DOSAGE Study: Upfront Dose-Reduced Chemotherapy in Older Patients with Metastatic Colorectal Cancer
- Conditions
- Candidates for Palliative ChemotherapyColorectal CancerOlder PatientsMetastatic Cancer
- Interventions
- Drug: Doublet Chemotherapy, Dose-reduced (75%)Drug: Monotherapy, Dose-reduced (75%)Drug: Monotherapy, Standard Dose (100%)Drug: Doublet Chemotherapy, Standard Dose (100%)
- Registration Number
- NCT06275958
- Lead Sponsor
- Leiden University Medical Center
- Brief Summary
The goal of this phase III, open-label, non-inferiority randomized controlled clinical trial is compare upfront dose-reduced chemotherapy with the standard dose chemotherapy in older patients ( ≥70 years) with metastasized colorectal cancer, with regard to progression-free survival (PFS). The choice between monotherapy (a fluoropyrimidine) and doublet chemotherapy (a fluoropyrimidine with oxaliplatin) will be made for each individual patient based on expected risk of chemotherapy toxicity (according to the G8 screening). Patients classified as low risk of toxicity will be randomized between doublet chemotherapy in either full-dose, or with an upfront dose-reduction of 25%. Patients classified as high risk will be randomized between monotherapy in either full-dose or upfront dose-reduction.
Primary outcome is PFS. Secondary endpoints include grade ≥3 toxicity, QoL, physical functioning, overall survival, number of treatment cycles, dose reductions, hospital admissions, cumulative received dosage and cost-effectiveness.
- Detailed Description
Treating older adults with chemotherapy remains a challenge, as they are strongly underrepresented in clinical trials and no robust guidelines for treating older patients exist. Moreover, older adults are at increased risk of chemotherapy-related toxicity, resulting in decreased quality of life (QoL), increased hospital admissions and high health care costs. Therefore, the aim of the DOSAGE study is to demonstrate that upfront dose-reduced chemotherapy in patients with metastasized colorectal cancer is non-inferior to full-dose treatment with regard to progression-free survival (PFS). Treatment plans (monotherapy or doublet chemotherapy) will be based on expected risk of treatment toxicity for the individual patient (according to the Geriatric 8 (G8) questionnaire). The investigators expect that this treatment strategy will lead to less grade ≥3 toxicity, less early treatment continuation and hospitalizations and a better QoL and physical functioning.
The DOSAGE study is a phase III, open-label, non-inferiority, randomized controlled clinical trial in patients aged ≥70 years with metastasized colorectal cancer eligible for palliative chemotherapy. All participating patients will undergo geriatric screening by the G8 questionnaire and will be classified as "low risk of toxicity" (G8-score of 15 or higher) or "high risk of toxicity" (G8-score of 14 or lower or judged as "high toxicity risk" by their treating oncologist). Patients classified as low risk will be randomized between a fluoropyrimidine and oxaliplatin in either full-dose, or with an upfront dose-reduction of 25%. Patients classified as high risk will be randomized between fluoropyrimidine monotherapy in either full-dose or upfront dose-reduction. Addition of targeted treatment (bevacizumab or epidermal growth factor receptor (EGFR) inhibition) is allowed. Patients with a moderate renal impairment (GFR 30- 50 mL/min) will be treated with 25% reduced starting dose of capecitabine when randomized for full dose treatment and treated with 40% reduced starting dose when randomized for upfront dose reduction.
Primary outcome is PFS. Secondary endpoints include grade ≥3 toxicity, QoL, physical functioning, overall survival, number of treatment cycles, dose reductions, hospital admissions, cumulative received dosage and cost-effectiveness. Given a non-inferiority margin of 8 weeks, 587 patients will be included (293/292 patients per arm).
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 587
- Patients aged 70 years or older with colorectal cancer and distant metastases without localized treatment options.
- Patients who are candidates for first-line palliative chemotherapy as judged by their treating oncologist
- Being able to understand the Dutch language
- Adequate bone marrow and organ function: Absolute neutrophil count (ANC) > 1.5 x 10^9 mmol/L, Hemoglobin (Hb) > 6.0 mmol/L, Platelets >100 x 109 / L, Serum bilirubin ≤ 2 x upper limit of normal (ULN), serum transaminases ≤ 3 x ULN without presence of liver metastases or ≤ 5x ULN with presence of liver metastases.
- Patients who received prior palliative chemotherapy
- Patients in whom local treatment of metastases is scheduled (i.e. liver surgery or stereotactic radiotherapy)
- Candidates for triple chemotherapy
- Patients who received prior adjuvant chemotherapy in the one year before inclusion in the study (chemotherapy before that time is allowed)
- Patients with complete or incomplete dihydropyrimidine dehydrogenase (DPD) deficiency
- Patients with Microsatellite instable (MSI)-high colorectal cancer
- Patients with HIV or active hepatitis
- Patients with severe kidney failure (defined as GFR ≤30ml/min)
- Patients with severe cognitive deficits making informed consent not possible
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Doublet therapy, dose-reduced (low toxicity risk based on G8) Doublet Chemotherapy, Dose-reduced (75%) Low risk of toxicity: G8-score of 15 or higher Fluoropyrimidine monotherapy, dose-reduced (high toxicity risk based on G8) Monotherapy, Dose-reduced (75%) High risk of toxicity: G8-score of 14 or lower or judged as "high toxicity risk" by their treating oncologist Fluoropyrimidine monotherapy, full dose (high toxicity risk based on G8) Monotherapy, Standard Dose (100%) High risk of toxicity: G8-score of 14 or lower or judged as "high toxicity risk" by their treating oncologist Doublet therapy, full dose (low toxicity risk based on G8) Doublet Chemotherapy, Standard Dose (100%) Low risk of toxicity: G8-score of 15 or higher
- Primary Outcome Measures
Name Time Method Progression-Free Survival Time from randomization until either radiological or clinical progression or death, whichever occurs first, assessed up to at least one year.
- Secondary Outcome Measures
Name Time Method Dose delay during treatment Through study duration, an average of 8 months Quality of Life Questionnaire At 1, 3, 6 and 12 months after randomization Measured by EORTC Core QLQ-C30 questionnaire
Overall Survival Time between randomization until death, assessed up to at least one year. Unplanned hospitalizations The first year after treatment initiation Physical functioning Questionnaire At 1, 3, 6 and 12 months after randomization Measured by Katz-Activities of Daily Living (ADL) questionnaire
Grade 3-5 chemotherapy-related toxicity Through study duration, an average of 8 months According to the CTCAE V5
Number of completed treatment cycles Through study duration, an average of 8 months Dose reductions during treatment Through study duration, an average of 8 months Defined as ≥25% reduction of the initial dosage
Cumulative received dosage Through study duration, an average of 8 months Adjusted for BSA
Cost-effectiveness 1 year
Trial Locations
- Locations (36)
Jeroen Bosch Ziekenhuis
🇳🇱's-Hertogenbosch, Netherlands
Noordwest Ziekenhuisgroep
🇳🇱Alkmaar, Netherlands
Ziekenhuis Amstelland
🇳🇱Amstelveen, Netherlands
Amsterdam UMC
🇳🇱Amsterdam, Netherlands
Rijnstate
🇳🇱Arnhem, Netherlands
Wilhelmina Ziekenhuis
🇳🇱Assen, Netherlands
Rode Kruis Ziekenhuis
🇳🇱Beverwijk, Netherlands
Haaglanden Medisch Centrum
🇳🇱Den Haag, Netherlands
Hagaziekenhuis
🇳🇱Den Haag, Netherlands
Slingeland Ziekenhuis
🇳🇱Doetinchem, Netherlands
Ziekenhuis Gelderse Vallei
🇳🇱Ede, Netherlands
Catharina Ziekenhuis
🇳🇱Eindhoven, Netherlands
Treant
🇳🇱Emmen, Netherlands
Admiraal de Ruyter Ziekenhuis
🇳🇱Goes, Netherlands
Beatrixziekenhuis
🇳🇱Gorinchem, Netherlands
Groene Hart Ziekenhuis
🇳🇱Gouda, Netherlands
Saxenburgh
🇳🇱Hardenberg, Netherlands
St. Jansdal Ziekenhuis
🇳🇱Harderwijk, Netherlands
Elkerliek Ziekenhuis
🇳🇱Helmond, Netherlands
Tergooi MC
🇳🇱Hilversum, Netherlands
Medisch Centrum Leeuwarden
🇳🇱Leeuwarden, Netherlands
Leiden University Medical Center
🇳🇱Leiden, Netherlands
Alrijne Ziekenhuis
🇳🇱Leiderdorp, Netherlands
Canisius Wilhelmina Ziekenhuis
🇳🇱Nijmegen, Netherlands
Laurentius Ziekenhuis
🇳🇱Roermond, Netherlands
Bravis ziekenhuis
🇳🇱Roosendaal, Netherlands
Ikazia Ziekenhuis
🇳🇱Rotterdam, Netherlands
Maasstad Ziekenhuis
🇳🇱Rotterdam, Netherlands
Ommelander Ziekenhuis
🇳🇱Scheemda, Netherlands
ZorgSaam Zorggroep Zeeuws-Vlaanderen
🇳🇱Terneuzen, Netherlands
Bernhoven
🇳🇱Uden, Netherlands
Diakonessenhuis
🇳🇱Utrecht, Netherlands
St Antonius
🇳🇱Utrecht, Netherlands
VieCuri Medisch Centrum
🇳🇱Venlo, Netherlands
Streekziekenhuis Koninging Beatrix
🇳🇱Winterswijk, Netherlands
Zaans Medisch Centrum
🇳🇱Zaandam, Netherlands