage I, 86 (19.4%) were Stage II, and 20 (4.7%) were Stage III. The 5 year actuarial survival rate (5 yr Sa) for all stages was 87%, and for Stages I, II and III: 94%, 74% and 32% respectively. In Stage II the 5-year Sa was significantly worse when palpable abdominal disease was present (62%, vs 87% when it was absent, p less than .02). Prophylactic mediastinal irradiation was not used for patients with Stage II disease. None of 40 Stage II patients without palpable abdominal disease recurred in the non-irradiated mediastinum. Ten of 46 Stage II patients with palpable abdominal disease recurred in the mediastinum; 7 of the 10 were cured with mediastinal irradiation at the time of relapse. Prophylactic mediastinal irradiation appears unnecessary in Stage II patients. The Stage III category includes a subgroup of patients who were curable with radiation therapy:L 5/6 with supradiaphragmatic nodal disease without palpable abdominal or visceral disease were cured. Exploration of new treatment methods appears indicated for the salvage of patients recurring in sites other than the mediastinum or supraclavicular fossa and for patients presenting with visceral disease.

Role of radiation therapy in localized non-Hodgkin's lymphoma*

Relapse occurs in 50% of patients receiving radiation for clinical stage (C.S.) I and II nodal and extranodal non-Hodgkins lymphoma (N.H.L.). Prior to the introduction of intensive chemotherapy those failing primary control with irradiation and most of those who relapsed died of their disease with a resultant overall mortality of 50%. An analysis of Princess Margaret Hospital results with radiation for C.S. I and II N.H.L. between January 1967 and December 1978 revealed that tumour bulk, age, stage and histology were of independent prognostic significance. It was possible to group patients using combinations of these attributes so that each group encompassed only patients with similar outcomes. Such prognostic groups were identified separately within the low grade and the intermediate plus high grade categories of the Working Formulation. Patients with a high probability of cure with radiation were so defined. Also those patients in whom chemotherapy would be optimal initial therapy were also defined. Such patients were in the intermediate plus high grade histology groups. Thirty percent of all patients with low grade histology lymphoma had an actuarial survival of 83%, and relapse-free rate of 63% at 10 years. By implication, approximately 20% of all patients with these histologies seen at the Princess Margaret Hospital for the same time period achieved prolonged relapse-free survival by localized therapy. This is at variance with the implications of staging from studies where laparotomy and multiple bone marrow biopsies have been used. Such aggressive staging procedures suggest truly localised disease in only 5-6% of patients with low grade lymphoma. A significant relationship between radiation dose and disease control was demonstrated only for patients with intermediate and high grade lymphoma of medium or large bulk. A minimum tumour dose of 30 Gy was required for optimal local control with radiation.

Concurrent radiation, mitomycin C and 5-fluorouracil in poor prognosis carcinoma of cervix: Preliminary results of a phase I-II study

Between July 1981 and June 1983, 27 patients with advanced primary squamous cell carcinoma (SCC) of cervix (FIGO Stages IIIB, IVA or extensive nodal involvement) and 8 with recurrent disease were treated using a pilot regimen of combination chemotherapy (CT): Mitomycin C (MIT), 5 Fluorouracil (5 FU), and radiation therapy (RT). CT and RT doses on this Phase I-II Study were escalated to the current regimen. A split course of RT was used, either pelvic RT alone (4560 Gy in 28 fractions) or the same pelvic RT plus para-aortic RT (3600 Gy in 24 fractions). CT was given: MIT 6 mg/M2 IV push day 1, and 5 FU 1.0 g/M2 (maximum daily 1.5 g) by continuous IV infusion days 1 through 4 of each half-course of RT. This was followed by one application of intrauterine 137Cs when possible. Three of the 8 patients with recurrence in the pelvis or para-aortic nodes had a complete response (CR) to CT-RT and are alive without disease at 19, 19 and 22 months after treatment, respectively. Twenty of the 27 (74%) primary patients had a CR. With a median duration of follow-up of 6 months 4/20 have relapsed, 1 in RT field, 2 at distant sites, and 1 in both. Pelvic disease remains controlled in 19/27 (70%) including one patient salvaged with surgery. The acute toxicity of this regimen was tolerable: 2/35 developed transient leukopenia with one febrile episode, 9/35 developed transient thrombocytopenia without bleeding. Symptomatic sigmoid strictures developed in two patients, one requiring surgical intervention. Sigmoid perforation occurred in one patient and contributed to death. Typically, near complete regression of tumor is noted on completion of the external RT, reproducing the dramatic responses that have been observed in SCC of the anal canal, esophagus and head and neck, with this CT-RT regimen. A Phase III Study is required to establish whether the enhanced response rates to CT-RT will result in increased pelvic control and cure rates compared to those after RT alone.

Choice of postoperative therapy based on prognostic factors

Several patient-tumor related characteristics have been recognized to predict the prognosis of patients with invasive epithelial carcinoma of the ovary. Among the commonly cited variables are stage, residuum, grade, histologic subtype and the age of the patient at diagnosis.3,x The relative importance of each of these variables has not been clarified in the literature. Treatment decisions are often made on the basis of one variable (stage) and treatment outcome is often reported in terms of one or two variables (stage and residuum). If the other factors mentioned are also independent prognostic factors, then it is reasonable to expect that their incorporation into the processes of treatment decision-making and reporting of results would have the effect of refining both. To accomplish this, techniques of multivariate analysis are required. We have recently performed a systematic study of these prognostic factors with a view, firstly, to determine their relative independence and importance, and secondly, to devise a classification which uses information from each of the significant variables for purposes of treatment decision making.’ The clinical data used for this study were taken from the first 430 postoperative patients with all stages studied on prospective treatment protocols at The Princess Margaret Hospital (PMH). Patients were entered on study between April 197 1 and September 1976.’ The age range at diagnosis was 21 to 79, median 54 years. Grading and pathologic subtyping were performed by a review of the material on every case by Dr. T. C. Brown, pathologistin-chief, PMH. Patients were excluded if stromal invasion was not identified. Moderately differentiated lesions were grouped with poorly differentiated ones. Unclassified (=undifferentiated) lesions were all too poorly differentiated to permit recognition of the original pathologic subtype. Meticulous intra-operative staging was not performed routinely. Patients were considered to have no macroscopic residuum if this was clearly implied in the surgical note. In some patients it was uncertain whether all identified disease had been removed. This category is referred to as “?-residuum” or “uncertain residuum.” Small residuum refers to macroscopic disease not removed when bilateral salpingo-oophorectomy and hysterectomy (BSOH) had been completely performed. The large residuum group was so defined if residual disease was present when a complete BSOH was not performed. Large residual masses were invariably larger than 2 cm.

Epithelial ovarian cancer: The role of radiotherapy

Although several studies during the last 10-15 years have served to clarify the role of postoperative external beam radiotherapy in patients with ovarian cancer, the subject remains controversial. This paper will review the following topics: 1. Stage I Ovarian Cancer. 2. The rationale for selecting whole abdominopelvic radiotherapy over other forms of radiotherapy, such as pelvic or lower abdominal radiotherapy. 3. The choice of radiation technique. 4. The evidence that radiotherapy is curative in ovarian cancer. 5. The toxicity of abdominopelvic radiotherapy. 6. The criteria by which patients are selected for abdominopelvic radiotherapy. 7. Radiotherapy versus chemotherapy in early disease. 8. Consolidation radiotherapy after chemotherapy in advanced disease.

Whole abdominal irradiation by a moving-strip technique for patients with ovarian cancer

Abstract A technique of moving-strip irradiation of the whole abdomen was utilized in a randomized trial for patients with ovarian cancer. Subjects were classified as being in stages III, II and III and a bilateral salpingo-oophorectomy and hysterectomy had been completed. With regards both to 5-year survival and control of occult upper abdominal metastases, abdominopelvic irradiation using this technique was significantly better than pelvic irradiation alone or followed by chlorambucil therapy. The essential features of the technique used are (1) Therapy began with pelvic irradiation 2250 rad in 10 fractions followed immediately by a downward moving-strip that encompassed the entire abdomen and pelvis. (2) The dose to the moving-strip was 2250 rad in 10 fractions. (3) The superior border was placed above the diaphragm. This was confirmed on a radiograph taken in expiration. (4) No liver shielding was used. (5) Posterior renal shielding was used throughout (5-half value layer (HVL)). (6) The patients were treated while in a prone position; two fields were treated per day, using an isocentric technique. Serious or symptomatic late complications were rare and were amply justified by a survival gain of approximately 30%.

Outcome analysis of localized gastrointestinal lymphoma treated with surgery and postoperative irradiation.

One hundred thirteen patients with localized gastrointestinal lymphoma treated by surgery and postoperative irradiation between 1967 and 1985 were reviewed. At 15 years, actuarial survival of this group was 40.6%, with a cause-specific survival of 69.2% and a relapse-free rate of 64%. Two-thirds of relapses occurred at distant sites. In Stage IA and IIA patients with no residuum or with positive resection margins, (N = 90) only site of involvement and stage predicted for relapse. Age, histologic subtype group, and depth of bowel wall invasion did not affect relapse risk. In the very favorable group (Stage IA, IIA, no residuum or microscopic residuum), 8.4% of patients with stomach lymphoma relapsed compared to 25% of patients with small bowel lymphoma. The risk of early relapse was higher in those with Stage IIA small bowel lymphoma than those with Stage IA small bowel lymphoma. We continue to recommend adjuvant abdominal irradiation for patients with Stage IA, IIA completely resected stomach lymphoma and Stage IA completely resected small bowel lymphoma. We recommend combined modality therapy for patients with completely resected Stage IIA small bowel lymphoma and all other localized gastrointestinal lymphoma where visible residual disease is present.

Radiation Therapy of Ovarian Carcinoma

There has been considerable energy devoted to the study of epithelial cancer of the ovary during the last decade. Although the impact of this effort on the overall mortality from the disease has been depressingly small, advances have been made. The principles of surgical, radiotherapeutic and chemotherapeutic management are better understood, even if there is uncertainty about the precise place of each in the overall therapeutic armamentarium. There is also improved understanding of the patterns of spread of the disease and of the prognostic importance of several tumor-related variables. Recognizing the significance of these factors has brought out the complexity of evaluating the results of treatment. This is because results are often reported in a univariate mode, e.g., by stage, or residium, or grade, but not by considering several variables at once in a multivariate manner. A pioneering example of multifactorial analysis in ovarian cancer was presented by Griffiths, but for the most part the multifactorial presentation of treatment outcome has been avoided [la]. In many ways, however, those techniques of analysis which allow us to take account of several prognostic factors at once provide the clearest understanding of this disease. A valuable perspective on the place of radiotherapy in ovarian cancer can be gained by considering it in the light of these issues. Accordingly this essay will be in three sections, dealing with problems in interpreting results of treatment, the use of prognostic factors in classifying patients for prediction of treatment outcome and choice of therapy, and finally a critical review of a few selected trials of external beam radiation therapy.