High-dose tamoxifen added to concurrent biochemotherapy with decrescendo interleukin-2 in patients with metastatic melanoma.

BACKGROUND: In vitro cell culture data and preclinical models suggest that tamoxifen modulates tumor cell sensitivity to a wide range of therapeutic agents. In the current study, the authors examined whether high-dose tamoxifen (HDT) improved the overall and complete response in patients with metastatic melanoma who were treated with concurrent biochemotherapy. METHODS: Forty-nine patients were treated with a biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo interleukin-2, interferon-alpha-2b, and tamoxifen. The study had a 2-step design, beginning with a tamoxifen dose escalation from 40 mg to 320 mg (17 subjects) to evaluate safety and tolerability, followed by Phase II accrual of 32 patients to HDT (320 mg) to assess clinical efficacy. Efficacy was compared with a similar modified biochemotherapy regimen with low-dose tamoxifen (LDT). Pharmacokinetic studies were performed to determine in vivo tamoxifen levels. RESULTS: Tamoxifen dose escalation was completed without any reported dose-limiting toxicity. The overall response rate in the HDT group was 50% (95% confidence interval, 33.2%-66.8%), with a complete response rate of 6% and a median survival of 9.5 months. The overall response rate was not improved and the complete response and survival appeared inferior compared with that of patients recently treated with concurrent biochemotherapy and LDT. Serum tamoxifen levels were found to correlate with the dose administered, with a mean of 0.9 microM at the 40-mg dose to 4.6 microM at the 320-mg dose. Ultrafiltered protein-free sera demonstrated low (< 0.01 microM) concentrations of tamoxifen. CONCLUSIONS: The addition of HDT to a regimen of concurrent biochemotherapy did not appear to improve response rates or overall survival, despite reaching the targeted plasma concentration. Unknown drug interactions or high protein binding of tamoxifen may account for the lack of clinical effectiveness.

Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma.

PURPOSE: Concurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen. PATIENTS AND METHODS: Forty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days. RESULTS: The overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths. CONCLUSION: The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

Breast cancer: lack of prognostic value of adrenal pathology at adrenalectomy.

The adrenal glands of 58 patients undergoing adrenalectomy for advanced breast cancer were reviewed and correlated with subsequent course of the patients' disease. Three patients had thecomatous metaplasia in the adrenal cortex, six patients had myelolipomatous changes, and 13 patients had metastatic breast cancer in their adrenal glands at the time of adrenalectomy. Neither the presence of metastases nor myelolipomatous changes were associated with a long disease-free interval, a long period from mastectomy to adrenalectomy, or a prolonged postadrenalectomy survival. The patients with metastatic breast cancer in the adrenal glands had more widespread disease than patients without adrenal metastases. The presence of breast cancer metastases in the adrenal glands at the time adrenalectomy identifies patients further advanced in the course of their disease, but is not related prognostically to the effect of adrenalectomy.

Case reports and studies of paraneoplastic hypotension: abnormal low pressure baroreceptor responses.

Intrathoracic stretch receptors regulate adjustments of the vasculature to gravitational changes and influence urinary water and solute excretion. Few reports of pathologic states involving interruption of these regulatory mechanisms have appeared. Two patients with orthostatic hypotenstion related to advanced intrathoracic carcinoma were studied, utilizing tilt-table examinations and immersion of the entire body in water to test the function of their intrathoracic baroreceptor reflex arcs. Both patients showed abnormalities of antidiuretic hormone level and sodium excretion as compared with normal controls. This suggests that total immersion is a safe and convenient test of the low-pressure baroreceptor system in patients with suspected dysfunction. Three patients are also reported whose charts were reviewed posthumously. Although they were not tested in the laboratory, their clinical data suggest that they too had been suffering from an interference with the transmission of impulses from the intrathoracic receptors.

Immunocompetence and spontaneous regression of metastatic renal cell carcinoma.

Spontaneous remission of pulmonary metastases from renal cell carcinoma was correlated with a positive response to dinitrochlorobenzene (DNCB). When first seen, the patient was DNCB negative and a chest radiograph showed nodular densities in the right lung and left midlung. Six months after sensitization, the patient had a positive response to DNCB and no evidence of lung metastases. Three mo later, the patient developed brain metastases although X-ray examination showed no pulmonary nodules. A diminished response to DNCB noted over the next several months and chest X ray verified the return of pulmonary metastases.