Short summary

Older patients (above 70 years) receiving first-line therapy for metastatic adenocarcinoma of colon or rectum (mCRC) AND who are considered unfit for standard combination therapy

Rationale

Approximately 40% of patients diagnosed with colorectal cancer (CRC) are 75 years or older. In unselected populations of mCRC patients median overall survival (OS) is only 10.7 months (Sorbye et al, Acta Oncol 2012, Sorbye et al, Cancer 2009). However, in a subgroup of patients treated with combination chemotherapy in clinical trials median OS was still 21.3 months. The low overall OS in unselected patients form the general population was due to a short survival in patients above 75 years of age and in patients not given any chemotherapy (Sorbye et al., Cancer 2009). The reported improvement over time in survival seen in mCRC patients is mainly seen in younger patients and not much improvement has been seen in older mCRC patients (Sorbye Ann Oncol 2013).

Thus uncertainty exists whether the reported improvement over time in survival is as well seen in a general mCRC population - and especially in an older frail population. Furthermore, older patients seem to be undertreated with chemotherapy. As S-1 seems to have a better toxicity profile compared to 5FU and capecitabine, it should be an ideal drug for this study population.

Therefore we planned the present study comparing full dose single agent S-1 therapy - and dose-reduced combination therapy in older patients not considered candidates for standard combination therapy. Several studies have shown that patients may safely start monotherapy if therapy with monotherapy is followed by new therapy upon progression (Koopman et al, Lancet 2007; Seymour et al, Lancet 2007; Seymour et al, Lancet 2011). Therefore patients in this study will receive first and second line therapy as part of the trial.

A recent randomized phase II study, AVEX, (Cunningham et al, Lancet Onc 2013) in fit older patients showed that bevacizumab improve efficacy (RR and PFS) of single agent capecitabine. Therefore, in this study it is possible to add bevacizumab to chemotherapy at the discretion of the treating physician. Patients will be stratified according to institution and planned therapy with bevacizumab.

In addition we will combine the study with geriatric assessment tools in order to identify at-risk individuals aiming to improve our knowledge on how to treat older patients not considered for inclusion in clinical trials with full dose therapy. Hopefully such a study can lead to more patients being able to receive and benefit from palliative chemotherapy.

Description of the cohort

Older patients (above 70 years) receiving first-line therapy for metastatic adenocarcinoma of colon or rectum (mCRC) AND who are considered unfit for standard combination therapy

12 departments in Scandinavia (expected)

3 departments in Norway

3 departments in Sweden

6 departments in Denmark

Data and biological material

Primary endpoint:

• Progression-free survival (PFS)

Secondary endpoints:

• Time-to failure of strategy (TTFS)
• Overall survival (OS)
• Response rate (RR) according to RECIST criteria version 1.1
• Toxicity
• EORTC QLQ-C30
• Correlation between tumour markers and outcome

Evaluation of pre-treatment characteristics (performance status and "Simple Geriatric Assessment") as predictive markers for efficacy and toxicity.

Collaborating researchers and departments

Department of Oncology, Odense University Hospital

• Professor Per Pfeiffer
• Camilla Qvortrup, MD, PhD

Department of Oncology, Haukeland University Hospital, Bergen, Norway

• Professor Halfdan Sorbye

Department of Oncology, Akademiske Sygehus, Uppsala University

• Professor Bengt Glimelius
• Associate Professor åke Berglund

Department of Geriatrics, Odense University Hospital

• Associate Professor Lars Matzen