Adjuvant high-dose interferon alfa-2b in patients with high-risk melanoma.

We performed an analysis of toxicity and survival in stage III melanoma patients receiving adjuvant interferon alfa-2b (IFN). This was a retrospective single-arm analysis of 40 patients with stage III melanoma who received (IFN) administered at maximum tolerated doses of 20 mU/m2/day intravenously (i.v.) for 1 month and 10 mU/m2 three times per week subcutaneously (s.c.) for 48 weeks. Toxicity in our series is comparable to that experienced in the Eastern Cooperative Oncology Group (ECOG) 1684 trial, except for higher rates of dose-limiting myelosuppression and hepatotoxicity. All 40 patients experienced constitutional symptoms, but only 14/40 (35%) experienced grade 3 to 4 symptoms. Of the 40 patients, 36 (90%) experienced neurologic symptoms, but only seven (17.5%) experienced grade 3 to 4 neurotoxicity. Two patients stopped treatment because of severe psychiatric symptoms; one patient attempted suicide, and a psychosis developed in another. Thirty-nine (97.5%) patients experienced myelosuppression; 31 (77.5%) developing grade 3 to 4 myelosuppression. Hepatotoxicity was evident in 39 (97.5%) patients, and 26 (65%) experienced grade 3 to 4 hepatotoxicity. Three patients (7.5%) experienced mild renal toxicity. At a median follow-up of 27 months from initiation of therapy, there have been 19 relapses (47.5% disease-free survival [DFS]) and 10 deaths (75% OS) resulting from progression of disease. The DFS compares with the treatment arm in ECOG 1684 at 27 months, but overall survival is higher in our series of patients at the same time point. In a single program setting, IFN can be administered with similar side effects and outcome profiles seen in multi-institutional studies. Modifications in the induction regimen resulted in notably higher hematologic and hepatic toxicities but did not preclude administering further therapy and did not result in increased attrition rate among patients: only nine patients (22.5%) had their treatment stopped as a result of IFN-related toxicity. In comparison, 26% of patients had to have their treatment discontinued because of toxicity in ECOG 1684.

The National Cancer Data Base report on breast carcinoma characteristics and outcome in relation to age.

BACKGROUND: Previous data from the National Cancer Data Base have examined time trends in stage of disease, treatment patterns, and survival for selected cancers. The most current (1993) data for breast carcinoma are described here. METHODS: Five Calls for Data have yielded a total of 508,724 breast cancer cases diagnosed from 1985 to 1993, from hospital cancer registries throughout the U.S. RESULTS: Women younger than age 35 had a lower rate of ductal carcinoma in situ, higher grade primary tumors, more advanced American Joint Committee on Cancer stage disease, and poorer 5-year relative survival than older premenopausal women. African American women were more likely to have advanced disease than non-Hispanic whites in all three age groups analyzed. Improved time trends of early detection of breast carcinoma and use of breast conservation treatment are reported. The overall prognosis for breast carcinoma remains relatively good for all age groups when compared with other cancers. CONCLUSIONS: These data are consistent with the hypothesis that younger women are at increased risk for biologically more aggressive breast carcinoma.

The presence of membrane-bound stem cell factor on highly immature nonmetachromatic mast cells in the peripheral blood of a patient with aggressive systemic mastocytosis.

BACKGROUND: Systemic mastocytosis is characterized by mast cell infiltration of bone marrow and tissues in the absence of identified circulating bone marrow-derived progenitors. A 58-year-old man was first seen with aggressive systemic mastocytosis manifested by urticaria pigmentosa, hepatosplenomegaly, generalized bone lesions, anemia, thrombocytopenia, monoclonal gammopathy, and increased urine histamine levels. OBJECTIVES AND METHODS: A rapidly progressive anemia and thrombocytopenia dictated a splenectomy. We sought to identify the mast cell progenitors in the peripheral blood and to provide evidence of their maturation in tissues with immunohistochemical and ultrastructural analyses. RESULTS: The peripheral blood contained 1% to 3% nonmetachromatic mononuclear cells with eccentric nuclei that expressed the mast cell proteases, tryptase and carboxypeptidase A, along with c-kit, stem cell factor (SCF), and high-affinity IgE receptor (Fc epsilon RI), but not chymase. Similar mononuclear cells colocalized in the spleen and lymph nodes with mature, metachromatic mast cells that expressed tryptase, chymase, carboxypeptidase A, c-kit, SCF, and Fc epsilon RI. Electron microscopy disclosed, at each site, a mature mast cell population with electron-dense, scroll-poor granules. CONCLUSIONS: The peripheral blood of a patient with aggressive systemic mastocytosis contained immature mononuclear cells of the mast cell lineage that express c-kit, SCF, tryptase, carboxypeptidase A, and Fc epsilon RI. These cells were also found in the skin, spleen, and lymph nodes where they presumably expand, differentiate, and mature, assuming the mast cell phenotype for those tissues characterized by metachromasia, expression of a full range of mast cell-related secretory granule proteases, and ultrastructural appearance. The presence of SCF on the surface membrane of the circulating, highly immature mast cells suggests an autocrine regulation of the c-kit-SCF interaction.

Patterns of breast cancer care in the elderly.

BACKGROUND: The elderly represent a large proportion of the women with breast cancer. However, there is a lack of information regarding breast cancer care in the elderly. METHODS: A patient care evaluation survey for breast carcinoma was conducted by the Commission on Cancer of the American College of Surgeons for 1983 and 1990. Data were obtained from hospital tumor registries from all 50 states, Puerto Rico, and Canada. Information regarding presentation, diagnostics, staging, treatment, recurrence, and survival were analyzed. Comparisons were made between women 75 years and older and those younger than 75 years. RESULTS: Included were 17,029 diagnosed with breast carcinoma during 1983 and 24,004 diagnosed during 1990. In 1983 and 1990, 20.4% and 23.4% of women, respectively, were 75 years or older. Fewer cancers were detected mammographically and needle localized biopsies were performed less often in the elderly. There was no difference in tumor location or histology. Stage at diagnosis appeared more advanced in the elderly. Most women regardless of age, underwent modified radical mastectomy. Of the elderly who did undergo breast conserving surgery in 1983 and 1990, 72% and 39%, respectively, did not receive radiation therapy. No difference was found in the local recurrence rates between the elderly and younger groups. In the elderly, 20% of deaths occurred from causes other than breast cancer. Overall disease specific survival was worse in the elderly but, when analyzed by stage, was significantly different for only certain stages. CONCLUSIONS: There are several differences in the detection, diagnostic methods, stage at diagnosis, treatment approaches, and outcome of breast cancer in elderly women compared with younger women.

A prospective study of conservative surgery alone in the treatment of selected patients with stage I breast cancer.

BACKGROUND: Randomized clinical trials have clearly demonstrated that the use of radiation therapy (RT) following breast-conserving surgery (CS) substantially reduces the risk of local recurrence. However, the low rate of local recurrence after CS and RT for patients without known risk factors, and the recent increase in the detection of smaller cancers due to mammographic screening have led to the speculation that a subgroup of patients who have a low risk of local recurrence without RT might be identified. In 1986, we initiated a one-arm, prospective clinical trial of CS alone for treatment of highly selected breast cancer patients without known risk factors for local recurrence. METHODS: The study had a sequential design with a planned accrual of 90 patients. Criteria for entry into the trial were: a unicentric, clinical TI infiltrating ductal, mucinous or tubular carcinoma without an extensive intraductal component or lymphatic vessel invasion; a wide excision with a pathologically-documented negative margin of at least 1 cm; and histologically negative axillary lymph nodes. No adjuvant RT or systemic therapy was administered. Seventy-six per cent of the lesions were detected by mammography alone. The median gross pathologic tumor size was 0.9 cm. The median patient age was 67 years. RESULTS: Eighty-seven patients were enrolled in the trial before it closed prematurely in 1992 because the predefined stopping boundary was crossed (i.e., the sixth local recurrence was observed). At that time, the average annual local recurrence rate was 4.2%. With a median follow-up of 56 months, there are now 14 patients (16%) with local recurrence as their site of first failure (average annual local recurrence rate: 3.6%). Four patients without local recurrence developed distant metastases. Three patients have died, one of metastatic breast cancer and two of unrelated causes. CONCLUSIONS: Even in a highly selected group of patients with early-stage breast cancer, there is a substantial risk of early local recurrence for those treated with wide excision alone.

Reconstruction after mastectomy.

Although reconstruction after mastectomy offers an opportunity for cosmetic rehabilitation that should make mastectomy more acceptable and contribute to overall rehabilitation, the procedure is relatively underutilized. The best cosmetic results usually come from breast conservation rather than from mastectomy and subsequent reconstruction, and most small (T0-T2) cancers can be treated by means of breast-conserving measures. The surgeon who is performing the mastectomy plays a key role in explaining reconstruction to the patient and encouraging her to consider the process. Surgeon- and patient-related factors contribute to under-utilization. Physician assessment of the results of reconstruction, particularly with use of implants, tends to be less favorable than that of the patient. Surgeons may overemphasize the inadequacies of the results and patients may be overwhelmed by the diagnosis and array of decisions that must be made. Immediate reconstruction poses little risk of treatment delay or limitation. Reconstruction after mastectomy does not interfere with follow-up for recurrence. Choices for reconstruction have been limited by the withdrawal of silicone implants from the market. The availability of reconstruction has encouraged the inappropriate use of mastectomy for low risk disease. Prophylactic mastectomies and reconstruction should be performed for appropriate indications. To be effective, prophylactic mastectomy must include the nipple areolar complex. The availability of genetic testing to define very high risk groups brings into question the adequacy of protection offered by this procedure. Whereas prophylaxis in humans for premalignant mastopathy appears to be nearly complete, mastectomy appears to offer little protection in a rodent carcinogen model. The effectiveness of mastectomy for prophylaxis in a genetically high risk human population is unknown.

Treatment trends for ductal carcinoma in situ of the breast.

BACKGROUND: As a result of clinical trial publications, breast conservation treatment has been increasingly used for invasive breast cancer. The patterns of care for ductal carcinoma in situ (DCIS) were analyzed for the years 1985, 1986, 1988, 1990, and 1991 to determine whether the same treatment principles had been applied to patients with non-invasive disease. METHODS: Data submitted on 20,556 patients with DCIS during the 5 study years were analyzed with regard to basic demographics and treatment trends. RESULTS: Breast-conserving surgery for DCIS increased from 20.9% in 1985 to 35.4% in 1991. Modified radical mastectomy remained constant at 42%. Axillary node surgery increased from 52% in 1985 to 58.5% in 1991. The use of radiation therapy for patients with partial mastectomy and no lymph node dissection ranges from 24.2% in 1990 to 37.7% in 1985, with 31.1% receiving radiation therapy in 1991. Patients undergoing lymph node dissection with partial mastectomy were more than twice as likely to receive postoperative radiation therapy than were patients without lymph node dissection. CONCLUSIONS: Modified radical mastectomy remains the most common surgical procedure, despite the eligibility of many women for breast conservation treatment. As of 1991 the majority of women were still undergoing axillary lymph node surgery despite a node positivity rate of approximately 1%. Radiation therapy is significantly underused in patients with partial mastectomy, especially when no nodes were removed. Clinical trial results and professional education for DCIS treatment should change these trends.

A national quality improvement effort: cancer registry data.

Cancer registries are sources of epidemiological, patterns-of-care, and outcome data for local, regional, state, and national studies of patients with cancer. Since 1976, these registries have formed a voluntary network of contributors to annual patient care studies under the aegis of the National Cancer Data Committee of the Commission on Cancer. These annual studies provide timely clinical information that is widely disseminated to physicians, allied health personnel, administrators, health care planners, and public and private agencies. The use of the data has grown exponentially and has been the basis for more than 90 publications. Merging this activity with the National Cancer Data Base has further expanded the demand and use of registry data. This study was undertaken to respond to inquiries as to the validity of the data and the qualifications and competency of cancer registrars. It provides the baseline for cancer registry data quality and serves as a quality management tool to identify opportunities to enhance data quality.

Insurance coverage of patients with breast cancer in the 1991 commission on cancer patient care evaluation study.

BACKGROUND: Trends in the care of patients with cancer are monitored annually by the Commission on Cancer of the American College of Surgeons. In 1991 a patient care evaluation study of breast cancer was conducted, which among other questions examined the correlation of health insurance with type or quality of care delivered for breast cancer on a national basis. METHODS: The tumor registry system of the American College of Surgeons was used to obtain data on patients with breast cancer diagnosed in 1983 and 1990. Trends in diagnosis and treatment were correlated with the type of insurance or lack of insurance. RESULTS: Data were obtained from hospitals in 50 states on a total of 41,651 patients. The largest number of patients were covered by Medicare. Fewer than 5% were considered medically indigent. Medically indigent patients presented with higher stage disease and did not participate in a trend toward downstaging, which occurred between the two study years. The treatment of medically indigent patients appeared to be appropriate and comparable with better insured patients. Insurance type (health maintenance organization vs. private) did not affect stage, treatment, or outcome. Decisions to use controversial therapies, such as chemotherapy for stage I disease, did not appear to be financially driven. CONCLUSION: A nationwide pattern of care study for breast cancer indicates that medically indigent patients present with more advanced disease compared with better insured patients, but once the diagnosis is made, treatment and outcome have little to do with insurance type.

Selection of patients for breast conserving surgery.

The majority of patients with breast cancer can be treated by partial mastectomy and radiation therapy. Ineligibility for breast conservation usually is related to previous radiation or the inability to receive radiation for other reasons. For patients who can receive radiation, selection for breast conservation involves the estimation of the risk for in-breast recurrence and the ability to achieve a satisfactory cosmetic result. Multiple sites of cancer within the breast and the inability to attain negative pathologic margins on the excised breast specimen are predictive for an increased risk of recurrence. The cosmetic result is compromised by excision of large volumes of breast tissue. Although the size of the tumor is not an important consideration for in-breast recurrence, the relation of the size of the tumor, and hence the volume of tissue excised, to the size of the breast is an important cosmetic consideration. Compared to invasive ductal carcinoma, an extensive intraductal component or invasive lobular carcinoma tends to be more difficult to define within the breast and may require excision of a large volume of tissue to obtain negative pathologic margins.

The National Cancer Data Base report on breast cancer.

BACKGROUND: Previous National Cancer Data Base data have been used to examine time trends in stage of disease and treatment patterns for breast cancer. The most current (1990) data are described here. METHODS: Two calls for data have yielded a total of 143,051 breast cancer cases for 1985, 1988, and 1990 from hospital cancer registries across the United States. RESULTS: The percentage of in situ cancers increased between 1985 and 1988 but was essentially constant between 1988 and 1990. The use of breast-conserving partial mastectomy across the country increased between 1988 and 1990. Some interesting regional differences appeared in the use of multimodality treatment. CONCLUSIONS: These data suggest a plateau in the use of mammographic screening.

Clinical highlights from the National Cancer Data Base: 1994.

The National Cancer Data Base, a joint project of the American Cancer Society and the American College of Surgeons Commission on Cancer, provides a mechanism for periodic assessment of hospital-based cancer patient care. From the National Cancer Data Base's annual summary, health care professionals can evaluate trends in patient care to make more efficient treatment decisions. This article provides a first look at highlights from the 1994 annual summary.

1991 national survey of carcinoma of the breast by the Commission on Cancer.

A nationwide survey of patterns of care for carcinoma of the breast was conducted by the Commission on Cancer of the American College of Surgeons. Information regarding patient history, diagnostic tests, treatment, survival and disease status was obtained for 17,295 patients treated during 1983 and 24,356 patients treated during 1990. The results indicate that patients diagnosed in recent years (1990) are being treated at an earlier stage of the disease compared with the 1983 survey and the findings of earlier years, probably because of the use of mammography. Surgical treatment for conservation of the breast is being used more frequently, but modified radical mastectomy remains the most commonly used surgical treatment.

Risk factors and management of local recurrence following breast conservation surgery.

Although a number of histologic and treatment factors that individually and in combination predict for an increased risk of local recurrence after breast conserving surgery can be identified, none so obviously compromises survival that breast conservation is contraindicated because that risk factor is present. In-breast recurrence is associated with the risk of any disease remaining after lumpectomy if the breast is not irradiated and the risk of large amounts of residual disease if irradiation is used. Some risk factors appear to predict for both local recurrence and distant recurrence, whereas others predict an increased risk of local recurrence but appear to have little effect on the risk of metastatic disease. Overall, the relation between in-breast recurrence and the risk of systemic metastases is poorly understood. Furthermore, the efficacy of chemotherapy in decreasing the risk of systemic metastases after in-breast recurrence has not been evaluated. Mastectomy is the treatment of choice for in-breast recurrence after breast conserving surgery and radiation therapy. A few patients are candidates for a second attempt at breast conservation.

Cancer of the stomach. A patient care study by the American College of Surgeons.

OBJECTIVE: The major purpose of this study was to document the modes of presentation, diagnostic methods, clinical management, and outcome of gastric cancer as reported by tumor registries of US hospitals and cancer programs approved by the American College of Surgeons. SUMMARY BACKGROUND DATA: Gastric cancer continues to diminish in the US, but the stage of disease and survival outcome after surgical resection is unchanged despite increased availability and sophistication of diagnostic techniques. This is in contrast to the marked improvement in survival outcome in Japanese and other Eastern series over the last decades. Possible reasons for the improved Japanese results have been earlier detection secondary to active diagnostic surveillance of the population and widespread adoption of aggressive surgical resection emphasizing wide-field node (R2) dissection. Although selected US centers using the Japanese approach report better survival data, the approach has not been widely adapted by US treatment centers. METHODS: Tumor registries at American College of Surgeons (ACS) approved hospitals were mailed a study protocol in 1987. They were instructed to review 25 consecutive patients with gastric cancer treated in 1982 (long-term study) and 25 patients treated in 1987 (short-term study). A detailed protocol included significant history, diagnostic results, staging, pathology findings, and treatment results. The data forms on 18,365 patients were returned and analyzed (11,264 patients in the long-term study and 7101 patients in the short-term study). RESULTS: Of 18,365 patients, 63% were males. The median ages were 68.4 years in males and 71.9 years in females. There was a history of gastric ulcer in 25.5% of the patients. Lesion location was upper third in 31%, middle third in 14%, distal third in 26%, and entire stomach in 10% of patients (and the site was unknown in 19%). Gastric resection was performed for 80% of upper third cancers and 85% of distal third cancers; 50% of patients with total gastric involvement had gastric resection. The extent of gastric resection varied according to location. For lower third lesions, subtotal gastrectomy was done in 55% of the cases, extended resection in 21%, and total gastrectomy in 6%. For proximal lesions, 29% had subtotal, 4.6% had total, and 41% had extended gastrectomies (including esophagus), and 13.6% had dissection of celiac nodes. The operative mortality rate was 7.2%. Staging (American Joint Committee on Cancer [AJCC]) was as follows: I, 17%; II, 17%; III, 36%; and IV, 31%. The overall survival rate reflecting deaths from all causes was 14% among 10,891 patients diagnosed in 1982, and it was 19% in patients having resection. The disease specific survival rate was 26%. The survival rate after resection was 19% and 21% for lower and mid third cancers, 10% for upper third cancers, and 4% if the entire stomach was involved. The stage-related survival rates were 50% (stage I), 29% (stage II), 13% (stage III), and 3% (stage IV). Among patients with pathologically clear margins, the survival rate was 35% versus 13% in those with microscopically involved margins, and it was 3% in those with grossly involved margins. CONCLUSION: This report of gastric cancer treatment by American College of Surgeons approved institutions in the US provides an overview of the disease as commonly treated throughout the US. Although the results are less favorable than those reported by centers with large institutional experiences with this disease and are inferior to those of the Japanese and other Eastern centers, they suggest potential for increasing survival by upstaging through earlier diagnosis and using resectional techniques demonstrated to more adequately control local regional disease.

Comparison of adjuvant chemotherapy with methotrexate and fluorouracil with and without cyclophosphamide in breast cancer patients with one to three positive axillary lymph nodes.

BACKGROUND: Alkylating agents administered as single agents or in combination with antimetabolites or anthracyclines delay the appearance of metastases and prolong the survival of breast cancer patients after surgery. PURPOSE: This phase III clinical trial was designed to evaluate the therapeutic efficacy and toxicity of the alkylating agent cyclophosphamide in combination with the antimetabolites methotrexate and fluorouracil adjuvant to breast cancer surgery. METHODS: This study consisted of 255 breast cancer patients (a) with one to three histologically positive axillary lymph nodes and either no detectable primary tumor or operable primary tumors 5 cm or less (T0-T2) (95% of the patients) or (b) with tumors larger than 5 cm (T3) and with negative axillary nodes. Patients were randomly allocated to receive either methotrexate (60 mg/m2) and fluorouracil (600 mg/m2) (MF) intravenously on days 1 and 8 every 28 days for eight cycles or cyclophosphamide (100 mg/m2) orally on days 1-14 plus MF (CMF) every 28 days for the same duration. Median follow-up was 7.8 years, and maximum follow-up was 13 years. RESULTS: There were no statistically significant differences in time to treatment failure or overall survival for patients treated with MF or CMF. At 8 years after completion of treatment, time to treatment failure was 55% (95% confidence interval [CI] = 50%-60%) and 59% (95% CI = 54%-64%) and overall survival was 69% (95% CI = 65%-73%) and 67% (95% CI = 62%-72%) for MF- and CMF-treated patients, respectively. The hazard ratios (MF to CMF) for time to treatment failure and for survival, estimated with a proportional hazards model, were 1.02 (95% CI = 0.69-1.50) and 0.87 (95% CI = 0.56-1.34), respectively. Myelosuppression was significantly greater (P < .0001) in CMF-treated patients during cycles 1-6. Median white blood cell count nadirs were between 4.4 x 10(3)/microL and 3.5 x 10(3)/microL in patients receiving MF and between 3.0 x 10(3)/microL and 2.4 x 10(3)/microL in those receiving CMF. Dose reductions were more frequent in CMF-treated patients, which led to statistically significant differences (P < .0001) in amounts of methotrexate and fluorouracil administered. Primary cancers at other sites occurred in 14 patients (5.5%)--six treated with MF and eight treated with CMF. CONCLUSIONS: Our findings suggest that the addition of cyclophosphamide to adjuvant chemotherapy with MF offers no therapeutic advantage but results in increased myelosuppression. IMPLICATIONS: Future trials will define the possible advantages of antimetabolites in adjuvant therapy. Further information will also become available when results of the ongoing National Surgical Adjuvant Breast and Bowel Project trial comparing adjuvant MF to CMF in node-negative breast cancer patients are presented.

Neoadjuvant therapy for unresectable pancreatic adenocarcinoma.

The purposes of this study were to determine whether continuous infusion of fluorouracil combined with external-beam radiation therapy improved the resectability and survival of patients with pancreatic carcinoma. Sixteen patients with unresectable disease confined to the pancreas and celiac nodes were treated, and their outcome was compared with that of 24 patients with potentially resectable disease who were treated concurrently. The neoadjuvant therapy was completed with acceptably few toxic effects but with only a minor decrease in tumor size. Two patients underwent resection and remained free of disease 20 and 22.5 months later. However, the median survival of the entire neoadjuvant group was 8 months. All 24 patients with potentially resectable carcinoma underwent surgical exploration. Fifteen of the 24 patients underwent resection and survived a median of 12.5 months. Neoadjuvant chemoradiation may have improved outcome and resectability for two (12.5%) of 16 patients with unresectable pancreatic carcinoma, but more effective therapy options must be developed to improve outcome.