Smitha Menon

Thromboembolic events with lenalidomide‐based therapy for multiple myeloma

The purpose was to evaluate the incidence and risk factors of thromboembolism associated with lenalidomide therapy in newly diagnosed myeloma.

Advances in Cancer Immunotherapy in Solid Tumors

Immunotherapy is heralded as one of the most important advances in oncology. Until recently, only limited immunotherapeutic options were available in selected immunogenic cancers like melanoma and renal cell carcinomas. Nowadays, there is an improved understanding that anti-tumor immunity is controlled by a delicate balance in the tumor microenvironment between immune stimulatory and immune inhibitory pathways. Either by blocking the inhibitory pathways or stimulating the activating pathways that regulate cytotoxic lymphocytes, anti-tumor immunity can be enhanced leading to durable anti-tumor responses. Drugs which block the immune regulatory checkpoints namely the PD-1/PDL1 and CTLA 4 pathway have shown tremendous promise in a wide spectrum of solid and hematological malignancies, significantly improving overall survival in newly diagnosed and heavily pretreated patients alike. Hence there is renewed enthusiasm in the field of immune oncology with current research focused on augmenting responses to checkpoint inhibitors by combination therapy as well as studies looking at other immune modulators and adoptive T cell therapy. In this article, we highlight the key clinical advances and concepts in immunotherapy with particular emphasis on checkpoint inhibition as well as the future direction in this field.

Placebo-Controlled Trial to Determine the Effectiveness of a Urea/Lactic Acid–Based Topical Keratolytic Agent for Prevention of Capecitabine-Induced Hand-Foot Syndrome: North Central Cancer Treatment Group Study N05C5

PURPOSE Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine for which no effective preventative treatment has been definitively demonstrated. This trial was conducted on the basis of preliminary data that a urea/lactic acid-based topical keratolytic agent (ULABTKA) may prevent HFS. PATIENTS AND METHODS A randomized, double-blind phase III trial evaluated 137 patients receiving their first ever cycle of capecitabine at a dose of either 2,000 or 2,500 mg/m(2) per day for 14 days. Patients were randomly assigned to a ULABTKA versus a placebo cream, which was applied to the hands and feet twice per day for 21 days after the start of capecitabine. Patients completed an HFS diary (HFSD) daily. HFS toxicity grade (Common Terminology Criteria for Adverse Events [CTCAE] v3.0) was also collected at baseline and at the end of each cycle. The primary end point was the incidence of moderate/severe HFS symptoms in the first treatment cycle, based on the patient-reported HFSD. RESULTS The percentage of patients with moderate/severe HFS symptoms was not different between groups, being 13.6% in the ULABTKA arm and 10.2% in the placebo arm (P = .768 by Fishers exact test). The odds ratio was 1.37 (95% CI, 0.37 to 5.76). Cycle 1 CTCAE skin toxicity was higher in the ULABTKA arm but not significantly so (33% v 27%; P = .82). No significant differences were observed in other toxicities between groups. CONCLUSION These data do not support the efficacy of a ULABTKA cream for preventing HFS symptoms in patients receiving capecitabine.

Adjuvant chemotherapy for resected stage II and III colon cancer: comparison of two widely used prognostic calculators.

Two Web-based prognostic calculators (Adjuvant! and Numeracy) are widely used to individualize decisions regarding adjuvant therapy among patients with resected stage II and III colon cancer. However, these tools have not been directly compared. Hypothetical scenarios were formulated for the Numeracy calculator based on all potential combinations of age, lymph nodes status, tumor stage, and grade of tumor. These were then applied to three postsurgical therapy choices: observation, 5-fluorouracil (5-FU), or FOLFOX (5-FU, leucovorin, and oxaliplatin chemotherapy) to obtain the predicted 5-year disease-free survival (DFS) and overall survival (OS). Wilcoxon signed rank tests were used to compare the numerical predictions between the Adjuvant! and Numeracy calculators for each combination. A total of 192 hypothetical patient scenarios were obtained. For these patients, DFS and OS predictions from Adjuvant! were statistically significantly different than Numeracy (P <.05), except for four of 144 categories. While the estimated benefit in DFS and OS for 5-FU compared to surgery obtained from Adjuvant! and Numeracy were similar, the benefit in DFS and OS for FOLFOX over 5-FU, obtained from the Adjuvant! tool was slightly lower than that estimated from Numeracy. Among patients with resected stage II and III colon cancer, the DFS and OS estimates obtained from Numeracy and Adjuvant!, regarding the benefit of 5-FU over surgery, are similar, but the benefits of FOLFOX over 5-FU differ. Validation studies are needed to clarify the discrepancy and to assess the accuracy of these tools for predicting actual patient outcomes.

Lenalidomide-associated hypothyroidism.

Lenalidomide is a novel immune modulatory drug widely used in multiple myeloma with trials ongoing in lymphoma and many other diseases. We report a case of lenalidomide-associated hypothyroidism preceded by subclinical hyperthyroidism. This highlights an important but under-recognized toxicity of the drug that may potentially impact therapeutic decisions. A 62-year-old woman was enrolled in a clinical trial evaluating lenalidomide for relapsed or refractory diffuse large B cell lymphoma. She had received R-CHOP at diagnosis in 2003. At progression, she was treated with cisplatin, cytosine arabinoside and dexamethasone (DHAP). Renal insufficiency secondary to cisplatin complicated her course. She was then treated with rituximab, ifosphamide, carboplatin, and etoposide (R-ICE) for tumor progression. She subsequently received experimental treatment with the farnesyl transferase inhibitor tipifarnib, resulting in a partial remission [1]. After progression on tipifarnib she enrolled in Celgene Trial 002 evaluating single-agent lenalidomide [2]. At trial entry in August 2006, she noted mild fatigue with an ECOG performance status of 1. She had chronic renal insufficiency with a creatinine of 2.2 mg/dL (0.6 – 1.1 mg/dL) that was secondary to prior platinum toxicity. There was no previous history of thyroid disease. As part of the trial, thyroid function tests were performed at baseline and were normal [TSH: 1.9 (0.3 – 5.0 mIU/L); total T4: 10.0 (5.0 – 12.5 ug/dL); total T3: 86(80 – 190 ng/dL) Table I]. The thyroid tests were repeated every 2 months while on lenalidomide. Per protocol, the patient was initiated on 25 mg of lenalidomide daily on days 1 – 21 of a 28-day cycle. At cycle 2, the dose was reduced to 20 mg due to grade 2 mucositis. The dose was further reduced to 15 mg the next cycle, for grade 2 fatigue. Her thyroid tests were essentially normal at this time (Figure 1), with only a mildly reduced T3 level (TSH: 1.4 mIU/ dL; total T4 10.2 ug/dL; total T3: 70 ng/dL). In December 2006, after 4 cycles of lenalidomide, the TSH was suppressed at 0.02 mIU/L, but the total T4 remained within normal limits at 12.4 ug/dL. The patient did not have any symptoms of thyrotoxicosis and appeared clinically euthyroid. When she returned after 6 cycles of lenalidomide in February 2007, she remained well without any new symptoms. Computed tomography documented a continued partial remission. The thyroid function tests showed that her sensitive TSH had normalized to 0.4 mIU/L, but the serum T3 had fallen further to 28 ng/dL, and the T4 was undetectable (50.5 ug/dL). These test results were difficult to interpret at that time point and since the patient was doing well with an antitumor response, it was elected to continue lenalidomide and recheck the thyroid function tests in 1 month. When she returned in 1 month to start the eighth cycle of lenalidomide, she complained of significant increase in fatigue and puffiness around the eyes. She reported waking up from sleep with a sensation of shortness of breath. Although this was reminiscent of paroxysmal nocturnal dyspnea, the patient was unable to get relief of the symptoms even after walking around for several hours. The interrupted sleep resulted in worsening fatigue. She denied other typical symptoms of hypothyroidism such as constipation or cold intolerance. The physical examination documented the development of periorbital

Alterations in genes other than EGFR/ALK/ROS1 in non-small cell lung cancer: trials and treatment options

During the last decade, we have seen tremendous progress in the therapy of lung cancer. Discovery of actionable mutations in EGFR and translocations in ALK and ROS1 have identified subsets of patients with excellent tumor response to oral targeted agents with manageable side effects. In this review, we highlight treatment options including corresponding clinical trials for oncogenic alterations affecting the receptor tyrosine kinases MET, FGFR, NTRK, RET, HER2, HER3, and HER4 as well as components of the RAS-RAF-MEK signaling pathway.

Maximizing Time with the Patient: the Creative Concept of a Physician Scribe.

The universal implementation of electronic health records has transformed the practice of medicine. However, there is a general perception that electronic health records impede effective communication with patients. Clinicians feel that they paradoxically spend more time doing nonclinical tasks like documentation and writing orders and less time interacting with their patients. This article evaluates the role of medical scribes in augmenting physician workflows and examines if employing a scribe can enhance physician-patient interactions.

Brigatinib in Patients With Alectinib-Refractory ALK-Positive NSCLC

Introduction: The second‐generation anaplastic lymphoma kinase (ALK) inhibitor alectinib recently showed superior efficacy compared to the first‐generation ALK inhibitor crizotinib in advanced ALK‐rearranged NSCLC, establishing alectinib as the new standard first‐line therapy. Brigatinib, another second‐generation ALK inhibitor, has shown substantial activity in patients with crizotinib‐refractory ALK‐positive NSCLC; however, its activity in the alectinib‐refractory setting is unknown. Methods: A multicenter, retrospective study was performed at three institutions. Patients were eligible if they had advanced, alectinib‐refractory ALK‐positive NSCLC and were treated with brigatinib. Medical records were reviewed to determine clinical outcomes. Results: Twenty‐two patients were eligible for this study. Confirmed objective responses to brigatinib were observed in 3 of 18 patients (17%) with measurable disease. Nine patients (50%) had stable disease on brigatinib. The median progression‐free survival was 4.4 months (95% confidence interval [CI]: 1.8–5.6 months) with a median duration of treatment of 5.7 months (95% CI: 1.8–6.2 months). Among 9 patients in this study who underwent post‐alectinib/pre‐brigatinib biopsies, 5 had an ALK I1171X or V1180L resistance mutation; of these, 1 had a confirmed partial response and 3 had stable disease on brigatinib. One patient had an ALK G1202R mutation in a post‐alectinib/pre‐brigatinib biopsy, and had progressive disease as the best overall response to brigatinib. Conclusions: Brigatinib has limited clinical activity in alectinib‐refractory ALK‐positive NSCLC. Additional studies are needed to establish biomarkers of response to brigatinib and to identify effective therapeutic options for alectinib‐resistant ALK‐positive NSCLC patients.

Should Vital Signs Be Routinely Obtained Prior to Intravenous Chemotherapy? Results From a 2-Center Study.

BACKGROUND The American Society of Clinical Oncology and the Oncology Nursing Society have issued guidelines stating that the vital signs of patients should be routinely checked on days that intravenous chemotherapy is administered. This study sought evidence to justify this approach. METHODS This trial focused on consecutive patients with cancer from 2 institutions and evaluated outcomes during the first cycle of gemcitabine-based chemotherapy. The primary end point of the study was a visit to the ED, hospitalization, or death during the first cycle of chemotherapy. RESULTS Medical records from 1,158 patients were reviewed, and vital signs were checked in 589 patients on day 1 and in 486 on day 8. A total of 148 patients (12.8%) were evaluated in the emergency department (ED), 145 (12.5%) were hospitalized, and 11 (0.9%) died during their first cycle of chemotherapy. In multivariate analyses, which were adjusted for age, sex, cancer type, role of chemotherapy, number of chemotherapy drugs administered on day 1, and institution, checking vital signs on day 1 was associated with neither higher rates of ED visits nor with increased hospitalization; however, checking vital signs on day 8 was associated with higher rates of ED visits (odds ratio [OR]: 3.71; 95% confidence interval [CI]: 2.18-6.22; P < .0001) and higher rates of hospitalizations (OR: 3.98; 95% CI: 2.34-6.73; P < .0001). CONCLUSION This study suggests a need for additional, evidence-based data to support the routine checking of vital signs prior to administering cancer chemotherapy.