Kishan J. Pandya

Multicenter, randomized, phase 2 study of zoledronic acid in combination with docetaxel and carboplatin in patients with unresectable stage IIIB or stage IV non-small cell lung cancer

This study was designed to evaluate the efficacy and safety of combined zoledronic acid and docetaxel/carboplatin in patients with non-small cell lung cancer (NSCLC) as preclinical studies showed synergistic antitumoral activity with bisphosphonates and docetaxel. Patients with inoperable stage IIIB or stage IV NSCLC were randomized 2:1 to receive docetaxel 75mg/m(2) and carboplatin area under the concentration time curve 6 with (Arm A) or without (Arm B) zoledronic acid 4mg every 3 weeks for 6 cycles. Patients responding in Arm A were rerandomized to receive monthly zoledronic acid (maximum: 12 months [Arm A1] or no zoledronic acid [Arm A2]). Patients responding in Arm B entered Arm B1 for follow-up evaluation only. The primary endpoint was the proportion of patients without disease progression; secondary endpoints were time to disease progression (TTP), TTP in bone, best overall response rate, 1-year overall survival (OS) time, and safety; study not powered to detect endpoint differences. Of 150 patients, 98 were randomized to Arm A and 52 to Arm B. In the treatment phase, results were similar between groups in the proportion of patients without disease progression (40.9% vs 38.8%; P=.8096) and median TTP (132d vs 132d; P=.9622). One-year OS times and best overall response rates were 266d vs 206d (P=.4855) and 64.1% vs 72% (P=.3423), respectively; the study was not powered to detect differences. In the follow-up phase, TTP and OS time were similar. Adding zoledronic acid to docetaxel/carboplatin in advanced stage NSCLC patients was well tolerated, but provided little to no effect on disease progression endpoints.

A Pilot Study (SWOG S0429) of Weekly Cetuximab and Chest Radiotherapy for Poor-Risk Stage III Non-Small Cell Lung Cancer.

Purpose: Stage III non-small cell lung cancer (NSCLC) patients with poor performance status (PS) or co-morbidities are often not candidates for standard chemoradiotherapy (chemoRT) due to poor tolerance to treatments. A pilot study for poor-risk stage III NSCLC patients was conducted combining cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR), with chest radiation (RT). Methods: Stage III NSCLC patients with Zubrod PS 2, or Zubrod PS 0–1 with poor pulmonary function and co-morbidities prohibiting chemoRT were eligible. A loading dose of cetuximab (400u2009mg/m2) was delivered week 1, followed by weekly cetuximab (250u2009mg/m2)/RT to 64.8u2009Gy in 1.8u2009Gy daily fractions, and maintenance weekly cetuximab (250u2009mg/m2) for 2u2009years or until disease progression. H-score for EGFR protein expression was conducted in available tumors. Results: Twenty-four patients were enrolled. Twenty-two were assessed for outcome and toxicity. Median survival was 14u2009months and median progression-free survival was 8u2009months. The response rate was 47% and disease control rate was 74%. Toxicity assessment revealed 22.7% overall ≥Grade 3 non-hematologic toxicities. Grade 3 esophagitis was observed in one patient (5%). The skin reactions were mostly Grade 1 or 2 except two of 22 (9%) had Grade 3 acne and one of 22 (5%) had Grade 3 radiation skin burn. Grade 3–4 hypomagnesemia was seen in four (18%) patients. One patient (5%) had elevated cardiac troponin and pulmonary emboli. H-score did not reveal prognostic significance. An initially planned second cohort of the study did not commence due to slow accrual, which would have added weekly docetaxel to cetuximab/RT after completion of the first cohort of patients. Conclusion: Concurrent weekly cetuximab/chest RT followed by maintenance cetuximab for poor-risk stage III NSCLC was well tolerated. Further studies with larger sample sizes will be useful to establish the optimal therapeutic ratio of this regimen.

Tumor Response Kinetics after Schedule-Dependent Paclitaxel Chemoradiation Treatment for Inoperable Non-small Cell Lung Cancer: A Model for Low-Dose Chemotherapy Radiosensitization

Purpose: Poor local disease control remains a major obstacle for inoperable non-small cell lung cancer (NSCLC) after radiotherapy. We previously reported results of a phase I/II clinical study based on preclinical investigations of paclitaxel radiation interactions for inoperable locally advanced NSCLC, which yielded remarkable local tumor responses and durable in-field tumor control using schedule-dependent low-dose paclitaxel for radiosensitization. Given our unique results, we analyzed the tumor response kinetics and conducted a statistical modeling of tumor response to characterize this regimen. Methods and Materials: A total of 104 chest CT scans from 27 patients treated in the clinical trial were evaluated. Tumor volumes were calculated by three-dimensional measurements of pretreatment and serial post-therapy CT scans. A nonlinear mixed effects model was used to model response kinetics. Results: The average tumor volume reduction at 1 month post-therapy was 69.9 ± 22.6% (standard deviation), and was 80.6 ± 17.9% at the last follow-up. The nonlinear mixed effects model predicts that tumor volume will ultimately shrink by at least 75% for more than 75% of patients treated by this regimen. The model also suggests that maximum shrinkage is reached within 2 months after treatment. Conclusion: Tumor volume response kinetics revealed a rapid shrinkage of gross tumors using schedule-dependent pulsed low-dose paclitaxel radiosensitization. This is contrary to the protracted tumor regression process observed in radiation alone or other chemoradiation combinations. Statistical modeling may prove useful in characterizing and comparing different therapeutic regimens.

PRECLINICAL AND PILOT CLINICAL STUDIES OF DOCETAXEL CHEMORADIATION FOR STAGE III NON-SMALL-CELL LUNG CANCER

PURPOSEnLocal and distant failure rates remain high despite aggressive chemoradiation (CRT) treatment for Stage III non-small-cell lung cancer. We conducted preclinical studies of docetaxels cytotoxic and radiosensitizing effects on lung cancer cell lines and designed a pilot study to target distant micrometastasis upfront with one-cycle induction chemotherapy, followed by low-dose radiosensitizing docetaxel CRT.nnnMETHODS AND MATERIALSnA preclinical study was conducted in human lung cancer cell lines NCI 520 and A549. Cells were treated with two concentrations of docetaxel for 3 h and then irradiated immediately or after a 24-h delay. A clonogenic survival assay was conducted and analyzed for cytotoxic effects vs. radiosensitizing effects of docetaxel. A pilot clinical study was designed based on preclinical study findings. Twenty-two patients were enrolled with a median follow-up of 4 years. Induction chemotherapy consisted of 75 mg/m(2) of docetaxel and 75 mg/m(2) of cisplatin on Day 1 and 150 mg/m(2) of recombinant human granulocyte colony-stimulating factor on Days 2 through 10. Concurrent CRT was started 3 to 6 weeks later with twice-weekly docetaxel at 10 to 12 mg/m(2) and daily delayed radiation in 1.8-Gy fractions to 64.5 Gy for gross disease.nnnRESULTSnThe preclinical study showed potent cytotoxic effects of docetaxel and subadditive radiosensitizing effects. Delaying radiation resulted in more cancer cell death. The pilot clinical study resulted in a median survival of 32.6 months for the entire cohort, with 3- and 5-year survival rates of 50% and 19%, respectively, and a distant metastasis-free survival rate of 61% for both 3 and 5 years. A pattern-of-failure analysis showed 75% chest failures and 36% all-distant failures. Therapy was well tolerated with Grade 3 esophagitis observed in 23% of patients.nnnCONCLUSIONSnOne-cycle full-dose docetaxel/cisplatin induction chemotherapy with recombinant human granulocyte colony-stimulating factor followed by pulsed low-dose docetaxel CRT is promising with regard to its antitumor activity, low rates of distant failure, and low toxicity, suggesting that this regimen deserves further investigation.

Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer: Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590)

13‐Cis retinoic acid (13‐CRA) is a synthetic vitamin A derivative. High‐dose 13‐CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long‐term results from a phase 3 randomized trial that compared treatment with low‐dose 13‐CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS).

Phase 3 Randomized Low-Dose Paclitaxel Chemoradiotherapy Study for Locally Advanced Non-Small Cell Lung Cancer

Introduction Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC) but is associated with poor chest tumor control. Here, we report results of a randomized phase 3 study comparing two CCRT regimens in improving chest tumor control by low-dose paclitaxel chemoradiation for LA-NSCLC. Methods Due to the logistics of local referral pattern, the study was designed to enroll patients with stage III LA-NSCLC who had completed 2–4 cycles of full-dose chemotherapy. One hundred thirty four were randomized to either Arm 1 [paclitaxel at 15u2009mg/m2, three times per week (Monday, Wednesday, and Friday) for 6u2009weeks, nu2009=u200974] or Arm 2 (weekly paclitaxel at 45u2009mg/m2 for 6u2009weeks, nu2009=u200960). Chest radiotherapy was 60–70u2009Gy in standard fractionation. Response rate was the primary endpoint, with recurrence-free survival (RFS) as the secondary endpoint. Results From March 2006 to February 2013, 71 patients completed Arm 1 treatment and 59 completed Arm 2 treatment. The response rate for Arm 1 was significantly higher (83.1%) than Arm 2 (54.2%) (p=0.001). RFS was superior in Arm 1: median 14.6 vs. 9.4u2009months, pu2009=u20090.005, Hazard ratio (HR) 1.87 [95% confidence interval (CI) 1.20, 2.90]. Overall survival was not significantly different: median 32.6u2009months in Arm 1 vs. 31.3u2009months in Arm 2, pu2009=u20090.91, HR 0.97 (95% CI 0.55, 1.70). Toxicity was significantly lower in Arm 1 for Grade 3 and 4 leukopenia/neutropenia (pu2009<u20090.001). Conclusion Pulsed low-dose paclitaxel CCRT resulted in significantly better RFS and tumor response rate, and less hematologic toxicities than weekly CCRT for LA-NSCLC.

Biotoxicity of Chemotherapy

With successful treatment of many malignancies, long-term toxicities began to emerge and are becoming increasingly important in the growing number of cancer survivors. Research has begun to investigate management options to mitigate these chemotherapy-related toxicities without compromising the therapeutic outcomes. This chapter will discuss these late adverse effects based on organ system, including cardiotoxicity, pulmonary toxicity, nephrotoxicity, peripheral neuropathy, ototoxicity, reproductive toxicity, cognitive impairment, and risks of second malignant neoplasms. We will review the underlying pathophysiology of each of these long-term complications and will provide the most up-to-date evidence-based prevention, follow-up and monitoring guidelines. In the latter part of the chapter, we will review the current literatures regarding the molecular basis of germline genetic susceptibility to some of the late effects of chemotherapy, including peripheral neuropathy, ototoxicity and therapy-induced myeloid leukemia. This rapidly emerging field within cancer survivorship does not only provide invaluable insights and inform the development of therapeutic agents to target the underlying molecular pathway of these adverse effects, but it may also allow development of a risk-classification system that incorporates genetic markers to predict risks of chemotherapy-related side effects. The final part of this chapter will attempt to look at future research directions in the development of genetic markers as well as therapeutic agents to prevent or treat late-effects of chemotherapy.

Five Tumors over Six Years in Eighth Decade of Life

Over a period of six years in the eighth decade of his life, a gentleman in our care (referred to as GH) developed five primary malignancies without any known etiological connection. There is little epidemiologic data for patients presenting with more than three primary malignancies. In reviewing some of the latest literature about the characteristics and risk factors of developing the malignancies that GH presented with, we find that aspects of GHs medical history often disagree with this information. We also calculated the probability of the occurrence of GHs specific tumors and find his case is indeed rare. We conclude at this point in time that unknown host or environmental factors may have played a role in this unusual presentation of malignancies. With great interest we continue to follow-up with GH to monitor his health.