Rohit Bishnoi

Efficacy and safety of carfilzomib in relapsed and/or refractory multiple myeloma: systematic review and meta-analysis of 14 trials

Objective Carfilzomib (Carf) is a second-generation proteasome inhibitor approved for patients with relapsed and/or refractory multiple myeloma (RRMM) who failed ≥ 1 prior lines of therapy. We performed a systematic review of Carf literature with meta-analysis to determine the efficacy and safety in RRMM patients. Methods Based on literature search, we included a total of 14 eligible phase I/II, phase II and phase III Carf based clinical trials. The cumulative incidence and odds ratios (OR) were calculated with random effect model, using ‘’R’’ software with metaphor package. Results 2906 evaluable RRMM patients from published clinical trials included. The pooled overall response rate (ORR) was 45% (95% CI: 29–62). The pooled clinical benefit rate (CBR) was 56% (95% CI: 41–71). OR from 3 randomized clinical trials showed that Carf significantly improved ORR and CBR compared to control groups (OR 2.4, P < 0.0001; 2.02, P = 0.0007, respectively). Subgroup analysis showed significantly better ORR (P < 0.0001) and CBR (P < 0.001) with combination regimens compared to monotherapy. Response was significantly higher with high dose of Carf (>20/27 mg/m2) compared to standard dose (ORR 65% vs. 35%, P = 0.03). Compared to control group, the OR of developing cardiotoxicity (P = 0.002) and hypertension (P < 0.0001) were significantly higher with Carf, while no difference in peripheral neuropathy (P = 0.28). Conclusions Carf produces significantly better responses with acceptable safety profile in RRMM patients. Combination regimens and higher dose Carf offers better response with no significant extra toxicity. Its efficacy is regardless of cytogenetics or disease stage. Incidences of cardiotoxicity and hypertension seem higher with Carf.

Cardiotoxicity associated with carfilzomib: systematic review and meta-analysis

Abstract Carfilzomib is a second-generation proteasome inhibitor (PI) that is approved for patients with relapsed or refractory multiple myeloma (RRMM) who failed ≥1 prior lines of therapy. We performed a systematic review of carfilzomib literature with meta-analysis to determine cumulative incidence of cardiotoxicity. After the literature search, we included a total of 29 eligible phase I/II, phase II and phase III clinical trials which used carfilzomib. The cumulative incidence and overall odds ratios (OR) were calculated with random effect model, using ‘R’ software with metaphor package. A total of 4164 patients with various malignancies were included. The overall estimated cumulative incidence of cardiotoxicity was 8.68% and 4.92%, respectively, for all-grade and high-grade (≥ grade 3) toxicity, which seems higher than other PIs. Compared to control group, the odds of developing cardiotoxicity due to carfilzomib was significantly higher with OR of 2.03 (95% CI: 1.19–3.46, p = .010) and 2.04 (95% CI: 1.31–3.17, p = .002) for all-grades and high grades, respectively. Concomitant immunomodulatory agents seem to increase the risk of cardiotoxicity (high-grade cardiotoxicity 6.45% and 4.34% with and without concomitant immunomodulatory agents, respectively (p = .033)). There was no variation in the incidence of cardiotoxicity among newly diagnosed versus RRMM (p = .38), and high versus standard dose carfilzomib (p = .86).

Palliative treatment of patients with inoperable locally advanced, recurrent or metastatic head and neck squamous cell cancer, using a low-dose and personalized chemotherapeutic regimen

Inoperable or metastatic head and neck squamous cell cancer (HNSCC) is known to be associated with a poor patient prognosis. First line therapies include a Taxol, platinum-based antineoplastic and fluorouracil (FU) treatment regimen (TPF) or a platinum-based antineoplastic, FU and EGFR inhibitor treatment regimen (PFE). The toxicity of these regimens is one of the major limiting factors, particularly for palliative treatment. The present study is a retrospective study of 15 patients with HNSCC, where the treatment goal was palliative. Of the 15 patients, 8 received a TPF, while 7 received a PFE. A total of 129 treatment cycles were administered with a median of 9 cycles (range, 3–14). Chemotherapy began with low doses and was subsequently titrated up based on tolerance and response. Positive responses were noted with the lower doses compared with the conventional doses, and maximal doses were not required. The median dose of cisplatin, paclitaxel and 5-FU administered was 40 mg/m2, 80 mg/m2 and 360 mg/m2/day for 5 days, respectively. Cetuximab was used at a standard dose. At the initial follow-up (mean, 64 days; 3 cycles), a 100% disease control rate (DCR) and 80% overall response rate (ORR) was achieved. A positive response, 60% DCR and 60% ORR, was maintained until the late stages of the study (mean, 217 days; 9 cycles). Following termination of chemotherapy after >9 cycles, 4 patients remained disease free for ~1 year. A total of 3 patients exhibited a pathologic complete response despite radiologically exhibiting residual disease. The median progression-free survival time was 10.03 months and the overall survival time was 15.77 months. The only grade 3 hematologic toxicity noted was neutropenia in 3 (20%) patients. Grade 3 vomiting was noted in 1 (6.67%) patient and grade 3 stomatitis was noted in 1 (6.67%) patient. Due to low toxicity patients exhibited improved tolerance to this approach, particularly in terms of palliative care. Furthermore, these results are in contrast to the axiom that increased doses are more effective.

Stereotactic body radiation therapy for the treatment of oligoprogression on androgen receptor targeted therapy in castration-resistant prostate cancer

Abstract Castration-resistant prostate cancer is an incurable disease. To date, six agents-abiraterone, enzalutamide, docetaxel, cabazitaxel, radium-223 and sipuleucel-T- have shown clinical efficacy in phase III clinical trials, leading to their FDA approval. Patients are typically sequenced through most or all of these agents, and then eventually succumb to their disease. Development of new treatments remains an unmet need. We report a case of a patient who progressed on enzalutamide with a single enlarging metastatic lesion, was treated with ablative stereotactic body radiation therapy while maintaining the same systemic treatment, who then had durable complete remission. Our findings have important clinical implications and suggest novel clinical trials for this difficult to treat disease.

Survival differences among patients with hepatocellular carcinoma based on the stage of disease and therapy received: pre and post sorafenib era

Background The incidence of hepatocellular carcinoma (HCC) is increasing. Development of newer therapeutic modalities has changed the paradigm of HCC treatment in recent years. So, the aim of our study is to analyze the impact of these treatment modalities into the survival of HCC patients, based on the stage of HCC in real life practice. Methods We analyzed the data from the SEER database: Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2015 Sub (1973-2013 varying). Relative survival rates (RSRs) and hazard ratios (HRs) were measured for patients diagnosed with HCC between 2001 and 2013. Rates were compared between pre sorafenib [2001-2007] and post sorafenib [2008-2013] eras. Results A total of 50,088 patients (21,435 in pre sorafenib era and 28,653 in the post-sorafenib era) were included with HCC from SEER database. The median relative survival for the entire population was 14 months with 5-year RSR of 21.20%; 11 months for those diagnosed in 2001-2007 with 5-year RSR 19.30% and 17 months for those diagnosed in 2008-2013 with 5-year RSR 22.40% (P<0.01). This survival improvement was largely limited to HCC patients with single nodule (5-year RSR; 35.1% vs. 37.00% for pre and post sorafenib era respectively; P value <0.01) and multiple nodules without vascular invasion (5-year RSR; 19.90% vs. 22.60% for pre and post sorafenib era respectively; P value <0.01). RSR remained extremely poor with no significant improvement for advanced stage HCC who had vascular invasion (P=0.37) or distant metastasis (P=0.10), respectively for pre and post sorafenib era in each category. Survival improved since 2008, for HCC patients who received either no surgical intervention (P<0.01) or received tumor-directed therapy (P<0.01), however, it remained significantly poor compared to the patients who received lobectomy or hepatectomy and transplant. Approximately 70% of patients from our study population did not receive any HCC directed surgical intervention and among this, more than 40% of patients were with single nodule in the liver. Conclusions Survival in patients with HCC has improved since 2008, which is limited to early stage HCC. Survival of advanced stage HCC patients is extremely poor and has not shown any significant improvement since the approval of sorafenib, emphasizing the need for better therapeutic options. Not receiving any surgical intervention is associated with significantly poor prognosis. Large numbers of early stage HCC patients were not able to receive surgical interventions. This can impose a significant financial burden, as these patients would progress on to the advanced stage, where treatment options are very limited and not as cost-effective. This emphasizes the need for further research to identify various barriers and the possible need for healthcare policy changes.

PTLD: Survival and analysis of prognostic factors in a cohort of 138 patients from a single institution

regression analyses were performed to identify predictors of OS for each subtype and B‐cell subgroup. Results: OS was significantly different among polymorphic (median 18 months), Hodgkin‐type (15 months), monomorphic B‐cell (14 months) and monomorphic T‐cell neoplasms (7 months, p < 0.001, Figure 1a). Significant differences in OS among B‐subgroups were not detected, but there was a trend towards decreased survival in Burkitt‐type PTLD (Figure 1b). Kidney transplant and treatment with reduction of immunosuppression were associated with increased OS in multivariable analysis in B‐cell neoplasms. Younger age and immunosuppression with azacitidine were associated with decreased OS in T‐cell neoplasms. Conclusions: Histologic subtype represents an important factor in PTLD prognosis, with T‐cell monomorphic subtype exhibiting a particularly poor OS. The possibility of lower survival in certain subsets of B‐cell PTLD should be explored in future studies and suggests the need for subtype‐specific treatment strategies to improve outcomes.