Robert A. Chapman

Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: Comparison of 30-, 60-, and 90-mg dosages

PURPOSE To determine the efficacy, dose-response relationship, and safety of 30, 60, and 90 mg of a single intravenous dose of an aminobisphosphonate, pamidronate (APD), for the treatment of moderate to severe hypercalcemia of malignancy. PATIENTS AND METHODS Patients with histologically proven cancer and a corrected serum calcium level of at least 12.0 mg/dL after 48 hours of normal saline hydration were enrolled in a double-blind, multicenter, randomized clinical trial. Pamidronate in 30-, 60-, or 90-mg doses was administered as a single 24-hour infusion. Serum calcium corrected for albumin, urine hydroxyproline, and calcium excretion, and serum parathyroid hormone (PTH) (1-84) were determined before and after pamidronate therapy. RESULTS Thirty-two men and 18 women entered the study. A dose-response relationship for normalization of corrected serum calcium was seen after pamidronate administration. Corrected serum calcium normalized in 40% of patients who received 30 mg, in 61% of patients who received 60 mg, and in 100% of patients who received 90 mg of pamidronate. The decline in the serum calcium level was associated with decreased osteoclastic skeletal resorption evidenced by a decrease in urine calcium and hydroxyproline excretion. Among those with a normalized corrected serum calcium level, the mean (median) duration of normalization of the corrected serum calcium value was 9.2 (4), 13.3 (5), and 10.8 (6) days in the 30-, 60-, and 90-mg treatment groups, respectively. The response of hypercalcemia to pamidronate was not significantly influenced by the presence of skeletal metastases. PTH 1-84, suppressed in patients on entry into this study, increased to a greater extent in those patients with osteolytic skeletal metastases compared with those with humoral hypercalcemia of malignancy. Clinical improvement, including improved mental status and decreased anorexia, accompanied the decline in the corrected serum calcium level in all three treatment groups. Side effects included low-grade fever, asymptomatic hypocalcemia, hypomagnesemia, and hypophosphatemia. CONCLUSIONS A single-dose infusion of 60 to 90 mg of pamidronate was highly effective and well tolerated and normalized corrected serum calcium in nearly all patients (61% to 100%) with hypercalcemia of malignancy.

Immunomodulatory activity of resveratrol: Suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production

trans-Resveratrol, a phytoalexin found in grapes, wine, and other plant products, has been shown to have anti-inflammatory, antioxidant, and antitumor activities. Many of these beneficial effects of resveratrol require participation of the cells of the immune system; however, the effect of resveratrol on the development of immunological responses remains unknown. We have investigated the effect of resveratrol on mitogen/antigen-induced proliferation of splenic lymphocytes, induction of cytotoxic T lymphocytes (CTLs) and lymphokine activated killer (LAK) cells, and the production of the cytokines interferon (IFN)-gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and IL-12. We found that mitogen-, IL-2-, or alloantigen-induced proliferation of splenic lymphocytes and the development of antigen-specific CTLs were suppressed significantly at 25-50 microM resveratrol. The generation of LAK cells at similar concentrations was less sensitive to the suppressive effect of resveratrol. The suppression of cell proliferation and CTL generation by resveratrol was not only reversible, but in some cases the response (mitogen/IL-2-induced proliferation and CTL generation) was actually enhanced following pretreatment of cells with resveratrol. Resveratrol also inhibited the production of IFN-gamma and IL-2 by splenic lymphocytes, and the production of TNF-alpha and IL-12 by peritoneal macrophages. The inhibition of cytokine production by resveratrol was irreversible. Further, resveratrol blocked the activation of the transcription factor NF-kappaB without affecting basal NF-kappaB activity. The latter result suggests that resveratrol inhibits cell proliferation, cell-mediated cytotoxicity, and cytokine production, at least in part through the inhibition of NF-kappaB activation.

Antiandrogen Withdrawal in Castrate-refractory Prostate Cancer : A Southwest Oncology Group Trial (SWOG 9426)

Antiandrogen withdrawal is a potential therapeutic maneuver for patients with progressive prostate cancer. This study was designed to examine antiandrogen withdrawal effects within the context of a large multi‐institutional prospective trial.

Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A southwest oncology group study

AbstractPurpose: To evaluate FAM [5-FU (5-fluorouracil), doxorubicin, mitomycin C] chemotherapy as adjuvant therapy for patients with resected TNM stage I, II, or III gastric carcinoma. Patients and Methods: One hundred ninety-three eligible patients were accrued from 1978 to 1991 in a phase III trial comparing six cycles (1 year) of postoperative FAM chemotherapy with observation only. Results: The median follow-up on this study was 9.5 years. For all patients, no differences (log-rank analysis) in disease-free survival (p=0.45) and overall survival (p=0.57) between FAM therapy (93 cases) and surgery (100 cases) were observed. Quality of surgical resection affected survival irrespective of FAM use. Cases with curative resection, defined in a retrospective review of pathology and surgical reports as cases having no evidence of residual disease in the abdomen and tumor-free margins >1 cm, had superior survival compared to cases not meeting these requirements (p<0.001). FAM was well tolerated with 6% (five of 90) of cases demonstrating grade IV hematologic toxicity. There were two drug-related fatalities (one cardiomyopathy, one hematolytic uremic syndrome). Conclusion: FAM is not effective adjuvant therapy for TNM stage I, II, and III patients with resected gastric cancer. Future adjuvant studies must emphasize prospective surgical quality control to assure enrollment of appropriately staged and resected cases and wide participation to assure adequate case accrual over a reasonable period.

Phase II Trial of Sorafenib in Patients with Advanced Anaplastic Carcinoma of the Thyroid

BACKGROUND Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogene is mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor that acts on the RAF-1 serine/threonine kinase. In preclinical mouse models, sorafenib inhibits the growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with ATC who had failed up to two previous therapies. METHODS The primary endpoint of the trial was the Response Evaluation Criteria In Solid Tumors (RECIST)-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. RESULTS Two of the 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months, respectively. For the patients with stable disease, the median duration was 4 months (range 3-11 months). The overall median progression-free survival was 1.9 months with a median and a 1-year survival of 3.9 months and 20%, respectively. Toxicity was manageable and as previously described for sorafenib, including hypertension and skin rash. CONCLUSION Sorafenib has activity in ATC, but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.

A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711)

PURPOSE The results of Southwest Oncology Group Study 8711 (Group 2B) are presented. The objective was to evaluate the natural history of sperm concentration and selected hormonal parameters in patients with testicular cancer treated with orchiectomy and radiotherapy. METHODS AND MATERIALS Of a total of 207 patients enrolled on SWOG 8711, 53 pure seminoma patients were identified who were treated with orchiectomy and radiotherapy only. Sperm concentration, follicle-stimulating hormone (FSH) levels, and sexual satisfaction scores were the main parameters followed. RESULTS A fraction of the patients were infertile prior to receiving radiotherapy. Our analysis indicates that incidental radiation dose to the remaining testicle affects time to recovery of fertility, and at an aggregate level, changes in FSH mirror changes in sperm concentration over time. This phenomenon is the same as that described in patients free from testicular cancer. These men evaluated their sexual activity as good after orchidectomy. CONCLUSION Our data support the use of clamshell-type testicular shields as a means of providing maximum protection to the remaining testicle.

Nonselective inhibition of proliferation of transformed and nontransformed cells by the anticancer agent curcumin (diferuloylmethane)

We have investigated the antiproliferative effect of curcumin, an antitumor agent with antioxidant and anti-inflammatory properties, against a variety of transformed and nontransformed cell types. At equimolar concentrations ranging from 6.25 to 50 microM, curcumin inhibited DNA synthesis, as revealed by 3H-incorporation, in five leukemia lines, three nontransformed hematopoietic progenitor cell populations, and four nontransformed fibroblastic cell lines in a concentration-dependent manner. Curcumin also inhibited the cellular growth of both transformed and nontransformed cells in clonogenic assays. Without discriminating between transformed or nontransformed cells, the inhibition of cell proliferation by curcumin was not always associated with programmed cell death. These findings have implications for developing curcumin-based anticancer and anti-inflammation therapies.

Chemotherapy in Patients ≥80 with Advanced Non-small Cell Lung Cancer: Combined Results from SWOG 0027 and LUN 6

Introduction: We report outcomes for the combined cohort of patients ages 80 or older from two chemotherapy trials in advanced non-small cell lung cancer (NSCLC) conducted by the Southwest Oncology Group (S0027) and an investigator-initiated trial (LUN 6). Methods: Patients with chemotherapy-naïve, stage IIIB/IV NSCLC, ages 70 years or older with a performance status (PS) of 0 or 1, or patients of any age with PS 2, were eligible. Treatment in the S0027 study was 25 mg/m2 of vinorelbine on days 1 and 8, every 21 days for three cycles, and then 35 mg/m2 of docetaxel on days 1, 8, and 15, every 28 days for three cycles. Treatment in the LUN 6 study was 30 mg/m2 of docetaxel on days 1, 8, and 15, every 28 days, or 75 mg/m2 every 21 days. Of the 228 patients treated, 49 (21.5%; 26 in LUN 6 and 23 in S0027) were ages 80 years or older. Analysis of outcome was conducted in the 80-and-older group and was compared with the under-80 cohort from S0027. Results: Among patients with measurable disease, disease-control rates (partial response + stable disease) were 54% (n = 48) and 46% (n = 89) in the 80-and-older and under-80 groups, respectively. Median survival was 7 and 11 months in PS 0/1 patients in the 80-and-older and under-80 groups, respectively. Median survival was 4 and 5 months in PS 2 patients in the 80-and-older and under-80 groups, respectively. Treatment was well tolerated. Five treatment-related deaths were noted: two (4%) and three (3.4%) in the 80-or-younger and the under-80 groups, respectively. Conclusions: These chemotherapy regimens were associated with an encouraging disease-control rate (54%) in patients 80 years or older with advanced NSCLC, with good tolerance. Selected octogenarians with advanced NSCLC may benefit from single-agent chemotherapy.

Sequential Vinorelbine and Docetaxel in Advanced Non-small Cell Lung Cancer Patients Age 70 and Older and/or with a Performance Status of 2: A Phase II Trial of the Southwest Oncology Group (S0027)

Background: This phase II study (S0027) evaluated the efficacy and tolerability of planned sequential single-agent chemotherapy with vinorelbine followed by docetaxel in patients with advanced non-small cell lung cancer (NSCLC) age 70 and older and/or a performance status (PS) of 2. Methods: Patients with stage IIIB (pleural effusion) or stage IV NSCLC, age 70 and older with a PS of 0-1 or 2, any age, received three cycles of vinorelbine 25 mg/m2 days 1 and 8 every 21 days followed by three cycles of docetaxel 35 mg/m2 days 1, 8, and 15 every 28 days. Results: A total of 125 patients entered the study; 117 patients were assessable for response, survival, and toxicity. Seventy-five patients were in stratum1 (age 70 and older, PS 0-1) and 42 patients in stratum 2 (PS 2, any age). Objective response was 19% (95% confidence interval [CI]: 11%–30%) and 11% (95% CI: 3%–25%) in strata 1 and 2, respectively. Median survival was 9.1 months (95% CI: 7.1–12.7) and 5.5 months (95% CI: 3.1–6.5) in strata 1 and 2, respectively. Survival at 12 months was 41% and 13% in strata 1 and 2, respectively. Grade 3/4 neutropenia was seen in 32% and 31% of patients in strata 1 and 2, respectively. Three deaths probably related to treatment were noted: one in stratum 1 and two in stratum 2. Conclusion: Sequential vinorelbine and docetaxel is a well-tolerated and effective regimen in comparison with reports of other treatments tested in patients with advanced NSCLC age 70 and older and/or with a PS of 2.

Development of a Question Prompt List as a Communication Intervention to Reduce Racial Disparities in Cancer Treatment

Racial disparities have been found in the use of chemotherapy as cancer treatment. These disparities may be, in part, due to well-documented differences in the quality of communication during clinical interactions with oncologists and Black versus White patients. In this study using a community-based participatory research approach, academic researchers, community members, and oncologists formed a partnership to develop a communication intervention to address racial disparities in cancer care. Partners developed a question prompt list (QPL), a simple tool that can be used to improve communication, and thus treatment, during clinical interactions in which oncologists and Black patients discuss chemotherapy. Partners endorsed the use of a QPL, provided specific suggestions for content and format, conducted and analyzed qualitative interviews with Black patients receiving chemotherapy, and approved the final version. The feasibility and effectiveness of the QPL that resulted from this research process are currently under evaluation in a separate study