James K. Schwarz

Pleural mesothelioma with cutaneous extension to chest wall scars

Background:  Cutaneous mesothelioma is rare but may occur following local surgical procedures for visceral mesothelioma or as a metastasis.

Phase I and pharmacokinetic study of weekly docetaxel, cisplatin, and daily capecitabine in patients with advanced solid tumors.

Purpose: Docetaxel, cisplatin, and capecitabine are three active chemotherapeutic agents with different mechanisms of action. This phase I study investigated the feasibility and pharmacokinetics of this combination given on a weekly schedule. Experimental Design: Docetaxel and cisplatin were given i.v. over 30 minutes on days 1 and 8 and capecitabine was given orally bid on days 1 to 14 (every 21 days). Escalation occurred in cohorts of three patients until the maximum tolerated dose was defined. Pharmacokinetics studies of docetaxel and total and ultrafiltrate platinum after cisplatin administration were done on cycle 1 (with capecitabine) and cycle 2 (without capecitabine). Results: Twenty-five patients were enrolled. Two of six patients at dose level 5 had a dose-limiting infection and diarrhea. One of six evaluable patients at dose level 4 (27 mg/m2 docetaxel, 27 mg/m2 cisplatin, 825 mg/m2 capecitabine) had a dose-limiting hypomagnesemia. Pharmacokinetics of docetaxel were similar on cycles 1 and 2. Area under the plasma concentrations versus time curves of total platinum was significantly greater in cycle 2 compared with cycle 1 (P = 0.001). There was no difference in the disposition of docetaxel on cycles 1 and 2. Conclusions: The recommended docetaxel, cisplatin, and capecitabine dose for phase II studies is 27/27/825 mg/m2. The alteration in total and ultrafiltrate platinum disposition on cycle 2 compared with cycle 1 may be inherent to sequential cisplatin administration; however, prior treatment with capecitabine cannot be ruled out as a factor.

Safety and efficacy of preoperative sorafenib therapy in facilitating cytoreductive surgery in renal cell carcinoma

With 65,000 new cases in the USA in 2013, the incidence of kidney cancer has doubled in last decade and accounted for 13,600 deaths in 2013 [1,2]. Renal cell carcinoma (RCC), which consists of 80% of kidney cancers in adults [3], presents with advanced or metastatic stage in approximately a third of patients. A third of earlystage RCC will subsequently recur or progress to metastatic disease after initial nephrectomy [4]. Historically, once surgical options were exhausted, metastatic RCC was regarded as refractory to any systemic therapy. The identification of the role of VEGF and mTOR in the development and progression of RCC has led to the discovery of several targeted therapies. Many of these agents, including tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib and axitinib), VEGF inhibitor (bevacizumab used in combination with IFN-α) and mTOR inhibitors (temsirolimus and everolimus) have now received US FDA approval. Despite all these advancements, metastatic RCC still remains an incurable disease with a median overall survival rate in the range of approximately 2 years [4]. In this article, we discuss the role of cytoreductive surgery in the era of targeted agents, and the role of preoperative use of sorafenib.

Organ preservation in patients with squamous cancers of the head and neck

Treatment strategies that have the potential to improve functional organ preservation in patients who have head and neck cancer are emerging. Clinical research in this field, however, has been limited by the lack of standardized, objective criteria of organ function post treatment and by lack of prospective assessment of organ function in treatment trials [56]. Advances in surgical techniques, radiation techniques, radiation protectants, and combined-modality therapies are promising, but well-planned and executed clinical trials are necessary to determine how best to apply these techniques to patient care.

Scheduled administration of low dose irinotecan before gemcitabine in the second line therapy of non-small cell lung cancer: a phase II study.

We had previously demonstrated that low dose irinotecan (CPT-11) leads to increased accumulation of cells in S-phase and shows a therapeutic synergy with S-phase specific chemotherapy such as gemcitabine and 5-fluorouracil. In this phase II study, our objectives were to evaluate the tolerability and activity of low dose CPT-11 followed 24 h later by gemcitabine as second line therapy in patients with metastatic non-small cell lung cancer (NSCLC). CPT-11 (60 mg/m2) was administered 24 h before gemcitabine (1000 mg/m2) on days 1, 2, 8, and 9 every 3 weeks. Twenty-nine patients were evaluable for response. The median follow-up was 7.4 months. Partial response (PR) was seen in two (6.9, 95% confidence interval (CI): 0.009–0.228). PR and stable disease were seen in 22 patients (75.9, 95% CI: 0.564–0.897). The median survival time was 13.8 months (95% CI: 8.1–19.3). The median time to progression was 4.6 months (95% CI: 2.6–6.2). Thirty-eight patients were evaluable for toxicity. Neutropenia (grade 3 or 4) was observed in 27 patients (71%). Eight patients did not receive cycle 2 of therapy owing to prolonged neutropenia. No treatment-related deaths occurred. Scheduled administration of low dose CPT-11, 24 h before gemcitabine in the second line therapy of NSCLC yielded comparable disease control rates (PR and stable disease) when compared with other studies using the two chemotherapy drugs in the traditional sequence. However, this approach was associated with higher grade 3/4 neutropenia and is not recommended for further study in metastatic NSCLC.

Phase I trial of metronomic cyclophosphamide (CTX) and lenalidomide (LEN) in patients with castration-resistant prostate cancer (CRPC).

164 Background: Angiogenesis and suboptimal antitumor immune response are important in the progression of CRPC. Both LEN and metronomic CTX have known anti-angiogenic and immunomodulatory activities. A phase I study of a novel combination of metronomic CTX with LEN in patients with CRPC who have failed prior docetaxel therapy was initiated to assess safety and effects on potential biomarkers. METHODS CTX was given 50 mg PO QD(day 1-28) and LEN 10-25 mg PO QD(day 1-21) on a 28 day cycle. Dose limiting toxicity was defined as any treatment-related grade 4 hematologic event or grade 3 / 4 non-hematologic event during cycles one. Quantification of circulating tumor cells (CTC), plasma cytokines, analgesic consumption and quality of life assessments were performed. Measurement of Treg and MDSCs were performed in some patients. RESULTS 17 patients with CRPC have been enrolled in L0-4; all patients are evaluable for toxicity. Patient characteristics include: ECOG performance status 0/1= 4/13; median age=77 (range 50-86); median PSA=36.7 (range 1.36-2287). Dose level 1 (CTX 50 mg/d, LEN 10 mg/d) was expanded to 6 patients after one out of three initial patients was removed from the study for Gr 3 gastrointestinal bleeding (in cycle 1). Dose level 1 (CTX 25 mg/d, LEN 10 mg/d) had no DLTs. The maximum tolerated dose has not yet been reached. Other Grade 3/4 toxicities observed after cycle 1 included grade 3 pain (N=1), grade 3 neutropenia (N=4), grade 3 thrombocytopenia (N=2), grade 4 neutropenia (N=2). Most frequent grade 1 and 2 toxicities included anemia, fatigue, neutropenia, and hypocalcemia. Overall, 9 of 14 patients (64%) have experienced a reduction in PSA. One patient had partial response after one cycle. Stable disease was documented in 5 of 14 (36%) evaluable patients. Two inflammatory cytokines, IL-6 (N = 19; r = 0.64; p = 0.0035) and IL-8 (N = 9; r = 0.86; p = 0.0028), were found to significantly correlated with PSA. CONCLUSIONS The combination of metronomic CTX and LEN can be safely administered. Preliminary clinical activity was observed in this heavily-pretreated patient population. Enrollment to this study continues and clinical and biomarker studies are ongoing.

A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors.

Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5‐fluorouracil (5‐FU).