Role and mechanism of action of tamoxifen in premenopausal women with metastatic breast carcinoma.

Tamoxifen was evaluated as initial hormone therapy for metastatic breast cancer in 85 premenopausal patients. Tamoxifen responders continued on tamoxifen, while tamoxifen failures and initial responders who later progressed were to receive ovarian ablation next. Of 74 evaluable patients, 5 had complete responses (CR) and 15 had partial responses (PR) while 12 remained stable (ST), giving response rates of 27% (CR + PR) or 43% (CR + PR + ST). Of the 23 patients who initially responded (CR + PR + ST) to tamoxifen but then progressed and received ovarian ablation alone, 15 are assessable. Nine (60%) responded (CR + PR + ST) to ovarian ablation. Sixteen patients who failed tamoxifen had ovarian ablation alone, and of 14 assessable patients 2 had ST while 12 progressed. Thus response to tamoxifen strongly predicted response to ovarian ablation (P = 0.021). Serial follicle stimulating hormone, prolactin, and estradiol levels suggested that tamoxifen does not act by induction of a "medical ovariectomy" or by alteration of prolactin levels in premenopausal patients.

Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group.

Five hundred forty-three patients with completely resected malignant melanoma who were considered to have a significant risk of developing recurrent disease were randomized to one of four study groups. One group received levamisole 2.5 mg/kg on 2 consecutive days weekly for 3 years, a second group received bacillus Calmette-Guérin (BCG) for 3 years. A third group alternated 8-week courses of BCG and levamisole for 3 years and a fourth group underwent clinical assessment at the same frequency as the three treatment groups. The median duration of follow-up is 8.5 years. The percentage of reduction in the death rate and the recurrence rate in the treatment groups compared with the control group was calculated using the Cox proportional hazards model and adjusted for age, sex, and stage as covariants. The patients treated with levamisole were estimated to have a 29% reduction in both the death rate (P = .08) and the recurrence rate (P = .09) compared with patients receiving no further treatment. Fifty-five patients discontinued levamisole early because of gastrointestinal intolerance or arthralgia, myalgia, fever, and immune leukopenia. The patients treated with BCG alternating with levamisole experienced a 10% reduction in the death rate and a 6% reduction in the recurrence rate, and the patients treated with BCG alone experienced a 4% reduction in the death rate and a 3% increase in the recurrence rate compared with the control group. The degree of improvement experienced by the patients that were treated by levamisole is of sufficient magnitude to warrant further investigation of this dose of levamisole as adjuvant treatment in patients with melanoma.

A real-time audit of radiation therapy in a regional cancer center.

PURPOSE: To report the development, structure, and implementation of a real-time clinical radiotherapy audit of the practice of radiation oncology in a regional cancer center. METHODS AND MATERIALS: Radiotherapy treatment plans were audited by a real-time peer-review process over an 8-year period (1989-1996). The overall goal of the audit was to establish a process for quality assurance (QA) of radiotherapy planning and prescription for individual patients. A parallel process was developed to audit the implementation of intervention-specific radiotherapy treatment policies. RESULTS: A total of 3052 treatment plans were audited. Of these, 124 (4.1%) were not approved by the audit due to apparent errors in radiation planning. The majority of the nonapproved plans (79%) were modified prior to initiating treatment; the audit provided important clinical feedback about individual patient care in these instances. Most of the remaining nonapproved plans were deviations from normal practice due to patient-specific considerations. A further 110 (3.6% of all audited plans) were not approved by the audit due to deviations from radiotherapy treatment policy. A minority of these plans (22%) were modified prior to initiating treatment and the remainder provided important feedback for continuous quality improvement of treatment policies. CONCLUSION: A real-time audit of radiotherapy practice in a regional cancer center setting proved feasible and provided important direct and indirect patient benefits.

A prospective trial of short-course radiotherapy plus chemotherapy for palliation of dysphagia from advanced esophageal cancer.

PURPOSE: Between 1994 and 1997, 22 patients with dysphagia from advanced incurable esophageal cancer were enrolled in a phase I/II prospective study to assess the palliative benefit and toxicity of a short course of radiotherapy with chemotherapy. METHODS: The study population included 17 men and five women with a median age of 69 (range 43-84). Patients were treated with 30 Gy in ten fractions to the mediastinum with a concurrent single course of chemotherapy (5-FU, 1000 mg/m(2), days 1-4 and mitomycin-C 10 mg/m(2), day 1). Swallowing ability was recorded each day on a self-administered diary card using the five point dysphagia index of the MRC (UK). The median baseline MRC swallowing score was 4 (cannot swallow solids). RESULTS: Treatment was generally well tolerated, but seven (32%) patients had transient worsening of dysphagia scores immediately following treatment because of esophagitis; fifteen (68%) achieved a complete response (score 1: no difficulty on swallowing) with a median time to normalization of swallowing of 5 weeks. For these patients, the median dysphagia-free interval from time of onset of improvement was 11 weeks (range 1-131 weeks) and 11 (73%) remained dysphagia-free until death. The remaining patients had no or marginal improvement. Univariate analysis showed no difference between responders and non-responders with respect to age, gender, or histology. Median survival for the entire study population was 20 weeks (range 3-135 weeks). CONCLUSIONS: This prospective trial shows that a short course of radiotherapy plus chemotherapy may produce complete relief of swallowing difficulties in a substantial proportion of patients with acceptable toxicity.

Toxicity of abdominopelvic radiation in advanced ovarian carcinoma patients after cisplatin/cyclophosphamide therapy and second-look laparotomy.

Twenty-seven advanced ovarian carcinoma patients who had received six courses of cyclophosphamide/cisplatin and had either microscopic disease (15 patients) or no pathologically detectable disease (12 patients) after second-look laparotomy were treated with abdominopelvic radiation (2250 cGy to the abdomen and pelvis and a 2250-cGy pelvic boost). Acute myelosuppression or gastrointestinal toxicity prevented completion of treatment in only three patients. However, bowel obstruction occurred in 13 (48%), ten of whom required surgery. Five of these ten had recurrent tumor, but the other five did not. Subsequently two of the latter five did develop a recurrence, one in the lung and one in the liver. A third patient died as an indirect result of radiation damage to the bowel. Median follow-up duration is 17 months from completion of radiation. So far, 13 (48%) have developed progressive disease: four (33%) of the 12 who had a negative second-look laparotomy and nine (60%) of the 15 who had microscopic disease before radiation. While acute toxicity is tolerable, the incidence of serious chronic bowel toxicity is high. Efforts should be made to alter this therapy in order to decrease the frequency of long-term morbidity.

Advanced carcinoma of the ovary with central nervous system relapse.

Interdisciplinary protocols for management of advanced adenocarcinoma of the ovary have resulted in prolonged patient survival. A subset of patients is emerging in whom central nervous system (CNS) relapse occurs even following negative second-look procedures (SLP). Seven of 342 eligible patients entered in a National Cancer Institute of Canada Trial for Ovarian Cancer, from February 1, 1980 to March 31, 1984, had CNS relapse. All patients received adriamycin and cisplatin. SLP was performed in 5 patients, 3 of whom were complete responders (CR). Two additional patients failed to complete their chemotherapy and had progressive pelvic disease. The median age of these 7 patients was 57 years, their overall survival time was 28 months, compared with an average age of 58 years and survival of 21.6 months, for the entire group. Two patients had prolonged survival after their CNS relapse; 1 patient lived 26 months, and the other, who underwent craniotomy for primary management of the metastasis survived 18 months. Confirmation of metastatic disease was obtained in 4 of the 7 patients. The results of this study suggest that management of CNS involvement in adenocarcinoma of the ovary should be determined by overall performance status even in the presence of generalized disease.

Breast irradiation in women with early stage invasive breast cancer following breast conservation surgery. Provincial Breast Disease Site Group.

GUIDELINE QUESTIONS: 1) Should breast irradiation be given to women with early stage invasive breast cancer (stage I and II) following breast conservation surgery (lumpectomy with clear resection margins and axillary dissection)? 2) Is there an optimal schedule for breast irradiation? 3) What is a reasonable interval between definitive surgery and the start of breast irradiation? 4) Are there patients who can be spared breast irradiation after lumpectomy? OBJECTIVE: To make recommendations about the use of breast irradiation in women with early stage invasive breast cancer following breast conservation surgery. OUTCOMES: Local control is the primary endpoint of interest. Survival, quality of life (addressed through the adverse effects of radiotherapy) and cosmesis are also considered. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 6 members of the Breast Disease Site Group (Breast DSG) of the Ontario Cancer Treatment Practice Guidelines Initiative. Earlier drafts of the evidence-based recommendation were reviewed, discussed and approved by the Breast DSG, which comprises medical oncologists, radiation oncologists, surgeons, epidemiologists, pathologists and a medical sociologist. There was no participation by a community representative in the development of this guideline. QUALITY OF EVIDENCE: There are 5 randomized controlled trials (RCTs) and 1 meta-analysis comparing breast irradiation with no breast irradiation following breast conservation surgery; 6 randomized trials comparing breast conservation surgery plus breast irradiation with mastectomy are also included, as well as several retrospective studies. BENEFITS: All of the 5 RCTs showed a significant decrease in local recurrence rates among patients receiving radiotherapy. In the 4 trials with a median follow-up of 5 years or longer, the relative risk reduction with breast irradiation ranged from 69% to 88%. The absolute differences ranged from 16% (p < 0.001) to 25% (p < 0.001). Despite the effect on local recurrence, no difference in survival was detected in any of the 5 trials. Most of the patients with local recurrence in these trials underwent mastectomy. HARMS: Major adverse effects of breast irradiation occur very infrequently. PRACTICE GUIDELINE: Women with early stage invasive breast cancer (stage I and II) who have undergone breast conservation surgery should be offered postoperative breast irradiation. The optimal fractionation schedule for breast irradiation has not been established, and the role of boost irradiation is unclear. Outside of a clinical trial, 2 commonly used fractionation schedules are suggested: 50 Gy in 25 fractions to the whole breast, or 40 Gy in 16 fractions to the whole breast with a local boost to the primary site of 12.5 Gy in 5 fractions. Shorter schedules (e.g., 40 or 44 Gy in 16 fractions) have also been used routinely in some centres. The enrollment of patients in ongoing clinical trials is encouraged. Women who have undergone breast conservation surgery should receive local breast irradiation as soon as possible after wound healing. A safe interval between surgery and the start of radiotherapy is unknown, but it is reasonable to start breast irradiation within 12 weeks after definitive surgery. For women who are candidates for chemotherapy, the optimal sequencing of chemotherapy and breast irradiation is unknown. It is reasonable to start radiotherapy after the completion of chemotherapy, or concurrently if anthracycline-containing regimens are not used. For further information, please refer to Ontario Cancer Treatment Practice Guidelines Initiative's practice guideline "Surgical Management of Early Stage Invasive Breast Cancer (stage I and II)."

Surgery without adjuvant chemotherapy for early epithelial ovarian carcinoma after comprehensive surgical staging.

From January 1981 to December 1987, 82 patients with carcinoma of the ovary, Stages 1A, 1B, and 1C (cytology negative) (FIGO 1988), were enrolled in this study following accurate surgical staging. No patient received adjunctive therapy and all were followed from 2 to 6 years with a mean duration of follow-up of 4 years. Sixty-eight patients were eligible for review--thirty-nine Stage 1A, six Stage 1B, and twenty-three Stage 1C (twenty-one with tumor rupture, two with excrescences). The mean age was 48.8 years. Three patients had a recurrence of their disease (one death). Forty patients in this series were Stage 1A or 1B (well or moderately well differentiated, no excrescences, no rupture). Only 1 patient in this group (with clear cell carcinoma) has recurred, suggesting that this patient population can be followed without adjunctive therapy. Adhesions or rupture in this series did not affect outcome. Clear cell tumors may have an ominous prognosis despite apparent local disease.

A predictive index of cure versus no cure in advanced ovarian carcinoma patients--replacement of second-look laparotomy as a diagnostic test.

Three hundred forty-two Stage III and IV epithelial ovarian carcinoma patients received cytoreductive surgery followed by Adriamycin and cisplatin, 50 mg/m2 each, q 4 weeks for 9 courses. One hundred ninety-seven were clinically NED at completion of treatment and 173 of these 197 had a second-look laparotomy. One hundred twenty had persistent disease. Fifty-three were second-look negative and had no further treatment. Thirty of these latter patients relapsed--all (with one exception) within 2 years. Those not relapsing after negative second-look are considered "cured" (median follow-up 42 months, range 24-68 months) and all others "failures." Stage was a significant predictor of treatment failure--there were no Stage IV "cures." In Stage III patients, age and largest residual tumor diameter post initial surgery were significant predictors of failure. Performance status was marginally significant. In our series, any patient with Stage IV disease or Stage III disease with at least two of the following three poor prognostic factors had a chance of cure of 2.2% (2 "cures" out of 90 patients): age greater than 60 years, macroscopic residual initially, or initial performance status of 2 or 3. Under normal circumstances a second-look procedure to identify persistent disease in this group of patients does not appear justified.

Adriamycin and cisplatin in the treatment of stage III and IV epithelial ovarian carcinoma.

A total of 342 eligible, previously untreated patients with Stage III or IV epithelial ovarian carcinoma were treated with Adriamycin and cisplatin, both at 50 mg/m2, for nine courses. Of the 210 patients who had clinically detectable disease after initial surgery, 85 (41%) had a complete clinical response and 45 (21%) had a partial clinical response. A total of 197 were clinically free of disease at the completion of chemotherapy and 175 of these had a second-look laparotomy; 55 had no macroscopic or microscopic evidence of residual disease after multiple random biopsies were examined histologically (complete surgical/histologic response). The major determinants of complete surgical/histologic response were diameter of largest residual tumor prior to treatment, ECOG performance status, and grade, patients with grade 3 tumors having a higher complete response rate than those with grade 1 or 2 tumors. The major determinants of survival were ECOG performance status and diameter of largest residual tumor prior to treatment. Median survival of the total group was 1.8 years.

Second-line chemotherapy of stage III-IV ovarian carcinoma: a randomized comparison of melphalan to melphalan and hexamethylmelamine in patients with persistent disease after doxorubicin and cisplatin.

A total of 205 women with stage III or IV ovarian cancer who had persistent disease after initial treatment with doxorubicin and cisplatin were randomized to receive melphalan (8 mg/m2 orally for 4 days) or the combination of melphalan (6 mg/m2 for 4 days) and hexamethylmelamine (120 mg/m2 for 14 days) every 4 weeks. Only one of 64 patients with measurable disease had an objective response. The major determinants of survival after randomization were the amount of residual disease after initial chemotherapy and the type of response to initial chemotherapy. There was no overall difference in survival between the two chemotherapy regimens, but the small group of patients whose disease progressed on initial chemotherapy survived significantly longer when treated with the two-drug combination. Neither of these regimens provided effective therapy for women whose disease was not eliminated by first-line treatment. However, the superior results obtained in one subgroup with the addition of hexamethylmelamine suggest that the place of this agent in treating ovarian cancer should be carefully evaluated.