Background
Maintaining sufficient health-related quality of life (HRQoL) is an important goal in the treatment of patients with metastatic colorectal cancer (mCRC) as well as for their caregivers, and in the evaluation of new anticancer therapies. Especially in the palliative setting, the impact of treatment on different domains of HRQoL is increasingly incorporated as a relevant endpoint in clinical trials.1 In addition, HRQoL is more often taken into account in therapeutic decision-making for individual patients.2
CRC is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related death, mostly due to metastatic disease.3 Approximately 50% of patients with CRC will develop metastases during the course of their disease. Approximately 20% of patients already present with metastases at initial diagnosis.4,5 Selected patients with limited metastatic disease are treated with a curative intent with local treatment of metastasis by resection, radiofrequency or microwave ablation, or stereotactic radiotherapy.6–12 When cure can no longer be pursued, patients are offered palliative treatment with the aim of improving survival while maintaining acceptable HRQoL. In an era in which multiple systemic and local treatment options are available, leading to improved overall survival (OS) in the last decade, reducing cancer-related symptoms should be well-balanced with treatment-related toxicities.13
Current palliative systemic treatment for mCRC consisting of chemotherapeutic and biologic agents targeting VEGF, BRAF, or EGFR results in a median OS of >30 months, depending on the location and mutation status of the primary tumor. For patients with microsatellite instability (MSI)–high tumors responding to immunotherapy, this is even longer.14–16
The toxicity of systemic palliative treatment in patients with mCRC may affect their HRQoL. Despite the fact that in most studies treatment-related (low-grade) toxicities do occur, HRQoL for the entire group generally remains unaffected.17–21 This could be explained by symptom relief as a result of tumor response compensating for treatment-related toxicity or could reflect patients’ perception of HRQoL adjusting continuously to new situations.22 Although less extensively investigated, studies evaluating HRQoL in patients with mCRC who were treated with local treatment of metastases showed no effect on HRQoL, despite severe toxicity of these often intensive treatment strategies.23–26
The randomized controlled ORCHESTRA trial (ClinicalTrials.gov identifier: NCT01792934) was designed to prospectively evaluate the OS benefit of tumor debulking in patients with multiorgan mCRC when added to palliative systemic therapy. This study provides a unique cohort of patients who have mCRC treated with first-line palliative systemic therapy in combination with local treatment of metastases versus palliative systemic therapy alone.
HRQoL was included as a prespecified exploratory secondary endpoint in the trial. The present study aims to assess the impact of local treatment of metastases in combination with palliative systemic therapy versus systemic therapy alone on HRQoL.
Methods
Study Design and Patients
The study protocol was reviewed and approved by the institutional ethics committee of Amsterdam University Medical Centers. All patients provided written informed consent before any study-related procedures were performed. Study design, eligibility criteria, and safety and feasibility results of the first 100 patients included in the ORCHESTRA trial have been reported previously.27 The study is currently ongoing.
In case of stable disease or response, according to RECIST 1.1,28 after 3 or 4 cycles of systemic therapy (with fluoropyrimidines and oxaliplatin with or without bevacizumab), patients were randomized between continuation of systemic therapy (standard arm) or maximal tumor debulking followed by continuation of systemic therapy (intervention arm). Maximal tumor debulking is deemed to occur if at least 80% of metastases as well as the primary tumor can be treated by a combination of surgical resection, ablative radiotherapy, or thermal ablative therapy.
Patients in the intervention arm who had a partial response received 1 more cycle of systemic therapy followed by debulking. Patients with stable disease received 3 or 4 more cycles of systemic therapy before tumor debulking. After debulking, systemic therapy was resumed to complete a total of at least 8 (CAPOX) to 12 (FOLFOX) cycles if tolerated (supplemental eFigure 1, available with this article at JNCCN.org). For all randomized patients included in the trial between May 2013 and November 2020, HRQoL analysis was performed.
HRQoL Assessments
HRQoL was investigated using the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).29,30 This questionnaire consists of 5 functional scales (physical, social, role, cognitive, and emotional functioning), 3 symptom scales (fatigue, pain, and nausea/vomiting), and single-item scores (dyspnea, insomnia, appetite loss, constipation, and diarrhea).
For each scale or item, a linear transformation was applied to standardize raw scores to a 0 and 100 score according to the manual. Higher scores represent higher global health status and functioning and worsening of symptoms.
In addition, a summary score was calculated by the mean of combined functional scales (physical, social, role, cognitive, and emotional functioning), symptom scales (fatigue, pain, and nausea/vomiting), and single-item scores (dyspnea, insomnia, appetite loss, constipation, and diarrhea), with a higher score indicating better HRQoL. The minimal clinically important difference (MCID) of this scale is 10 points.31 In addition to the summary score, we focused on global health status and physical and emotional functioning because these scales have been found to be most strongly associated with toxicity or survival.17
Fatigue was assessed using the Multidimensional Fatigue Inventory.32 This instrument evaluates general fatigue, physical fatigue, emotional fatigue, reduced motivation, and reduced activity. Based on most common fatigue-related toxicity, general and physical fatigue were selected for analysis.33 The MCID of this scale is 2 points.34
Patients completed both questionnaires at prespecified time points: at baseline (before the start of chemotherapy), at randomization, and at every follow-up moment (every 3 months) until disease progression. Questionnaires up to 1 year after inclusion were included in the analysis.
Serious Adverse Events
Serious adverse events (SAEs) were documented according to CTCAE version 4.03 and documented to be related to systemic therapy, related to local therapy, or not related to study treatment. SAEs were defined as any adverse event that required inpatient hospitalization or prolongation of an existing hospitalization (grade 3), resulted in persistent or significant disability or incapacity (grade 3), was life-threatening (grade 4), or resulted in death (grade 5).
Statistical Analyses
A chi-square test of independence was performed to compare the proportion of patients who encountered SAEs between study arms. Between-group differences in HRQoL at various time points were compared with linear mixed model analysis, including study arm, time (ie, follow-up moments), and the interaction between group and time. The analyses were adjusted for the HRQoL at randomization. The linear mixed model automatically deals with missing values under the missing-at-random assumption. Accordingly, questionnaires that were not completed because of progressive disease (per protocol) or death of the study patient were classified as nonrandom missing questionnaires. Other reasons for missing questionnaires (eg, if not handed out by the local investigator or refusal to complete assessment) were categorized as random missing questionnaires.
Nonrandom missing questionnaires could potentially influence the results; therefore, a pattern mixture approach was applied to identify whether missing patterns were informative and should be included as covariables in the model.35 Four patterns of missing data were identified: pattern 1 (study dropout after randomization or follow-up 1), pattern 2 (study dropout after follow-up 2), pattern 3 (study dropout after follow-up 3), and pattern 4 (no study dropout until follow-up 4).
Subsequently, we examined whether between-group differences in HRQoL over time varied by missing data pattern by adding to the model missing data pattern and interaction term with time. Significant patterns and interaction terms were added to the model as covariables. This appeared to be the case for pattern 1 and global QoL and physical fatigue and for pattern 4 and summary score, emotional functioning, and general fatigue. There was significant interaction for nonrandom missings after randomization/follow-up 1 for global QoL and physical fatigue. Nonrandom missings at 1 year after inclusion showed a significant interaction for summary score, emotional functioning, and general fatigue. In addition, we explored effect modification by the number of metastatic sites (2 vs >2) by adding this variable and interaction with study arm to the model. Estimated marginal means, standard errors, and P values of between-group differences were reported.
Because timing of tumor debulking depended on response to chemotherapy, we performed an ancillary analysis to explore differences in HRQoL just before and after tumor debulking of patients in the intervention arm who completed both questionnaires using the Wilcoxon signed-rank test (data were not normally distributed). Statistical analyses were performed using SPSS Statistics, version 25 (IBM Corp.), and P<.05 was considered to be statistically significant.
Results
Patients
Of 344 patients enrolled in the trial, 300 patients were randomized to the intervention arm (n=148) or the standard arm (n=152). See the CONSORT diagram (Figure 1) for more details.
CONSORT diagram.
Abbreviation: PD, progressive disease.
Citation: Journal of the National Comprehensive Cancer Network 21, 10; 10.6004/jnccn.2023.7050
Patients’ clinical and sociodemographic characteristics were well-balanced between study arms (supplemental eTable 1). Debulking was performed in 87% of patients in the intervention arm (n=129). After debulking, chemotherapy was resumed in 78% (n=100) of patients. See supplemental eTable 2 for details on local treatment of patients in the intervention arm. Details on the proportion of nonrandom missings (due to progressive disease or death) or random missings per time point are shown in Figure 1.
SAEs
A total of 144 SAEs were reported in 95 of 300 patients. In the standard arm, 45 events occurred in 32 patients, and in the intervention arm, 99 events occurred in 63 patients. The difference in the proportion of patients who encountered SAEs between study arms was statistically significant (P≤.001). Of the SAEs in the intervention arm, 46 were related to local treatment (in 33 patients) (Table 1).
Serious Adverse Events According to CTCAE Version 4.03
HRQoL Analysis
There were no statistically significant or clinically relevant differences between study arms over time for all preselected HRQoL and fatigue scales (Figure 2). The overall mean differences in scores over time in the standard arm versus the intervention arm were as follows: −3.1 (95% CI, −6.21 to 0.04); global health status, −2.9 (95% CI, −7.81 to 1.97); physical functioning, −3.5 (95% CI, −7.45 to 0.40); emotional functioning, +1.0 (95% CI, −3.50 to 5.52); general fatigue, +0.9 (95% CI, −0.21 to 1.96); and physical fatigue, +0.8 (95% CI, −0.37 to 1.89).
Estimated marginal means in health-related quality of life and fatigue per study arm over time: (A) EORTC QLQ-C30 summary score, (B) EORTC QLQ-C30 global quality of life, (C) EORTC QLQ-C30 physical functioning, (D) EORTC QLQ-C30 emotional functioning, (E) MFI general fatigue, and (F) MFI physical fatigue. Error bars indicate the standard deviation. Higher EORTC QLQ-C30 scores represent better health status or functioning, and higher scores for fatigue indicate increased symptom severity.
Abbreviations: EORTC QLQ-C30, EORTC Quality of Life Questionnaire-Core 30; FU, follow-up; FU1, ±3 months after randomization; FU2, ±6 months after randomization; FU3, ±9 months after randomization; FU4, ±12 months after randomization; MFI, Multidimensional Fatigue Inventory; QoL, quality of life.
Citation: Journal of the National Comprehensive Cancer Network 21, 10; 10.6004/jnccn.2023.7050
In addition, there were no significant changes in HRQoL and fatigue from randomization to 1 year after treatment within each study arm, except for the QLQ-C30 summary score in the intervention arm, which increased from 80.9 points at randomization to 88.0 points 10 months after inclusion (P=.04). This difference, however, did not reach the MCID of 10 points.31 The number of metastatic sites did not significantly modify the effect. Estimated marginal means per scale for each time point are shown in supplemental eTable 3. Additionally, the ancillary analyses of 74 patients in the intervention arm who completed HRQoL and fatigue questionnaires before and after tumor debulking showed no significant or clinically relevant change in HRQoL and fatigue (supplemental eTable 4).
Discussion
In this prespecified exploratory analysis of the ORCHESTRA trial, we found that maximal tumor debulking in combination with first-line palliative systemic therapy in patients with multiorgan mCRC did not affect HRQoL compared with systemic therapy alone. Patients in the intervention arm encountered SAEs twice as often as patients in the standard arm, with no change in HRQoL in all included domains.
Despite the lack of between-group differences in HRQoL and fatigue over time, an increase in the summary score was found in the intervention group, whereas it remained stable in the standard arm. However, this result should be interpreted with caution because the increase in HRQoL may not be clinically relevant.
Our finding that HRQoL did not differ by treatment arm is in line with prior reports (25 of 30 in total) that were systematically reviewed by Schuurhuizen et al.17 More recent reports, however, found deterioration in HRQoL in patients with mCRC treated with chemotherapy.18,19 Contrary to the ORCHESTRA trial, these studies only included specific subgroups of patients with CRC (those with MSI-high or RAS wild-type CRC), but their HRQoL baseline scores were comparable with the scores in the ORCHESTRA cohort. In the KEYNOTE-177 study comparing pembrolizumab with doublet chemotherapy as first-line palliative systemic treatment in patients with MSI-high mCRC, deterioration was found for most HRQoL domains over time for patients treated with chemotherapy.19 In addition, in the VALENTINO study, patients with RAS wild-type mCRC were randomized to receive induction treatment with FOLFOX-panitumumab for 8 cycles, followed by either 5-FU/leucovorin with panitumumab or panitumumab alone as maintenance. The prespecified HRQoL analysis showed deterioration of global QoL during the induction treatment phase with chemotherapy, which recovered in the maintenance phase.18
There are only a few papers available reporting on HRQoL after local treatment of metastases in multiorgan mCRC. In the prospective phase II trial conducted by Wei et al,11 metastasectomy was performed in 26 patients with intrahepatic and extrahepatic metastatic disease. The extrahepatic disease burden was limited compared with the ORCHESTRA study population, with a maximum of 3 metastases outside the liver. In this study, HRQoL scores of patients deteriorated after the surgical interventions but recovered within 1 year after treatment.11
The QoL analysis of the SABR-COMET trial, including patients with oligometastatic disease (not restricted to CRC) who were treated with standard of care versus stereotactic ablative radiotherapy of all metastatic lesions, showed that global QoL declines slowly over time, regardless of treatment approach. Only 18 patients with CRC participated in this trial, and most of them had 1 to 3 metastases.23
In the randomized controlled phase III PulMiCC trial, patients with only 1 to 4 lung metastases from CRC were randomized between active monitoring versus metastasectomy. Due to poor recruitment, the trial was prematurely closed after randomization of 65 of the planned 300 patients. QoL analysis showed no significant change in HRQoL in patients who underwent metastasectomy of lung metastases compared with active monitoring.24
In contrast to the aforementioned studies, patients in the present study have extensive, multiorgan metastatic disease with an evident palliative treatment intent. Investigating and reporting on the impact on HRQoL of new interventions in the palliative setting is important for optimal outcomes of patients with mCRC. For each treatment strategy, it is important to consider whether a potential OS or progression-free survival benefit compensates for toxicity or deterioration of HRQoL. Therefore, we investigated different domains of the HRQoL to make a legitimate statement about the impact of a new treatment strategy or intervention. Schuurhuizen et al17 concluded that scientific reports on oncologic phase III randomized clinical trial in patients with mCRC frequently refer exclusively to global QoL, which contains only 2 general questions of the EORTC QLQ-C30, ignoring the domain scores. Global QoL did not differ across treatment arms, despite consistently higher toxicity during treatment of the experimental study arm compared with the standard treatment arm in the ORCHESTRA trial as well. This demonstrates the relevance of analyzing different domains of HRQoL to investigate the impact of an experimental treatment on HRQoL.
Our finding that HRQoL did not differ between study arms is remarkable because patients treated in the intervention arm experienced SAEs almost twice as often as patients in the standard arm. This is consistent with the previously reported safety and feasibility analyses.27 Despite a substantial difference in toxicity, no change in HRQoL between the 2 treatment arms of all included domains was found. A possible explanation for this apparent contradiction might be that patients treated in the intervention arm have a potential psychological benefit. Because of a more aggressive treatment approach and therefore hope for a better outcome, patients in the intervention arm may complete HRQoL questionnaires more positively. As well as for systemic therapy, it is also conceivable that local treatment provides symptom relief, which can compensate for toxicity, especially because toxicity is often temporary. Another explanation could be that a watchful waiting strategy is more often applied in the patient group receiving local treatment, leading to less side effects of chemotherapy. Furthermore, it is also possible that patients adapt their perception of HRQoL to new situations. Currently, standard guidelines on the optimal tools and measures for HRQoL analysis are not available. It could be that providing multiple QoL questionnaires at fixed time points is inadequate for HRQoL assessment and needs further evaluation and improvement.17,36
The main focus of this study was the effect of tumor debulking on HRQoL and fatigue in patients with mCRC. Future research will need to determine which primary QoL-limiting symptoms most affect HRQoL in this patient group.
Strengths of the present study include the analysis of several domains of HRQoL to obtain a more comprehensive view of HRQoL and the use of a pattern mixture approach to adjust for nonrandom missings. Most studies do not apply this method and therefore consider all missing questionnaires as random missings. This may overestimate the HRQoL. Therefore, because patients with metastatic cancer more often drop out due to progressive disease or death, reducing this bias is especially important in the palliative setting.
Conclusions
Maximal tumor debulking in combination with palliative systemic therapy in patients with multiorgan mCRC was correlated with significantly more treatment-related toxicity and complications from local therapy, but no difference in HRQoL was observed compared with palliative systemic therapy alone. There is a remarkable lack of association between the occurrence of SAEs and the impact on HRQoL.
Acknowledgments
This publication is on behalf of the ORCHESTRA study group, which further includes J.B. Tuynman, M.R. Meijerink, E. van Meerten, J.J.M.E. Nuyttens, D.J. Grunhagen, C.M.I. Grootscholten, H. Torrenga, A.A. van Zweeden, H.H. Helgason, P. Hamberg, M. Los, R. Hoekstra, G. Vreugdenhil, H. van Halteren, J.M. van Dodewaard-de Jong, L.V. Beerepoot, J.F.M. Pruijt, D. Mathijssen-van Stein, B.C.M. Haberkorn, F. Terheggen, M.B. Polee, M. Troost, M. Vermaas, M. Trajkovic-Vidakovic, H. Meulenbeld, M. Vleugel, S. Bakker, L.J.M. Mekenkamp, J.N. Primrose, and J. Bridgewater.
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