INTRODUCTION

Colorectal cancer is responsible for the second highest mortality among all cancer types and primarily affects adults aged 70 years or older. Due to the aging global population, the number of older adults with cancer, including colorectal cancer, is rapidly increasing. Although the majority of patients with metastatic colorectal cancer (mCRC) are older than 70 years, there are very few clinical trials specifically focused on this large patient group.

The investigator-initiated randomized phase II NORDIC9-study prospectively assessed an approach for older patients with mCRC who were not considered candidates for full-dose combination treatment, comparing reduced-dose combination therapy to full-dose single-agent chemotherapy.

NORDIC9 included 160 patients from four Nordic countries between March 2015 and October 2017. The study established that reduced-dose combination chemotherapy resulted in significantly prolonged progression-free survival, with a trend towards prolonged overall survival, fewer toxicities, and fewer hospital admissions compared to full-dose monotherapy. Additionally, patients receiving reduced-dose combination treatment maintained their quality of life and physical performance, and experienced a lower symptom burden compared to those in the full-dose monotherapy arm.

QUESTIONS

Thanks for taking the time to discuss this study Gabor. Firstly, it is great to see a clinical trial which considers older adults from the outset, and is truly designed around them. What are some factors that others seeking to establish dedicated trials for older patients need to consider from the outset?

During the drug development process the focus is mainly on the maximum tolerated dose from a historical perspective. The minimum effective dose concept, which aimed for balancing safety and efficacy, however, is more important and useful for patients in the palliative setting, especially for the older and vulnerable ones. Testing thus the utility and the efficacy of an upfront reduced-dose doublet concept compared to full-dose single agent strategy was an interesting area to discover. This led to the planning of the NORDIC9-study. It is worth mentioning, one of the novelties of the NORDIC9-study was the use of an innovative, “older patient friendly” fluoropyrimidine (FP) backbone, the S1 (Teysuno®).

Being able to conduct studies successfully exploring vulnerable older populations, feasibility is the key. The “keep it simple” principle regarding the design is essential; it makes the study attractive for both the patients, the investigators, and the staff. Important to note that some studies failed to include the proper number of patients due to attrition or low accrual rates, these factors are common and unavoidable challenges in older populations. However, some studies even conducted in young and fit cohorts failed due to complicated study design or overwhelming procedures emphasizing the importance of a reasonable design, and eventually, a pilot-study testing feasibility. Due to the aforementioned considerations, the NORDIC9-study was designed in a simple and pragmatic way.

 

This study focused on the first-line treatment of older patients with metastatic colorectal cancer, who were treated with oxaliplatin +/- S1 in the first line setting, followed by irinotecan +/- S1 in the second-line setting. Patients receiving treatment with doublet therapy received this at reduced doses. S1 is a fluoropyrimidine which has a good safety profile, but may be less commonly available in some regions. Do you think the results of this study are likely to apply equally among patients treated with alternative fluoropyrimidines?

Yes – several studies showed comparable efficacy with the well-established FPs and their combinations. We considered S1 as reasonable in vulnerable older populations due to the markedly decreased rates of palmar-plantar erythrodysesthesia (PPE), also called hand-foot syndrome (HFS), allowing the preservation of ADL and IADL, moreover, owing to the feasibility in patients with prior FP-induced cardiotoxicity. These features made S1 especially suitable and attractive for our target population. However, S1 was developed and predominantly used in Japan and Asia, and its use is not widespread in Europe yet. Especially not in CRC/mCRC indication. Furthermore, in case of both severe PPE and cardiotoxicity, S1 is now recommended by the European Medicines Agency (EMA) either as monotherapy or in combination with oxaliplatin or irinotecan as an equivalent alternative of the well-established FPs and their combination regimens. Hopefully, this would also facilitate that S1 will be accessible for more patients across Europe.

 

Can you discuss the study’s findings relating to RAS/BRAF status and the use of EGFR targeted therapy in this population?

The RAS/BRAF mutation status is one of the most important prognostic and predictive factors when it comes to therapeutic decision-making in younger and fit patients. Older, especially vulnerable patients have often limited life expectancy and are less likely to get offered and complete intensive chemotherapy (doublet or triplet), eventually with an additional targeted agent (e.g., an EGFRi). The RAS/BRAF mutation status and the use of targeted agents are therefore less commonly considered in RCT and in daily clinical practice in the older population. Hence, it seemed reasonable to us looking at the prognostic value of the mutational status and the predictive value of treatment allocation, even though it was not a pre-planned sub-study of the NORDIC9 project.

In patients with RAS/BRAFwt and RASmut disease, we did not find statistically significant differences regarding OS and PFS when we compared sub-groups according to the treatment allocation (reduced-dose doublet vs full-dose monotherapy), while we found a significant difference between the sub-groups with BRAFV600E mutation. In my opinion, the pragmatic design of the NORDIC9-study properly models the real-world setting where physicians often avoid the use of an EGFRi in combination with chemotherapy as first-line option in vulnerable older patients (even with left-sided primary tumor), mainly due to the need for injection port, skin toxicities, and the related supportive care issues.

 

This study demonstrated improvements in quality of life for those patients randomised to reduced dose combination therapy relative to those treated with full dose monotherapy. This is an interesting finding – could you discuss this a little?

We found that reduced-dose doublet is a better treatment option compared to full-dose monotherapy considering not only the efficacy endpoints but also the additional patient-centered benefits like the preservation of QoL, physical functioning, and symptom relief. Hence, the reduced-dose doublet should be the preferred first-line treatment in vulnerable older patients with mCRC.

According to the anchor-based MID (minimal important difference) specifically developed in patients with mCRC receiving palliative chemotherapy, there was a clinically meaningful difference in global QoL favoring the doublet arm at the pre-specified time point, thus, the primary endpoint was met; the global QoL was preserved. This difference, however, was not statistically significant. Regarding the secondary endpoints, both statistically significant and clinically relevant differences in physical functioning and in symptom domains were demonstrated. We concluded that reduced-dose doublet maintained the physical functioning and alleviated the symptoms.

The most reasonable explanation for our findings is that the global QoL deteriorated in patients receiving full-dose monotherapy during the first two months of the treatment, while in the reduced-dose doublet arm QoL remained constant during this period. This occurred most likely due to a less efficient treatment in the monotherapy arm; lacking symptom relief combined with toxicity manifested in a more prominent symptom burden.

 

Many geriatric oncology centres routinely undertake geriatric screening using tools such as G8, including to triage referrals for comprehensive geriatric assessment. Did this study identify any significant clinical patient variables or clinical scores which predicted for toxicity, hospitalisation, or survival?

We found that all four applied tools (ECOG PS, frailty phenotype, G8, and VES-13) were significantly associated with OS in multivariable analyses. ECOG PS and VES-13 demonstrated moderate prediction according to C-statistics. Patient stratification in the NORDIC-9 study was based on ECOG PS at inclusion, while G8 and VES-13 were completed after study entry, which might have influenced our results.

The frailty phenotype had poor predictive performance, likely because it is more relevant in geriatric medicine than oncology practice. Our results align with a systematic review showing frailty phenotype had low sensitivity (31%) but high specificity (91%). G8 and VES-13 had better sensitivity (87% and 68%) and specificity (61% and 78%), making them more suitable for oncology.

The prognostic value of ECOG PS in older patients with cancer is less clear but demonstrated comparable prognostic value to VES-13 in our cohort. Both tools are a form of ADL assessment, though ECOG PS provides less detailed information compared to VES-13. Combining tools like G8 and VES-13 increased sensitivity and specificity for identifying frailty and seems reasonable, especially with restricted access to geriatric services. Combining ECOG PS with geriatric screening information might provide further details on challenges faced by vulnerable older patients, such as weight loss, fatigue, depression, cognitive issues, polypharmacy, caregiver burden, and the need for assistance in ADL and IADL. This approach could improve prognostic understanding, communication, and shared decision-making.

 

What about laboratory biomarkers (CRP, dNLR, YKL-40, and IL-6) – Can you explain what associations you found? How would you envisage integrating testing of these biomarkers into routine clinical practice, and do you envisage that these biomarkers should have broadly equivalent validity for older and vulnerable patients in the setting of, for example, FOLFOX or capecitabine monotherapy? If so, is this something that geriatric oncology clinics should consider adding to their workflow?

Our main findings from the biomarker analysis established that elevated baseline CRP, dNLR, and IL-6 were associated with shorter OS and PFS; while higher YKL-40 was also associated with short OS, but not PFS. CRP demonstrated a good prognostic model, whereas the other markers provided moderate value in this cohort of vulnerable older patients with mCRC treated with palliative chemotherapy.

Blood sampling is a frequently performed procedure during the diagnostic work-up and has the potential to provide useful prognostic information. However, biomarkers cannot stand alone; we need to evaluate the whole patient. Biomarkers may indicate an infection, not necessarily cancer progression or clinical deterioration.

All investigated plasma biomarkers of systemic inflammation showed prognostic value. Depending on the clinical setting and available resources, these biomarkers can be applied in daily clinical practice along with other clinical parameters. Such findings can provide valuable information about systemic inflammation, sarcopenia, and life expectancy, facilitating discussions regarding prognosis and treatment plans, and supporting the shared decision-making process.

Our analysis was pre-planned and described in the study protocol, allowing us to collect data prospectively in a homogenous cohort. Most patients (94%) were available for this biomarker analysis regarding CRP and dNLR. The centralized processing and analysis of YKL-40 and IL-6 likely reduced the risk of bias, although 19% of YKL-40 and IL-6 samples were missing due to procedural error or institutional decisions, and plasma CRP together with WBC and ANC were measured at local laboratories, which might cause some heterogeneity in the data.

The most important perspective of this work is its implementability into a busy clinical workday. CRP is a routinely used, easily available, and affordable biomarker. Hence, it should be routinely used when prognosis is discussed with older patients and their caregivers. However, the correct use demands the right context and a holistic approach to the patient.

 

This was a large, multinational study. How significant was the collaboration across countries in executing this study, and what logistical challenges did you face regarding language, data transfer, patient expectations, culture etc?

The NORDIC9 study was initiated, designed, and conducted by the Nordic Colorectal Cancer Biomodulation Group, which has a long tradition of carrying out clinical research through extensive collaboration involving Scandinavian countries, that is why the collaboration, logistics went well.

 

SUMMARY

NORDIC9 demonstrates that lower-dose combination chemotherapy is the treatment of choice in older adults with mCRC who are ineligible for intensive chemotherapy. Its use resulted in prolonged survival, less toxicities, fewer hospital admissions, and preserved quality of life and physical performance. Using biomarkers, measurements of physical functioning, and RAS/BRAF mutation status provide important prognostic information and have therapeutic implication, thus, contribute to proper patient selection. These factors may influence survival and enhance communication in the shared decision-making process.

 

References

  1. Liposits G, Skuladottir H, Ryg J, et al. The Prognostic Value of Pre-Treatment Circulating Biomarkers of Systemic Inflammation (CRP, dNLR, YKL-40, and IL-6) in Vulnerable Older Patients with Metastatic Colorectal Cancer Receiving Palliative Chemotherapy-The Randomized NORDIC9-Study. J Clin Med Res. 2022;11. doi: 10.3390/jcm11195603
  2. Liposits G, Ryg J, Skuladottir H, et al. Prognostic value of baseline functional status measures and geriatric screening in vulnerable older patients with metastatic colorectal cancer receiving palliative chemotherapy – The randomized NORDIC9-study. J Geriatr Oncol. 2023;14:101408.
  3. Liposits G, Eshøj HR, Möller S, et al. Quality of Life in Vulnerable Older Patients with Metastatic Colorectal Cancer Receiving Palliative Chemotherapy-The Randomized NORDIC9-Study. Cancers . 2021;13. doi: 10.3390/cancers13112604
  4. Winther SB, Liposits G, Skuladottir H, et al. Reduced-dose combination chemotherapy (S-1 plus oxaliplatin) versus full-dose monotherapy (S-1) in older vulnerable patients with metastatic colorectal cancer (NORDIC9): a randomised, open-label phase 2 trial. Lancet Gastroenterol Hepatol. 2019;4:376–88.
  5. Liposits G, Winther SB, Ryg J, et al. The effect of BRAF mutation on survival and treatment efficacy in vulnerable older patients with metastatic colorectal cancer – A post-hoc exploratory analysis of the randomized NORDIC9-study. J Geriatr Oncol. 2024;15:101632.
  6. Winther SB, Zubcevic K, Qvortrup C, et al. Experience with S-1 in older Caucasian patients with metastatic colorectal cancer (mCRC): Findings from an observational chart review. Acta Oncol. 2016;55:881–5.