Neil Majithia

National Cancer Institute-supported chemotherapy-induced peripheral neuropathy trials: outcomes and lessons

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and debilitating complications of cancer treatment. Due to a lack of effective management options for patients with CIPN, the National Cancer Institute (NCI) sponsored a series of trials aimed at both prevention and treatment. A total of 15 such studies were approved, evaluating use of various neuro-modulatory agents which have shown benefit in other neuropathic pain states. Aside from duloxetine, none of the pharmacologic methods demonstrated therapeutic benefit for patients with CIPN. Despite these disappointing results, the series of trials revealed important lessons that have informed subsequent work. Some examples of this include the use of patient-reported symptom metrics, the elimination of traditional—yet unsubstantiated—practice approaches, and the discovery of molecular genetic predictors of neuropathy. Current inquiry is being guided by the results from these large-scale trials, and as such, stands better chance of identifying durable solutions for this treatment-limiting toxicity.

Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents

Outcomes for patients with multiple myeloma (MM) have improved in recent years owing to use of novel agents and high-dose therapy followed by autologous stem cell transplant (ASCT). We analyzed the outcomes of 511 consecutive patients treated with novel therapies at our institution between 2006 and 2014 to determine the impact of relapse within 12 months of initiating treatment. A total of 82 patients (16.0%) experienced early relapse, with median time to relapse of 8.0 months (95% confidence interval (CI); 6.3, 8.9). Median overall survival (OS) was significantly worse for this group at 21.0 months (95% CI; 16.3, 27.2) vs not reached (NR) (95% CI; 96.3, NR) for those with late relapse (P<0.001). Survival outcomes remained poor among early relapse patients irrespective of depth of response to initial therapy. In multivariate analysis, low albumin and high-risk cytogenetics predicted early relapse. Outcomes of early relapse from early ASCT were also considered; median OS from ASCT for those relapsing within 12 months was 23.1 months (95% CI; 15.7, 32.4) vs 122.2 months (95% CI; 111.5, 122.2) for the remaining patients (P<0.001). Early relapse remains a marker of poor prognosis in the current era, and such patients should be targeted for clinical trials.

Outcomes of primary refractory multiple myeloma and the impact of novel therapies

Over the past decade, use of novel agents, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has resulted in high response rates and improvement in overall survival (OS) for patients with multiple myeloma (MM); however, the prognostic significance of refractoriness to these agents when used as initial therapy has not been extensively studied. We reviewed the outcomes of 816 consecutive patients treated for MM at our institution since 2006 to evaluate the survival difference between those achieving at least a partial response (PR) to induction therapy and those who were primary refractory. The median OS from start of therapy was significantly shorter for the primary refractory group at 3.6 vs. 7.6 years for the responding patients (P < 0.001). The difference in median OS persisted when only patients receiving a novel agent as part of induction therapy were considered (3.6 vs. 7.9 years, P < 0.001) and in a 4‐month landmark analysis (4.2 vs. 7.6 years, P < 0.001). The median OS for patients achieving a complete response (CR), very good partial response (VGPR), PR, or less than PR was not reached (NR), 6.1, 6.4, and 4.2 years from the 4‐month landmark, respectively (P < 0.001). The comparatively poor outcomes of patients refractory to induction therapy in the current era of novel agents suggests that this high‐risk subpopulation must be further studied for predictors of resistance and, when identified, should be targeted for clinical trials. Am. J. Hematol. 90:981–985, 2015.

Scrambler Therapy for the management of chronic pain

PurposeChronic pain is a widespread and debilitating condition, encountered by physicians in a variety of practice settings. Although many pharmacologic and behavioral strategies exist for the management of this condition, treatment is often unsatisfactory. Scrambler Therapy is a novel, non-invasive pain modifying technique that utilizes trans-cutaneous electrical stimulation of pain fibers with the intent of re-organizing maladaptive signaling pathways. This review was conducted to further evaluate what is known regarding the mechanisms and mechanics of Scrambler Therapy and to investigate the preliminary data pertaining to the efficacy of this treatment modality.MethodsThe PubMed/Medline, SCOPUS, EMBASE, and Google Scholar databases were searched for all articles published on Scrambler Therapy prior to November 2015. All case studies and clinical trials were evaluated and reported in a descriptive manner.ResultsTo date, 20 reports, of varying scientific quality, have been published regarding this device; all but one small study, published only as an abstract, provided results that appear positive.ConclusionThe positive findings from preliminary studies with Scrambler Therapy support that this device provides benefit for patients with refractory pain syndromes. Larger, randomized studies are required to further evaluate the efficacy of this approach.

Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history

PurposePanel-based genetic testing has identified increasing numbers of patients with pancreatic ductal adenocarcinoma (PDAC) who carry germ-line mutations. However, small sample sizes or number of genes evaluated limit prevalence estimates of these mutations. We estimated prevalence of mutations in PDAC patients with positive family history.MethodsWe sequenced 25 cancer susceptibility genes in lymphocyte DNA from 302 PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreatic Research Registry. Kindreds containing at least two first-degree relatives with PDAC met criteria for familial pancreatic cancer (FPC), while the remaining were familial, but not FPC.ResultsThirty-six patients (12%) carried at least one deleterious mutation in one of 11 genes. Of FPC patients, 25/185 (14%) were carriers, while 11/117 (9%) non-FPC patients with family history were carriers. Deleterious mutations (n) identified in PDAC patients were BRCA2 (11), ATM (8), CDKN2A (4), CHEK2 (4), MUTYH/MYH (3 heterozygotes, not biallelic), BRCA1 (2), and 1 each in BARD1, MSH2, NBN, PALB2, and PMS2. Novel mutations were found in ATM, BARD1, and PMS2.ConclusionMultiple susceptibility gene testing in PDAC patients with family history of pancreatic cancer is warranted regardless of FPC status and will inform genetic risk counseling for families.

Regorafenib in the treatment of colorectal cancer

Introduction: Colorectal cancer (CRC) is among the most frequently diagnosed malignancies, and is commonly associated with metastatic disease at presentation. While chemotherapy represents a mainstay of management, options at the time of disease progression are limited. Regorafenib is a novel multikinase inhibitor which has been evaluated for patients with chemo-refractory metastatic CRC (mCRC) and is currently approved for use in a last-line-of-treatment setting. Areas covered: Articles searchable on MEDLINE/PubMed were reviewed to provide context for use of regorafenib in the management of mCRC. Specific drug properties are discussed, including chemistry, pharmacodynamics, pharmacokinetics, and metabolism. Additionally, clinical efficacy is reported with consideration of Phases I–III data. Expert opinion: Phase III evaluation has confirmed the efficacy of regorafenib for patients with chemo-refractory mCRC. Importantly, the rapid accrual of the CORRECT trial revealed the degree of unmet need for this patient population, and proved that it was feasible to compare novel agents to placebo when multiple lines of standard therapy have failed. In the coming years, the role of regorafenib in the management of mCRC should be further clarified, especially through identification of the patient population with greatest anticipated benefit and exploration of its use as an adjuvant or maintenance agent.

Management of hot flashes in women with breast cancer receiving ovarian function suppression

Most breast cancers express estrogen and/or progesterone receptors, allowing the opportunity to use anti-estrogen therapies, which have demonstrated substantial efficacy in both the metastatic and adjuvant settings. Young premenopausal women with early-stage high-risk or with metastatic hormone-receptor positive breast cancer may benefit from ovarian function suppression in addition to anti-estrogen medications. While these endocrine manipulations have successfully improved breast cancer outcomes, they may lead to a significant proportion of women experiencing vasomotor symptoms. While not life-threatening, vasomotor symptoms adversely impact quality of life and can result in early treatment discontinuation. For these reasons, supportive management of this treatment-related toxicity is crucial, and clinicians caring for breast cancer patients and survivors should be familiar with the options available and the data behind them. This manuscript will review the pathophysiology, clinical manifestations, quality of life implications and non-estrogenic management options of vasomotor symptoms for women with breast cancer undergoing estrogen depletion.

Management of Menopause in the Breast Cancer Patient

Abstract Many women with breast cancer are menopausal at the time of their cancer diagnosis, and a significant number will enter menopause during treatment. Achievement of adequate control of menopausal symptoms has a meaningful impact on quality of life for breast cancer survivors. Although hormone therapy has proved efficacious in the management of various menopausal conditions, its use in women with a history of breast cancer remains controversial due to a dearth of safety data. This is true even of topical estrogens, which are typically used for vulvovaginal symptoms, given that systemic absorption of unclear significance has been demonstrated in studies. Alternative therapies, such as antidepressants, have proved particularly helpful in the management of vasomotor symptoms, especially considering that comorbid depression is common in this patient population. To counteract the increased risk of bone density loss and fracture, bisphosphonates have emerged as favored treatment, with data suggesting that these agents may also reduce risk of disease recurrence. With advances in diagnosis and treatment, an increasing percentage of women are becoming breast cancer survivors, and comprehensive care of this patient population requires effective management of menopausal symptoms and related disease states.