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.

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.

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.

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.

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.

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.

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.

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.

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

Following surgery and regional radiotherapy for operable carcinoma of the breast in premenopausal women, ovarian irradiation (2000 rad in five daily fractions) plus prednisone (7.5 mg per day) results in delayed recurrence and prolonged survival.

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.

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.

Ectopic production of human chorionic gonadotropin: a case report.

The ectopic production of the beta-subunit of human chorionic gonadotropin (hCG) is described in a patient with an anaplastic carcinoma. After chemotherapy the marker decreased in a logarithmic fashion to undetectable levels but the neoplasm progressed and the patient died. The specificity of the beta-subunit of hCG is discussed. Discordance of the marker and clinical disease is pointed out, and several possible explanations are outlined. The lack of specificity of the beta-subunit of hCG and the discordance that it may exhibit means that its use in diagnosing and following disease progression may be limited.

The Princess Margaret Hospital study of ovarian cancer: stages I, II, and asymptomatic III presentations.

An analysis of 231 patients with stages I, II, and asymptomatic III ovarian cancer, studied in a prospective randomized-stratified trial, is presented. None of the stage IA patients with well-differentiated tumors have had disease relapses; one fourth of the patients with poorly differentiated tumors have had disease relapses throughout the peritoneal cavity. There is therefore little justification for pelvic radiation alone as postoperative therapy for stage IA ovarian carcinoma. For stage IB, II, and asymptomatic III presentations, patients with an incomplete initial pelvic operation had poor survival characteristics with all tested therapies. For patients in whom the operation was completed, abdominopelvic radiation was superior to pelvic radiation alone or followed by chlorambucil, with respect to long-term survival and control of abdominal disease. The effectiveness of abdominopelvic radiation was independent of stage or histology. The value of abdominopelvic radiation was most strikingly seen in patients with no visible residual tumor.

Treatment of epithelial carcinoma of the ovary: operation, irradiation, and chemotherapy.

This paper presents an interim analysis of 279 patients with epithelial carcinoma of the ovary who were entered into a prospective study started in April, 1971. One hundred and three patients were available for analysis three years after diagnosis. Apart from the survival differences by stage and treatment method, this study has shown that the completeness of the initial pelvic operation, in Stages II and III, is of greater prognostic importance than the stage. The importance of the features of the pelvic disease which interfere with the removal of all pelvic organs led the authors to conclude that factors other than stage should be considered in prescribing postoperative treatment. To date, the disease-free survival trends in Stages IB, II, and asymptomatic Stage III show that physicians should place much greater emphasis on the initial operative features when they are seeking the most effective combination of irradiation and chemotherapy. Analysis of failures shows that upper abdominal irradiation is more effective than daily chlorambucil in preventing progression of disease to that area. However, early evidence indicates that chlorambucil added to pelvic irradiation improves the control of pelvic disease. Improved methods of treatment have not yet been identified for early Stage I (IA) and advanced presentations (symptomatic Stages III and IV).

Definitive evidence for hypoxic cells influencing cure in cancer therapy.

From an analysis of 2803 patients with carcinoma of the cervix treated by radiation therapy, a 62% cure rate can be shown. In those patients with Stage IIb and III disease, a haemoglobin level during treatment of below 12 g% was associated with a significantly higher pelvic recurrence rate, and also lower cure rate, than for those with a haemoglobin level 12g% or more. A prospective study shows that the correction of anaemia is associated with a decreased pelvic recurrence rate and an increased cure rate consistent with tumour hypoxia being greater in anaemic patients than in those with a normal haemoglobin level. It is also consistent with the thesis that hypoxia controls the radiation local control rate in patients with advanced carcinoma of the cervix.

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.

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.

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.