Common cancers--genetics, origin, prevention, screening: Parts I and II.

Carcinogenesis is a stepwise process that occurs through mutations of cancer-related genes. Five or more genes must be mutated before malignant transformation occurs in most adult cancers; in some childhood cancers as few as two mutated genes may be sufficient. A rare inherited mutation of a critical gene may predestine cancer to occur in one or more sites. This germline mutation is present in virtually every cell in the body, except half of the germ cells, which do not contain the mutated gene in their haploid chromosome set. These and other genes have been used to piece together a puzzle of regulatory systems that govern cell division and proliferation, as well as apoptosis or programmed cell death. Mutations of these genes result not only in increased cell proliferation but also in diminished cell death. Most genetic changes that occur during carcinogenesis are not inherited or germline. They are acquired after birth and are called somatic mutations. A somatic mutation affects only the mutated cell and its progeny. Each time a cell divides, there is a chance of somatic mutation, and therefore there always is a low, background risk for cancer and other malignant lesions. A far more prevalent cause of cancer-related death in the United States is environmental exposure. Such exposure causes somatic mutations of cancer-related genes through direct damage to DNA or through alteration of proliferation or cell death, which enhances the baseline risk for mutation. As carcinogenesis becomes understood, interventions may be designed that selectively interfere in important steps. Screening for cancer is based on the premise that one can treat a patient for a cancer that has not spread from its primary site. Nevertheless, cancer screening is controversial and often confusing. Issues of costs, risks versus benefits, physical time and effort, and patient compliance all affect the clinician's view of screening, often to the extent that the true value of this approach to cancer control is underappreciated and underutilized. A clinician should consider the following questions when assessing the priority, scope, and intensity of cancer screening. Is the cancer an important public health problem? Can preclinical stages be detected and cured? Are effective screening tests available? Are the tests feasible and acceptable? Have screening programs reduced cancer-specific mortality? Is the screening program cost effective? Is screening generally recommended? There is clear-cut evidence of benefit from screening for cancer of the cervix, breast, colon and rectum, and skin and some specific genetic syndromes. Evidence of survival benefit from screening for prostate cancer is lacking, although prostate specific antigen screening is widely used. Screening for lung and ovarian cancer is ineffective.

Methotrexate content in squamous cell carcinoma of the head and neck after low-dose methotrexate.

Eleven patients with squamous carcinoma of the head and neck who were scheduled for surgical resection or endoscopic biopsy of tumor received 15 mg/m2 of methotrexate (MTX). Samples of tumor, normal mucosa, and plasma were obtained at surgery or endoscopy, 18-24 hours after the last MTX dose. Tissue content and plasma concentration of MTX and folate were measured using sequential radioligand-binding assays. Median MTX content was 50.0 pmol/g wet weight in tumor, 19.0 in normal mucosa, and < 0.5 nM (pmol/ml) in plasma. Since dihydrofolate reductase (DHFR) content of human tumors has previously been shown to be less than 5 pmol enzyme/g wet weight, tumor MTX content exceeded expected DHFR content in all but one patient. These data support the concept that low doses of MTX saturate tumor DHFR and that, in this regard, dose escalation may have limited value.

Radiation therapy and 5-fluorouracil modulated by leucovorin for adenocarcinoma of the pancreas. A phase I study.

This Phase I study was designed to build on the Gastrointestinal Tumor Study Group's experience with combined modality therapy in patients with pancreatic cancer. Thirteen patients with adenocarcinoma of the pancreas received weekly 5-fluorouracil by rapid intravenous infusion midway through a 2-h infusion of high dose leucovorin during external beam radiation therapy. Twelve patients received 100% of planned external beam radiation; treatment delays occurred in only three. Four patients received 100% of planned chemotherapy doses. Leukopenia and thrombocytopenia caused reduction of the number of chemotherapy doses given during radiation in six patients; diarrhea, severe nausea and vomiting, and wound abscess caused reduction in three patients. Ten patients were evaluable for response; two had complete responses, one had a partial response, and two had minor responses. In this small series baseline and post-treatment CA 19-9 levels predicted and correlated with response. We conclude that radiation and 5-FU modulated by leucovorin is a tolerable treatment regimen for carcinoma of the pancreas, with preliminary suggestion of activity, that warrants further Phase II testing.

Fluoxymesterone as third line endocrine therapy for advanced breast cancer. A phase II trial of the Piedmont Oncology Association.

The Piedmont Oncology Association conducted a Phase II trial of fluoxymesterone (Halotestin) in 28 patients who failed to respond to prior hormonal therapy with tamoxifen and a progestational agent. Of nine patients who had responded to prior endocrine therapy, one had a partial response (PR) as defined by strict criteria and remains on study at 17 + months for an 11% response rate [95% confidence interval (CI), complete response (CR) + PR, 0-48%]. None of 19 previously unresponsive patients achieved remission (95% CI, CR + PR, 0-18%). Eleven patients' performance status deteriorated during therapy. Five of them had not received prior chemotherapy, and their response to subsequent chemotherapy may have been adversely affected. Third-line hormonal therapy with fluoxymesterone can be recommended only as a temporizing measure in patients with indolent disease who have responded to prior hormonal therapy.

Early diagnosis of breast cancer. Universal screening is essential.

Breast cancer strikes 1 in 10 women in the United States. Early diagnosis of breast cancer improves chances of survival. With universal screening and expert evaluation of early clinical signs and symptoms of breast cancer, mortality rates can be reduced by 30% to 40%. Physicians can help achieve this goal by taking an active role in patient education and promoting the availability of affordable screening mammography.

Intraoperative electron beam radiation therapy (IOEBRT) for carcinoma of the exocrine pancreas.

The abdominal cavities of 50 patients were explored in a specially constructed intraoperative radiotherapy operating amphitheater at the Medical College of Ohio. Twenty-six patients were treated with intraoperative and postoperative precision high dose external beam therapy, 12 with intraoperative irradiation but no external beam therapy, and 12 with palliative surgery alone. All but two patients completed the postoperative external beam radiation therapy as initially prescribed. The median survival time for patients treated with palliative surgery alone was 4 months, and that for patients treated with intraoperative radiotherapy without external beam therapy was 3.5 months. Patients undergoing intraoperative irradiation and external beam radiation therapy had a median survival time of 10.5 months. Four patients died within 30 days of surgery and two patients died of gastrointestinal hemorrhage 5 months posttreatment.

Multimodality therapy of stage III adenocarcinoma of the breast.

The results of a pilot multimodality program (surgery + radiotherapy + chemotherapy) are reported in 34 women with advanced stage III and IV adenocarcinoma of the breast. The median relapse-free survival for all patients was 24 months, with 74% of the premenopausal patients and 37% of the postmenopausal alive at five years (P = 0.18). The relapse rate was significantly lower in premenopausal patients when compared to the postmenopausal subgroup. Estrogen receptor status was not predictive for relapse or survival.

Prognostic value of the estrogen receptor level in pathologic stage I and II adenocarcinoma of the breast.

The relationship between estrogen receptor levels and recurrence of breast cancer was examined in 302 patients with adenocarcinoma of the breast, pathologic stage (PS) I and II. All 117 patients with PS II adenocarcinoma of the breast received adjunctive chemotherapy. In this series, there was no association between the estrogen receptor level and recurrence in either the 185 patients with PS I adenocarcinoma of the breast or the 117 patients with PS II adenocarcinoma of the breast. The most important prognostic variable was the presence or absence of axillary metastases.