Evaluation of Metronomic Therapy as a Low-Cost, Sustainable, Standard-of-Care Option in Desmoid Fibromatosis: Real-World Data From a Tertiary Care Center in India.

PURPOSE: Desmoid fibromatosis (DF) is a locally aggressive tumor with low mortality but significant morbidity. There is a lack of standard of care, and existing therapies are associated with significant barriers including access, cost, and toxicities. This study aimed to explore the efficacy and safety of the metronomic therapy (MT) in DF in a large, homogenous cohort from India. PATIENTS AND METHODS: This study involved histologically confirmed DF cases treated with MT comprising vinblastine (6 mg) and methotrexate (15 mg) both once a week, and tamoxifen (40 mg/m2) in two divided doses once daily between 2002 and 2018. RESULTS: There were 315 patients with a median age of 27 years; the commonest site was extremity (142 of 315; 45.0%). There were 159 (50.1%) male patients. Of the 123 (39.0%) prior treated patients, 119 had surgery. Of 315 patients, 263 (83.5%) received treatment at our institute (MT-151, 77-local treatment, 9-tyrosine kinase inhibitor, and 26 were observed). Among the MT cohort (n = 163, 61.2%), at a median follow-up of 36 (0.5-186) months, the 3-year progression-free and overall survival were 81.1% (95% CI, 74.3 to 88.4) and 99.2% (95% CI, 97.6 to 100), respectively. There were 35% partial responses. Ninety-two patients (56.4%) completed 1-year therapy, which was an independent prognosticator (P < .0001; hazard ratio, 0.177 [95% CI, 0.083 to 0.377]). MT was well tolerated. Predominant grade ≥3 toxicities were febrile neutropenia, 12 (7.4%) without any chemotoxicity-related death. The annual cost of MT was $130 US dollars. CONCLUSION: The novel, low-cost MT qualifies as one of the effective, less toxic, sustainable, standard-of-care options for the treatment of DF with global reach and merits wide recognition.

Modified FOLFIRINOX (mFOLFIRINOX) as neoadjuvant therapy and 'salvage' in patients with high risk locally advanced rectal cancers - tolerance and early outcomes.

BACKGROUND: There is limited data with regard to the use of modified 5-fluoroural-leucovorin-irinotecan-oxaliplatin (mFOLFIRINOX) in terms of tolerance and enabling total mesorectal excision (TME) of locally advanced rectal adenocarcinomas (LARC) with high-risk characteristics (T4b status, signet ring histology etc) post standard neoadjuvant long course chemoradiation (NACTRT) or short course radiation (SCRT) and chemotherapy. MATERIALS AND METHODS: Patients with LARC from January 2018 to December 2020 receiving mFOLFIRINOX post NACTRT/SCRT to facilitate TME were evaluated. The primary endpoint was assessment of grade 3 and grade 4 treatment related toxicity and TME rates. Event free survival (EFS), where event was defined as disease progression or recurrence post resection after mFOLFIRINOX, was calculated by Kaplan Meier method. RESULTS: Forty-seven patients were evaluated with a median age of 33 years (Range:18-59), 45% T4b status, 96% radiological circumferential margin (CRM) involved (79% CRM positive post NACTRT/SCRT), 43% extramural venous invasion (n=33) and 36% signet ring histology. 62% had received prior NACTRT and 38% had received SCRT with chemotherapy before receiving mFOLFIRINOX. The most common grade 3 and grade 4 treatment related side effects included diarrhoea (7%), anaemia (4%) and infections (4%). Intended duration of mFOLFIRINOX or beyond was completed in 94% of patients. 60% of patients underwent curative local resection with R0 resection rates of 100% (n=28) and pathological complete response rates of 21%. The most common surgeries done were exenterations and abdominoperineal in 22% and 17% patients respectively. With a median follow up of 19 months, 24 patients had recurred or progressed for a median EFS of 20 months [95% confidence interval (CI): 15-24]. CONCLUSIONS: Locally advanced rectal cancers with high-risk characteristics are a niche group of cancers with less-than-optimal outcomes post standard neoadjuvant strategies. mFOLFIRINOX appears to be well tolerated and enables TME in a significant proportion of these patients.

Phase 3 RCT comparing docetaxel-platinum with docetaxel-platinum-5FU as neoadjuvant chemotherapy in borderline resectable oral cancer.

BACKGROUND: Neoadjuvant chemotherapy (NACT) with TPF (docetaxel, cisplatin, and 5FU) is one of the treatment options in very locally advanced oral cancer with a survival advantage over PF (cisplatin and 5FU). TP (docetaxel and cisplatin) has shown promising results with a lower rate of adverse events but has never been compared to TPF. METHODS: In this phase 3 randomized superiority study, adult patients with borderline resectable locally advanced oral cancers were randomized in a 1:1 fashion to either TP or TPF. After the administration of 2 cycles, patients were evaluated in a multidisciplinary clinic and further treatment was planned. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and adverse events. RESULTS: 495 patients were randomized in this study, 248 patients in TP arm and 247 in TPF arm. The 5-year OS was 18.5% (95% CI 13.8-23.7) and 23.9% (95% CI 18.1-30.1) in TP and TPF arms, respectively (Hazard ratio 0.778; 95% CI 0.637-0.952; P = 0.015). Following NACT, 43.8% were deemed resectable, but 34.5% underwent surgery. The 5-year OS was 50.7% (95% CI 41.5-59.1) and 5% (95%CI 2.9-8.1), respectively, in the surgically resected versus unresected cohort post NACT (P < 0.0001). Grade 3 or above adverse events were seen in 97 (39.1%) and 179 (72.5%) patients in the TP and TPF arms, respectively (P < 0.0001). CONCLUSION: NACT with TPF has a survival benefit over TP in borderline resectable oral cancers, with an increase in toxicity which is manageable. Patients who undergo surgery achieve a relatively good, sustained survival.

Low-dose versus standard-dose olanzapine with triple antiemetic therapy for prevention of highly emetogenic chemotherapy-induced nausea and vomiting in patients with solid tumours: a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Olanzapine is an effective antiemetic agent but it results in substantial daytime somnolence when administered at the standard dose. Our aim was to compare the efficacy of low-dose versus standard-dose olanzapine after highly emetogenic chemotherapy in patients with solid tumours. METHODS: This was a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial done in a tertiary care referral centre in India (Tata Memorial Centre, Homi Bhabha National Institute, Mumbai). Patients aged 13-75 years with an Eastern Cooperative Oncology Group performance status of 0-2, who were receiving doxorubicin-cyclophosphamide or high-dose cisplatin for a solid tumour were eligible. Patients were randomly assigned (1:1), with block randomisation (block sizes of 2 or 4) and stratified by sex, age (≥55 or <55 years), and chemotherapy regimen, to receive low-dose (2·5 mg) oral olanzapine or standard-dose (10·0 mg) oral olanzapine daily for 4 days, in combination with a triple antiemetic regimen. Study staff were masked to treatment allocation but patients were aware of their group assignment. The primary endpoint was complete control, defined as no emetic episodes, no rescue medications, and no or mild nausea in the overall phase (0-120 hours), assessed in the modified intention-to-treat (mITT) population (ie, all eligible patients who received protocol-specified treatment, excluding those who had eligibility violations and who withdrew consent after randomisation). Daytime somnolence was the safety endpoint of interest. Non-inferiority was shown if the upper limit of the one-sided 95% CI for the difference in the complete control proportions between the treatment groups excluded the non-inferiority margin of 10%. This study is registered with the Clinical Trial Registry India, CTRI/2021/01/030233, is closed to accrual, and this is the final data analysis. RESULTS: Between Feb 9, 2021, and May 30, 2023, 356 patients were pre-screened for eligibility, of whom 275 patients were enrolled and randomly assigned (134 to the 2·5 mg olanzapine group and 141 to the 10·0 mg olanzapine group). 267 patients (132 in the 2·5 mg group and 135 in the 10·0 mg group) were included in the mITT population, of whom 252 (94%) were female, 15 (6%) were male, and 242 (91%) had breast cancer. 59 (45%) of 132 patients in the 2·5 mg olanzapine group had complete control in the overall phase versus 59 (44%) of 135 in the 10·0 mg olanzapine group (difference -1·0% [one-sided 95% CI -100·0 to 9·0]; p=0·87). In the overall phase, there were significantly fewer patients in the 2·5 mg olanzapine group than in the 10·0 mg olanzapine group with daytime somnolence of any grade (86 [65%] of 132 vs 121 [90%] of 135; p<0·0001) and of severe grade on day 1 (six]5%] vs 54 [40%]; p<0·0001). INTERPRETATION: Our findings suggest that olanzapine 2·5 mg is non-inferior to 10·0 mg in antiemetic efficacy and results in reduced occurrence of daytime somnolence among patients receiving highly emetic chemotherapy and should be considered as a new standard of care. FUNDING: Progressive Ladies Welfare Association.

Trastuzumab Plus Gemcitabine-Cisplatin for Treatment-Naïve Human Epidermal Growth Factor Receptor 2-Positive Biliary Tract Adenocarcinoma: A Multicenter, Open-Label, Phase II Study (TAB).

PURPOSE: Human epidermal growth factor receptor 2 (HER2) overexpression is seen in 4%-16% of biliary tract cancers (BTCs). We aimed to evaluate the clinical activity of gemcitabine-cisplatin (GC) plus anti-HER2 antibody trastuzumab as initial treatment in HER2-positive BTCs. METHODS: This study was an investigator-initiated, open-label, single-arm, multi-institutional, phase II trial in adult patients with HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+ and fluorescent in situ hybridization-positive), treatment-naïve BTCs. The primary end point of the study was 6-month progression-free survival (PFS). Next-generation sequencing was performed on tissue samples to evaluate mutational status. RESULTS: From March 2020 to August 2022, of the 876 screened patients, 118 (13.4%) were found to have HER2-positive status, of whom 90 were enrolled in the study. Most patients had GBC (n = 96; 96%) with two or more sites of metastatic disease (n = 70; 78%). With a median follow-up of 17.3 (95% CI, 15.22 to 19.32) months, 72 patients had disease progression with a median PFS of 7 (95% CI, 6.2 to 7.8) months. The diagnosis to event 6-month PFS rate was 75.6% (95% CI, 66.6 to 84.6). A complete or partial response was seen in 50 (55.5%) patients and 22 (24.4%) patients had stable disease as the best response to treatment, for an overall disease control rate of 80%. The presence of isolated TP53 mutations was associated with inferior PFS compared with other mutations (TERT promoter, HER2, PIK3CA, etc) or no detected mutations (6.51 v 12.02 v 10.58 months; P < .001). CONCLUSION: The combination of GC and trastuzumab achieved its primary end point of improving PFS compared with historical data in the treatment-naïve HER2-positive BTC. Evaluating additional mutations such as TP53 and PIK3CA along with HER2 testing may help to preferentially select patients for anti-HER2 therapy in the future (Clinical Trial Registry India number: CTRI/2019/11/021955).

Survival of Trial-Like and Non-Trial-Like Patients With Immunotherapy in Advanced Hepatocellular Carcinoma in Real World: A Collaborative Multicenter Indian Study (IMHEP).

PURPOSE: Immune checkpoint inhibitors (ICIs) is the initial line of management in advanced hepatocellular carcinoma (HCC), but survivals in the real world are not known. MATERIALS AND METHODS: A retrospective study of patients with advanced HCC receiving ICIs (as first-line therapy or as later lines of therapy) across 11 Indian institutions was conducted. Patients were divided into either cohort 1 (trial-like receiving ICI as first-line therapy), with a Child Pugh score (CTP) of ≤6, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1, and no VP4 (main portal vein thrombosis [MPVT]) or cohort 2 (trial unlike) who did not satisfy at least one of the above criteria. The primary end point was 12-month overall survival (OS). RESULTS: Between January 2017 and January 2022, 133 patient data were analyzed. The presence of MPVT was seen in 33 patients (25%). The ICIs used were atezolizumab-bevacizumab, nivolumab, and pembrolizumab in 89 (66%), 44 (33%), and one (1%) patients, respectively. With a median follow-up of 13.8 months, the 12-month OS for the entire cohort was 33.4% (95% CI, 23.6 to 43.2). Patients in cohort 1 (n = 31) had a significantly improved OS compared with patients in cohort 2 (n = 102; 12-month OS, 57.9% [95% CI, 38.5 to 77.3] v 24% [95% CI, 13.4 to 34.6]; P = .005). Patients with CTP A as compared with CTP B (9.7 v 4.3 months; P < .001) and an ECOG PS of 0/1 as compared with a PS of ≥2 (8.7 v 7.2 months; P = .04) and without MPVT (9.4 v 4.0; P < .001) had superior survivals. CONCLUSION: Patients with advanced HCC in the real world, trial-like have survivals in consonance with trial data, whereas patients with features excluding them from trials, such as main portal vein thrombosis, poor ECOG PS, and child Pugh B status, have markedly inferior survivals, despite good tolerance to immunotherapy.

Practice Patterns and Survival in Patients with Resected Pancreatic Ductal Adenocarcinomas (PDAC) - Results from the Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) Study.

BACKGROUND: There is limited data from India with regard to presentation, practice patterns and survivals in resected pancreatic ductal adenocarcinomas (PDACs). METHODS: The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) included data from 8 major academic institutions across India and presents the outcomes in upfront resected PDACs from January 2015 to June 2019. RESULTS: Of 288 patients, R0 resection was achieved in 81% and adjuvant therapy was administered in 75% of patients. With a median follow-up of 42 months (95% CI: 39-45), median DFS for the entire cohort was 39 months (95% CI: 25.4-52.5), and median overall survival (OS) was 45 months (95% CI: 32.3-57.7). A separate analysis was done in which patients were divided into 3 groups: (a) those with stage I and absent PNI (SI&PNI-), (b) those with either stage II/III OR presence of PNI (SII/III/PNI+), and (c) those with stage II/III AND presence of PNI (SII/III&PNI+). The DFS was significantly lesser in patients with SII/III&PNI+ (median 25, 95% CI: 14.1-35.9 months), compared to SII/III/PNI + (median 40, 95% CI: 24-55 months) and SI&PNI- (median, not reached) (p = 0.036)). CONCLUSIONS: The MIPPAP study shows that resectable PDACs in India have survivals at par with previously published data. Adjuvant therapy was administered in 75% patients. Adjuvant radiotherapy does not seem to add to survival after R0 resection.

Gemcitabine, Cisplatin, and Nab-Paclitaxel as a First-Line Therapy for Advanced Biliary Tract Cancers.

INTRODUCTION: Locally advanced, inoperable, or metastatic gallbladder cancers (GBC) are treated with either gemcitabine-platinum combinations or gemcitabine alone based on physician discretion. However, the combination of gemcitabine, cisplatin, and nab-paclitaxel (GCNP) has shown increased response rates and prolonged survival in a phase II trial of biliary tract patients. MATERIALS AND METHODS: Consecutive series of patients diagnosed with locally advanced (liver infiltration > 5 cm, large nodes at porta, abutting duodenum), inoperable, and metastatic biliary tract patients between January 2018 and August 2022 were evaluated for first-line chemotherapy GCNP, in the multidisciplinary joint clinic (MDJC). The primary endpoint was ORR, and the major secondary endpoint was event-free survival (EFS). RESULTS: A total of 142 patients received GCNP during the specified time period. The median age of the cohort was 52 years (range: 21-79), the majority were females (61.3%), and the majority were GB (81.7%). Response rates were available in 137 patients. Complete response, partial response, and stable disease were seen in 9 (6.3%), 87 (61.3%), and 24 (16.9%), respectively, for an ORR of 67.6% and a clinical benefit rate of 84.5%. The median EFS was 9.92 (95% CI, 7.69-12.14) months. Of the 52 patients in whom GCNP was given with NACT intent for locally advanced GBC, 17 patients underwent surgery (34%). CONCLUSION: Our study indicates that GCNP leads to improved response rates, increased chances of resectability, and possibly better survival in patients with GBC.

Modified FOLFIRINOX compared to Gemcitabine & nab-Paclitaxel in advanced pancreatic ductal adenocarcinoma - results of a match-pair analysis.

Background & objectives: FOLFIRINOX and gemcitabine plus nab-paclitaxel (GN) are the most commonly used regimens in advanced pancreatic ductal adenocarcinomas (PDACs). As there is limited data on comparison of these two regimens, the present study was aimed to compare survivals and tolerance for both regimens through a match-pair analysis. Methods: The data of 350 patients with metastatic and locally advanced PDAC, treated between January 2013 and December 2019, were retrieved. A 1:1 matching, using age and performance status, without replacement was performed by using nearest neighbour matching method. Results: A total of 260 patients (130 modified FOLFIRINOX and 130 GN) were matched. The median overall survival (OS) was 12.98 months [95% confidence interval (CI) 7.257-8.776 months] in modifications of FOLFIRINOX (mFOLFIRINOX) cohort and 12.06 months (95% CI 6.690-8.88 months) in GN group (P=0.080). The incidence of grade 3 and 4 infections, diarrhoea, oral mucositis, and fatigue was higher with mFOLFIRINOX. Patients who received second line therapy had improved OS as compared to those who did not (14.06 vs. 9.07 months, P<0.001). Interpretation & conclusions: GN and mFOLFIRINOX appear to have similar survival outcomes in an unselected match paired patient population with advanced PDAC. A markedly increased incidence of non-myelosuppressive grade 3 and grade 4 side-effects and lack of survival improvements suggest a need for nuanced use of the mFOLFIRINOX regimen. Administration of second-line chemotherapy improves OS in patients with advanced PDAC.

Perioperative Modified FLOT Versus EOX in Locally Advanced Resectable Gastric and Gastro-Oesophageal Junction Adenocarcinoma: Results of a Matched-Pair Analysis.

BACKGROUND AND OBJECTIVES: There is limited real-world data on the efficacy of 2-weekly cycles of docetaxel, oxaliplatin, leucovorin, and fluorouracil (FLOT) compared to epirubicin, oxaliplatin, and capecitabine (EOX) as perioperative therapy in esophagogastric adenocarcinomas (EGAC). METHODS: The data of 611 patients with EGAC treated with perioperative chemotherapy and planned for curative resection between January 2013 and December 2019 were retrieved. Patients receiving EOX and a dose-modified version of FLOT (mFLOT) were evaluated. A 1:1 matching, using age, tumour location, signet ring histology, and Eastern Cooperative Oncology Group performance status, without replacement was performed by using nearest neighbour matching method. The primary endpoint of the study was 3-year event-free survival (EFS). RESULTS: A total of 593 patients (261 with EOX and 332 with mFLOT) were matched. One hundred and nighty-eight patients (76%) and 285 patients (86%) in the EOX and mFLOT cohorts underwent curative resection, respectively (p = 0.002). With a median follow-up of 35 and 53 months, respectively, the primary outcome of 3-year EFS was statistically superior in patients receiving mFLOT as compared to the EOX regimen (60% vs. 39%; p < 0.001). There was a greater incidence of grade 3 and grade 4 neutropenia (neoadjuvant: 18% vs. 2%; p < 0.001, adjuvant: 18% vs. 1%; p = 0.001) and febrile neutropenia (neoadjuvant: 8% vs. 1.1%; p < 0.001, adjuvant: 6% vs. 0; p = 0.001) with mFLOT. INTERPRETATION AND CONCLUSION: mFLOT is associated with improved resection rates and survival in comparison to EOX as perioperative therapy in gastric adenocarcinomas in this large real-world cohort, with manageable increase in clinically relevant toxicities such as grade 3 and grade 4 febrile neutropenia and neutropenia.

An Analysis of Tolerance and Early Survival Outcomes with Perioperative Modified FLOT in Gastric Cancers.

Anant RamaswamyPurpose Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) is a current standard of care for locoregionally advanced gastric adenocarcinomas. There is limited real world data with regard to the tolerance and efficacy of this regimen. Materials and Methods This is a retrospective analysis of gastric cancer patients who were offered neoadjuvant perioperative modified FLOT regimen between December 2016 and October 2018, at the Tata Memorial Hospital, Mumbai. Chemotherapy-related side-effects are reported along with overall survival (OS), as calculated by Kaplan-Meier method. Results Three hundred and forty-three consecutive patients were started on neoadjuvant chemotherapy (NACT) with mFLOT of which 298 patients (87%) completed the planned treatment. A total of 294 patients (86%) underwent curative resection of gastric cancer. Common grade 3 and grade 4 toxicities during NACT were diarrhea in 42 patients (12%) and febrile neutropenia in 27 patients (8%). Toxic death was seen in nine (2.6%) patients. A total of 264 patients (77%) completed planned adjuvant chemotherapy. Common grade 3 and grade 4 toxicities during adjuvant therapy were diarrhea in 42 patients (12%) and febrile neutropenia in 16 patients (6%). With a median follow-up of 19 months, the estimated 2-year median OS was 69.4%. Conclusion Administration of modified FLOT regimen in locoregionally advanced gastric cancers is feasible in clinical practice with high completion rates, though requiring dose modifications due to the incidence of clinically relevant grade 3 to 5 toxicities. Early outcomes with the regimen are on par with survivals from the FLOT-AIO study.

A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer: results of a prospective open label phase II single-arm study (RESCU III study).

It has been reported that chemotherapy toxicity is primarily not due to the drugs themselves, but is caused by cell-free chromatin particles (cfChPs) that are released from chemotherapy-induced dying cells. cfChPs from dying cells are readily internalized by healthy cells, wherein they inflict dsDNA breaks and activate inflammatory cytokines. cfChPs can be deactivated by oxygen radicals that are generated upon admixing the nutraceuticals resveratrol (R) and copper (Cu). Pre-clinical studies have shown that administration of R-Cu can reduce chemotherapy toxicity via the generation of oxygen radicals which deactivate cfChPs released from chemotherapy-induced dying cells. We investigated if R-Cu would reduce toxicity of docetaxel-based multi-agent chemotherapy in advanced gastric cancer. This single-arm phase II study was designed to assess the efficacy of orally administered R-Cu in ameliorating toxic side effects, as per National Cancer Institute Common Terminology Criteria for Adverse Events v4.03, in patients with advanced gastric cancer receiving docetaxel-based multi-agent chemotherapy. The primary objective was to reduce the proportion of patients experiencing grade ≥ 3 toxicity from 90 to 70%. Between October 2019 and April 2021, 30 patients, with a median age of 54 years, were enrolled of whom 73% were male. R-Cu treatment did not reduce the overall cumulative incidence of grade ≥ 3 toxicity (77%), or of ≥ 3 haematological toxicity (73%). However, the incidence of non-haematological toxicities comprising hand-foot syndrome (N = 4), diarrhoea (N = 3) and vomiting (N = 1) were markedly reduced (13%). Median progression-free survival (PFS) was 8 months (95% CI: 5.9-10.1), and overall survival (OS) was 16 months (95% confidence interval: 6.3-28.3). A marked reduction in non-haematological toxicities was seen in patients receiving R-Cu compared to historical data without adversely affecting PFS or OS. (292).Clinical trial information CTRI/2019/07/020289.

Outcomes of Ewing sarcoma in adults over 40 years of age from a low-middle income country.

Introduction: The data on outcomes and toxicity in adult Ewing sarcoma (ES) patients, particularly those aged ≥40 years, is exceedingly scarce around the world, particularly in low- and middle-income countries (LMICs) and mandates research. Methods: The study involved histologically ascertained ES patients aged ≥40 years who registered at our institute from 2013 to 2018. Prospectively collected data were analysed for overall survival (OS), event-free survival (EFS) and chemotherapy-related toxicities. Results: There were 66 patients, of which 34 were non-metastatic, and 32 were denovo metastatic, recurrent or had doubtful metastasis. At presentation, median age was 46 years, and 42 (63.6%) had extra-skeletal primary and 24 (36.3%) had extremity tumours. Curative treatment was offered to 40 (60.6%) patients. Significant grade 3/4 toxicities in non-metastatic and metastatic cohort, respectively, were febrile neutropenia (61.3%, 37.5%), anaemia (58.1%, 37.5%), thrombocytopenia (45.2%, 25.0%), peripheral neuropathy (25.8%, 12.5%) and dyselectrolytemia (25.8%, 6.25%). Chemotherapy-related toxicity led to death in three patients in the metastatic cohort, versus none in the non-metastatic patients. The 5 year EFS and OS for non-metastatic cohort were 53.8% and 67.8%, while the same for metastatic cohort were 20.7% and 27.5%, respectively. On multivariate analysis, Eastern Cooperative Oncology Group-performance status >2 and metastasis at presentation predicted poorer EFS and OS. Additionally, raised lactate dehydrogenase, larger tumours (>8 cm) and palliative intent treatment predicted worse EFS, while extra-skeletal primary and female gender were indicators of worse OS. Conclusions: Older adult ES patients benefit from aggressive multimodality treatment even in LMIC infrastructure. However, careful patient selection, close monitoring and pertinent dose modifications is imperative due to higher propensity for potential toxicities.

Systemic therapy in pancreatic ductal adenocarcinomas (PDACs)-basis and current status.

A major shift in the approach to the management of pancreatic ductal adenocarcinomas (PDACs) has been the recognition of the systemic nature of the disease even in clinically and radiologically limited disease stages. The recalcitrant nature of PDAC is intrinsically related to the lack of therapeutic targets and dense surrounding stroma that limits the activity of currently available chemotherapeutic options. However, research is increasingly focusing on intensifying systemic management options in PDAC, resulting in gradual improvements in survival. Currently effective chemotherapeutic regimens like modified 5-fluorouracil-leucovorin-irinotecan-oxaliplatin and gemcitabine-nab-paclitaxel have improved outcomes in resectable and advanced PDAC. An increasing use of these regimens has also resulted in greater conversion of borderline resectable and locally advanced cancers to resection, though the most effective approach in this subgroup is yet to be identified. The current review presents an outline of the basic systemic nature of PDAC and current options of systemic therapy, predominantly chemotherapy .

RMAC study: A randomized study for evaluation of metronomic adjuvant chemotherapy in recurrent head and neck cancers post salvage surgical resection in those who are ineligible for re-irradiation.

BACKGROUND: Adjuvant re-chemoradiation after salvage surgery improves disease-free survival in recurrent head and neck cancer. However, most patients are ineligible for re-irradiation and are kept on observation. We investigated the efficacy of metronomic adjuvant chemotherapy (MAC) in this group of patients compared to observation. METHODS: This was a randomized integrated phase II/III clinical trial. Adults with recurrent head and neck cancer, who had undergone salvage surgery, but were ineligible for adjuvant re-irradiation were randomized in a 1:1 ratio to either MAC arm or observation. MAC consisted of weekly oral methotrexate (at a dose of 15 mg per square meter of body surface area) and celecoxib (at a dose of 200 mg orally twice daily) for 6 months. The primary endpoint of phase 2 was disease-free survival (DFS) while that of phase 3 was overall survival (OS). For phase 2, to detect an improvement in the hazard ratio (HR) 0.67 with MAC, with a type 1 error of 10% (1-sided), type 2 error of 30%, 105 patients were required. While for phase 3, with a target HR of 0.77, with a type 1 error of 5%, type 2 error of 20%, 318 patients were required. Here we report the results of phase 2 part of the study. RESULTS: At a median follow up of 30.2 months (95% confidence interval (CI), 25.3 to 35.1) the 1 year and 2-year DFS were 57.4% (95% CI, 42.8-69.5) and 37.6% (95% CI, 24.1-51) in MAC arm whereas the corresponding numbers were 62.3% (95% CI, 47.8 to 73.8) and 54.2%(95% CI, 39.8 to 66.5) in observation arm, respectively (hazard ratio for progression, 1.45; 95% CI, 0.87 to 2.47; P = 0.15). In the MAC arm, the 1 and 2 year OS was 78.7% (95% CI, 64.9 to 87.6) and 48% (95% CI, 34.1 to 62).The corresponding figures in the observation arm were 79.2% (95% CI, 65.7 to 87.9) and 65.5% (95% CI, 50.9 to 76.7) (hazard ratio for death, 1.7, 95% CI, 0.94 to 3.08; P = 0.08). CONCLUSION: The adjuvant 6-month metronomic schedule was ineffective in improving outcomes in recurrent head and neck cancers post salvage surgery who are ineligible for re-radiation. TRIAL REGISTRATION: Clinical trial registry of India (CTRI)- CTRI/2016/04/006872 [Registered on 26/4/2016].

Phase I Study Evaluating Dose De-escalation of Sorafenib with Metformin and Atorvastatin in Hepatocellular Carcinoma (SMASH).

BACKGROUND: This phase I dose de-escalation study aimed to assess the tolerability, safety, pharmacokinetics (PK), and efficacy of sequentially decreasing doses of sorafenib in combination (SAM) with atorvastatin (A, 10 mg) and metformin (M, 500 mg BD) in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients were enrolled in 1 of 4 sequential cohorts (10 patients each) of sorafenib doses (800 mg, 600 mg. 400 mg, and 200 mg) with A and M. Progression from one level to the next was based on prespecified minimum disease stabilization (at least 4/10) and upper limits of specific grade 3-5 treatment-related adverse events (TRAE). RESULTS: The study was able to progress through all 4 dosing levels of sorafenib by the accrual of 40 patients. Thirty-eight (95%) patients had either main portal vein thrombosis or/and extra-hepatic disease. The most common grade 3-5 TRAEs were hand-foot-syndrome (grade 2 and grade 3) in 3 (8%) and transaminitis in 2 (5%) patients, respectively. The plasma concentrations of sorafenib peaked at 600 mg dose, and the concentration threshold of 2400 ng/mL was associated with higher odds of achieving time to exposure (TTE) concentrations >75% centile (odds ratio [OR] = 10.0 [1.67-44.93]; P = .01). The median overall survival for patients without early hepatic decompensation (n = 31) was 8.9 months (95% confidence interval [CI]: 3.2-14.5 months). CONCLUSION: The SAM combination in HCC patients with predominantly unfavorable baseline disease characteristics showed a marked reduction in sorafenib-related side effects. Studies using sorafenib 600 mg per day in this combination along with sorafenib drug level monitoring can be evaluated in further trials.(Trial ID: CTRI/2018/07/014865).

Neoadjuvant chemotherapy in technically unresectable head and neck cancers: a retrospective audit.

Background: The data regarding the use of neoadjuvant chemotherapy in technically unresectable head and neck cancer (HNC) is limited and real-world studies are needed to look for the efficacy and toxicities of this approach. Patients and methods: This is a retrospective study conducted in the Medical Oncology department of our hospital. All technically unresectable HNC patients who underwent neoadjuvant chemotherapy between May 2018 and May 2020 were included in this analysis. Patients received three-drug regimen docetaxel, cisplatin and 5-fluorouracil (DCF) regimen, two-drug regimens included docetaxel + cisplatin, paclitaxel + carboplatin both weekly and 3-weekly. The resectability assessment was done clinically and radiologically after completing three neoadjuvant cycles. Overall survival was calculated from the first day of chemotherapy to the date of last follow-up or date of death. Results: A total of 119 patients received neoadjuvant chemotherapy during the specified time. Response assessment showed partial response in 41.9% of patients with three-drug regimens and 37.5% of patients with other regimens. Out of 119 patients, 56 (47%) patients were offered radical intent therapy. Resectability was achieved in 32.3% of three-drug regimen patients and 26.1% of other patients. Surgery was feasible in 33 (27.7%) patients, and postoperative radiotherapy and concurrent chemotherapy were done in 30 patients (25.2%), and surgery with only postoperative radiotherapy was done in 3 patients (2.5%). Radical chemoradiotherapy was done in 23 patients (19.3%). The estimated median survival for patients who could undergo surgery was 18 months [95% confidence interval (CI), 14.9-21.0], and nonsurgical patients were 9 months (95% CI, 7.3-10.6) (p = 0.0001). Conclusion: Our study shows that neoadjuvant chemotherapy in technically unresectable HNC patients can make the disease resectable in around one-third of the patients. The patients who could undergo surgery after neoadjuvant chemotherapy had significantly improved survival as compared to those who could not.

The Prevalence of BRAF, PIK3CA, and RAS Mutations in Indian Patients with Colorectal Cancer.

Omshree ShettyVikas OstwalIntroduction The present study evaluates the mutation pattern and frequency of BRAF , PIK3CA and RAS in colorectal carcinoma observed in the tertiary cancer center in India. Materials and Methods Consecutive cases of colorectal adenocarcinoma ( n = 330) registered from January 2015 to December 2019 (5-year duration) were selected for the study. Molecular analysis for BRAF . PIK3CA (exon 9 and 20) and RAS ( KRAS & NRAS ) was performed on representative formalin-fixed paraffin-embedded tissues by Sanger sequencing. Results were correlated with clinicopathological features. Patient overall survival (OS) was obtained using Kaplan-Meier method. Results The study cohort was in the age range of 22 to 81 years (median age: 52 years) that included 202 males and 96 females (male: female ratio 2.1:1). BRAF V600E mutation was observed in three cases (1%), while 17 cases (5.7%) had mutations in the PIK3CA gene (exon 9 or exon 20). Mutation analysis for RAS gene ( KRAS & NRAS ) was observed among 42 (15.4%) cases with KRAS mutation and 11 (4%) cases were positive for NRAS mutations. Among RAS, KRAS G12D was the predominant mutation. Median OS with wild-type RAS was 46.6 months (95% confidence interval [CI]: 22.4-70.8), while for RAS mutated patients, it was 25.6 months (95% CI: 16.7-34.5), hazard ratio: 1.7 (95% CI: 1.1-2.7, p = 0.025). Conclusion This study evaluated the prevalence of BRAF, PIK3CA and RAS mutations in the Indian cohort and its impact on clinical behavior. There was lower incidence of BRAF mutations in this cohort and PIK3CA mutation (single) did not impact survival of the patients.

Demographics, Pattern of Care, and Outcome Analysis of Malignant Melanomas - Experience From a Tertiary Cancer Centre in India.

BACKGROUND: Treatment of malignant melanoma has undergone a paradigm shift with the advent of immune checkpoint inhibitors (ICI) and targeted therapies. However, access to ICI is limited in low-middle income countries (LMICs). PATIENTS AND METHODS: Histologically confirmed malignant melanoma cases registered from 2013 to 2019 were analysed for pattern of care, safety, and efficacy of systemic therapies (ST). RESULTS: There were 659 patients with a median age of 53 (range 44-63) years; 58.9% were males; 55.2% were mucosal melanomas. Most common primary sites were extremities (36.6%) and anorectum (31.4%). Nearly 10.8% of the metastatic cohort were BRAF mutated. Among 368 non-metastatic patients (172 prior treated, 185 de novo, and 11 unresectable), with a median follow-up of 26 months (0-83 months), median EFS and OS were 29.5 (95% CI: 22-40) and 33.3 (95% CI: 29.5-41.2) months, respectively. In the metastatic cohort, with a median follow up of 24 (0-85) months, the median EFS for BSC was 3.1 (95% CI 1.9-4.8) months versus 3.98 (95% CI 3.2-4.7) months with any ST (HR: 0.69, 95% CI: 0.52-0.92; P = 0.011). The median OS was 3.9 (95% CI 3.3-6.4) months for BSC alone versus 12.0 (95% CI 10.5-15.1) months in any ST (HR: 0.38, 95% CI: 0.28-0.50; P < 0.001). The disease control rate was 51.55%. Commonest grade 3-4 toxicity was anemia with chemotherapy (9.5%) and ICI (8.8%). In multivariate analysis, any ST received had a better prognostic impact in the metastatic cohort. CONCLUSIONS: Large real-world data reflects the treatment patterns adopted in LMIC for melanomas and poor access to expensive, standard of care therapies. Other systemic therapies provide meaningful clinical benefit and are worth exploring especially when the standard therapies are challenging to administer.

Utility of Panfungal PCR in the diagnosis of invasive fungal infections in febrile neutropenia.

BACKGROUND: The prevalence of invasive fungal infections (IFIs) is increasing due to the increasing population of immunocompromised patients. Fungal culture is the gold standard for diagnosis but not sensitive and the turnaround time is long. Samples for histopathology are difficult to obtain because of profound cytopenias. We conducted this study with the aim to evaluate panfungal PCR for the diagnosis of IFIs in patients of febrile neutropenia. METHODS: This was a single-centre, cross-sectional observational study. Patients of febrile neutropenia suspected of having IFI were included in the study. Panfungal PCR was performed on the blood of included patients along with other investigations for diagnosis of IFI. The sensitivity, specificity, positive predictive value, and negative predictive value of panfungal PCR were calculated using EORTC/MSG 2008 criteria as the gold standard. RESULTS: Fifty patients of febrile neutropenia were included in the study, of which 52% were diagnosed positive by panfungal PCR assay. The sensitivity, specificity, positive predictive value, and negative predictive value of panfungal PCR assay was found to be 82.76%, 90.48%, 92.31% and 79.17% respectively. CONCLUSION: Panfungal PCR is a promising and highly sensitive diagnostic test for screening at-risk patients suspected to have IFIs. The use of panfungal PCR assay in combination with other diagnostic modalities and clinical judgment can be very helpful in the early diagnosis of IFI.