Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23.

PURPOSE: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor-negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study. PATIENTS AND METHODS: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status. RESULTS: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and.8, respectively), for those aged < or = 49 years (P =.97,.5, and.9, respectively), or for those aged > or = 50 years (P =.7,.6, and.6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P =.6), or S (89% and 90%, P =.4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged < or = 49 or > or = 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P =.6), 87% in patients aged < or = 49 (P =.9), and 88% and 87%, respectively (P =.4), in those aged > or = 50 years. CONCLUSION: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.

Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26.

PURPOSE: Paclitaxel is an active drug for the treatment of breast cancer; however, the appropriate duration of administration is unknown. We assessed and compared the response rate, event-free survival, survival, and toxicity of paclitaxel 250 mg/m(2) delivered every 3 weeks as a 3-hour or 24-hour infusion. PATIENTS AND METHODS: A total of 563 women with stage IV or IIIB breast cancer were randomized into one of two groups: 279 received 3-hour paclitaxel and 284 received 24-hour paclitaxel. Patients were stratified by age, stage of disease, and prior therapy. RESULTS: A significantly higher rate of tumor response occurred in the first four cycles of therapy in patients who received the 24-hour infusion of paclitaxel (51% v 41%, respectively; P =.025). Tumor response over all cycles was also significantly higher in the group that received 24-hour infusion (54% v 44%, respectively; P =.023). There were no significant differences in event-free survival or survival between the two arms of the study (P =.9 and.8, respectively). No treatment by stage or by age interactions were observed. During the first four cycles of therapy, at least one episode of >/= grade 3 toxicity (excluding nadir hematologic values, alopecia, and weight change) occurred in 45% of patients who received the 3-hour paclitaxel infusion and in 50% of those who received the 24-hour paclitaxel infusion. Febrile neutropenia, >/= grade 3 infection, and >/= grade 3 stomatitis were less frequent, and severe neurosensory toxicity was more frequent in those who received the 3-hour paclitaxel infusion. Ten treatment-related deaths occurred in the first four cycles. Age, stage, and prior chemotherapy did not influence the effect of treatment. CONCLUSION: When administered as a continuous 24-hour infusion, high-dose paclitaxel results in a higher tumor response rate than when administered as a 3-hour infusion but does not significantly improve event-free survival or survival. Paclitaxel as a 24-hour infusion results in increased hematologic toxicity and decreased neurosensory toxicity.

Suppression of basement membrane type IV collagen degradation and cell invasion in human melanoma cells expressing an antisense RNA for MMP-1.

During progression from benign nevus to vertical growth phase melanoma, melanocytes acquire the ability to invade into the dermis. This process requires rupture of the basal lamina and dissolution of dermal type I collagen. Metastases-derived human melanoma MIM cells have an invasive ability in vitro which is dependent on metalloproteinases. In the present study we analysed the role of type I collagenase (MMP-1) in melanoma invasion using MIM cells in which the constitutive expression of MMP-1 was suppressed by stable transfection with a plasmid vector expressing a 777 bp antisense fragment of MMP-1 genomic DNA. Two clones were isolated in which MMP-1 mRNA expression was blocked by 90-96% with a corresponding loss in protein synthesis. In their morphological appearance and growth rate in vitro these cells were indistinguishable from wild type cells or control cells transfected with the same vector expressing the MMP-1 fragment in the sense orientation. Their mRNA and protein levels for type IV collagenase (MMP-2) were unchanged as assessed by Northern and Western blot analyses and by gelatin zymography. However, when the invasive ability of the cells was measured, we found that in addition to type I collagen, invasion through type IV collagen and a reconstituted, type IV collagen-containing basement membrane (Matrigel) were also significantly inhibited as compared to normal or sense-transfected cells. The results indicate that despite the presence of functional MMP-2, degradation of type IV collagen matrices by the melanoma cells was dependent on expression of MMP-1.

Small-bowel resection for metastatic melanoma.

OBJECTIVE: To determine whether complete resection of small-bowel metastases from melanoma improves patient survival. DESIGN: A computer-aided chart review. SETTING: Hospitals associated with McGill University. PATIENTS: Twenty patients (17 men, 3 women), identified from 1524 patients with melanoma, who underwent surgery to the small bowel for metastases. Patient age and clinical presentation, tumour site and stage were recorded. INTERVENTION: Exploratory laparotomy with complete or partial resection of involved small bowel. MAIN OUTCOME MEASURES: Operative morbidity, mortality and length of survival related to the extent of small-bowel resection. RESULTS: Eleven patients had complete resection, 8 patients had partial resection and 1 patient had a palliative bypass only. Long-term survival (ranging from 2 to 10 years) was 36% in those who had complete resection and 0% in those who had partial resection; operative morbidity and mortality were 20% and 15% respectively. CONCLUSION: Complete resection of small-bowel metastases in patients with metastatic melanoma can result in long-term survival.

Hormone replacement therapy: boon or bane?

The steadily increasing frequency of breast cancer, especially in elderly women, may be owing to the following three factors, among others: natural aging, the increased use of mammography leading to earlier diagnosis of in-situ carcinoma and occult carcinoma, and the indiscriminate use of hormone replacement therapy (HRT). That there is a correlation of estrogen with breast cancer cannot be refuted. Early menarche, late menopause, late first pregnancy, obesity and dietary factors are directly or indirectly connected with an increased likelihood of breast cancer. The recent flurry of interest in attempting to prevent osteoporosis-induced bony fractures and coronary artery disease among elderly women has not been fully tested as to its efficacy by a scientific, prospectively randomized clinical trial. Therefore, it seems timely to indicate clearly that the use of HRT should be made on an individual basis, with the tacit understanding and approval of the patients, some of whom are symptomatic but the majority of whom have no signs or symptoms of the diseases for which prevention is being advocated.

Coordinated expression of the vitronectin receptor and the urokinase-type plasminogen activator receptor in metastatic melanoma cells.

Integrin alpha v beta 3 is a marker of progression in malignant melanoma. Previously we reported that human melanoma cells derived from regional lymph node metastases had increased alpha v beta 3-mediated adhesion to lymph node vitronectin. In the present study, the expression and function of alpha v beta 3 were further investigated with emphasis on the functional relationship between alpha v beta 3 and the urokinase-type plasminogen activator system of proteolysis. We found that metastases-derived melanoma MeWo LNI 6I (6I) and MIM/8 LNI cells had a markedly increased expression of alpha v mRNA transcripts relative to the parent lines which was reflected in significantly elevated levels of the alpha v beta 3 heterodimers on the cell surface. These cells also expressed elevated levels of urokinase plasminogen activator receptor (uPAR) mRNA and had higher levels of surface bound urokinase plasminogen activator as detected by immunolabeling. To determine whether the expression of uPAR and alpha v were linked, alpha v synthesis in the metastatic melanoma cells was suppressed using alpha v antisense phosphorothioate oligonucleotides. This resulted in a marked decrease in detectable alpha v mRNA and protein and a corresponding substratum-specific reduction in cell adhesion to vitronectin. When uPAR expression in these cells was subsequently analyzed, we found a reduction of approximately 50% in uPAR mRNA levels. On the other hand, ligation of the alpha v beta 3 receptor on the melanoma cells by immobilized antibody resulted in a twofold increase in uPAR mRNA. The results suggest that the expression of uPAR in metastatic melanoma cells is linked to the expression and function of the vitronectin receptor.

HIV-1 associated Kaposi's sarcoma in an African population.

Eighty-seven patients with Kaposi's sarcoma were studied for human immunodeficiency virus (HIV-1) status, age and gender pattern during a three year period from 1990 to 1992. The results of this prospective study were compared with other Tanzanian series. The mean age in males decreased from 44.9 to 37.2 years for the periods of 1980-82 and 1990-92 respectively (p = 0.0001). No significant change in mean age was observed in females. The gender distribution was altered significantly: the present study recorded a male-female ratio of 2.6:1 compared with that of the pre-AIDS era 1980-82 which was 4:1. The role of HIV-1 infection as a potential cofactor of KS is discussed.

Prognostic significance of proliferating cell nuclear antigen expression in colorectal cancer.

BACKGROUND: Recognition of a biologic marker in colorectal cancer tissue that correlates with recurrence and poor survival would offer a rationale for planning aggressive adjuvant therapy. This study assessed the prognostic significance of proliferation activity in cancer cells and nonneoplastic epithelial cells in patients with colorectal cancer, using proliferating cell nuclear antigen (PCNA) immunohistochemical analysis. METHODS: A mouse monoclonal antibody that reacted with PCNA was used to measure proliferation indexes in neoplastic and nonneoplastic colonic tissues of two sex-matched and age-matched groups of 40 patients with different clinical outcomes. In one group of 20 patients, there was no evidence of recurrence or residual disease after a median follow-up of 5.3 years. In the other group, all 20 patients had died within 3.6 years of recurrent disease. RESULTS: The proliferation indexes in both cancer cells and epithelial cells of adjacent nonneoplastic crypts were elevated significantly in those who died compared with survivors; this finding was independent of other variables. There was evidence of an upward shift in the proliferation compartment of the normal crypt that occurred to the same extent in both patient groups. No correlation between Dukes stage and any of the proliferation indexes was observed. CONCLUSION: Proliferation indexes in neoplastic and adjacent normal mucosa, as defined by PCNA immunohistochemical analysis, are independent predictors of recurrence and poor survival in patients with colorectal cancer, indicating that they may be helpful as predictors of long-term survival and in planning prophylactic adjuvant therapy.

Eradication of hepatic metastases of carcinoma H-59 by combination chemoimmunotherapy with liposomal muramyl tripeptide, 5-fluorouracil, and leucovorin.

We have investigated the effect of a combined chemoimmunotherapy protocol with liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE), 5-fluorouracil (5-FU), and 5-formyltetrahydrofolate (leucovorin) on the growth of hepatic metastases using carcinoma H-59, a liver-homing subline of the Lewis lung carcinoma (P. Brodt, Cancer Res., 46: 2442-2448, 1986). C57BL/6 mice inoculated with the tumor cells via the intrasplenic route received three i.v. injections of liposomal MTP-PE, the first of which was administered 3 days prior to tumor cell inoculation. Chemotherapy with 5-FU and leucovorin at the maximal tolerated doses (30 mg/kg per injection) was initiated immediately after tumor inoculation and continued on alternate days for a total of 4 injections. The incidence of liver metastases in animals which received the combined therapy was compared to that in animals treated with chemotherapy or immunotherapy alone. We found that while the number of liver metastases was reduced in all of the treatment groups as compared to control untreated or placebo-treated animals, the combined effect of 5-FU leucovorin and liposomal MTP-PE was significantly better than that of chemotherapy or immunotherapy alone. This was reflected in a reduced incidence (70% as compared to 100% in all other groups) and in a significant reduction in the number and size of the liver nodules. Our results suggest that the efficacy of 5-FU and leucovorin in the treatment of hepatic metastases could be significantly augmented by the addition of the liposome-encapsulated immunoadjuvant MTP-PE.

Productivity of needle localization to facilitate excision of nonpalpable, mammographically suspicious lesions.

The use of needle localization to aid excisional biopsy of nonpalpable breast lesions is now common, and the literature suggests that 13% to 33% of such lesions are malignant. During the 4 years from 1984 to 1988, all women who underwent fine-needle localization in preparation for biopsy were studied to identify factors that might facilitate the selection of those more likely to harbour a cancer, thus sparing patients with benign disease operative intervention. In all, 124 biopsies were performed on nonpalpable lesions that were suspicious on mammography; 51 lesions were malignant and 73 benign. The average age of the patients was 56 years (55 years for those with benign lesions and 61 for those with malignant lesions). The family history, history of breast disease, symptoms and calcification seen on mammography were not significantly different between the two groups. Only 25% of the malignant lesions were noninvasive. In 10% of the patients who had invasive lesions there was lymph-node involvement. The rate of malignancy in this patient population (41%) was slightly better than that reported in the literature, and a larger proportion of patients had noninvasive disease. The authors conclude that none of the above-mentioned risk factors could be used in the preoperative selection of patients for open biopsy.

Development of critical appraisal skills in medical students: opportunities in oncology-related learning situations.

Considering the increasing need for medical students to acquire critical appraisal skills, we have reviewed the curriculum at McGill as to where and how this subject is taught. It is apparent that critical evaluation is covered formally and informally in the course of the four years of medical school. However, this effort is limited by other demands on curriculum time. It could be extended by practical applications, utilizing opportunities arising in oncology-related learning situations, identifiable during periods of clinical electives, clerkship and options, and laboratory research. The elements of a core curriculum to develop critical appraisal skills and a pertinent bibliography have been identified. This information will be transmitted to oncologists supervising medical students, with the intention of eventually providing it to teachers in other specialties with the hope thereby of reaching all medical students. Concurrently, means of evaluating the method and results need to be formulated.

Clinical evaluation of liposomal tumor antigen vaccines in patients with stage-III melanoma.

In this study, we report the results of an active-specific immunotherapy phase I study using autologous tumor-associated antigens (TAA) incorporated within liposomal carriers in patients with metastatic malignant melanoma. A group of 13 patients were entered into the study and given subcutaneous (s.c.) injections of liposome-TAA preparations at 2- to 4-week intervals. Clinical and laboratory monitoring did not reveal any short- or long-term systemic or local toxicity. Three patients had a complete response, and two patients had a partial response (50% or greater size reduction in one or more tumor sites). The remaining eight patients showed no response with disease progression. Two of these eight patients are still undergoing treatment. The TAA preparations stimulated peripheral blood lymphocyte proliferation (PBL) in vitro in those patients exhibiting a clinical response: no such responses were observed in the nonresponder patients. NK cell activity did not correlate with PBL proliferation or clinical response status, whereas PBL cytostatic activity against heterologous melanoma tumor cells correlated with clinical responsiveness. This form of immunotherapy appears to be a safe and feasible candidate for a much larger phase I/II study.

Identification and importance of lymphocyte subpopulations in the regional lymph nodes of breast cancer patients.

To determine whether the presence of metastatic cancer cells in lymph nodes is accompanied by changes in lymphocyte subpopulations identified in tissue sections, the authors studied metastatic and nonmetastatic lymph nodes from eight patients with breast cancer and lymph nodes of three control patients. In all metastatic lymph nodes, T cells were seen in close contact with infiltrating cancer cells; B cells tended to accumulate focally, apart from cancer cell nests. In both metastatic and nonmetastatic lymph nodes from breast cancer patients, the fractional areas occupied by the T4 (helper) and T8 (suppressor/cytotoxic) lymphocytes were comparable. The B-cell fractional area was significantly (p less than 0.01) greater in nonmetastatic than in metastatic nodes. The fractional area occupied by the T8 lymphocytes in the breast cancer patients was significantly (p less than 0.01) greater than in the normal lymph nodes, but no difference was noted in the fractional area occupied by the T4 cells. These findings indicate that all lymph nodes in breast cancer patients are characteristically increased in suppressor/cytotoxic lymphocytes, and the presence of metastatic cancer cells in the nodes is manifested by a depletion of B lymphocytes.

Definitive surgical management for soft-tissue sarcomas.

The surgical management of soft-tissue sarcomas, a seemingly heterogeneous group of malignant tumours, depends on the circumstances (e.g., untreated primary tumour, inadequately resected primary tumour, local recurrence, metastasis) and site. The basic steps in managing a primary tumour include using the correct method to establish a diagnosis, obtaining adequate tumour-free resection margins and giving consideration to adjuvant radiotherapy or chemotherapy, or both. Local recurrences and metastatic lesions require a multidisciplinary approach. The relative rarity of this group of sarcomas and the low survival rate associated with them make it mandatory that such patients be treated in centres able to provide specialized care from the beginning.

Double blind randomized prospective trial of levamisole/placebo in stage I cutaneous malignant melanoma.

One hundred and fifty-six Stage I, Clark's Level III, IV, and V cutaneous malignant melanoma patients were randomized, 83 to Levamisole and 73 to placebo. One hundred and thirty-seven patients were evaluable. Their median follow-up time was 5 years. The 2 groups were comparable in terms of patient characteristics, except for a slightly higher percentage of Clark's level III in the placebo group (57.8 vs 52%). Severe toxicity leading to discontinuation of the medication occurred in 32 patients in the Levamisole arm, versus 10 in the placebo arm. Thirty per cent of patients receiving Levamisole have recurred in comparison with 26% of those on placebo treatment, and despite a trend in the delay of appearance of distant metastasis in the patients receiving Levamisole (30 months versus 9 months in the placebo patients), this drug does not appear to be effective in altering the disease-free survival or the survival of Stage I patients in the dosage schedule utilized in this study.

Gastrointestinal complications after radiotherapy for carcinoma of the uterine cervix.

Radiotherapy for invasive carcinoma of the uterine cervix caused gastrointestinal complications in 52 of 441 patients. External beam and intracavitary radiation together caused greater bowel damage than either method alone. Twenty-eight of the 52 patients required surgical intervention. Ileal stenosis in nine patients required primary resection with anastomosis in seven while the stenosis was bypassed in the other two. Acute perforation with peritonitis would require a diverting ileostomy and creation of a mucous fistula. A defunctioning colostomy was indicated for relief of pain, bleeding and stenosis of the rectum in 11 of 15 patients; 2 patients were treated by primary resection, 1 underwent abdominoperineal resection and another a pelvic exenteration. Of four patients with ileal and rectal involvement, one underwent right hemicolectomy and transverse colostomy, two had ileal resection and sigmoid colostomy and the other had hemicolectomy and rectal resection. All patients were well at follow-up from 3 to 120 months after operation. A Hartmann's procedure is indicated when it appears that primary closure may not succeed. Individualized management is essential.

Combined surgery and cryotherapy for diffuse malignant melanoma of the conjunctiva.

Two patients who had refused exenteration for widespread conjunctival melanoma were treated by a combination of cryotherapy and surgical excisions. Cryotherapy was delivered only to the extensive areas of flat intraepithelial melanocytic proliferation (precancerous melanosis), while the surgical excisions were performed on the focal nodules, representing localized invasive melanoma. In our two patients, the invasive nodules measured, respectively, 1.2 and 1.5 mm in greatest thickness, placing them in a low to borderline risk group for metastasis. Repeated cryoapplicatons were required to control the widespread flat intraepithelial disease. The conjunctiva tolerated these procedures well because the substantia propria is not sacrificed as it must be in surgical conjunctivectomy, allowing comparatively normal reepithelialization to occur from adjacent zones, after the treated epithelium containing the melanocytes sloughs. No evidence of invasive melanoma (cancerous melanosis) has developed in any of the cryotreated areas of intraepithelial disease (precancerous melanosis); sequential biopsies have established that the atypical melanocytes have disappeared from the epithelium.