Ashish Singh

Locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) are one of the most common cancers globally and in India. Though many treatment options are available for LA-SCHHN, chemotherapy administered concurrently with radiotherapy (CCRT) is the most common treatment modality. Cisplatin-based CCRT is the guideline-recommended standard of care (SoC) in definitive and adjuvant settings. However, cisplatin-based CCRT often fails or cannot be administered due to toxicity. Hence, 60% of LA-SCCHN patients experience locoregional recurrence, and 20% experience distant metastasis. Many of these patients are cisplatin-ineligible/unfit due to absolute or relative contraindications; thus, continued cisplatin-based CCRT is unsuitable for them. Hence, alternative treatment strategies have been suggested for cisplatin-unfit LA-SCCHN patients and include docetaxel, carboplatin, and cetuximab-based regimens. Of these, docetaxel and carboplatin-based regimens have an unfavorable toxicity profile when compared with cetuximab-based regimens. Additionally, cetuximab-based regimens have demonstrated good locoregional control (LRC), improved disease-free survival (DFS), and OS (including 5-year OS) in LA-SCCHN patients. Therefore, Indian and international guidelines recommend cetuximab-based regimens for cisplatin-ineligible/unfit LA-SCCHN patients, Cetuximab is a costly drug for Indian patients. However, with the availability of cetuximab biosimilars, it has become possible to extend the drug’s benefits to cisplatin-ineligible/unfit LA-SCCHN patients in India. Hence, this Expert opinion from India was organized, and nine consensus statements were drafted to highlight the various clinical settings where cetuximab-based regimens can benefit cisplatin-ineligible/unfit LA-SCCHN patients. An attempt was also made to understand the burden and causes of cisplatin ineligibility and toxicity in Indian patients.

Background Fertility-sparing surgery (FS) is a viable option for women with early-stage epithelial ovarian cancer (EOC) desiring fertility preservation. However, its oncological outcomes remain debated. Methods This retrospective cohort study analysed 135 patients with FIGO (International Federation of Gynaecology and Obstetrics) stage I EOC, operated between 1st January 2011 and 31st December 2020, comparing clinicopathological characteristics and oncologic outcomes between women who underwent FS (n = 26) and comprehensive staging surgery (CS) (n = 109). Continuous variables were compared using a t-test and Mann-Whitney test, while categorical variables were compared using the Chi-Square test. Disease-free and overall survival were plotted using Kaplan–Meier curves and compared using a log-rank test. Results During this period, Stage I EOC constituted 13.9% of the patients with EOC who underwent surgery. Patients in the FS group were younger (mean age 28.6 years versus 43 years, p = 0.00), with higher rates of nulliparity (77% versus 15%, p = 0.00). Though the pathological profile of the tumours in both groups was similar, 12(46%) in the FS group had high-grade histology. The FS group had a poorer follow-up rate (70% versus 83%, p = 0.033), a higher recurrence rate (30% vs. 8%, p = 0.001), and shorter mean disease-free survival (84.78 months vs. 124.86 months, p = 0.002). Older age and FS were significant predictors of recurrence at 2 and 5 years. Conclusion This study suggests that FS may be associated with higher recurrence rates in early-stage EOC. Careful patient selection, precise surgical information, and thorough follow-up protocols are crucial to balancing oncological safety with reproductive goals.

PURPOSE: There is a lack of literature on treating stage III non–oncogene-driven non–small cell lung cancer (NSCLC) with low-dose immunotherapy in combination with chemotherapy for patients who are not candidates for local therapy up front. MATERIALS AND METHODS: We performed an institutional retrospective analysis of patients with stage III non–oncogene-driven NSCLC deemed ineligible for up-front local therapy. The NACT + I/O group comprised those who received induction chemotherapy in combination with low-dose nivolumab, and the NACT-alone group comprised those who received chemotherapy alone. Propensity score matching was performed based on stage, histology, and respiratory comorbid status. The primary end point was objective response rate (ORR). Secondary end points were conversion rates to local therapy, progression-free survival (PFS), overall survival (OS), and Grade ≥3 adverse events. RESULTS: Eighty-two patients were equally divided into the NACT + I/O and NACT-alone groups. The most common histology was squamous cell (60%), followed by adenocarcinoma (34%) and mixed (5%). Majority (85%) had stage IIIB or IIIC disease. The ORR to induction was 73.1% (complete response 1, partial response [PR] 29, stable disease [SD] 10, progressive disease [PD] 1) in the NACT + I/O group versus 39% (PR-16, SD-13, PD-12) in the NACT-alone group ( P = .002). The NACT + I/O group had a higher proportion of patients undergoing sequential local therapy (66% v 46.3%, P = .075), a better median PFS (not reached [NR] v 11 months, P = .0014), and median OS (NR v 28 months, P = .22) compared with the NACT-alone group at a median follow-up of 13.5 months. There were no new safety signals identified. CONCLUSION: Adding low-dose immunotherapy to chemotherapy improved ORRs, conversion rates to local therapy, and PFS in patients with stage III non–oncogene-driven NSCLC, who were ineligible for up-front local therapy.

PURPOSE: We examined the efficacy of topical capsaicin in reducing delayed chemotherapy-induced nausea and vomiting (CINV). METHODS: Adults on highly emetogenic chemotherapy regimens applied 2 g of capsaicin ointment (0.075%) or matching placebo four times a day to the abdomen for 5 days in addition to standard antiemetic regimen in this blinded randomized controlled trial. Patients were monitored for nausea and vomiting in the immediate (day 1), delayed (days 2-5), and extended phases (days 2-15). Self-reported incidence and daily episodes of CINV were compared between the groups. Onset, severity, need for rescue antiemetics, cumulative vomiting episodes, and safety were also compared. RESULTS: In total, 160 patients were enrolled. The final modified intention-to-treat population included 75 patients each in the capsaicin and placebo groups. Fewer patients experienced nausea (36.0% [n = 27] v 53.3% [n = 40]; P = .033) and vomiting (28.0% [n = 21] v 42.7% [n = 32]; P = .060) in the capsaicin arm during the delayed phase. During the extended phase, there was a significantly lower incidence of nausea (44% v 64.0%; P = .014) in the capsaicin arm. No difference in nausea (26.7% v 25.3%) or vomiting (22.7% v 18.7%) was evident in the immediate phase. The average daily episodes of nausea and vomiting were significantly fewer in the capsaicin arm during the delayed and extended phases. With capsaicin, no grade 3 nausea (9.3% v 0.0%; P = .007) was observed, and the time to first nausea and vomiting was significantly prolonged. There were no differences between the groups with respect to rescue antiemetics, unscheduled hospital visits, and adverse events. CONCLUSION: Topical capsaicin reduced the incidence of nausea and the average number of vomiting episodes during delayed and extended phases without increasing adverse effects.

Intestinal-type sinonasal adenocarcinoma is a rare epithelial malignancy primarily treated with surgery and chemoradiation. The combination of low-dose immunotherapy and a tyrosine kinase inhibitor in recurrent disease has not been previously studied. A man in his 20s with papillary adenocarcinoma of the sinonasal region, following surgical resection, was treated with six cycles of concurrent chemoradiotherapy, followed by four cycles of docetaxel, cisplatin and capecitabine. While on treatment, he was found to have extensive residual disease and he was started on low-dose nivolumab and cabozantinib. Repeat imaging after ten months of treatment revealed a significant reduction in lesions. Non-squamous head and neck cancers are often excluded from major trials, and the effect of immunotherapy in these histologies is poorly understood. The response seen with low-dose immunotherapy underscores the need for further research in this setting.

Purpose Total neoadjuvant therapy (TNT) with pre-operative chemotherapy and chemoradiotherapy results in improved survival and is becoming the new standard of care in locally advanced rectal cancer (LARC). We describe our experience with TNT consisting of induction chemotherapy followed by chemoradiotherapy using full dose 5FU without oxaliplatin. Methods Adults with biopsy-proven, newly diagnosed LARC with high-risk characteristics on pelvic MRI (T4a or T4b, extramural vascular invasion, N2, mesorectal fascia involvement, enlargement/tumor deposits on lateral lymph nodes) were included. The TNT protocol comprised of six biweekly courses of modified FOLFOX6 followed by pelvic RT with four concurrent cycles of biweekly 5-FU 2600 mg/m2 + LV 200 mg/m2 without oxaliplatin to complete 20 uninterrupted weeks of full dose 5FU. Surgery was planned 11–13 weeks after completing chemoradiotherapy. Results Eighty-four LARC patients, including 26% with signet-ring cell carcinoma, with high-risk MRI characteristics were treated with the TNT protocol with a 96% completion rate. Significant (> grade 3) toxicities included neutropenia (23.8%), diarrhea (14.2%) anemia (10.7%), and two deaths. The median DFS at 2 years was 22.5 months with better survival noted for those who underwent surgery or had cCR (with NOM) compared to those who did not undergo surgery (due to progression, inadequate regression, or patient preference despite residual disease) -mDFS 27.7 months versus 11.4 months, p = < 0.0001 and mOS 29.2 months versus 15 months p = < 0.0001. Conclusion The hybrid TNT regimen was administered without significant dose delays or interruptions. Toxicity was manageable but with two treatment-related deaths. Ability to undergo surgery after TNT predicted for improved DFS and OS.

PURPOSE: Tyrosine kinase inhibitors such as sunitinib and pazopanib are the mainstay of treatment of metastatic renal cell carcinoma (mRCC) in India. However, pembrolizumab and nivolumab have shown significant improvement in the median progression-free survival and overall survival among patients with mRCC. In this study, we aimed to determine the cost-effectiveness of the first-line treatment options for the patients with mRCC in India. METHODS: A Markov state-transition model was used to measure the lifetime costs and health outcomes associated with sunitinib, pazopanib, pembrolizumab/lenvatinib, and nivolumab/ipilimumab among patients with first-line mRCC. Incremental cost per quality-adjusted life-year (QALY) gained with a given treatment option was compared against the next best alternative and assessed for cost-effectiveness using a willingness to pay threshold of one-time per capita gross-domestic product of India. The parameter uncertainty was analyzed using the probabilistic sensitivity analysis. RESULTS: We estimated the total lifetime cost per patient of ₹ 0.27 million ($3,706 US dollars [USD]), ₹ 0.35 million ($4,716 USD), ₹ 9.7 million ($131,858 USD), and ₹ 6.7 million ($90,481 USD) for the sunitinib, pazopanib, pembrolizumab/lenvatinib, and nivolumab/ipilimumab arms, respectively. Similarly, the mean QALYs lived per patient were 1.91, 1.86, 2.75, and 1.97, respectively. Sunitinib incurs an average cost of ₹ 143,269 ($1,939 USD) per QALY lived. Therefore, sunitinib at current reimbursement rates (₹ 10,000 per cycle) has a 94.6% probability of being cost-effective at a willingness to pay threshold of 1-time per capita gross-domestic product (₹ 168,300) in the Indian context. CONCLUSION: Our findings support the current inclusion of sunitinib under India's publicly financed health insurance scheme.

PURPOSE Preoperative long course chemoradiation (LCCRT) followed by total mesolectal excision (TME) results in excellent local control but distant failure rates remain high. Total neoadjuvant therapy (TNT) with pre-operative delivery of systemic chemotherapy and chemoradiotherapy results in a higher pathological response, improved event free and overall survival and is becoming the new standard of care. We describe our experience with a hybrid TNT consisting of induction chemotherapy followed by chemoradiotherapy using full dose 5FU without oxaliplatin. METHODS In this single center study, adults with a LARC were included. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, biopsy-proven, newly diagnosed LARC, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumor [cT] stage cT4a or cT4b, extramural vascular invasion (EMVI), clinical nodal [cN] stage cN2, mesorectal fascia involvement and enlargement/tumor deposits on lateral lymph nodes). The hybrid TNT protocol comprised of six biweekly courses of modified FOLFOX6 (m FOLFOX6) followed by addition of pelvic LCCRT with four concurrent cycles of biweekly 5-FU 2600 mg/m2 + LV 200 mg/m2 without oxaliplatin to complete uninterrupted 20 weeks of full dose 5FU + LV chemotherapy. Pelvic chemoradiotherapy consisted of 28 daily fractions of 2 Gy up to 50.4-54Gy including boost to extra-mesorectal nodes. Surgery was planned 11-13 weeks after completing chemoradiotherapy. Outcomes of interest were pathological complete response (pCR), 2 year disease free survival (DFS) and overall survival (OS). RESULTS Between July 2017 to August 2020, 84 adults, predominantly male (65.5%) aged 42.5±13 years with LARC were treated with the TNT protocol. High risk features were T3/T4 in 80 (95.3%), N2 nodes 51(60.7%), signet ring cell histology 22(26.2%), meso-rectal fascia involvement 73(86.9%), EMVI 54 (64.3%) and lateral pelvic nodes 25(29.8%). Eighty- one (96.4%) completed all planned chemotherapy. All but two patients completed the planned RT. pCR was noted in 27 (32%). Twenty-five (29%) did not undergo surgery- 6(7%) opted for non-operative management (NOM) after complete clinical response (cCR), 5 refused surgery, 13(15.4%) were deemed inoperable due to inadequate tumor regression despite TNT (R0 resection was not feasible) and 2 did not complete treatment. Grade 3 &4 toxicities included neutropenia in 20 (23.8%), diarrhea in 12 (14.2%) and anemia in 9(10.7%) patients. Grade 5 toxicities were seen in one patient who died from neutropenic sepsis, and another who developed a cerebrovascular accident on therapy. After 24.5 months of median follow-up, 23 (27%) patients recurred, with local recurrence in 5(6%), systemic recurrence in 16 (19%) and both in 2(2.4%). The median disease-free survival (DFS) of the whole cohort was 22.5 months. Those who did not undergo surgery(n=19) despite residual disease (no cCR) had the worst outcomes (mDFS 11.4 months versus 27.7months, p= and mOS 15 months versus 29.2 months p= CONCLUSION The hybrid TNT regimen was administered without significant dose delays or interruptions. Toxicity was manageable but with two treatment related deaths. pCR of 32% is comparable to contemporary trials, however the 2-year recurrence rates were not improved. Ability to undergo surgery after TNT predicted for improved DFS and OS.