Ten years survival results of randomized study comparing weekly vs. triweekly cisplatin with concurrent radiation in locally advanced carcinoma cervix.

Background: The current standard of treatment for locally advanced cervical cancer is concurrent chemo-radiation with improved overall survival (OS) by 6% with manageable toxicities. The cisplatin 40 mg/m2 given weekly is the widely practiced regimen for 4-6 cycles concurrently with irradiation. Materials and methods: Two hundred and twelve patients with histologically proven squamous cell carcinoma of cervix with stages IIB to IIIB were enrolled between 2007-2011. External beam radiation dose of 45 Gy in 25 fractions was delivered over 5 weeks. Brachytherapy was delivered by manual afterloading cesium-137 (Cs137) low dose brachytherapy (LDR) using modified Fletcher suit intracavitary applicators to a total dose of 30 Gy to Point A or interstitial template to dose of 21 Gy/3 fractions with remote afterloading iridium-192 (Ir192) high dose brachytherapy (HDR). Patients were randomized to arm A receiving 40 mg/m2 of concurrent cisplatin weekly and arm B receiving 100 mg/m2 of concurrent cisplatin triweekly. Results: One hundred and nine patients were randomized to weekly cisplatin and one hundred and three patients to triweekly cisplatin at the end of recruitment. At ten years, the OS was higher in the weekly arm (79.8%) compared to triweekly arm (70.9%). Disease free survival (DFS) was almost equal (76.1% and 73.8%) in the weekly and three-weekly arms. There is definite significance in overall DFS with patients receiving the cumulative cisplatin doses of more than 250 mg (p = 0.028). The patients with more than 45 years of age had better overall survival (OS) (79%) with statistical significance 31 (p = 0.020). Conclusion: Both cisplatin based triweekly and weekly concurrent chemotherapy are equally effective in terms of OS and DFS.

Consensus guidelines for the management of HR-positive HER2/neu negative early breast cancer in India, SAARC region and other LMIC by DELPHI survey method.

BACKGROUND: Precise prognostication is the key to optimum and effective treatment planning for early-stage hormone receptor (HR) positive, HER2/neu negative breast cancer patients. Differences in the breast cancer incidence and tumor anatomical features at diagnosis, pharmacogenomics data between Western and Indian women along with the vast diversity in the economic status and differences in insurance policies of these regions; suggest recommendations put forward for Western women might not be applicable to Indian/Asian women. Opinions from oncologists through a voting survey on various prognostic factors/tools to be considered for planning adjuvant therapy are consolidated in this report for the benefit of oncologists of the sub-continent, SAARC and Asia's LMIC (low and middle-income countries). METHODS: A three-phase DELPHI survey was conducted to collect opinions on prognostic factors considered for planning adjuvant therapy in early-stage HR+/HER2/neu negative breast cancer patients. A panel of 25 oncologists with expertise in breast cancer participated in the survey conducted in 2021. The experts provided opinions as 'agree' or disagree' or 'not sure' in phases-1 and 2 which were conducted virtually; in the final phase-3, all the panel experts met in person and concluded the survey. RESULTS: Opinions on 41 statements related to prognostic factors/tools and their implications in planning adjuvant endocrine/chemotherapy were collected. All the statements were supported by the latest data from the clinical trials (prospective/retrospective). The statements with opinions of consensus less than 66% were disseminated in phase-2, and later in phase-3 with supporting literature. In phase-3, all the opinions from panelists were consolidated and guidelines were framed. CONCLUSIONS: This consensus guideline will assist oncologists of India, SAARC and LMIC countries in informed clinical decision-making on adjuvant treatment in early HR+/HER2/neu negative breast cancer patients.

The clinical utility and safety of short-course immune checkpoint inhibitors in multiple tumours-A real-world multicentric study from India.

The real-world data on short course of immune checkpoint inhibitor (ICI) use are sparse and merit exploration. A multicentric observational study on the safety and efficacy of ICI in oncology patients between August 2014 and October 2020 involves 1011 patients across 13 centers in India. The median age was 59 (min 16-max 98) years with male preponderance (77.9%). The predominant cohort received short-course ICI therapy; the median number of cycles was 5 (95% confidence interval [CI] 1-27), and the median duration of therapy was 3 (95% CI 0.5-13) months. ICIs were used commonly in the second and third line setting in our study (66.4%, n = 671). Objective response rate (complete or partial response) was documented in 254 (25.1%) of the patients, 202 (20.0%) had stable disease, and 374 (37.0%) had progressive disease. The clinical benefit rate was present in 456 (45.1%). Among the patients whom ICI was stopped (n = 906), the most common reason for cessation of ICI was disease progression (616, 68.0%) followed by logistic reasons like financial constraints (234, 25.82%). With a median follow-up of 14.1 (95% CI 12.9-15.3) months, there were 616 events of progression and 443 events of death, and the median progression free survival and overall survival were 6.4 (95% CI 5.5-7.3) and 13.6 (95% CI 11.6-15.7) months, respectively, in the overall cohort. Among the immune-related adverse events, autoimmune pneumonitis (29, 3.8%) and thyroiditis (24, 2.4%) were common. Real-world multicentric Indian data predominantly with short-course ICI therapy have comparable efficacy/safety to international literature with standard ICI therapy.

Metastatic hormone receptor-positive breast cancer in CDK 4/6 era: An outcome audit.

BACKGROUND: The treatment landscape of metastatic hormone receptor (HR) positive breast cancer has been changed in recent years. Availability of CDK 4/6 inhibitor and other hormone therapy has changed the treatment algorithm for these patient, we retrospectively analyzed our metastatic HR positive breast cancer patients. MATERIALS AND METHODS: In this study, we retrospectively analyzed the case records of hr positive metastatic breast cancer patient treated at department of medical oncology from October 2016 to September 2018. Demographical characteristics, site of metastasis, objective response and clinical benefit response and toxicity profile were analyzed. RESULTS: We treated a total of 178 patients of MBC with HT at our center during the study period. One hundred fifty-two patients received HT alone (control group) and 26 patients received HT and CDK 4/6 inhibitor (study group). The median age of patients was 56 and 58 years in the control group and study group. The ORR was 41.7 versus 57.9 (95% CI [1.01-2.56]), and the CBR was 66.1% versus 78.9%; (CI [1.18-3.56]) (P < 0.05) of the patients in control and study groups, respectively. CONCLUSIONS: Among patients with HR-positive, advanced breast cancer, hormone therapy is efficacious addition of CDK 4/6 inhibitor improve the efficacy with tolerable side effects.

JAK-STAT inhibitor as a potential therapeutic opportunity in AML patients resistant to cytarabine and epigenetic therapy.

The prognosis of AML is generally poor, with 5-year survival rate of 25%. There has been substantial progress in identification of new therapeutic targets, along with approval of at least three targeted therapies for AML in recent years. Nevertheless, treatment has largely remained unchanged over couple of decades, with ~40% patients not achieving remission. AML is a highly heterogenous disease and there is a need for a preclinical platform to understand the heterogeneity and tumor microenvironment that can guide therapy selection. In this study, we employed an ex vivo tumor explant model to study tumor microenvironment and to select a treatment course for AML patients. Our data reveal dysregulation of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) in a subset of AML patients. Based on this observation, epigenetic modulators azacitidine and panobinostat alone and in combination, were evaluated as treatment regimens in cytarabine refractory tumors. More than 50% of the treated samples showed response to the combination therapy. In order to explore alternate treatment modalities for tumors refractory to these epigenetic modulators, TCGA data analysis was done which revealed increased expression and hypomethylation of IFNGR1/2, suggesting activation of JAK/STAT pathway in AML. This was further interrogated ex vivo, with p-STAT3 expression in patients' samples. Fedratinib, a JAK/STAT inhibitor was evaluated and 78% tumor efficacy response was achieved. Taken together, our data indicate that ex vivo platform derived from patient samples is capable in guiding optimal therapy selection for various classes of drugs including identification of novel targeted therapies.

Practical Consensus Recommendations for Optimizing Risk versus Benefit of Chemotherapy in Patients with HR Positive Her2 Negative Early Breast Cancer in India.

Breast cancer is a public health challenge globally as well as in India. Improving outcome and cure requires appropriate biomarker testing to assign risk and plan treatment. Because it is documented that significant ethnic and geographical variations in biological and genetic features exist worldwide, such biomarkers need to be validated and approved by authorities in the region where these are intended to be used. The use of western guidelines, appropriate for the Caucasian population, can lead to inappropriate overtreatment or undertreatment in Asia and India. A virtual meeting of domain experts discussed the published literature, real-world practical experience, and results of opinion poll involving 185 oncologists treating breast cancer across 58 cities of India. They arrived at a practical consensus recommendation statement to guide community oncologists in the management of hormone positive (HR-positive) Her2-negative early breast cancer (EBC). India has a majority (about 50%) of breast cancer patients who are diagnosed in the premenopausal stage (less than 50 years of age). The only currently available predictive test for HR-positive Her2-negative EBC that has been validated in Indian patients is CanAssist Breast. If this test gives a score indicative of low risk (< 15.5), adjuvant chemotherapy will not increase the chance of metastasis-free survival and should not be given. This is applicable even during the ongoing COVID-19 pandemic.

Weekly vs. tri-weekly cisplatin based chemoradiation in carcinoma cervix: a prospective randomized study of toxicity and compliance.

BACKGROUND: Addition of chemotherapy to radiation has improved 5-year survival by 6%. However, the optimal dose and schedule of concurrent cisplatin is not well defined, though widely accepted practice is the weekly schedule of 40 mg/m2 for 5 weeks. Repeated admissions for weekly cisplatin drain the limited resources in high volume centres. We intended to study the compliance and toxicity of two cisplatin schedules in our patients diagnosed with carcinoma cervix. MATERIALS AND METHODS: Between 2007-2011, 212 patients, histologically proven squamous cell carcinoma with stages IIB to IIIB were randomized into two arms. All patients were planned for external beam radiotherapy 45 Gy/25 frs over 5 weeks followed by Intracavitary or Interstitial brachytherapy to a total BED dose of 75-85 Gy. Single agent cisplatin given concomitantly, was scheduled weekly (40 mg/m2/cycle, 5 cycles) in an arm A and three weekly (100 mg/m2/cycle, 2 cycles) in an arm B. Toxicity and compliance were evaluated weekly according to the RTOG guidelines. Analysis of the compiled data was done using SSPS version 20. RESULTS: Of the evaluable 212, 109 patients received weekly cisplatin chemotherapy and 103 patients received three weekly cisplatin. The most common acute toxicity observed was grade I-II leucopoenia. The upper and lower gastrointestinal reactions were high in three weekly arms, which was statistically significant (57% and 42.7%, p < 0.05). Proctitis was observed in 10% of patients in both of the arms and only two patients had Gr1 Cystitis after 6 months of treatment. CONCLUSIONS: Tri-weekly cisplatin based concurrent chemoradiation can be adopted in high volume centres with manageable haematological and gastrointestinal acute toxicities.

Prognostic and predictive role of gene mutations in chronic lymphocytic leukemia: results from the pivotal phase III study COMPLEMENT1.

Next generation sequencing studies in Chronic lymphocytic leukemia (CLL) have revealed novel genetic variants that have been associated with disease characteristics and outcome. The aim of this study was to evaluate the prognostic value of recurrent molecular abnormalities in patients with CLL. Therefore, we assessed their incidences and associations with other clinical and genetic markers in the prospective multicenter COMPLEMENT1 trial (treatment naive patients not eligible for intensive treatment randomized to chlorambucil (CHL) vs. ofatumumab-CHL (O-CHL)). Baseline samples were available from 383 patients (85.6%) representative of the total trial cohort. Mutations were analyzed by amplicon-based targeted next generation sequencing (tNGS). In 52.2% of patients we found at least one mutation and the incidence was highest in NOTCH1 (17.0%), followed by SF3B1 (14.1%), ATM (11.7%), TP53 (10.2%), POT1 (7.0%), RPS15 (4.4%), FBXW7 (3.4%), MYD88 (2.6%) and BIRC3 (2.3%). While most mutations lacked prognostic significance, TP53 (HR2.02,p<0.01), SF3B1 (HR1.66,p=0.01) and NOTCH1 (HR1.39,p=0.03) were associated with inferior PFS in univariate analysis. Multivariate analysis confirmed the independent prognostic role of TP53 for PFS (HR1.71,p=0.04) and OS (HR2.78,p=0.02) and of SF3B1 for PFS only (HR1.52,p=0.02). Notably, NOTCH1 mutation status separates patients with a strong and a weak benefit from ofatumumab addition to CHL (NOTCH1wt:HR0.50,p<0.01, NOTCH1mut:HR0.81,p=0.45). In summary, TP53 and SF3B1 were confirmed as independent prognostic and NOTCH1 as a predictive factor for reduced ofatumumab efficacy in a randomized chemo (immune)therapy CLL trial. These results validate NGS-based mutation analysis in a multicenter trial and provide a basis for expanding molecular testing in the prognostic workup of patients with CLL. ClinicalTrials.gov registration number: NCT00748189.

Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7).

BACKGROUND: This analysis evaluated patient-reported outcomes (PROs) to assess health-related quality of life (HRQoL) in the phase III MONALEESA-7 trial, which previously demonstrated improvements in progression-free survival (PFS) and overall survival (OS) with ribociclib (cyclin-dependent kinase 4/6 inhibitor) + endocrine therapy (ET) compared with placebo + ET in pre- and perimenopausal patients with hormone-receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC). METHODS: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire C30 (QLQ-C30) and the EQ-5D-5L were used to evaluate HRQoL. RESULTS: EORTC QLQ-C30 assessments were evaluable for 335 patients in the ribociclib arm and 337 patients in the placebo arm. Adherence rates at baseline and ⩾1 postbaseline time point were 90% and 83%, respectively. Patients treated with ribociclib + ET had a longer time to deterioration (TTD) ⩾ 10% in global HRQoL {hazard ratio (HR), 0.67 [95% confidence interval (CI), 0.52-0.86]}. TTD ⩾ 10% in global HRQoL was delayed in ribociclib-treated patients without versus with disease progression [HR, 0.31 (95% CI, 0.21-0.48)]. TTD ⩾ 10% in pain was longer with ribociclib + ET than with placebo + ET [HR, 0.65 (95% CI, 0.45-0.92)]. Patients who received a nonsteroidal aromatase inhibitor experienced similar benefits with ribociclib versus placebo in global HRQoL and pain. CONCLUSION: HRQoL was maintained longer in patients who received ribociclib + ET versus placebo + ET. These data, combined with previously reported improvements in PFS and OS, support a strong clinical benefit-to-risk ratio with ribociclib-based treatment in pre- and perimenopausal patients with HR+/HER2- ABC.

Evolution of the treatment of primary central nervous system lymphoma in a Regional Cancer Center of South India: Impact of high-dose methotrexate on treatment outcome.

OBJECTIVE: Primary central nervous system lymphoma (PCNSL) is a rare form of aggressive extranodal non-Hodgkin lymphoma. This study attempts to delineate the clinicopathological and radiological profile of PCNSL cases at our center. MATERIALS AND METHODS: All the pathologically confirmed PCNSL cases between January 2007 and July 2016 were analyzed retrospectively. The influence of potential prognostic parameters and therapeutic strategies on survival was investigated by log-rank test and Cox regression analysis. RESULTS: Of the 53 PCNSL patients, 34 (64%) patients were males. Median age at diagnosis was 44 years (range 22-65 years). The most common location in the brain was the cerebral hemispheres in 32 patients (60%), and 16 patients (30%) had multiple intracranial lesions. Histologically, all patients were diffuse large B-cell lymphomas, except one case of anaplastic large-cell lymphoma. The median survival of the patients received whole-brain radiation alone ( n = 6), standard CHOP chemotherapy + radiation ( n = 14), and DeAngelis protocol ( n = 31) was 8 months, 13 months, and 23 months, respectively. Among the 31 patients treated with DeAngelis protocol, Memorial Sloan Kettering Cancer Center Class 1 ( n = 23) and Class 2 ( n = 8) patients had a median overall survival (OS) of 25 months and 13 months, respectively. The incidence of treatment-related neurotoxicity was significantly higher with DeAngelis protocol, in comparison to CHOP + whole-brain radiation therapy (26% vs. 14%, P < 0.05). CONCLUSION: None of the potential prognostic factors had a statistically significant influence on OS in our patients. High-dose methotrexate-based chemotherapy combined with radiation was the only factor, which had a significant impact on survival (log-rank P = 0.000) but at the cost of increased neurotoxicity.

Gender climate in Indian oncology: national survey report.

INTRODUCTION: There is evidence of under-representation of women in leadership roles and publications in oncology. However, there is little knowledge about their perceptions of professional environment, unique challenges and opportunities compared with male counterparts. The problem is more prominent in lower-income and middle-income countries like India and merits exploration. MATERIALS AND METHODS: A survey, 'Exploratory Study on the Challenges of Female Oncologists in India', was conducted among oncology professionals. We included questions on demography, working team details, role at work, perceived challenges for advancement of career, gender-related values brought into the team and the measures for improvement of gender disparity. Lead authorship data were collected from two Indian oncology journals. RESULTS: Of the 324 respondents, 198 (61.1%) were women. Majority of the respondents were medical oncologists (46.3%), ≤45 years old (69.4%) and working in universities and corporate hospitals (71.6%). One hundred eighty-nine (58.3%) respondents worked in teams with male majority, 50 (15.4%) in women-majority teams, while 85 (26.2%) worked in teams with gender equality. Of the 324 respondents, 218 (67.3%) had men managers, while 106 (32.7%) had women managers. Men led 160 (84.7%) male-majority teams; 45 (52.9%) gender-equal teams; and 13 (26%) female-majority teams (p<0.00001). Age >45 years was found to be associated with a leadership role (43% vs 25%, p=0.0012). The most significant barrier perceived for advancement of career for women was finding a work-life balance. Most respondents suggested provision of flexible training programmes to improve the disparity. Of the 558 journal publications inspected, 145 (26%) articles had a female first or corresponding author. CONCLUSIONS: The study brought out the current figures regarding gender climate in oncology practice and academia across India. We identified lead thrust areas and schemes to improve the gender bias. There needs to be action at international, national and personal levels to bring about an efficient gender-neutral workforce.

Indian clinical practice consensus guidelines for the management of squamous cell carcinoma of head and neck.

Head and neck cancers (HNCs) are malignant tumors of the upper aerodigestive tract and are the sixth most common cancer worldwide. In India, around 30-40% of all cancers are HNCs. Even though there are global guidelines or recommendations for the management of HNCs, these may not be appropriate for Indian scenarios. In an effort to discuss current practices, latest developments and to come to a consensus to recommend management strategies for different anatomical subsites of HNCs for Indian patients, a group of experts (medical, surgical and radiation oncologists and dentists) was formed. A review of literature from medical databases was conducted to provide the best possible evidence base, which was reviewed by experts during a consensus group meeting (January, 2019) to provide recommendations.

Every distant deposit is not a metastasis: Synchronous primaries do exist.

BACKGROUND: Synchronous occurrence of two malignant tumors is a rare event. With increasing use of sophisticated imaging modalities for staging, synchronous multiple tumors are more commonly detected now. Assuming the second primary malignancy as metastasis will change the intent of treatment from curative to palliative, greater awareness among oncologists is of paramount importance. This study is an example where thorough clinical examination and proper judgment resulted in correct diagnosis and appropriate treatment. MATERIALS AND METHODS: This is a prospective descriptive study. Patients diagnosed with synchronous primary tumors from January 2016 to November 2017 at our center were reviewed. RESULTS: Ten cases of synchronous primary malignancies were detected during this period. A total of 20 primary tumors were diagnosed. Lung carcinoma and gastrointestinal malignancies were the most common (five patients each). The median age was 59.5 years. Seven patients were male. Second primary tumor was suspected in four patients during clinical examination, while in six patients it was suspected on imaging. Even in the presence of two primary tumors, three patients were treated with curative intent. CONCLUSION: Possibility of synchronous second primary malignancy should always be kept whenever a distant deposit is detected at an unusual site. Histopathological evaluation of the lesion before assuming a metastasis will lead to accurate diagnosis, staging, and appropriate treatment.

A prospective study to compare the measured glomerular filtration rate compared to estimated glomerular filtration rate in patients undergoing definitive chemoradiation, with platinum agents for various malignancies.

CONTEXT: Renal function assessment is of paramount importance before using the platinum agents especially cisplatin. Glomerular filtration rate (GFR) estimation by diethyl-triamine-penta-acetic acid (DTPA) scan (measured GFR [mGFR]) is considered gold standard. AIMS: The aim of this study is to know if we can replace the mGFR with the GFR estimation with Cockcroft-Gault formula (eGFR) in patients undergoing chemoradiation. SETTINGS AND DESIGN: This is a prospective, descriptive study. SUBJECTS AND METHODS: Patients who are planned for definitive chemoradiation will be eligible for the study. Renal function will be measured DTPA scan and Cockcroft-Gault (CG) formula. Subgroup analysis based on the weight, age, and sex will be done. STATISTICAL ANALYSIS USED: Demographic and renal function parameters were analyzed using summary measures. To test the significance of the difference between mGFR and cGFR, a paired t-test will be used; to look for an association between various estimates of renal function, the Pearson's correlation coefficient will be calculated using a two-tailed test. RESULTS: Median mGFR of patients was 82.7 (range: 65-125 ml/min, standard deviation [SD] =14.0 ml/min) while the median eGFR as per the CG formula was 83.9 ml/min (range: 37-137 ml/min, SD = 24.4 ml/min). The median mGFR was only 1.2 ml/min lesser when measures by the CG formula with no significance difference between them (P = 0.66, 95% confidence interval: -4.5-6.3). CONCLUSIONS: We concluded that in resource-limited setting eGFR using CG formula can replace mGFR, especially in patients with age <60 years. Although weight did not showed a significant difference by two methods, a study with large sample is needed to confirm the result.