Assessing frailty in older Indian patients before cancer treatment: Comparative analysis of three scales and their implications for overall survival.

INTRODUCTION: Frailty, characterized by ageing-related vulnerability, influences outcomes in older adults. Our study aimed to investigate the relationship between frailty and clinical outcomes in older Indian patients with cancer. MATERIALS AND METHODS: Our observational single-centre study, conducted at Tata Memorial Hospital from February 2020 to July 2022, enrolled participants aged 60 years and above with cancer. Frailty was assessed using the Clinical Frailty Scale (CFS), G8, and Vulnerable Elders Survey (VES)-13. The primary objective was to explore the correlation between baseline frailty and overall survival. Statistical analyses include Kaplan-Meier, Cox proportional hazards, and Harrell's C test. RESULTS: A total of 1,177 patients (median age 68, 76.9% male) were evaluated in the geriatric oncology clinic. Common malignancies included lung (40.0%), gastrointestinal (35.8%), urological (11.9%), and head and neck (9.0%), with 56.5% having metastatic disease. Using CFS, G8, and VES-13 scales, 28.5%, 86.4%, and 38.0% were identified as frail, respectively. Median follow-up was 11.6 months, with 43.3% deaths. Patients fit on CFS (CFS 1-2) had a median survival of 28.02 months, pre-frail (CFS 3-4) 13.24 months, and frail (CFS ≥5) 7.79 months (p < 0.001). Abnormal G8 (≤14) and VES-13 (≥3) were associated with significantly lower median survival (p < 0.001). Multivariate analysis confirmed CFS's predictive power for mortality (p < 0.001), with hazard ratios [HRs] for pre-frail at 1.61(95% confidence interval [CI] 1.25 to 2.06) and frail at 2.31 (95%CI 1.74 to 3.05). G8 ≤ 14 had HR 2.00 (95%CI 1.42 to 2.83), and abnormal VES-13 had HR 1.36 (95%CI 1.11-1.67). In the likelihood ratio test, CFS significantly improved the model fit (p < 0.001). Harrell's C index for survival prediction was 0.62 for CFS, 0.54 for G8, and 0.58 for VES-13. DISCUSSION: In conclusion, our study highlights varying frailty prevalence and prognostic implications in older Indian patients with cancer, emphasizing the need for personalized care in oncology for this aging population. We would recommend using CFS as a tool to screen for frailty for older Indian patients with cancer.

The current status of geriatric oncology in India.

Geriatric oncology in India is relatively new. The number of older persons with cancer is increasing exponentially; at our institution, 34% of patients registered are 60 years and over. Apart from the Tata Memorial Hospital in Mumbai, there are currently no other Indian centers that have a dedicated geriatric oncology unit. Geriatric assessments (GAs) are done sporadically, and older patients with cancer are usually assessed and treated based on clinical judgement. Challenges to increasing the uptake of GA include a lack of training/time/interest or knowledge of the importance of the GA. Other challenges include a lack of trained personnel with expertise in geriatric oncology, and a paucity of research studies that seek to advance the outcomes in older Indian patients with cancer. We anticipate that over the next 10 years, along with the inevitable increase in the number of older persons with cancer in India, there will be a commensurate increase in the number of skilled personnel to care for them. Key goals for the future include increased research output, increased number of dedicated geriatric oncology units across the country, India-specific geriatric oncology guidelines, geriatric oncology training programs, and a focus on collaborative work across India and with global partners. In this narrative review, we provide a broad overview of the status of geriatric oncology in India, along with a description of the work done at our center. We hope to spark interest and provide inspiration to readers to consider developing geriatric oncology services in other settings.

Feasibility of therapeutic drug monitoring of sunitinib and its implications on response and toxicity in patients with metastatic renal cell cancer.

PURPOSE: Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). High variability in pharmacokinetics coupled with a proven exposure-effect relationship makes sunitinib an ideal candidate for therapeutic drug monitoring (TDM). The feasibility of TDM of sunitinib in patients with mRCC was evaluated in this prospective observational study in a real-world scenario. METHODS: Seventy patients with mRCC treated with sunitinib at a fixed dose of 50 mg per day were enrolled in the study. Total trough plasma level (TTL) of sunitinib (sunitinib and its active metabolite, SU12662), was measured between days 14/15 of cycle 1. The discriminatory potential of TTL of sunitinib for the prediction of responders and occurrence of grade ≥ 3 toxicity was determined using receiver operating characteristic (ROC) curve. RESULTS: The median TTL of sunitinib was 76 ng/mL. Forty six out of 70 patients were evaluable for response, whereas 60 out of 70 patients were evaluable for toxicity. Threshold concentrations obtained from ROC analysis showed that TTL of 60.75 ng/mL and 82.3 ng/mL was discriminatory for response and occurrence of grade ≥ 3 toxicity respectively. 31/34 (91.7%) patients having TTL ≥ 60.75 ng/mL responded to treatment, while only 5/12 (41.6%) responded when TTL was < 60.75 ng/mL (P = 0.001). On the other hand, the incidence of grade ≥ 3 toxicity was 9/24 (37.7%) in patients with TTL ≥ 82.3 ng/mL compared to 4/36 (11.1%) in patients with TTL < 82.3 ng/mL (P = 0.024). CONCLUSION: The TTL range of 60.75-82.3 ng/mL was found to be optimal in terms of safety and efficacy. More than 50% of patients in our cohort attained TTL of sunitinib outside the optimal range, thus demonstrating the feasibility of TDM to improve safety and efficacy of sunitinib in mRCC.

ADME gene polymorphisms do not influence the pharmacokinetics of docetaxel: Results from a population pharmacokinetic study in Indian cancer patients.

BACKGROUND: Pharmacokinetics (PK) of docetaxel is characterized by high inter-individual variability (IIV). While covariate models that explain the PK variability of docetaxel exist, not much is known about the effects of genetic variations on docetaxel disposition. METHODS: Fifty patients with head and neck or prostate cancer were enrolled of whom two patients withdrew consent before the start of the study. Docetaxel was administered at either 50 or 75 mg/m2 as intravenous infusion over 1 h. One pharmacogenetic sample and a series of PK samples, either intensive (N = 5; 13 samples each) or sparse (N = 43; 6 samples each), were collected from each patient. Docetaxel levels were estimated using a validated HPLC method. Polymorphic loci on the Absorption, Distribution, Metabolism, and Elimination (ADME) genes were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. RESULTS: Docetaxel PK was well characterized by a three-compartment model. Clearance (Cl) was found to be 18 L/h with an IIV of 45.3%. None of the genetic variants showed significant covariate effect on the Cl of docetaxel. Patients with abnormal alanine aminotransferase (ALT) were found to have 25% lower Cl as compared to patients with normal ALT values. However, the covariate effect could not be established in the final model possibly due to lack of adequate number of patients with abnormal ALT. CONCLUSION: Genetic polymorphisms in the ADME gene do not explain the IIV in PK of docetaxel. However, patients with abnormal liver function might require dose reduction. CLINICAL TRIAL REGISTRATION: Not applicable since participants in this study received treatment that was standard of care.

Effect of body mass index on pharmacokinetics of paclitaxel in patients with early breast cancer.

BACKGROUND: Paclitaxel is dosed according to body surface area (BSA) but there is scant information on actual drug exposure in overweight and obese patients. METHODS: Early breast cancer patients receiving paclitaxel at 175 mg/m2 every 3 weeks, in two BMI groups (normal, 18-24.9 kg/m2 and overweight/obese, ≥25 kg/m2 , respectively), matched for age, serum albumin and bilirubin levels using minimization technique, were included. Sparse pharmacokinetic (PK) sampling was performed at 7 time points from 0 h until 24 h of starting paclitaxel in cycle 1. Paclitaxel concentration was measured using a validated LCMS/MS method. Covariate effect on paclitaxel PK was evaluated by population PK analysis using NONMEM software. RESULTS: Eighteen female patients each were enrolled in normal and overweight groups with mean BMI of 21.62 ± 2.06 and 28.16 ± 2.31 kg/m2 , mean BSA of 1.44 ± 0.11 and 1.69 ± 0.14 m2 and mean paclitaxel dose of 250 ± 18 and 293 ± 21 mg, respectively. Model predicted AUC and dose normalized AUC (mean ±SD) in the normal BMI versus overweight obese groups were 23 ± 11.0 µmol*h/L versus 25.7 ± 13.7 µmol*h/L (two-sample t-test p > 0.05) and 0.08 ± 0.04 (µmol*h/L)/ µmol versus 0.08 ± 0.04 (µmol*h/L)/ µmol (2-sample t-test p > 0.05), respectively. No significant correlation was observed between BMI and standardized dose normalized AUC (Pearson's correlation coefficient, -0.009; p > 0.05). CONCLUSION: When dosed according to BSA calculated using actual body weight there is no significant difference in paclitaxel exposure between normal and overweight women. Using alternative descriptors of weight to calculate BSA could lead to under-dosing of this drug. TRIAL REGISTRATION: This study is registered in the Clinical Trials Registry of India CTRI/2015/09/006193.

Safety and CSF distribution of high-dose erlotinib and gefitinib in patients of non-small cell lung cancer (NSCLC) with brain metastases.

PURPOSE: Patients of non-small cell lung cancer (NSCLC) with brain metastases have limited treatment options. High-dose erlotinib (HDE) and gefitinib (HDG) have been tried in the past. This study investigates the cerebrospinal fluid (CSF) disposition and safety of both, high-dose erlotinib and gefitinib regimens. METHODS: Eleven and nine patients were treated with erlotinib and gefitinib, respectively. All patients received 1 week of standard dose of erlotinib (150 mg OD) or gefitinib (250 mg OD), followed by the high dose (1500 mg weekly for erlotinib and 1250 mg OD for gefitinib) from day 8. Blood and CSF samples were collected on days 7 and 15, 4 h after the morning dose and drug levels determined using LC-MS/MS. Adverse events were documented as per CTCAE 4.03 till day 15. RESULTS: Pulsatile HDE and daily HDG resulted in 1.4- and 1.9-fold increase in CSF levels, respectively. A constant 2% CSF penetration rate was observed across both doses of erlotinib, while for gefitinib the penetration rate for high dose was half that of the standard dose suggesting a nonlinear disposition. Three patients on HDE treatment discontinued treatment after the first dose due to intolerable toxicities, whereas HDG was better tolerated with no treatment discontinuations. Since CSF disposition of gefitinib followed saturable kinetics, a lower dose of 750 mg was found to achieve CSF concentrations comparable to that of the 1250 mg dose. CONCLUSIONS: HDG was better tolerated than HDE. CSF disposition of gefitinib was found to be saturable at a higher dose. Based on these findings, the dose of 750 mg OD should be considered for further evaluation in this setting.

A Limited Sampling Strategy for Therapeutic Drug Monitoring of Mycophenolate Mofetil for Prophylaxis of Acute Graft-Versus-Host Disease in Allogeneic Stem Cell Transplantation.

A universally accepted strategy for therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) in the prevention of acute graft-versus-host disease (aGVHD) in allogenic hematopoietic stem cell transplantation (alloHSCT) does not exist. We explored the feasibility of developing a limited sampling strategy (LSS) for TDM of MMF in this setting. Patients undergoing alloHSCT received standard MMF-cyclosporine prophylaxis, with MMF administered twice daily (BD) for matched transplant recipients or thrice daily (TID) in haploidentical transplantation. Intensive blood sampling was carried out on day 7 and area under the concentration-time curve (AUC) of mycophenolic acid (MPA), the active metabolite, was estimated using noncompartmental analysis. The ability of MPA exposure defined by AUC0-12 to discriminate between responders (patients who did not develop GVHD) and nonresponders (patients who developed GVHD) was determined by receiver operating characteristic curve analysis. Patients were divided into training and validation sets within BD and TID groups. Mathematical equations were developed from the training set to predict AUC0-12 from an abbreviated AUC involving a limited number of sampling points. The equations were validated in the validation set by comparing the MPA AUC0-12 predicted from LSS with the observed AUC0-12. It was observed that patients with AUC0-12 ≤18.99 mg*h/L had a higher risk of developing aGVHD [odds ratio (OR) = 2.63 (1.17 to 5.87), P = 0.06]. The benefit was more in matched transplant recipients [OR = 3.5 (1.30 to 9.49), P = 0.05] as compared to haploindentical transplant [OR = 2.8 (0.49 to 15.91), P = NS]. Using the mathematical equations, the observed AUC0-12 was predicted with 92.31% accuracy in the BD subset and 100% accuracy in the TID subset for a combined accuracy of 94.76%. A set of just three samples that constituted the abbreviated AUC1-4 was used to develop the predictive models. The LSS could be employed for the therapeutic monitoring of MMF particularly in patients undergoing matched hematopoietic stem cell transplantation.

An HPLC method for simultaneous quantification of sunitinib and its active metabolite, SU12662, using hydrophilic interaction chromatography principle.

Aim: To develop a sensitive HPLC method for the quantitation of sunitinib (SU) and its active metabolite N-desethyl-sunitinib (SU12662) in human plasma. Materials & methods: The analytes were extracted from 500 µl of plasma using liquid-liquid extraction followed by protein precipitation. Chromatographic separation of two analytes and internal standard, vandetenib, was achieved on a hydrophilic interaction liquid chromatography analytical column using a gradient program. Calibration curves were linear over the range of 10-250 ng/ml for both SU and SU12662. The method was validated according to the US FDA guidelines for bioanalytical methods. Accuracy of the method at 10 ng/ml for SU and SU12662 was 8.7 and 6.7%, respectively, and precision was 10.18% and 17.3%, respectively. Conclusion: This method allows a specific, sensitive and reliable determination of SU and SU12662 in human plasma in a single analytical run which makes it useful for therapeutic drug monitoring.

Prognostic significance of pretreatment sodium levels in patients of nonsmall cell lung cancer treated with pemetrexed-platinum doublet chemotherapy.

BACKGROUND: Recent studies have shown pretreatment sodium level to be a predictive and prognostic marker in nonsmall cell lung cancer (NSCLC) patients treated with erlotinib. The objective of this study was to evaluate the prognostic significance of pretreatment sodium levels on progression-free survival (PFS) and overall survival (OS) in patients of NSCLC treated with pemetrexed-platinum doublet chemotherapy. PATIENTS AND METHODS: Stage IIIb/IV NSCLC patients aged ≥18 years for whom baseline serum sodium level was available were included in this retrospective study. All patients received standard pemetrexed-cisplatin/carboplatin doublet for six cycles followed by maintenance pemetrexed till progression. Electronic medical record database of our hospital was used to retrieve demographic data, pretreatment sodium levels, and survival data. Normal serum sodium (NSS) was defined as serum sodium ≥136 mEq/L, and low serum sodium (LSS) was defined as serum sodium <136 mEq/L. The impact of sodium levels on PFS and OS after adjusting other prognostic factors was estimated using Cox proportional hazard model. RESULTS: Data were available for 257 patients (male/female = 182/75) with median age of 55 (21-78) years. A total of 120 (46%) patients had LSS whereas 137 (54%) had NSS. Patients with NSS had significantly longer median PFS (7 months vs. 6 months; P < 0.05) and OS (16 months vs. 11 months; P < 0.05) compared to LSS group. Multivariate analysis showed LSS as an independent prognostic variable for poor survival (hazard ratio = 2.07, 95% confidence interval = 1.11-3.84). CONCLUSION: Pretreatment serum sodium level is an important prognostic marker in Stage IIIb/IV NSCLC patients. The simple possibility of testing coupled with low cost makes it an attractive biomarker.

Quality of informed consent in cancer clinical trials in India: A cross-sectional survey.

Background: An 'informed consent' is a legal and ethical requirement for research involving human subjects. Studies assessing the validity of informed consent and determinants of its quality have highlighted problems in consent delivery and comprehension by trial participants. We report the findings of a questionnaire-based survey conducted to understand the quality of informed consent (QuIC) in cancer clinical trials. Methods: The survey was conducted in a single tertiary care cancer centre in India. Patients enrolled in phase 1, 2 or 3 interventional studies were administered the QuIC questionnaire by a trained study coordinator. The QuIC, expressed as knowledge score, was calculated from the proportion of correct responses expressed as a percentage. Results: The mean (SD) knowledge score was 60.46% (1 5.21%). It was considerably higher in industry-sponsored trials compared to investigator-initiated trials (65.32% v. 52.21%, respectively; p<0.001). Faith in the treating oncologist positively influenced the patients' decision to participate in a trial. Nearly 97% of the respondents anticipated better care, while 85% felt that the new drug/procedure would be better than the existing treatment. Free treatment emerged as a strong inducement for patients to take part in clinical trials. Patients were aware of their autonomy, and responses showed that none of the patients were coerced or unduly influenced to participate in clinical trials. Conclusion: Our study revealed important deficiencies in research participants' understanding of essential elements of informed consent. Thorough patient counselling is crucial to minimize 'therapeutic misconception' to preserve the validity of informed consent in cancer trials.