Managing oncology clinical trials during COVID-19 pandemic.

São Paulo city is the epicenter of the Brazilian COVID-19 pandemic. The Instituto do Cancer do Estado de São Paulo is currently conducting 161 multinational sponsored trials plus 116 in house studies in the oncologic population. There are 242 currently active participants and 180 patients in follow-up. The management of the tightly controlled environment of clinical research becomes a challenge, and the Food and Drug Administration set of priority recommendations for patient safety while maintaining study integrity. Fast adaptations are necessary, and actions coalesce to participant protection from COVID-19. We pointed out critical processes for adjustments, and we believe that our experience may help other academic health centers.

Prophylactic Cranial Irradiation for Extensive-Stage Small-Cell Lung Cancer: A Retrospective Analysis.

PURPOSE: Extensive-stage small-cell lung cancer (esSCLC) is an incurable disease and represents a therapeutic challenge because of its poor prognosis. Studies in prophylactic cranial irradiation (PCI) in esSCLC have shown a decreased incidence of symptomatic brain metastases in patients who respond to systemic chemotherapy. However, its effect on overall survival is debatable. We evaluated the benefit of PCI in patients with esSCLC in terms of overall survival, progression-free survival, incidence of brain metastases, recurrence rate, and exposure to postrecurrence therapies. MATERIALS AND METHODS: We retrospectively reviewed electronic charts from patients diagnosed with esSCLC from 2008 to 2014 at our institution. All patients had negative baseline brain imaging before chemotherapy and PCI and received at least 4 cycles of platinum-based chemotherapy in the first-line setting without progressive disease on follow-up. PCI was performed at the discretion of the treating physician. Analyses were based on descriptive statistics. Survival curves were calculated by Kaplan-Meier method. RESULTS: Among 46 eligible patients, 16 (35%) received PCI and 30 (65%) did not. Compared with no PCI, PCI led to improved progression-free survival (median, 10.32 v 7.66 months; hazard ratio, 0.4521; 95% CI, 0.2481 to 0.8237; P < .001) and overall survival (median, 20.94 v 11.05 months; hazard ratio, 0.2655; 95% CI, 0.1420 to 0.4964; P < .001) as well as lower incidence of brain metastases (19% v 53%; P = .0273) and higher exposure to second-line chemotherapy (87% v 57%; P = .0479). CONCLUSION: Careful patient selection for PCI can improve not only brain metastases control and higher second-line chemotherapy exposure but also patient survival.

A Patient-Derived, Pan-Cancer EMT Signature Identifies Global Molecular Alterations and Immune Target Enrichment Following Epithelial-to-Mesenchymal Transition.

PURPOSE: We previously demonstrated the association between epithelial-to-mesenchymal transition (EMT) and drug response in lung cancer using an EMT signature derived in cancer cell lines. Given the contribution of tumor microenvironments to EMT, we extended our investigation of EMT to patient tumors from 11 cancer types to develop a pan-cancer EMT signature. EXPERIMENTAL DESIGN: Using the pan-cancer EMT signature, we conducted an integrated, global analysis of genomic and proteomic profiles associated with EMT across 1,934 tumors including breast, lung, colon, ovarian, and bladder cancers. Differences in outcome and in vitro drug response corresponding to expression of the pan-cancer EMT signature were also investigated. RESULTS: Compared with the lung cancer EMT signature, the patient-derived, pan-cancer EMT signature encompasses a set of core EMT genes that correlate even more strongly with known EMT markers across diverse tumor types and identifies differences in drug sensitivity and global molecular alterations at the DNA, RNA, and protein levels. Among those changes associated with EMT, pathway analysis revealed a strong correlation between EMT and immune activation. Further supervised analysis demonstrated high expression of immune checkpoints and other druggable immune targets, such as PD1, PD-L1, CTLA4, OX40L, and PD-L2, in tumors with the most mesenchymal EMT scores. Elevated PD-L1 protein expression in mesenchymal tumors was confirmed by IHC in an independent lung cancer cohort. CONCLUSIONS: This new signature provides a novel, patient-based, histology-independent tool for the investigation of EMT and offers insights into potential novel therapeutic targets for mesenchymal tumors, independent of cancer type, including immune checkpoints.

Activity and safety of sunitinib in poor risk metastatic renal cell carcinoma patients

Purpose To assess the activity, safety and treatment patterns of sunitinib in patients with poor-risk metastatic renal cell carcinoma (mRCC). Materials and Methods We retrospectively reviewed the charts of poor risk patients treated with sunitinib from October 2006 to July 2013 who met the eligibility criteria. The primary endpoint was overall survival (OS). Tumor radiological response was measured according to RECIST 1.1 and adverse events (AEs) were assessed through standard criteria. Results Median OS was 8.16 months (95% CI, 5.73-10.59). Of the 53 patients included in this analysis, 9 (17.0%) achieved partial response, 12 (22.6%) had stable disease. Median treatment duration was 3.30 months (95% CI: 1.96-4.63) and 26.4% of patients discontinued treatment due to toxicity. Grade 3 or higher AEs occurred in 39.6% of patients, the most common being fatigue (15.1%), neutropenia (9.5%), nausea, vomiting and diarrhea (7.5% each). Discussion Sunitinib may benefit some unselected poor-risk patients, although the rates of AEs and drug discontinuation suggest a need for careful patient monitoring. .

Is there still a role for induction chemotherapy in locally advanced head and neck cancer?

PURPOSE OF REVIEW: Despite decades of research, the role of induction chemotherapy (ICT) in the treatment of locally advanced head and neck squamous cell carcinoma remains controversial. When nonsurgical approaches are preferred, chemoradiation (CRT) is the standard of care. However, ICT continues to be investigated, as it can cytoreduce tumors, improve radiotherapy feasibility and tolerability, select patients for organ preservation with radiation, and decrease the risk of distant metastasis. RECENT FINDINGS: Herein, we review the recent randomized trials that investigated the role of taxanes in ICT, compared with surgery or CRT alone. A metaanalysis of older trials comparing taxane-containing ICT to cisplatin and 5-fluorouracil is discussed. In addition, long-term results from Radiation Therapy Oncology Group 91-11, a three-arm trial of larynx preservation approaches, are discussed, as well as a recent trial of sequential CRT for larynx preservation. As in previous randomized trials, no survival benefit for ICT was demonstrated. However, two studies showed a reduced risk of distant metastasis in advanced nodal stage patients. As regards larynx preservation, ICT followed by radiation alone in responders to chemotherapy remains an effective option. SUMMARY: ICT is still controversial and in general, should remain investigational. An exception may be its use in a larynx preservation approach, albeit with a lower crude larynx preservation rate compared with CRT. The results of recent trials provide rationale and support hypothesis generation for future research, which should focus on subsets of patients most likely to benefit, for example, high nodal stage. It will be critical to study human papillomavirus (HPV)-associated oropharynx cancer separately or, at least, stratify by HPV status given its influence on prognosis and attendant implications for statistical design.

Targeting the epidermal growth factor receptor for head and neck cancer chemoprevention.

The epidermal growth factor receptor (EGFR) has been implicated in head and neck squamous cell carcinoma (HNSCC) carcinogenesis. It is currently the only molecular target in head and neck cancers for which there are pharmacologic therapeutic interventions approved by regulatory agencies worldwide to treat advanced disease. Oral pre-malignant lesions have increased EGFR protein expression and increased egfr gene copy number compared to normal mucosa. Oral pre-malignant lesions with overexpression of EGFR or egfr gene copy number gain are at higher risk for malignant transformation. Inhibition of EGFR in pre-clinical models of oral pre-malignancies validates this approach as an effective way to reduce the incidence of oral cancer, and supports investigation of this strategy in the clinic. Clinical trials with EGFR targeted agents, including cetuximab, erlotinib, and vandetanib, are currently under way, some with promising preliminary results. If ultimately shown to reduce the risk of oral cancer, chemoprevention with EGFR inhibitors may significantly reduce morbidity and possibly mortality from HNSCC.

Multiagent chemotherapy for metastatic adenocarcinoma of the seminal vesicle.

Adenocarcinoma of the seminal vesicle is a rare condition, with fewer than 60 cases described in the literature. Most reports highlight the histopathological characteristics of the tumor; however, the role of chemotherapy, especially in the metastatic setting, is poorly described. In this paper, we describe a patient with metastatic disease, who sustained a response to modified FOLFOX6 as first-line therapy. This platinum-based combination therapy seems effective in this scenario and may provide an opportunity for extended survival and relief of symptoms.

Activity and safety of sunitinib in poor risk metastatic renal cell carcinoma patients.

PURPOSE: To assess the activity, safety and treatment patterns of sunitinib in patients with poor-risk metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: We retrospectively reviewed the charts of poor risk patients treated with sunitinib from October 2006 to July 2013 who met the eligibility criteria. The primary endpoint was overall survival (OS). Tumor radiological response was measured according to RECIST 1.1 and adverse events (AEs) were assessed through standard criteria. RESULTS: Median OS was 8.16 months (95% CI, 5.73-10.59). Of the 53 patients included in this analysis, 9 (17.0%) achieved partial response, 12 (22.6%) had stable disease. Median treatment duration was 3.30 months (95% CI: 1.96-4.63) and 26.4% of patients discontinued treatment due to toxicity. Grade 3 or higher AEs occurred in 39.6% of patients, the most common being fatigue (15.1%), neutropenia (9.5%), nausea, vomiting and diarrhea (7.5% each). DISCUSSION: Sunitinib may benefit some unselected poor-risk patients, although the rates of AEs and drug discontinuation suggest a need for careful patient monitoring.

Modified FLOX as first-line chemotherapy for metastatic colorectal cancer patients in the public health system in Brazil: Effectiveness and cost-utility analysis.

Incorporation of new drugs for treatment of metastatic colorectal cancer (mCRC) has led to a clear improvement in overall patient survival, the added cost of treatment, however, is a major concern worldwide. The cost-effectiveness of using a modified FLOX (mFLOX) regimen for treating mCRC patients was delineated. In this study, 82 consecutive mCRC patients were treated with leucovorin (LV) at 20 mg/m2 in combination with weekly bolus of 5-fluorouracil (5-FU) (500 mg/m2) for 6 consecutive weeks and oxaliplatin (85 mg/m2) at weeks 1, 3 and 5, every 8 weeks. Overall survival (OS) and toxicity were evaluated. A Markov Model with a 2-year time horizon and 2-week cycles was developed, comparing mFLOX and mFOLFOX6 in a Brazilian environment. Health outcomes were measured in quality-ajusted life years (QALYs). The median overall period of survival was 19 months, while the estimated 1-year survival was 75%. Response by RECIST was assessed in 33 patients. Partial response was observed in 39.4% of patients, while 36.3% were stable. The mFLOX regimen cost was BRL 9,000, while the mFOLFOX6 BRL 22,000 (1 EUR=2.29 BRL), leading to an incremental costed of BRL 13,000, considering a 20-week period of first-line therapy. The incremental effect of the mFOLFOX was of 0,117 QALY. The incremental cost-effectiveness ratio of mFOLFOX6 was of BRL 110,344/QALY. The sensitivity analysis detected no differences in the outcome measures. In conclusion, the mFLOX is an active regimen in mCRC patients, possibly providing a cost-effective option in public health systems.

A multicenter, multinational analysis of mitomycin C in refractory metastatic colorectal cancer.

BACKGROUND: A considerable number of metastatic colorectal cancer (mCRC) patients who progress on standard treatment with 5-fluorouracil (5FU), oxaliplatin, irinotecan and monoclonal antibodies, still have adequate performance status and desire further treatment. Mitomycin C (MMC) has been widely used in this context, and despite good tolerability, there are doubts regarding its true benefit. METHODS: In order to assess the activity of MMC in the refractory mCRC setting, we retrospectively evaluated 109 heavily pre-treated patients who received MMC as single agent or in combination for mCRC at three different institutions in two countries. RESULTS: Median patient's age was 54 years old, 57% were male and 94% had performance status ECOG 0 or 1. MMC was used in second line in 11%, third line in 38% and fourth line or beyond in 51% of patients. 58% received MMC combinations, mainly with capecitabine. Grade 3 or 4 toxicity was observed in 5% of patients and 6% required dose reductions. Median time to treatment failure (TTF) was 1.7 months with MMC and 3.6 months on the regimen prior to MMC, with a ratio between these TTF below 1 in 82% of patients. Median survival was only 4.5 months (95% confidence interval (CI) of 3.48-5.56). CONCLUSIONS: This retrospective data represent the largest reported series of unselected refractory mCRC patients treated with MMC. The median survival of 4.5 months is similar to the survival expected for best supportive care. This lack of activity strongly suggests that MMC should not be routinely used in refractory mCRC.