Effects of commercially available soy products on PSA in androgen-deprivation-naïve and castration-resistant prostate cancer.

OBJECTIVE: No standard therapeutic option exists for men with prostate cancer who have failed local therapy, have no gross metastatic disease, and whose only manifestation of disease is a rising prostate-specific antigen (PSA) level. Soy products are able to affect PSA kinetics in some men with prostate cancer, and this effect has been attributed to the decreased expression of the androgen receptor and other mechanisms. METHODS: We treated 10 men with rising PSA levels after radical prostatectomy and salvage radiotherapy with commercially available soy products. Scans revealed no gross metastatic disease. Three men also had been receiving androgen-deprivation therapy (ADT) and had rising PSA levels that were consistent with castration-resistant (CR) disease. We reported the results of this modality on PSA levels, PSA kinetics, and the duration of PSA response. RESULTS: Responses occurred in 4 of 7 (57%) patients with ADT-naïve disease and 1 of 3 (33%) patients with CR disease. The median duration of treatment response was 24 months. The overall clinical benefit, therefore, was noted in 5 of 10 (50%) patients. Therapy was well tolerated. CONCLUSIONS: Our findings are fairly congruent with what has been described in the literature on the use of this modality in prostate cancer. We used commercially available soy products. We also show that soy can provide benefit in CR prostate cancer. Our clinical experience suggests that soy supplementation using commercially available soy products can have durable beneficial effects on PSA levels and PSA kinetics in some men with prostate cancer.

Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients.

Efforts to improve efficacy and minimize toxicity have led to pharmacokinetic monitoring of plasma 5-Fluorouracil (5-FU) levels in colorectal cancer patients undergoing chemotherapy. We observed variation in basal 5-FU levels in 21 patients and significant variation during subsequent dose optimization. Tumor KRAS, BRAF mutations and TS mRNA levels were determined. Regimens included FOLFOX6 + Avastin (N = 8), FOLFOX6 (N = 11), FOLFIRI (N = 1) and FOLFOX4 (N = 1). Mutations identified in tumors included G12V KRAS (N = 2), G12A KRAS (N = 1), and V600E BRAF (N = 3). Six-of-eleven patients with normalized tumor TS mRNA levels < 4.0 had a 5-FU AUC of 20 mg.h/L or greater, and 80% of patients (4 of 5) with TS levels > 4.0 had a plasma 5-FU AUC of less than or equal to 20 mg.h/L. Approximately 2/3 of patients achieved therapeutic 5-FU AUC levels with 0-2 dose adjustments while a sub-group of ~1/3 of patients slowly achieved therapeutic levels (> 3-4 dose increases leading to supra-therapeutic 5-FU and subsequent reductions to lesser than original doses). Liver metastases and tumor TS levels did not fully account for variable 5-FU AUC optimization patterns. The 5-FU level during continuous infusion was half-therapeutic in one patient who received FOLFOX4. The observed heterogeneous patterns at baseline and during dose optimization of 5-FU levels suggest variations in 5-FU metabolism among treated patients. Physiological and/or genetic differences underlying heterogeneity in 5-FU levels during dose optimization require further study of patient demographics, single nucleotide polymorphisms in Dihydropyrimidine Dehydrogenase (DPD), TS, or other genes that impact 5-FU metabolism and gene expression changes in liver after 5-FU therapy.

Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice.

Tyrosine kinase is a key enzyme activity utilized in many intracellular messaging pathways. Understanding the role of particular tyrosine kinases in malignancies has allowed for the design of tyrosine kinase inhibitors (TKIs), which can target these enzymes and interfere with downstream signaling. TKIs have proven to be successful in the treatment of chronic myeloid leukemia, renal cell carcinoma and gastrointestinal stromal tumor, and other malignancies. Scattered reports have suggested that these agents appear to affect blood glucose (BG). We retrospectively studied the BG concentrations in diabetic (17) and nondiabetic (61) patients treated with dasatinib (8), imatinib (39), sorafenib (23), and sunitinib (30) in our clinical practice. Mean declines of BG were dasatinib (53 mg/dL), imatinib (9 mg/dL), sorafenib (12 mg/dL), and sunitinib (14 mg/dL). All these declines in BG were statistically significant. Of note, 47% (8/17) of the patients with diabetes were able to discontinue their medications, including insulin in some patients. Only one diabetic patient developed symptomatic hypoglycemia while on sunitinib. The mechanism for the hypoglycemic effect of these drugs is unclear, but of the four agents tested, c-kit and PDGFRß are the common target kinases. Clinicians should keep the potential hypoglycemic effects of these agents in mind; modification of hypoglycemic agents may be required in diabetic patients. These results also suggest that inhibition of a tyrosine kinase, be it c-kit, PDGFRß or some other undefined target, may improve diabetes mellitus BG control and it deserves further study as a potential novel therapeutic option.

Unsuccessful high dose IL-2 therapy followed immediately by near continuous low dose temozolomide can result in rapid durable complete and near-complete remissions in metastatic melanoma.

Metastatic melanoma remains a disease with a very poor prognosis. High dose Interleukin-2 (HD IL-2) and temozolomide (TMZ) are both approved treatments for this malignancy but response rates remain poor. HD IL-2 is the only approved therapy that has been shown to induce durable complete responses albeit in a very small percentage of patients. The combination of TMZ followed by HD IL-2 as biochemotherapy has been studied previously but did not improve responses over what had been observed for HD IL-2 alone. In our clinical practice, we noted surprising rapid and dramatic responses to TMZ when given as therapy at 75 mg/m2 for 21 days per one month cycles in 6/9 (67%) sequentially treated patients who had just completed a full course of HD IL-2 and either had failed to respond (11%) or frankly progressed (89%). The TMZ therapy began on average within 6 weeks of stopping the IL-2. All responding patients had complete or near complete responses (CR and nearCR) to TMZ. The responses became evident rapidly, typically within 1 or 2 cycles of TMZ. Three patients remain alive and completely disease free, two are off of all therapy to date. Two patients recurred after initial CR and nearCR. One patient died from an acute myocardial infarction while in a CR. One patient had prolonged stable disease and 2 patients progressed. These were much better responses than what is typically observed for single agent TMZ; indeed, durable CR to TMZ that persists off therapy is an unrecognized phenomenon to our knowledge. TMZ is an oral atypical alkylating agent that in addition to having cytotoxic activity against melanoma has also been shown to decrease the T regulatory population of lymphocytes (T-regs). We hypothesize that the TMZ may be synergistic with HD IL-2 in a sequence-specific fashion by allowing the immune activation induced by the HD IL-2 to proceed without negative feedback applied by the T-reg population of cells whose major function is to inhibit an exuberant immune response. This postulated mechanism would result in the sequence-specific activity noted in our patients. Of interest, 3/6 responding patients and 1/3 stable/ non-responding patients also exhibited persistent polyarthralgias that began on TMZ suggesting the induction of autoimmunity which may be related to anti-melanoma effects. The durable CRs that persist after the cessation of treatment suggest that this sequence-specific combination should be studied further, ideally in a prospective trial of repeated courses of HD IL-2 followed strategically by continuous TMZ.

Bevacizumab demonstrates prolonged disease stabilization in patients with heavily pretreated metastatic renal cell carcinoma: a case series and review of the literature.

There are now a variety of therapies approved for the treatment of metastatic renal cell carcinoma (RCC). These include the immunotherapeutics, alfa-interferon, and interleukin-2, and agents that target the vascular endothelial growth factor receptor (VEGFR) via its tyrosine kinase, such as sorafenib, sunitinib, and pazopanib, or the mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus. Bevacizumab, a monoclonal antibody directed against the ligand, VEGF, has shown activity against RCC as a single agent in patients who had failed prior cytokine therapy and as first line therapy in combination with interferon. The activity of bevacizumab in patients who had received and failed prior therapy has not been described. We report our experience in 4 patients with metastatic RCC who had failed prior cytokine, TKI, and mTOR inhibitors who were treated with bevacizumab as single agent therapy. These heavily pretreated patients sustained very prolonged periods of stable disease (median of 12 months) with very little toxicity and excellent quality of life. The activity of this agent in patients who had failed prior therapies directed against the VEGFR and mTOR suggests that therapy targeting the ligand, VEGF, is still a viable approach in these patients and deserves further study.