David W. Braun

Antiemetic Efficacy of High-Dose Metoclopramide: Randomized Trials with Placebo and Prochlorperazine in Patients with Chemotherapy-Induced Nausea and Vomiting

In a study of the effectiveness of high intravenous doses of metoclopramide as an antiemetic, 41 patients with advanced cancer who were being treated with cisplatin were entered into two double-blind trials. In the first trial patients were randomly assigned to receive either metoclopramide or placebo, and in the second trial they received either metoclopramide or prochlorperazine. Patients given metoclopramide had significantly fewer episodes of emesis than patients given placebo (medians, 1.0 vs. 10.5; P = 0.001) or prochlorperazine (medians, 1.5 vs. 12.0; P = 0.005). Metoclopramide was superior to placebo and to prochlorperazine in reducing the volume of emesis (P = 0.001 and P = 0.022, respectively) and was more effective than placebo in shortening the duration of nausea (P = 0.042) and vomiting (P = 0.028). Side effects from metoclopramide were minor, with mild sedation frequently observed; one patient had a brief extrapyramidal reaction. We conclude that metoclopramide in high intravenous doses has greater antiemetic activity than placebo or prochlorperazine in patients receiving cisplatin chemotherapy.

Lobular carcinoma in situ of the breast Detailed analysis of 99 patients with average follow-up of 24 years

Ninety-nine patients with in situ lobular carcinoma (LCIS) of the breast, not treated by mastectomy, were identified in a review of consecutive breast biopsies performed at Memorial Hospital between 1940 and 1950. Follow-up for an average of 24 years was obtained in order to determine the frequency of subsequent breast carcinoma. Detailed analysis of important clinical and pathologic features was undertaken to identify predictive factors that would serve to distinguish between patients with the greatest and least risk for subsequent carcinoma. Thirty-nine breast carcinomas other than the original LCIS were diagnosed in 32 patients. Half of the carcinomas occurred in the same and half in the opposite breast. The hazard rate for subsequent carcinoma increased with increasing length of follow-up and increasing age.When compared with general population data, the frequency of subsequent breast carcinoma was nine times greater than expected and deaths due to breast carcinoma were 11 times more frequent than expected. None of the currently recommended choices for therapy is entirely satisfactory. Follow-up without further surgery should be considered an investigative procedure until more information is available. This recommendation should be made only if the patient and physician are prepared to accept the responsibility of lifetime surveillance. At present, we consider it prudent in most cases to recommend ipsilateral mastectomy with low axillary dissection and concurrent biopsy of the opposite breast. Contralateral mastectomy is most appropriate when carcinoma is detected in the biopsy.

Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung: A randomized trial investigating two dosage schedules

Eighty-five patients with advanced squamous carcinoma or adenocarcinoma of the lung were randomly assigned to receive vindesine with either high dose (120 mg/m2 of body surface area) or low dose (60 mg/m2) cisplatin. All patients had measurable disease and had not previously received chemotherapy. The response rate was similar with both treatments (43% complete and partial remission rate), but the high dose cisplatin regimen was superior to the low dose in median duration of response (12 versus 5.5 months; p = 0.05) and in median survival for responding patients (21.7 versus 10 months; p = 0.02). Myelosuppression was generally not a treatment problem; peripheral neuropathy and moderate azotemia were the major dose-limiting toxicities. With improved survival and response rates over those reported for conventional regimens, this combination of new agents supports the approach of new drug investigation in patients with lung cancer and the importance of the incorporation of active new agents into initial chemotherapy regimens.

The clinical significance of pre‐invasive breast carcinoma

Improvements in mammography in the past 25 years have made it possible to detect before surgery many lesions with a high probability of being pre‐invasive carcinoma. Because these cancers are virtually all cured by mastectomy, there has been considerable interest in alternative types of treatment. Retrospective studies of pre‐invasive carcinoma treated by biopsy only revealed subsequent carcinoma in 30 to 40% of patients. Among women with lobular carcinoma in situ (LCIS), the frequency of subsequent carcinoma was nine times the expected rate, and mortality due to the disease was 11 times greater than expected. The risk of later invasive carcinoma appeared to involve both breasts equally when LCIS was present and to be largely limited to the breast that harbored intraductal carcinoma (IDC). When mastectomy was performed for pre‐invasive carcinoma, unsuspected invasion was found in 4% of patients with LCIS and 6% with IDC.

Angiosarcoma and other vascular tumors of the breast.

Vascular tumors of the breast, with the exception of perilobular hemangiomas, are generally considered to be malignant. The pathologic and clinical features of 40 patients with angiosarcoma of the breast and 12 with other vascular tumors of the breast were reviewed. Three general histologic patterns of growth were identified among the angiosarcomas and were found to correlate closely with prognosis. Whereas 10 of the 13 patients in histologic Group I were alive and free of disease with an average follow-up of nearly 6 years, only two of 16 Group III patients were free of disease, and 14 have died. The six Group II patients had a survival similar to those in Group I. In this series the disease-free survival at 3 years was 41% and at 5 years 33%, much better than that reported in previous reviews of mammary angiosarcoma. The data also indicated that adjuvant chemotherapy, specifically actinomycin D, is effective in some and possibly all patients with angiosarcoma of the breast. The 12 other vascular lesions had distinctly different morphologic features, a benign clinical course, and should probably not be viewed as angiosarcomas. However, total excision of all vascular lesions of the breast is essential in order to determine both the diagnosis and the appropriate therapy.

Axillary micro- and macrometastases in breast cancer. Prognostic significance of tumor size

Recurrence and survival data at 10 years were examined for 147 women with single axillary lymph node metastases found in a modified radical or standard radical mastectomy. The cases were identified through a review of all patients with primary operable breast cancer treated at Memorial Hospital from 1964 to 1970. The patients were stratified into groups according to size of the primary tumor and of the metastatic deposit (micro < 2 mm; macro > 2 mm) as well as level of the positive node. In the entire series, there was a significantly poorer prognosis among those patients with single macrometastases (30/ 77 patients: 39% recurrence rate) when compared with those having micrometastases (17/70 patients: 24% recurrence rate). A major prognostic difference emerged after stratification by tumor size. Within the first six years of the follow-up period, T| patients with negative nodes and those with single micro-metasteses had similar survival curves, significantly better than those with macrometastases. However, at 12 years, the survival rate of those patients with either a micro- or macrometastasis was nearly identical, and significantly worse than for those patients with negative lymph nodes. On the other hand, among women with primary tumors 2.1–5.0 cm (T2), patients with negative lymph nodes or single micrometastases had survival curves that did not differ significantly throughout the course of the follow-up period. Both had an outcome significantly better than observed for patients with macrometastases. These findings have important implications for our understanding of the clinical behaviour of breast cancer and for the stratification of patients entered into randomized treatment trials

Predictors of recurrence in stage I (T1N0M0) breast carcinoma.

A ten-year follow-up study of 382 women with Stage I (T1N0M0) breast carcinoma revealed recurrence and/or death due to cancer in 16% of the patients. Among 134 patients (35%) with a primary tumor 1.0 cm or less in diameter (Group A), 7% had recurrences and 5% died of breast carcinoma. Recurrences were observed in 21% of the 248 women with a tumor 1.1-2.0 cm in diameter (Group B), and 15% died of disease. These differences in recurrence and mortality rates were statistically significant. All recurrences were due to infiltrating duct or lobular carcinoma which accounted for 91% of the 382 carcinomas. Most strongly linked to recurrence was the finding of tumor emboli in lymphatics of the breast. This was found in 23 Group B patients and ten of them (43%) died of disease. No recurrences were observed among the seven Group A patients with lymphatic emboli. Other features associated with a significantly increased risk of recurrence were poorly differentiated carcinoma, marked lymphoid reaction to tumor, and menarche before age 12 years or after age 14 years. No combination of variables proved to identify a subset of patients with an especially increased or low risk of recurrence. Stage I patients with lymphatic tumor emboli in the breast surrounding a carcinoma 1.1-2.0 cm in diameter have a sufficient risk for recurrence to warrant consideration of adjuvant systemic therapy. A very low risk of recurrence was observed for the following: any tumor 1.0 cm or smaller; and tubular, medullary or colloid carcinoma up to 2.0 cm.

Prognostic factors in advanced colorectal carcinoma: Importance of lactic dehydrogenase level, performance status, and white blood cell count

In 220 patients with advanced colorectal carcinoma, objective tumor response to chemotherapy and survival were related to the following parameters: age, sex, performance status, time interval from diagnosis to metastases, initial site of metastases, and initial white blood cell count, lactic dehydrogenase, alkaline phosphatase, and carcinoembryonic antigen levels. Each variable was first evaluated separately. By conventional statistical methods, none of the variables significantly predicted response, although the following parameters significantly (p less than 0.01) predicted survival: Patients with an initially normal level of lactic dehydrogenase versus those with an abnormal level of lactic dehydrogenase had median survivals of 16 and 7.0 months, respectively; normal versus abnormal carcinoembryonic antigen levels, 23 and 9.2 months, respectively; white blood cell count of less than 10,000 versus greater than 10,000 cells/mm3, 11 and 7.0 months, respectively; performance status of greater than 70 versus less than 60, 11 and 6.6 months, respectively; and lung versus liver metastases, 12 and 8.0 months, respectively. By studying the variables together with multivariate analysis, we found that the most important variables in predicting response were the lactic dehydrogenase level and the white blood cell count. In predicting survival, the most important variables were the lactic dehydrogenase level, performance status, and lung involvement. We recommend that future randomized therapeutic trials for advanced colorectal carcinoma should delineate and perhaps stratify for the lactic dehydrogenase level, performance status, white blood cell count, and/or the presence of lung involvement.

Methotrexate: An active drug in bladder cancer

Forty‐nine patients with transitional urothelial tract tumors received methotrexate: 0.5–1.0 mg/kg I.V. Q W (40 patients) or 250 mg/M2 in a 2‐hour infusion with citrovorum factor rescue 24 hours later (nine patients). Eleven (26%, 95% confidence limits 13–39%) of 42 patients with bidimensionally measurable metastases achieved partial remission. Most responses occurred within 2–3 weeks and persisted for a median duration of six months (range, 2–20). Response rates were increased to 38% (6/16 patients, 95% confidence limits 18–65%) in patients who had no prior chemotherapy, and a 90–100% performance status (50,5/10 patients, 95% confidence limits 22–78%) compared with 19% (5/26, 95% confidence limits 8–37%) in patients who had prior chemotherapy and a ≦80% performance status (19%, 6/32 cases, 95% confidence limits 9–32%). Toxicity included mucositis and myelosuppression. A review of the literature coupled with the present data suggest that methotrexate is as active as cisplatin in the treatment of patients with advanced urinary bladder cancer.

Prognosis in stage II (T1N1M0) breast cancer.

As part of a detailed study of prognostic factors in breast cancer, we have analyzed the ten year survival rates of 524 patients with primary invasive carcinomas 2.0 cm or less in diameter (T,). This report describes the subset of 142 patients (27%) who had metastases only in axillary lymph nodes (T|N|M0). All the patients were treated initially by at least a modified radical mastectomy. Factors associated with a significantly poorer prognosis were: axillary lymph node metastases suspected on clinical examination; perimenopausal menstrual status at diagnosis; tumor larger than 1.0 cm; prominent lymphoid reaction; infiltrating duct or lobular rather than medullary, colloid and tubular carcinoma; and blood vessel invasion. When compared with those patients with negative nodes (T|N0M0), the patients with one or more lymph node metastases had a significantly poorer prognosis. Generally, survival rates tended to diminish as the number of involved lymph nodes increased. In this respect, comparison of patients with one-three and four or more nodal metastases provided a significant discrimination of prognostic groups in the entire series. However, for patients with disease limited to Level I, the same discrimination was obtained comparing those with one-two and three or more positive nodes. In the subset with a single lymph node metastasis, the size of the metastasis (micro or <2 mm vs macro or ≥2 mm) was not significantly related to prognosis. Lymph node metastases were significantly less frequent among tumors smaller than 1 cm and special tumor types (medullary, colloid, lobular and tubular). However, no factor proved to be a reliable predictor of the presence of axillary metastases for the single largest group consisting of patients with infiltrating duct carcinoma 1–2 cm in diameter