Long-term results of concurrent radiation and chemotherapy for carcinoma of the cervix recurrent after surgery.

Between 1981 and 1991, 41 patients with carcinoma of the cervix recurrent only in the pelvis, or pelvis and para-aortic nodes after initial surgery, were treated with concurrent chemo-radiation (CT-RT). The total dose of radiation was tailored to the disease extent. Radiation was delivered to the pelvis and/or pelvis plus para-aortic nodes. Concurrent infusional 5-fluorouracil 1.5 g m-2 day-1 was delivered with bid radiation for one to three courses of 3 or 4 days. In addition, 10 patients received one or two courses of intravenous mitomycin C (Mit C) 6 mg m-2. Twenty-three of 40 evaluable (58%) had a complete response to CT-RT. Five have subsequently relapsed, two in pelvis alone, one in pelvis and distant sites and two with distant metastases only. Eighteen of 40 (45%) remain alive without disease from 3 to 113 months (median 57 months) after CT-RT. Sustained complete remissions and apparent cure have occured even in poor pronosis patients with pelvic side wall or common iliac nodal diease and those recurrent at short intervals from surgery. Using logistic regression the following varibles were examined for their prognostic significance for pelvic control and survival: Mit C, extent of pelvic diseases number of course of 5-FU, nodal status at original surgery and radiation dose. On multivariate analysis only the number of courses of 5-FU used was predictive of pelvic control and survival. Concurrent 5-FU and radiation is recommended as salvage therapy for patients wth recurrent locoregional cervical cancer.

Integrating radiation therapy into the management of ovarian cancer.

Several studies during the last 15 years have elucidated the role of postoperative external beam radiation therapy as curative management of some subsets of patients with ovarian cancer. Despite this, the use of radiation therapy in patients with ovarian cancer has remained a controversial subject. Substantially improved cure rates have not been realized during the past decade despite the early promise of high response rates to cisplatin chemotherapy. Thus, it is important that all currently effective therapies be used for maximum therapeutic gain. This article will review the evidence that radiation therapy is curative in ovarian cancer and highlight the criteria, including stage and grade of disease and tumor residuum, by which patients suitable for such therapy are selected. The rationale for the use of whole abdominopelvic irradiation rather than pelvic or lower abdominal treatment will be discussed, as will the optimal radiation technique and its attendant morbidity. Limited data pertinent to the controversy over the use of radiation therapy versus chemotherapy in early disease, will be reviewed. The possible benefits of consolidation abdominopelvic radiation therapy after chemotherapy in highly selected patients with well-differentiated microscopic residual disease at second-look laparotomy or with no residual disease but high a risk for relapse will be considered.

Testing the validity of a prognostic classification in patients with surgically optimal ovarian carcinoma: a 15-year review.

A retrospectively designed classification using stage, residuum and a variable which combines prognostic information from both grade and histology (histology-grade variable) has been used at our institution to predict prognosis, and choose therapy in patients with ovarian carcinoma, stages I-III having no or small residuum. In this study, multivariate analysis of prognostic factors were performed over two time periods: Group 1 (1971-1978), contains the patients from which the original classification was derived, and Group 2 (1979-1985), contains a different cohort of patients who are used to test the validity and reproducibility of the original classification. Multivariate analysis showed that the prognostic significance of two variables changed over the two study periods: tumor grade, and residuum. It was found that in the ideal combination of grade and histologic type, when used in conjunction with stage and residuum in a prognostic classification, was unique to each patient cohort. Because of these changes, new and more accurate prognostic classifications were derived for Group 2. However, when all classifications were examined, (including the original), the differences in their ability to stratify patients into risk categories was negligible, and there was no major advantage to using one classification over another for clinical applications. Thus, the retrospectively derived prognostic classification using grade, instead of a combined histology-grade variable, in conjunction with the other significant prognostic factors (stage and residuum), is preferred for prospective application, and for its simplicity.

The clinical significance of malignant peritoneal cytology in stage I endometrial carcinoma.

The prevalence of malignant peritoneal cytology in patients with International Federation of Obstetrics and Gynecology (1971) stage I endometrial carcinoma and its predictive value for recurrence of disease following hysterectomy were analyzed by numerically pooling the crude results of independent studies. Malignant cytology occurred in 8.3, 12.1 and 15.9% of patients with grade 1, 2 and 3 histology, respectively, and in 7.6% and 17.2% of patients with superficial and deep myometrial invasion, respectively. Prevalence was heterogeneous in the groups with grade 1 histology, grade 2 histology and superficial invasion, and homogeneous in the groups with grade 3 histology and deep invasion. This, together with a technical false positive rate of approximately 5% in the diagnosis of malignant cytology, suggests that the pooled values of prevalence for the low grade and superficially invasive groups may be overestimated. Malignant cytology was strongly associated with disease recurrence (pooled odds ratio of 4.7 with a 95% confidence interval of 3.5-6.3). Qualitative review of the literature suggests that this is largely due to the association of malignant cytology with other adverse prognostic factors which dominate the clinical course of the disease. In the absence of other adverse prognostic factors, the true prevalence of malignant cytology is low. This limits the clinical utility of cytology as an independent predictor of either overall recurrence or site of recurrence. Routine adjuvant treatment of patients with malignant cytology is therefore not justified.

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.

Analysis of complications in patients treated with abdomino-pelvic radiation therapy for ovarian carcinoma.

Between 1971 and 1985, 598 patients with ovarian carcinoma were treated with abdomino-pelvic radiation therapy. Acute complications included nausea and vomiting in 364 patients (61%) which were severe in 36, and diarrhea in 407 patients (68%), severe in 35. Leukopenia (less than 2.0 x 10(9) cells/liter) and thrombocytopenia (less than 100 x 10(9) cells/liter) occurred in 64 patients (11%) each. Treatment interruptions occurred in 136 patients (23%), and 62 patients (10%) did not complete treatment. In both situations the most common cause was myelosuppression. Late complications included chronic diarrhea in 85 patients (14%), transient hepatic enzyme elevation in 224 (44%), and symptomatic basal pneumonitis in 23 (4%). Serious late bowel complications were infrequent: 25 patients (4.2%) developed bowel obstruction and 16 required operation. Multivariate analysis was unable to determine any significant prognostic factors for bowel obstruction; however, the moving-strip technique of radiation therapy was associated with a significantly greater risk of developing chronic diarrhea, pneumonitis, and hepatic enzyme elevation than was the open beam technique. We conclude that abdomino-pelvic radiation therapy as used in these patients is associated with modest acute complications and a low risk of serious late toxicity.

Complications of whole abdominal and pelvic radiotherapy following chemotherapy for advanced ovarian cancer.

We examined the records of 105 patients with advanced ovarian cancer who had been treated with cisplatin combination chemotherapy followed by abdominopelvic radiotherapy. The purpose was to define the morbidity of this approach, and identify those factors predictive of toxicity. Acute toxicity resulting in delay or failure to complete treatment was most commonly due to myelosuppression. Nine of 105 patients (8.6%) required surgery for bowel obstruction that was not due to recurrent disease, 3 had an episode of bowel obstruction that settled conservatively, and a further 5 underwent surgery for obstruction due to recurrent tumor. The presence of both a dose of abdominopelvic radiotherapy over 2250 cGy, as well as a second-look laparotomy prior to radiotherapy, was associated with an increased risk of serious bowel complications. The increased frequency of late bowel morbidity seen in the combined modality group is likely explained by the presence of these two factors, rather than the exposure to chemotherapeutic agents per se. These observations are supported by the published literature.

Analysis of supradiaphragmatic clinical stage I and II Hodgkin's disease treated with radiation alone.

Patients with clinical Stage I and II Hodgkin's disease have been managed at the Princess Margaret Hospital for over 20 years, without the use of routine staging laparotomy. Our experience identified as adverse prognostic factors presence of a large mediastinal mass, B symptoms, and advanced age in presence of unfavorable histology (20). We had suggested previously that the use of extended field radiation therapy (XRT) was associated with a lower risk of relapse than involved field XRT or mantle XRT. There has been a trend over the past decade to select those patients with favorable prognostic factors for treatment with XRT alone and to use mantle plus upper abdominal XRT (extended field XRT) to treat them. A retrospective study of patients with clinical Stage I and II Hodgkin's disease treated at the Princess Margaret Hospital between 1978 and 1986 was conducted to determine the impact of patient selection and extended field radiation on outcome. The study involved 250 patients with supradiaphragmatic disease selected for treatment with radiation alone on the absence of adverse prognostic factors. Radiation techniques included involved field radiation in selected patients (those with upper neck involvement), mantle radiation in the earlier years, and mantle plus upper abdominal radiation in the later years of the study. Actuarial survival was 83.3% at 8 years; cause-specific survival was 90.1% and the relapse-free rate 71.6%. Local tumor control was 94.6%; only two patients had true infield failure. Multivariate analysis showed that significant prognostic factors included age, histology, and erythrocyte sedimentation rate. Extent of the radiation treatment volume was significant and influenced the risk of relapse, particularly out-of-field relapse, independently of other factors. A dose of 35 Gy was found to be sufficient for control of clinical disease. This study validated a previously developed model for the selection of clinically staged patients with Stage I and II Hodgkin's disease for treatment with radiation alone. Careful selection of these patients can yield excellent results without requiring that staging laparotomy be routinely performed or the use of systemic chemotherapy as the initial treatment.

Borderline epithelial ovarian tumors: a review of 81 cases with an assessment of the impact of treatment.

Optimal management of borderline epithelial ovarian tumors remains controversial because of the lack of clear, universally accepted pathologic criteria for diagnosis, the lack of complete understanding of the significance of intraperitoneal implants, and the desire to employ more limited surgery in young women. We reviewed the experience with borderline epithelial ovarian tumors at Princess Margaret Hospital in order to assess the natural history of the disease, to determine prognostic factors that would aid in management decisions, and to determine if adjuvant therapy influenced outcome. Eighty-one patients were analyzed. The mean age was 48 years. Seventy-two percent of tumors were of the serous histologic sub-type and 28% were mucinous. Seventy-eight percent were Stage I, 11% Stage II, and 11% Stage III. Peritoneal washings contained malignant cells in 14 of 32 patients (not recorded or obtained in 49), cyst rupture occurred in 25%, surface excrescences in 40%, and adhesions in 46%. None of these factors had a significant effect on recurrence rate or survival. Eleven patients received adjuvant radiation therapy (10 abdomino-pelvic and 1 pelvic alone), four adjuvant chemotherapy, and one both radiation therapy and chemotherapy. The rest (65) received no adjuvant therapy. Due to the small numbers and infrequent events, it was not possible to analyze and thus draw valid conclusions regarding the effect of adjuvant therapy on survival or recurrence. The overall survival (OS) and cause specific survival (CSS) were 85% and 96% at 10 years, respectively. No Stage I patient died of tumor. OS for Stage I patients was 90% at 10 years, the majority of whom (61 of 63) received no adjuvant therapy, and is thus unnecessary in Stage I disease. The adequacy of unilateral oophorectomy or ovarian cystectomy could not be confirmed because of small numbers. The 10 year OS and disease-free survival in Stage II and III were 75% and 50%, respectively, despite the use of adjuvant radiation therapy, chemotherapy, or both. It is necessary to create a multi-center tumor registry in order to acquire a prospective data base from which to develop sound therapeutic decisions.

Changing concepts in the management of vulvar cancer.

Vulvar carcinoma varies widely in its clinical presentations and prognosis. The reviewed literature outlines the achievements of conventional surgery, radiation, or chemoradiation therapy in its management. Currently therapeutic concepts are evolving. New treatment strategies replacing the uniform use of radical vulvectomy and bilateral groin dissection are proposed. These strategies are tailored to the clinical and pathological disease extent and location and integrate the possible therapeutic advantages of both surgery and chemoradiation. The testing and use of the proposed multimodality therapy protocols require the expertise of gynecologic, radiation, and medical oncologists. This approach should lead to improved anatomic and functional preservation in early disease and improved locoregional in advanced disease.

Outcome of patients with unfavorable optimally cytoreduced ovarian cancer treated with chemotherapy and whole abdominal radiation.

There is a subgroup of patients with Stage II or III ovarian cancer whose survival is poor despite optimal cytoreduction of tumor and abdominopelvic radiation. This study examined whether the survival of these patients, who have tumor with unfavorable histopathological characteristics and/or small residual disease, could be improved by giving chemotherapy before radiation. Forty-four out of fifty-one eligible patients, seen between 1981 and 1985, with Stage II or III disease were entered into the study. Following six courses of cisplatin-based chemotherapy, 33 (75%) received abdominopelvic radiotherapy. Survival was compared to that of 48 eligible matched control patients, treated with radiation between 1978 and 1981. The median follow-up is 6.6 years. The median survival was extended from 2.4 to 5.7 years (P = 0.13), and 42.6% of patients receiving combined therapy were free of relapse at 5 years, compared to 21.6% (P = 0.03) in the historical control group, treated with abdominopelvic irradiation alone. Only 2 of 44 patients in the combined group required surgery for bowel obstruction, as did 1 of 48 in the control group. Tolerance and toxicity of the combined approach were acceptable. Although we cannot be certain that the entire benefit we observed was not attributable to the chemotherapy alone, there is evidence that the radiotherapy may have been additive. Chemotherapy followed by abdominopelvic radiotherapy seems a reasonable management policy in these patients.

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.

Prognostic factors in patients with stage I epithelial ovarian cancer.

We analyzed factors predictive of relapse risk in patients with stage I invasive epithelial ovarian cancer: 252 patients from the Princess Margaret Hospital provided a data base for hypothesis generation, and data on 267 patients from the Norwegian Radium Hospital were used for hypothesis testing. The outcomes in most analyses in the two series were very similar, validating the following conclusions. Differentiation (grade) was the most powerful predictor of relapse, followed by dense adherence (which resulted in outcomes equivalent to those in stage II) and, finally, large-volume ascites. When the effects of these three factors were accounted for, then none of the following were prognostic: bilaterality (stage Ib), cyst rupture (stage Ic), capsular penetration (stage Ic), tumor size, histologic subtype, patient age, year of diagnosis, and postoperative therapy. These results allow simplification of stage I substaging, as only differentiation, dense adherence, and large-volume ascites (? peritoneal cytology) need be considered. The 5-year relapse-free rate was 98% in patients with grade 1 tumors in whom both dense adherence and large-volume ascites were absent. These patients are adequately treated by operation alone. Although the relapse risk was high enough in the remaining patients to warrant postoperative treatment, a significant benefit could be shown only for a small subset of patients, namely those with densely adherent tumors treated with abdominopelvic radiotherapy. In grades 2 and 3, none of the therapies used in either series was superior to pelvic radiotherapy or operation alone.

Advances in radiotherapy in the gynecologic malignancies.

We review, for their wider applicability, four advances in the radiotherapeutic management of the gynecologic malignancies. Attempts at improving upon results obtained with radiotherapy by the addition of chemotherapy have usually followed one of two temporal strategies: Sequential chemotherapy-radiotherapy (so-called neo-adjuvant chemotherapy), or chemotherapy given concurrently with radiotherapy. The pros and cons of both models are discussed. Recent work suggests that there is a differential response between the acutely reacting normal tissues, as well as tumor, and the late-reacting normal tissues, which is dependent upon the radiation fraction size. The rationale and some important clinical applications are reviewed. Advances in brachytherapy include the high dose rate treatment and the use of rigid templates to guide the accurate placement of the interstitial implant. The controversies surrounding these approaches require further study before the precise place of these techniques is known. Finally, in vulvar cancer, the addition of radiotherapy to surgery is being studied to permit less radical operations in early disease, and greater local tumor control in advanced disease.

Minimizing drug resistance. The somatic mutation model and gestational trophoblastic neoplasia.

Because of its curability, gestational trophoblastic neoplasia provides a valuable framework within which models of tumor chemotherapy can be examined. The Goldie-Coldman hypothesis, one such model, holds that resistance to chemotherapeutic drugs can be acquired in human tumors as a result of spontaneous mutation. This paper examines in depth some implications of this hypothesis in gestational trophoblastic neoplasia. Several observed treatment phenomena in this disease are in accord with the predictions of the somatic mutation model, and the model may be used to guide future clinical investigation. In particular, there is a need to elaborate cross-resistance profiles between drugs commonly used to treat trophoblastic neoplasia. This information could be used to develop new combination chemotherapy regimens as well as strategies for alternating non-cross-resistant combination chemotherapy regimens.

Current therapy for dysgerminoma of the ovary.

It is important that therapy of ovarian dysgerminoma be optimized because of the young age of women affected and the threat that therapy may pose to fertility. Our understanding of dysgerminoma has improved, so that treatment schemes with better therapeutic ratio may now be used. Approximately 65% of patients present with stage IA disease. For those wishing to preserve fertility, conservative surgery with close clinical, radiologic, and serologic follow-up is the treatment of choice, with chemotherapy for relapse. Cure rates should approach 100%, and fertility is usually preserved. Intra-abdominal relapse in those not wishing to preserve fertility should be treated with modest-dose pelvic and abdominal irradiation. For those patients with disease presenting in stages IB, II, and III who wish to maintain fertility, unilateral oophorectomy followed by combination chemotherapy may be curative and spare ovarian function. Otherwise, complete surgery, followed by abdominopelvic radiation therapy, is recommended. This treatment produces less morbidity than chemotherapy and will cure approximately two-thirds of patients. Chemotherapy should be used for salvage of subsequent relapse. Both radiation and chemotherapy are highly effective treatment modalities for dysgerminoma. This information, coupled with better understanding of the patterns of disease spread and improved ability to identify nondysgerminomatous elements using serum tumor markers, means that a more conservative approach can be taken to management without compromising the chance of cure. Cure rates for dysgerminoma should now approach the role of 97% achieved in the comparable tumor, testicular seminoma.

Concurrent radiation and chemotherapy for carcinoma of the cervix recurrent after radical surgery.

Results of salvage therapy in patients with carcinoma of the cervix, recurrent after primary surgery, have been dismal even when disease was apparently confined to the pelvis. Further surgery or radiation therapy cured only some with central pelvic disease alone who had recurred at intervals longer than 6 months after primary therapy. To try to improve the results of salvage therapy, we used a combination of concurrent chemotherapy, 5-Fluorouracil with or without Mitomycin-C, and radiation therapy. Seventeen patients were treated. Recurrent disease was present in the pelvis or pelvis and paraaortic nodes after radical surgery for Stage IB carcinoma of the cervix. Eight of seventeen (47%) are alive, disease-free, 21 to 58 months after therapy. Seven of the eight had biopsy proven recurrence. Five of eight had recurred within 9 months of primary surgery and 7/8 had a component of pelvic side wall disease. Thus the survivors had unfavorable prognostic features. Nevertheless, the use of concurrent radiation and chemotherapy produced an exceptionally high proportion of sustained complete remissions and possible cures.