Edward G. Mansour

Initial results of a phase II trial of high dose radiation therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292): An eastern cooperative oncology group study

PURPOSE A prospective clinical trial was performed to assess the response and toxicity associated with the use of high dose radiation therapy, 5-fluorouracil, and cisplatin in patients with anal cancer. METHODS AND MATERIALS Patients with anal cancer without distant metastasis were eligible for this study. Radiation therapy consisted of 59.4 Gy in 33 fractions; a 2 week break in treatment was taken after 36 Gy had been given. A treatment of 5-fluorouracil, 1,000 mg/m2 per day intravenously, was given for the first 4 days of radiation therapy, and cisplatin, 75 mg/m2 intravenously, was given on day 1 of radiation therapy. A second course of 5-fluorouracil and cisplatin was given after 36 Gy of radiation, when the radiation therapy was resumed. RESULTS Nineteen patients entered this study and received treatment. Thirteen (68%) had a complete response, 5 (26%) had a partial response, and 1 (5%) had stable disease. The patient with stable disease and one of the patients with a partial response had complete disappearance of tumor more than 8 weeks after completion of radiation therapy. Fifteen patients had toxicity of Grade 3 or higher: the worst toxicity was Grade 3 in eight patients, Grade 4 in six patients, and Grade 5 in one patient. The most common form of toxicity of Grade 3 or higher was hematologic. The one lethal toxicity was due to pseudomembranous colitis, which was a complication of antibiotic therapy for a urinary tract infection. CONCLUSION Radiation therapy, cisplatin, and 5-fluorouracil resulted in an overall response rate of 95%. Significant toxicity occurred, an indication that this regimen is near the maximal tolerated dose. A Phase III clinical trial is planned in which radiation therapy, cisplatin, and 5-fluorouracil will be used as an experimental arm.

Estrogen receptor status as a prognostic indicator for stage I breast cancer patients

SummaryThe prognostic value of estrogen receptor determination was studied for 510 stage I (axillary node negative) breast cancer patients treated by mastectomy alone.Results at 60 months after mastectomy indicate that stage I patients whose tumors lack estrogen receptors fall into a significantly poorer prognostic group for both recurrence and survival than those whose tumors contain estrogen receptors.Within the postmenopausal group, estrogen receptor negative (ER −) patients are recurring more rapidly than estrogen receptor positive (ER +) patients. Within the premenopausal group, ER + patients have a recurrence rate identical to ER− patients, which is apparent only after prolonged follow-up.In contrast to postmenopausal ER + patients, premenopausal ER + patients appear to have no prognostic advantage over the ER − patients, and thus constitute a high risk group for which adjuvant endocrine therapy might prove beneficial.

Hormonal treatment for metastatic breast cancer. An eastern cooperative oncology group phase III trial comparing aminoglutethimide to tamoxifen

Background. Tamoxifen and aminoglutethimide are two hormone therapies reported to be effective palliative approaches for patients with metastatic breast cancer. The current trial was designed to evaluate their relative therapeutic effectiveness.

Squamous cell carcinoma of the breast: A clinical approach

AbstractBackground: Squamous cell carcinoma (SCC) of the breast is rare. It remains unclear whether a “pure” form of SCC exists or if all known cases actually represent an extreme form of squamous metaplasia within adenocarcinoma. Due to its rarity and controversy ovr its definition, there are no good data on appropriate management and prognosis. Methods: All cases of breast carcinoma indexed at our institution were reviewed to identify seven cases where squamous metaplasia was a significant component of the pathologic diagnosis. Slides and electron micrographs were reviewed by a single pathologist. Clinical information was obtained from medical records. Results: These cases support the concept of a disease continuum with varying degrees of squamous metaplasia. When tumors identified as “pure” SCC on light microscopy are subjected to ultrastructural analysis, either separate squamous and glandular cells are present or both histologic features are noted to coexist in the same cell. Conclusions: Identification of “pure” cases of SCC appears clinically unimportant. All patients presented with advanced disease, thus necessitating aggressive management regardless of histology. Mastectomy was performed due to large tumor size and adjuvant chemotherapy given rather than hormones because of receptor negativity. The mixed histology should direct future drug choice. The role of radiation remains unclear.

Adjuvant therapy of stage II breast cancer

SummaryA prospective, randomized clinical trial of adjuvant treatment of 318 stage II breast cancer patients, using chemotherapy, the antiestrogen tamoxifen, and immunotherapy is reported at 48 months follow-up.Women whose primary tumors have no estrogen receptors fall into a significantly poorer prognostic group than those whose tumors contain estrogen receptors. None of the adjuvant regimens appeared to offer any clear-cut advantage for the estrogen receptor negative patients.Those women whose primary tumor contains estrogen receptors appear to be in a prognostically favorable group, when their treatment regimen included the antiestrogen, tamoxifen. The adjuvant use of BCG immunotherapy does not appear to offer additional benefit, but the follow-up period of these treated patients is too brief to be conclusive.A longer period of observation is needed to determine whether this systemic treatment in estrogen receptor positive patients is preventing recurrence or merely delaying it.

Tissue and plasma carcinoembryonic antigen in early breast cancer. A prognostic factor.

A prospective study of plasma and tissue carcinoembryonic antigen (P‐CEA and T‐CEA) levels in 63 patients with early (Stage I and II) breast cancer was undertaken to determine if the presence of CEA in tissue and/or plasma at the time of primary surgery can be used as a prognostic factor. Thirty‐two Stage I and 31 Stage II patients were evaluable with a median follow‐up time of 26 months: 29/63 were T‐CEA and/or P‐CEA positive while 34/63 were T‐CEA and P‐CEA negative; 9/63 were both T‐CEA and P‐CEA positive; 13/63 were P‐CEA positive alone, while 25/63 were T‐CEA positive alone; 5/29 T‐CEA and/or P‐CEA positive showed disease progression with a mean DFI of 11.8 months, compared with 0/34 T‐CEA and P‐CEA negative patients (P < 0.02); 2/9 T‐CEA and P‐CEA positive compared with 0/34 negative patients progressed (P < 0.01). There was a significant difference (P < 0.05) between P‐CEA positive (3/13) patients with recurrence and P‐CEA negative (2/50). When T‐CEA positive patients (4/25) were compared with T‐CEA negative (1/38), the difference approaches significance. When the recurrences were analyzed with respect to CEA, estrogen receptor (ER) and nodal status, only in the CEA+ versus CEA– group was there a significant difference. The early data show that patients with positive T‐CEA and/or P‐CEA have a higher recurrence rate with probable poor prognosis. Prognosis correlates better with CEA status than with ER or nodal status.

Long-term follow-up of a Phase II trial of high-dose radiation with concurrent 5-fluorouracil and cisplatin in patients with anal cancer (ECOG E4292).

PURPOSE Although chemoradiation using 5-fluorouracil (5-FU) and mitomycin-C (MMC) is the standard of care in the treatment of anal cancer, many patients are unable to tolerate MMC. This Phase II clinical trial was performed to determine whether cisplatin could replace MMC in the treatment of anal cancer. METHODS AND MATERIALS Thirty-three patients with localized anal cancer were enrolled. One patient registered but never received any assigned therapy and was excluded from all analyses. Between February 1, 1993, and July 21, 1993, 19 patients were accrued to Cohort 1. Radiation consisted of 45 Gy to the primary tumor and pelvic nodes, followed by a boost to the primary and involved nodes to 59.4 Gy. A planned 2-week treatment break was used after 36 Gy. Concurrent chemotherapy consisted of 5-FU 1,000 mg/m(2)/day on Days 1 to 4 and cisplatin 75 mg/m(2) on Day 1. A second course of 5-FU and cisplatin was given after 36 Gy, when the patient resumed radiation therapy. Between April 4, 1996, and September 23, 1996, an additional 13 patients (Cohort 2) were accrued to the study and received the same treatment except without the planned treatment break. RESULTS Complete response was seen in 78% (90% CI, 63-89) of patients and was higher in patients who did not get a planned treatment break (92% vs. 68%). The overall Grade 4 toxicity rate was 31%. One treatment-related death (Grade 5) occurred in a patient who developed sepsis. The 5-year overall survival was 69%. CONCLUSIONS Radiation therapy, cisplatin, and 5-FU resulted in an overall objective response (complete response + partial response) of 97%. Although the 5-year progression-free survival was only 55%, the overall 5-year survival was 69%. Given the excellent salvage provided by surgery, this study affirms that cisplatin-based regimens may be an alternative for patients who cannot tolerate the severe hematologic toxicities associated with mitomycin-based chemoradiation regimens.

Adjuvant endocrine therapy, cytotoxic chemotherapy, and immunotherapy in stage-II breast cancer: Five-year results

SummaryFive-year results of a prospective, randomized clinical trial of three treatment regimes—(a) cytoxan, methotrexate, and 5-fluorouracil (CMF); (b) CMF plus the antiestrogen drug, tamoxifen (CMFT); and (c) CMFT plus bacillus Calmette-Guerin (BCG) vaccinations—in 312 women with stage-II breast cancer are reported. Estrogen receptors (ER) were measured in all of the primary tumors. Addition of tamoxifen to CMF therapy significantly decreased the number of recurrences at five years in ER positive patients with four or more positive axillary lymph nodes. Addition of tamoxifen to CMF had no effect on disease-free survival in ER-positive patients with 1–3 positive axillary lymph nodes or in patients with ER-negative tumors. Addition of BCG vaccinations had no discernible effect on disease-free survival. ER measurements in the primary tumor provide important prognostic information regardless of treatment, with ER-positive patients having lower recurrence rates and mortality after five years. ER measurements also have predictive value for response to endocrine therapy. Further follow-up is needed to determine whether tamoxifen is delaying recurrence or preventing it in a subset of these patients.

Trace elements that act to inhibit neoplastic growth.

Utah’s Mrs. John Doe runs far less risk of dying from breast cancer than the District of Columbia’s Mrs. Richard Roe. Similarly, lung cancer threatens John Doe much less than it does Richard Roe. Geographic variations in death rates from cancer in the United States have been well documented.’ The age-adjusted rate for cancer mortality per 100,000 of both sexes in 1960 was 153.4 in the District of Columbia, and 97.4 in Utah. New York ranked fourth with an age-adjusted rate of 143.5/100,000, and Ohio was thirteenth with a rate of 133.0/ 100,000. These large differences suggest that environmental factors may be the principal and preventable causes of cancer. Soil, water, and air are the obvious areas for investigation. In the past, considerable attention has been paid to trace substances which play causative roles in cancer but little effort has been expended to determine which elements may play protective roles. It is apparent from animal investigations that some of the trace elements inhibit experimental neoplastic growth. Iodine is perhaps the best known example. A deficient intake of iodine results in hyperplastic and, eventually, neoplastic changes in the thyroid gland. Adequate intake of iodine prevents these changes.? Similarly, other trace elements have recently been shown to have specific metabolic properties which may prevent, or can be utilized to inhibit, the growth of tumor. The mechanisms of action are not clear, and many of the reports require further substantiation.

Comparison of the membrane-related effects of cytarabine and other agents on model membranes

UNLABELLED The membrane-associated effects of a series of chemotherapeutic and other drugs were examined via differential scanning calorimetry and by their modulation of the action of porcine phospholipase A2 (PLA2) on bilayer substrates. The drugs examined included: cytarabine, amino-glycoside antibiotics, adriamycin, dibucaine, butacaine, and VP-16. The bilayers employed were phase-separated ternary lipid mixtures containing dimyristoylphosphatidylcholine: palmitoyllysolecithin: and either hexadecanoic acid (fatty acid ternary mixture) or hexadecanol (alcohol ternary mixture). Effects of the more hydrophilic drugs (cytarabine and aminoglycoside antibiotics) on the calorimetric profiles of the negatively charged (fatty acid-containing) and the neutral (hexadecanol-containing) ternary lipid mixtures indicate that the interaction of these drugs with biomembranes is likely to be dominated by electrostatic interactions. All of the drugs investigated, including the more hydrophobic adriamycin, dibucaine, butacaine, and VP-16, affected the phase equilibrium in the membrane and exhibited apparent noncompetitive inhibition of the action of PLA2 on bilayers composed of ternary lipid substrates. In addition, cytarabine inhibited fusion of fatty acid-containing ternary mixtures. CONCLUSIONS These drug:membrane interactions leading to a shift in the phase equilibria were apparently regiospecific. Hydrophilic drug:membrane interactions included an important electrostatic component. The effects of all of the drugs employed in this study on the action of PLA2 on a bilayer substrate (fatty acid-containing ternary lipid mixture) are hypothesized to be a result of the drug-mediated shift in phase equilibria away from the optimally active phase distribution. As a result, PLA2 binds with normal affinity to the membrane, but its membrane substrate is not catalytically turned over. It is evident that these drugs can directly affect cellular homeostasis in a manner that can show a dependence on the nature of the membrane surface.