Management of leptomeningeal metastases in non-small cell lung cancer Shekar Patil, Krishna Kumar Rathnum Indian Journal of Cancer 2019 56(5):1-9 In leptomeningeal metastasis (LM), malignant lung cancer cells reach the sanctuary site of the leptomeningeal space through haematogenous or lymphatic route and thrive in the leptomeninges because of restricted access of chemotherapeutic agents across the blood brain barrier. The incidence of LM is 3%–5% in non-small cell lung cancer (NSCLC) patients; the incidence is higher in patients with anaplastic lymphoma kinase (ALK) gene rearrangement or epidermal growth factor receptor (EGFR) mutations. However, the real-world burden of undiagnosed cases may be higher. LM diagnosis is based on clinical, radiological, and cytological testing. Disease management remains a challenge because of low central nervous system penetration of drugs. The prognosis of NSCLC patients with LM is poor with an overall survival (OS) of 3 months with contemporary treatment and <11 months with novel therapies. Therapy goals in this patient population are to improve or stabilize neurologic status, improve quality of life, and prolong survival while limiting the toxicity of chemotherapeutic regimens. We reviewed therapeutic options for management of LM in NSCLC patients with or without genetic mutations. Radiotherapy, systemic, or intrathecal chemotherapy, and personalized molecularly targeted therapy prolong the OS in patients with LM. Newer third generation EGFR-tyrosine kinase inhibitors have considerable brain penetration property and have been vital in increasing the OS especially in patients with EGFR mutations. Sequential or combination therapy third generation EGFR agents with radiotherapy or chemotherapy might be effective in increasing the quality of life and overall survival.

Adverse effects of immuno-oncology drugs—Awareness, diagnosis, and management: A literature review of immune-mediated adverse events Shyam Aggarwal Indian Journal of Cancer 2019 56(5):10-22 Immuno-oncology (IO) approaches such as cytokine therapy, immune-checkpoint blockers (ICBs), cancer vaccines, and cell-based therapies have revolutionized cancer treatment. ICBs provide better response-to-toxicity profile among various IO approaches; however, they can cause dysregulation of host immune system resulting in immune-mediated adverse events (imAEs). The skin and gastrointestinal system are most commonly affected. Although reversible, imAEs may cause life-threatening conditions if untreated. Risk assessment and appropriate patient selection before treatment initiation may prevent most imAEs. Key factors in effectively managing imAEs include baseline clinical evaluation, appropriate diagnostic tests, severity grading, timely decision on discontinuation or reintroduction of ICB treatment, and intervention with immunosuppressive and/or immunomodulatory agents. Patient and healthcare provider awareness is critical for identifying and managing lower grade imAEs. Immediate reporting is important for successfully managing and preventing or worsening of imAEs. Pretreatment sensitization of patients should address barriers to reporting such as fear of ICB discontinuation, ignorance of symptoms, financial constraints, and self-medication. Physicians should rely on clinical presentation and diagnostic work-up (including imaging) to accurately identify, characterize, and differentiate imAEs from metastasis. Treatment-related new symptoms should be dealt with a high level of suspicion. Corticosteroids are initiated if symptoms do not resolve within a week from onset and tapered over a month to avoid rebound of symptoms. ICB therapy should be permanently discontinued in most cases of grade 3-4 imAEs. A multidisciplinary approach involving oncologists, oncosurgeons, primary care physicians, and nurses is necessary in effectively managing imAEs and facilitating better clinical outcomes.

Molecularly targeted therapies in non-small cell lung cancer: The evolving role of tyrosine kinase inhibitors DC Doval, CJ Desai, TP Sahoo Indian Journal of Cancer 2019 56(5):23-30 Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer. Patients with NSCLC are diagnosed at a locally advanced or metastatic stage where prognosis with palliative chemotherapy is poor. The discovery of epidermal growth factor receptor (EGFR) mutations has revolutionized cancer treatment for NSCLC by promoting the development of molecularly targeted therapies like tyrosine kinase inhibitors (TKIs). This review summarizes the clinical efficacy and tolerability of EGFR-TKIs, including osimertinib, in EGFR-mutated advanced NSCLC. EGFR-TKIs have demonstrated superior response and overall survival rates compared with chemotherapy in EGFR-mutated NSCLC. However, despite the initial rapid and durable clinical responses, acquired resistance to first- and second-generation TKIs eventually develops in most cases, with disease progression observed mostly within 12 months of treatment initiation. Osimertinib, a potent third-generation TKI, irreversibly inhibits mutated EGFR alleles, including T790M. In addition to longer survival and higher response rate, osimertinib has a favorable safety profile with a lower incidence of grade ≥3 treatment-related adverse events compared with other TKIs. Based on the efficacy and safety results, recently the National Comprehensive Cancer Network (NCCN) has included osimertinib as the “preferred first-line of treatment” in patients with metastatic EGFR mutationpositive NSCLC. Thus, osimertinib as first-line therapy for EGFRpositive patients irrespective of the T790M mutation status could be an ideal choice in the Indian setting where only 50% of patients opt for any second-line therapy after first-line failure.

Management of CNS metastases in patients with EGFR mutation-positive NSCLC Vijith Shetty, Suresh Babu Indian Journal of Cancer 2019 56(5):31-37 Central nervous system (CNS) metastases are a frequent and severe complication associated with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) have shown considerable efficacy in EGFR-mutated NSCLC. However, their limited potential to cross the blood–brain barrier (BBB) renders them less effective in the management of CNS metastases in NSCLC. Osimertinib, a third-generation irreversible EGFR-TKI with good potential to cross the BBB, has shown significant clinical activity and acceptable safety profile in patients with EGFR-positive NSCLC brain and leptomeningeal metastases. The progression-free survival (PFS) of up to 15.2 months in CNS metastases patients in the FLAURA trial and the CNS objective response rates (ORRs) of 54% and 43% in the AURA/AURA2 and BLOOM trials, respectively, have established the role of osimertinib in patients with NSCLC with CNS metastases. The AURA3 trial also reported a PFS of 8.5 months and overall ORR of 71%. These data have supported osimertinib to be recognized as a “preferred” first-line treatment for EGFR-positive metastatic NSCLC by the National Comprehensive Cancer Network (NCCN). With limited treatment options available, upfront administration of osimertinib in patients with NSCLC irrespective of EGFR T790M and CNS metastases may improve the overall response rate and potentially reduce the adverse effects of radiotherapy. Our review focuses on the management of EGFR-mutated NSCLC CNS metastases in the context of recent NCCN guidelines.

Mainstreaming genetic counseling for BRCA testing into oncology clinics – Indian perspective Amit Verma, Shona Nag, Qurratulain Hasan, Veda Padma Priya Selvakumar Indian Journal of Cancer 2019 56(5):38-47 BReastCAncer (BRCA) susceptibility genes BRCA1 and BRCA2 are mainly associated with hereditary breast and ovarian cancer (HBOC) syndrome and present an estimated 45%–65% cumulative lifetime risk of developing breast cancer and an 11%–39% risk of ovarian cancer. HBOC is also linked to triple-negative breast cancer (TNBC). BRCA1 mutations in TNBC are observed in 36% of women age <40 years and 27% of women age <50 years. In India, the prevalence of BRCA1/2 mutation varies from 2.9% to 38% among families with genetic predisposition toward hereditary cancers. With HBOC being linked to early-onset breast cancer and increased susceptibility to other cancers, early screening for BRCA mutations has become a pressing need. Though genetic counseling (GC) for BRCA mutation testing is common in most of the developed countries, India still faces several challenges in mainstreaming the same. Many barriers to effective GC for BRCA testing are unique to India. There is a dearth of trained geneticists which puts the pressure on oncologists to give GC for which they neither have the time or training. Presence of multiethnic/linguistic population acts as a major hindrance along the way toward development of robust predictive and effective GC models for BRCA testing. The current review discusses the need and benefits of GC in breast cancer prevention, through BRCA testing, from an Indian perspective. The functional framework of GC and the role of genetic counselors are discussed in detail. In addition, importance of GC training and role of a multidisciplinary team approach for mainstreaming pre- and post-BRCA test GC is highlighted.