Patient reported outcomes for cisplatin and radiation followed by carboplatin/paclitaxel versus carboplatin/paclitaxel for locally advanced endometrial carcinoma: An NRG oncology study

Abstract

Introduction: Chemotherapy plus radiation (Cis-RT + CP) did not demonstrate superiority in prolonging relapse-free survival compared to chemotherapy alone in patients with stage III or IVA endometrial carcinoma. The impact of treatment on quality of life (QOL), neurotoxicity (NTX) and psychometric properties of the gastrointestinal (GI) symptoms subscale during treatment and up to 1 year are described herein.

Methods: QOL assessments were scheduled at baseline, 6 weeks (post completion of RT (Cis-RT + CP) or prior to cycle 3 (CP)), then 18 weeks (end of treatment) and 70 weeks (1 year after the end of treatment) after starting treatment. QOL instruments included the FACT-En TOI, FACT/GOG-neurotoxicity (Ntx) subscale (short), and the gastrointestinal (GI) symptoms subscale.

Results: At the end of treatment, patients receiving Cis-RT + CP reported a statistically significant decreased QOL when compared to CP. The decline in QOL was reflected in physical well-being, functional well-being, and endometrial cancer specific concerns, but the minimally important differences (MID) were not considered clinically meaningful. Patients in both groups reported increased chemotherapy-induced Ntx symptoms with the CP group having worse scores and reaching peak symptoms at the time of chemotherapy completion. Patients on Cis-RT + CP reported statistically significantly worse GI symptoms after radiation therapy compared to patients on CP, this occurred across assessment intervals, though the MID was not meaningful. Psychometric evaluations indicated that the GI symptom scale is reliable, valid, and responsive to change.

Conclusions: PROs indicate that the chemoradiotherapy group experienced worse HRQoL and GI toxicity compared to patients randomized to chemotherapy alone for locally advanced endometrial cancer though based on the MID, these were not clinically meaningful differences. The GI symptom subscale was a reliable and valid scale that has value for future trials.

Trial registration: NCT00942357.

Keywords: Chemotherapy; Combined radiation therapy; Endometrial cancer; Patient reported outcomes; Quality of life.

Conflict of interest statement

Declaration of Competing Interest Dr. Matulonis reports receiving consulting fees received from Merck, Novartis, Blueprint Medicine and Next Cure as well as participating on a Data Safety Monitoring Board or Advisory Board for Symphogen and Advaxis. Ms. Helen Huang, Dr. Marcus Randall, Dr. Paul DiSilvestro, Dr. Fowler, Dr. Powell, Dr. Dr. Spirtos, Dr. Tewari, Dr. Nakayama, Dr. Mutch have no conflicts of interest to disclose. Dr. Virginia L. Filiaci reports receiving support for the present manuscript from NCTN and NCORP SDMC grant funding from the NIH/NCI. She also reports grants from GOG Foundation, Inc. for contracts with institution for clinical trial work and NCI/NIH for IOTN, BIQSFP, MP2PRT and miscellaneous other subcontracts. Dr. Filiaci also reports receiving support for attending IDMC meeting from VBL Therapeutics as well as participating on Advisory Board for Tesaro. Monitoring Board. Dr. Katherine Moxley reports P20 grant to University of Oklahoma for Drug Resistance Core from the NIH as well as support for travel to attend NRG Oncology 2019 Winter and Summer meetings. Additionally, Dr. Moxley reports serving in a Leadership role for the SGO Program Committee. Dr. David Miller reports grants received from EMD Serono Research and Development Institute to him as well as grants to his Institution from the following entities: US Biotest, Advenchen Laboratories, Tesaro, Xenetic Biosciences, Advaxis, Janssen, Aeterna Zentaris, TRACON Pharma, Pfizer, Immunogen, Mateon Therapeutics, Merck Sharp & Dohme, AstraZeneca, Millenium Pharmaceuticals, Aprea AB, Regeneron, NVision, Leap Therapeutics, Novartis, Syros Pharmaceuticals, Karyopharm Therapeutics, Agenus and Akesobio. Dr. Miller also personally received consulting fees from the following: Genentech, Tesaro, Eisai, AstraZeneca, Guardant Health, Janssen Oncology, Alexion Pharmaceuticals, Karyopharm Therapeutics, Incyte, Guardant Health, Janssen, Alexion Pharmaceuticals, Clovis Oncology, Asymmetric Therapeutics, LLC, Boston Biomedical Research Institute, Tarveda Therapeutics, Myriad Genetic Laboratories Inc., GlaxoSmithKline LLC, AbbVie Inc., Incyte, EMD Serono Inc. and Seager Inc. as well as consulting fees paid to his Institution from Merck Sharp & Dohme. Dr. Miller also received honoraria from Clovis Oncology and Genentech. He also reports participating on an Advisory Board for Incyte. Dr. Lari Wenzel reports serving as Co-Chair of the NRG Oncology PCOR Committee. Dr. Daniela Matei reports NCI NRG Support grant received. Due to his unfortunate passing before publication, no statement is available for Dr. William Richards.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Figure 1:

Consort Diagram describing all 736 patients enrolled and randomized in GOG258

Figure 2:

Figure 2a:The plot lines present the patient-reported FACT-En TOI scores. CP: Carboplatin/Paclitaxel (6 cycles); Cis-RT+CP: Cisplatin /RT+ CP (4 cycles). The least-squares means estimates were obtained from a fitted mixed model adjusting for pre-treatment score (baseline score) and patient’s age at the enrollment. A larger score indicates favorable or better QOL. The least squares means differences (Cis-RT+CP vs CP) were estimated from the fitted mixed models. The p-values for the least squares means differences were adjusted with Hochberg step-up method first for multiple time points and then adjusted with Bonferroni method for multiple measures. Figure 2b: Figure 2b shows the patient-reported physical well-being subscale scores. CP: Carboplatin/Paclitaxel (6 cycles); Cis-RT+CP: Cisplatin /RT+ CP (4 cycles). The least-squares means estimates were obtained from a fitted mixed model adjusting for pre-treatment score (baseline score) and patient’s age at the enrollment. A larger score indicates favorable or better QOL. The least squares means differences (Cis-RT+CP vs CP) were estimated from the fitted mixed models. The p-values for the least squares means differences were adjusted with Hochberg step-up method first for multiple time points. Figure 2c: The plot lines in Figure 2c present the patient-reported functional well-being subscale scores. CP: Carboplatin/Paclitaxel (6 cycles); Cis-RT+CP: Cisplatin /RT+ CP (4 cycles). The least-squares means estimates were obtained from a fitted mixed model adjusting for pre-treatment score (baseline score) and patient’s age at the enrollment. A larger score indicates favorable or better QOL. The least squares means differences (Cis-RT+CP vs CP) were estimated from the fitted mixed models. The p-values for the least squares means differences were adjusted with Hochberg step-up method first for multiple time points. Figure 2d: The plot lines present the patient-reported endometrial cancer subscale scores. CP: Carboplatin/Paclitaxel (6 cycles); Cis-RT+CP: Cisplatin /RT+ CP (4 cycles). The least-squares means estimates were obtained from a fitted mixed model adjusting for pre-treatment score (baseline score) and patient’s age at the enrollment. A lager score indicates favorable or better QOL. The least squares means differences (Cis-RT+CP vs CP) were estimated from the fitted mixed models. The p-values for the least squares mean differences were adjusted with Hochberg step-up method first for multiple time points.

Figure 2:

Figure 2a:The plot lines present the patient-reported FACT-En TOI scores. CP: Carboplatin/Paclitaxel (6 cycles); Cis-RT+CP: Cisplatin /RT+ CP (4 cycles). The least-squares means estimates were obtained from a fitted mixed model adjusting for pre-treatment score (baseline score) and patient’s age at the enrollment. A larger score indicates favorable or better QOL. The least squares means differences (Cis-RT+CP vs CP) were estimated from the fitted mixed models. The p-values for the least squares means differences were adjusted with Hochberg step-up method first for multiple time points and then adjusted with Bonferroni method for multiple measures. Figure 2b: Figure 2b shows the patient-reported physical well-being subscale scores. CP: Carboplatin/Paclitaxel (6 cycles); Cis-RT+CP: Cisplatin /RT+ CP (4 cycles). The least-squares means estimates were obtained from a fitted mixed model adjusting for pre-treatment score (baseline score) and patient’s age at the enrollment. A larger score indicates favorable or better QOL. The least squares means differences (Cis-RT+CP vs CP) were estimated from the fitted mixed models. The p-values for the least squares means differences were adjusted with Hochberg step-up method first for multiple time points. Figure 2c: The plot lines in Figure 2c present the patient-reported functional well-being subscale scores. CP: Carboplatin/Paclitaxel (6 cycles); Cis-RT+CP: Cisplatin /RT+ CP (4 cycles). The least-squares means estimates were obtained from a fitted mixed model adjusting for pre-treatment score (baseline score) and patient’s age at the enrollment. A larger score indicates favorable or better QOL. The least squares means differences (Cis-RT+CP vs CP) were estimated from the fitted mixed models. The p-values for the least squares means differences were adjusted with Hochberg step-up method first for multiple time points. Figure 2d: The plot lines present the patient-reported endometrial cancer subscale scores. CP: Carboplatin/Paclitaxel (6 cycles); Cis-RT+CP: Cisplatin /RT+ CP (4 cycles). The least-squares means estimates were obtained from a fitted mixed model adjusting for pre-treatment score (baseline score) and patient’s age at the enrollment. A lager score indicates favorable or better QOL. The least squares means differences (Cis-RT+CP vs CP) were estimated from the fitted mixed models. The p-values for the least squares mean differences were adjusted with Hochberg step-up method first for multiple time points.

Figure 3:

The plot lines present the patient-reported FACT/GOG-Ntx Subscale (short) scores. CP: Carboplatin/Paclitaxel (6 cycles); Cis-RT+CP: Cisplatin /RT+ CP (4 cycles). The least-squares means estimates were obtained from a fitted mixed model adjusting for pre-treatment score (baseline score) and patient’s age at the enrollment. A lager score indicates favorable or less NTX symptoms. The least squares means differences (CisRT+CP vs CP) were estimated from the fitted mixed models. The p-values for the least squares means differences were adjusted with Hochberg step-up method first for multiple time points and then adjusted with Bonferroni method for multiple measures.

Figure 4:

The plot lines present the patient-reported Gastrointestinal Symptoms scores. CP: Carboplatin/Paclitaxel (6 cycles); Cis-RT+CP: Cisplatin /RT+ CP (4 cycles). The least-squares means estimates were obtained from a fitted mixed model adjusting for pre-treatment score (baseline score) and patient’s age at the enrollment. A lager score indicates favorable or better QOL. The least squares means differences (Cis-RT+CP vs CP) were estimated from the fitted mixed models. The p-values for the least squares means differences were adjusted with Hochberg step-up method for multiple time points.