Ovarian irradiation and prednisone following surgery and radiotherapy for carcinoma of the breast.

Following mastectomy, patients aged 35 to 76 years with operable breast cancer underwent postoperative irradiation of the chest wall and regional lymph nodes. They were then assigned at random to receive no further therapy (NT), ovarian irradiation (R) 2000 rads in 5 days, or ovarian irradiation in the same dosage plus prednisone (R + P) 7.5 mg daily for up to five years. A total of 703 eligible patients received the randomly assigned treatment. The median follow up was 21 years with a range of 14 to 25 years. Overall, there was a delay in recurrence (p = 0.03) and survival was prolonged (p = 0.19) for patients who received R, but in neither case was the difference significant after adjusting for the multiplicity in our data. Overall, patients who received R + P experienced a significant delay in recurrence (p = 0.0003) and a significantly prolonged survival (p = 0.005), even after adjusting for multiple comparisons. In premenopausal patients who received R, the recurrence of breast cancer was delayed and survival prolonged, but not significantly. In premenopausal women aged 45 years or more, R + P therapy significantly prolonged survival (p = 0.0004), while the delay in recurrence although significant (p = 0.02) was only marginally so after allowance for multiple comparisons. No value was demonstrated for ovarian irradiation with or without prednisone therapy in postmenopausal patients. A new finding in this review was that contralateral breast cancer as the first failure was reduced by R + P compared to NT in the overall group.

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.

Second primary malignancies following diagnosis of small-cell lung cancer.

PURPOSE AND METHODS: The records of 800 patients with small-cell carcinoma of the lung (SCLC) treated between 1971 and 1985 at University of Toronto-affiliated hospitals were reviewed for the occurrence and relative risk of second primary malignancies (SPMs). Almost all patients who developed a SPM were treated previously with chemotherapy and radiation therapy. RESULTS: Nineteen metachronous SPMs (MSPMs) and 11 synchronous SPMs (SSPMs) were identified. SSPMs were detected between 1 and 12 months after the diagnosis of SCLC. The MSPMs were identified between 1 and 10 years after the diagnosis of SCLC. MSPMs included non-small-cell lung cancer (NSCLC) (four patients), hematologic malignancies (HM) (three patients), and 12 with other solid tumors (OST). The median survival times after the diagnosis of MSPM was 33 months, 10 months, and 1 month, respectively, for those with NSCLC, OST, and HM. Expected cancer incidence rates were used to compute a relative risk rate for developing a MSPM in a subset of 392 patients on whom accurate follow-up information was available. The calculated relative risk for all tumors was 3.73. The relative risk for the development of secondary NSCLC was 6.83. CONCLUSION: We suggest that increased predisposition to SPM may relate to secondary effects of multimodality treatment and biologic considerations.

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.

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.

Small-cell carcinoma of the lung: derivation of a prognostic staging system.

Retrospective data on 22 pretreatment attributes were evaluated in 614 patients with small-cell carcinoma of the lung (SCCL). The series included 284 patients with limited disease (LD) and 328 patients with extensive disease (ED) managed between 1974 and 1986. Prognostic factors were evaluated by univariate analysis and by the Cox multivariate regression model. Recursive partition and amalgamation algorithm (RECPAM), two clustering methods well suited for obtaining strata and adapted for censoring survival data, were developed and used in the formulation of a new prognostic staging system. In univariate analysis, prognosis was significantly influenced by extent of disease (DE), the number of metastatic sites, and the detection of mediastinal spread in LD. Poor performance status (PS), male sex, and advanced age were negatively correlated with survival, as were increased serum levels of alkaline phosphates (AP), lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), total WBC count (WBCC), and low platelet count and low serum sodium. The Cox model identified plasma LDH and mediastinal spread as the only significant factors in LD; the influence of PS, number of metastatic sites, bone metastasis, brain metastasis, and platelet count were identified as significant in ED. The RECPAM model identified four distinct risk groups defined in a classification tree by the following eight attributes: DE, PS, serum AP, serum LDH, mediastinal spread, sex, WBCC, and liver metastasis. The four groups were distinguished by median survival times of 59, 49, 35, and 24 weeks, respectively (P = .0001). Interactions among prognostic factors are emphasized in the RECPAM classification model as evidenced by reassignment of patients across conventional staging barriers into alternate prognostic groups. The advantages of using RECPAM over the more conventional Cox regression techniques for a new staging system are discussed.

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.

Late neurological complications after prophylactic cranial irradiation in patients with small-cell lung cancer: the Toronto experience.

We retrospectively analyzed the charts of 58 long-term survivors of small-cell lung cancer (SCLC) (greater than 2 years) for neurological complications and their impact on the well-being of these patients. We also attempted to have patients complete a questionnaire regarding any possible neurological problems. This was done in 14 patients. Metastasis to the CNS occurred significantly less often in patients who received prophylactic cranial irradiation (PCI) in a dose of 20 Gy in five equal fractions (two of 48), compared with patients who did not receive it (four of 10) (P less than .006). Delayed neurological complications occurred in nine of 48 (19%) patients who received PCI. However, in only two patients did PCI appear to be responsible for progressive dementia. In the other seven patients (one with weakness in the arms and legs, one with transient left hemiparesis, two with hearing loss, and three with various visual disturbances), chemotherapeutic agents (mainly cisplatin and vincristine) and underlying diseases probably contributed significantly to the occurrence of these complications. In addition, these neurological disturbances were transient or ran a stable course and did not adversely affect the daily life of these patients. In comparison, amongst the 10 patients who did not receive PCI one had progressive dementia and another had hemiparesis secondary to probable brain embolism. We conclude that the use of PCI in these doses was effective in reducing the frequency of CNS metastases and had an adverse effect on the daily life and well-being only in a minority of the patients. Until results of controlled randomized studies show otherwise, PCI should continue to be used as a part of the combined modality treatment of completely responding patients with limited SCLC.

Neurologic disorders in patients with small cell lung cancer.

In a series of 641 patients with small cell lung cancer, 189 (29.5%) had at least one neurologic disorder either at the time of presentation or during the subsequent clinical course of the cancer. The total number of neurologic disorders was 210, which included brain metastases (75.7%), meningeal carcinomatosis (6.7%), intramedullary metastases (2.4%), epidural metastases (11.0%), hyponatremia producing CNS symptoms (3.3%), and Eaton-Lambert syndrome (1.0%). The most common signs and symptoms were motor dysfunction and confusion. The overall survival of patients with any neurologic disorder was compared to that of patients without neurologic problems. There was no difference between the survival curves for the first year and a half, but patients without neurologic complications had a greater probability of long-term survival (log-rank P = 0.03). There were no statistically significant differences when this comparison was made according to stage of disease. When a neurologic disorder related to cancer occurred, the survival time from the date of that diagnosis was usually short. The neurologic disorder was the immediate cause of death in the majority of cases. In patients who achieved a complete remission, the administration of prophylactic cranial irradiation (PCI) significantly reduced the risk of developing brain metastases as the initial site of the relapse (log-rank P = 0.0034). After adjustment for performance status and extent of disease, the survival of complete responders treated with and without PCI was not significantly different. We conclude that neurologic complications are a frequent and serious problem in patients with SCLC.

Superior vena caval obstruction syndrome in small cell lung cancer.

In a series of 643 patients with small cell lung cancer (SCLC), 55 patients (8.6%) had signs or symptoms of superior vena caval obstruction syndrome (SVCO). Relatively long intervals from the onset of the first symptoms of SVCO to the start of therapy were observed, and invasive diagnostic procedures were safely performed in most patients. The pretreatment characteristics of patients with SVCO were not significantly different from those of patients without signs of the syndrome, and survival was similar in both groups. Patients with SVCO were usually treated first with induction chemotherapy, and prompt resolution of signs and symptoms occurred in the majority. Radiation was effective in controlling SVCO at relapse or after failure of initial chemotherapy. It was concluded that SVCO in patients with SCLC should be treated initially with systemic chemotherapy, as for other presentations of this disease. The current data do not support the commonly held view that SVCO in SCLC should be approached as an oncologic emergency.

Stage III endometrial carcinoma. A review of 90 cases.

The authors present a retrospective review of 90 cases of Stage III endometrial carcinoma seen over a 10-year period at the Princess Margaret Hospital, Toronto. Overall 5-year survival was 45.5% and disease-free survival was 36.0%. Prognostic factors identified within Stage III were tumor grade, geographic distribution of disease, the presence of symptoms other than vaginal bleeding or discharge, and completeness of surgery. Isolated involvement of the ovary or fallopian tube emerges as a distinct syndrome with a good prognosis (5-year survival of 82.3%). Surgery is the treatment of choice for operable cases, but 13 of 36 patients with inoperable disease who completed radical radiotherapy were alive and free of disease at 5 years.

Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung.

One hundred fifty-three patients with limited and 167 with extensive small cell carcinoma of the lung (SCCL) were evaluable for response to treatment with six courses of chemotherapy (cyclophosphamide, doxorubicin, and vincristine), irradiation to intrathoracic disease, and prophylactic cranial irradiation (PCI). No maintenance chemotherapy was given. Fifty-two percent of patients with limited disease (LD) and 10% of extensive disease patients (ED) achieved a complete response. The median survival times for LD and ED patients were 49 and 34 weeks, respectively. These results were compared to a previous experience with 147 patients who were treated with three courses of similar induction chemotherapy and thoracic irradiation, as well as one year of maintenance chemotherapy (CCNU, procarbazine, and methotrexate) but without PCI. Although the use of PCI was found to reduce the frequency of brain metastases as the site of first relapse, detailed comparisons of response rates and survival showed no significant differences between the two study populations. Prolonged maintenance chemotherapy of the type used in the first study does not favorably influence outcome after intensive induction therapy for SCCL.

Upper half body irradiation (UHBI) for extensive small cell carcinoma of the lung.

Upper half body irradiation (UHBI) was given to 41 of 121 patients with extensive small cell carcinoma of the lung. All patients were treated with 6 courses of cyclophosphamide, doxorubicin, and vincristine (CAV). Responding patients also received prophylactic cranial irradiation and local irradiation to prechemotherapy intrathoracic disease. Among the 70% (85/121) of patients who responded to chemotherapy, 41 have received UHBI, given one to two months later. The single fraction midline dose given has been increased in successive patients from 300 to 720 cGy (uncorrected for inhomogeneities). Actual lung doses were higher by 9-22%, (determined in 31 patients by CT scanning and lung density measurements). Adverse effects seen were vomiting, fever, drowsiness, myelosuppression, liver dysfunction and dry mouth. All were transient, and no pneumonitis or treatment deaths occurred. Adverse effect rates were similar at all dose levels. UHBI is well tolerated in patients who have received chemotherapy and merits further study.

Ovarian irradiation and prednisone following surgery and radiotherapy for carcinoma of the breast.

Following mastectomy, patients with operable breast cancer underwent postoperative irradiation of the chest wall and regional lymph nodes. They were then assigned at random to receive no further therapy, ovarian irradiation (2000 rad in five days) or ovarian irradiation in the same dosage plus prednisone, 7.5 mg daily. A total of 705 patients received the randomly assigned treatment and were followed for up to 15 years. In premenopausal patients who received ovarian irradiation, the recurrence of breast cancer was delayed and survival prolonged, but not significantly. In premenopausal women aged 45 years or more, ovarian irradiation plus prednisone therapy significantly delayed the recurrence of breast cancer (p = 0.04) and prolonged survival (p = 0.02). No value was demonstrated for ovarian irradiation with or without prednisone therapy in postmenopausal patients.

Combined modality treatment of small cell carcinoma of the lung.

Ninety patients with extensive and 61 with limited small cell carcinoma of the lung were treated with three courses of intravenous chemotherapy (cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate) followed by radiotherapy to intrathoracic disease, and a second three-drug oral combination consisting of lomustine, procarbazine, and methotrexate for one year. Among the 147 patients who were evaluated, 55 of 66 (83%) with limited disease and 53 of 81 (65%) with extensive disease showed response after three courses of chemotherapy. The complete response rate in patients with limited disease prior to radiotherapy was 24%, but increased to 58% when evaluated following radiotherapy. The median survival was 47 weeks for patients with limited disease and 36 weeks for those with extensive disease. A 24% two-year survival is projected for complete responders. Important prognostic factors for survival are performance status, extent of disease, and sex, with female subjects doing somewhat better than male subjects. Among patients with limited disease, 45% failed within the CNS despite the use of chemotherapeutic agents that cross the blood-brain barrier. The initial induction regimen and radiotherapy were well tolerated; the oral three-drug combination was more toxic and did not prevent CNS metastases.

Ovarian carcinoma: improved survival following abdominopelvic irradiation in patients with a completed pelvic operation.

A prospective, stratified, randomized study of 190 postoperative ovarian patients with Stages IB, II, and III (asymptomatic) presentations is reported. The median time of follow-up was 52 months. Patients in whom bilateral salpingo-oophorectomy and hysterectomy (BSOH) could not be completed because of extensive pelvic tumor had a poor prognosis which did not differ for any of the therapied tested. When BSOH was completed, pelvic plus abdominopelvic irradiation (P + AB) with no diaphragmatic shielding significnatly improved patient survival rate and long-term control of occult upper abdominal disease in approximately 25% more patients than pelvic irradiation alone or followed by adjuvant daily chlorambucil therapy. The effectiveness of P + AB in BSOH-completed patients was independent of stage or tumor grade and was most clearly appreciated in patients with all gross tumor removed. Chlorambucil added to pelvic irradiation delayed the time to treatment failure without reducing the number of treatment failures.