Impact of Chemotherapy Dose Reductions on Survival Outcomes Among Older NSCLC Patients Without Actionable Mutations

Official title

Impact of Chemotherapy Dose Reductions on Survival Outcomes Among Older NSCLC Patients Without Actionable Mutations: A Retrospective Cohort Study.

Overview

Evidence suggests that appropriately selected older adults can tolerate standard-dose chemotherapy and achieve survival outcomes comparable to younger patients. However, older adults are usually under-represented in clinical trials and often receive reduced doses of chemotherapy due to concerns regarding age-related frailty, polypharmacy, and toxicity. This study seeks to evaluate chemotherapy dosing patterns and associated survival outcomes in older patients.

Detailed description

Lung cancer remains the leading cause of cancer-related mortality globally, responsible for approximately 1.8 million deaths annually. Non-small cell lung cancer (NSCLC) comprises about 85% of all lung cancer cases, with adenocarcinoma (ADC) now the predominant histological subtype. In Malaysia, NSCLC is similarly the most common form of lung cancer, with high proportions of EGFR and ALK mutations in certain subgroups.

Despite the emergence of targeted therapy and immunotherapy, cytotoxic chemotherapy, particularly platinum-based doublets remains the backbone of treatment for many NSCLC patients lacking actionable mutations. These patients often present with advanced disease and limited survival prospects, with median overall survival (OS) of 8- 10 months. These includes older patients with advanced NSCLC and no actionable mutations who depend on chemotherapy for disease control.

Clinical decisions regarding dosing are frequently influenced by perceptions of frailty rather than individual fitness. Evidence suggests that appropriately selected older adults can tolerate standard-dose chemotherapy and achieve survival outcomes comparable to younger patients. However, older adults are usually under-represented in clinical trials and often receive reduced doses of chemotherapy due to concerns regarding age-related frailty, polypharmacy, and toxicity. This raises an important question: does dose reduction compromise survival outcomes in older NSCLC patients?

This study seeks to address this knowledge gap by retrospectively evaluating chemotherapy dosing patterns and associated survival outcomes in older patients treated at three centres in Malaysia: Universiti Malaya Medical Centre (UMMC), Hospital Tengku Ampuan Afzan, Kuantan and Hospital Wanita dan Kanak-kanak, Likas, Sabah and one centre in Hong Kong: Queen Mary Hospital, The University of Hong Kong. It will evaluate whether chemotherapy dose reductions are associated with poorer survival outcomes in older NSCLC patients. It will also assess clinical predictors such as ECOG performance status, BMI, comorbidities, and gender to identify factors influencing treatment tolerance and survival.

Interventions

• Other Progression free survival
  PFS
• Other Overall survival
  OS

Primary outcome measures

• To compare the overall survival (OS) between older NSCLC patients treated with standard-dose versus reduced-dose first-line platinum-doublet chemotherapy OR single agent non-platinum chemotherapy. [Time frame: From enrollment to the end of study on 31 Dec 2026]

Secondary outcome measures (2)

• To compare the progression free survival (PFS) between older NSCLC patients treated with standard-dose versus reduced-dose first-line platinum-doublet chemotherapy OR single agent non-platinum chemotherapy. [Time frame: From enrollment to end of study on 31 Dec 2026]
• To assess objective response rates in patients who complete FOUR cycles of chemotherapy. [Time frame: From enrollment to end of study period on 31 Dec 2026]

Eligibility criteria

Inclusion criteria

• Age ≥65 years
• Histologically confirmed stage IV NSCLC
• Negative for EGFR mutation, ALK rearrangement, and ROS1 fusion
• Treated with at least ONE cycle of first-line chemotherapy

Exclusion criteria

• Patients who received targeted therapy or immunotherapy as monotherapy in the first-line setting
• Incomplete survival data

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Malaysia · 3 centers

• Hospital Tengku Ampuan Afzan — Kuantan
• Hospital Wanita dan Kanak-Kanak Sabah — Kota Kinabalu
• Universiti Malaya Medical Centre — Kuala Lumpur

Hong Kong · 1 center

• Queen Mary Hospital, The University of Hong Kong — Hong Kong

Publications

• Tan DS, Yom SS, Tsao MS, Pass HI, Kelly K, Peled N, Yung RC, Wistuba II, Yatabe Y, Unger M, Mack PC, Wynes MW, Mitsudomi T, Weder W, Yankelevitz D, Herbst RS, Gandara DR, Carbone DP, Bunn PA Jr, Mok TS, Hirsch FR. The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in 2016. J Thorac Onc PMID 27229180
• Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167-77. doi: 10.1056/NEJMoa1408440. PMID 25470694
• Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. doi: 10.1056/NEJMoa0810699. Epub 2009 Aug 19. PMID 19692680
• 7. Sedrak MS, Sun CL, Liu X, et al. Aging and tolerance to chemotherapy: Impact of dose reduction and treatment delays on survival outcomes. Journal of Clinical Oncology, 2021 39, 1714-1723.
• Hurria A, Kris MG. Management of lung cancer in older adults. CA Cancer J Clin. 2003 Nov-Dec;53(6):325-41. doi: 10.3322/canjclin.53.6.325. PMID 15224973
• Maione P, Perrone F, Gallo C, Manzione L, Piantedosi F, Barbera S, Cigolari S, Rosetti F, Piazza E, Robbiati SF, Bertetto O, Novello S, Migliorino MR, Favaretto A, Spatafora M, Ferrau F, Frontini L, Bearz A, Repetto L, Gridelli C, Barletta E, Barzelloni ML, Iaffaioli RV, De Maio E, Di Maio M, De Feo G, Sigoriello G, Chiodini P, Cioffi A, Guardasole V, Angelini V, Rossi A, Bilancia D, Germano D, La PMID 16192578
• Sundararajan V, Hershman D, Grann VR, Jacobson JS, Neugut AI. Variations in the use of chemotherapy for elderly patients with advanced ovarian cancer: a population-based study. J Clin Oncol. 2002 Jan 1;20(1):173-8. doi: 10.1200/JCO.2002.20.1.173. PMID 11773167
• 3. Liam, Chong-Kin, Toh-Yoon Evelyn Goh, Nur Syafikah Shamsudin, and Chee-Chee Khoo. 2022. "Driver Gene Alterations and PD-L1 Expression in Non-Small Cell Lung Cancer and Their Association with Smoking and Gender in a Malaysian Population." Asian Pacific Journal of Cancer Prevention 23 (6): 1911-1917.

Identifiers

NCT: NCT07369596 · 20258615434

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗