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Cytotoxic chemotherapy is usually scaled to the body surface area (BSA), and is currently not adjusted to the body proportions of lean and fat (i.e. body composition) of individual patients. Patients with low muscle mass behave like patients "overdosed" with chemotherapy resulted in dose-limiting toxicities (e.g. dose reductions, treatment delays or permanent treatment discontinuation), independently of the patient's weight.
Adjuvant chemotherapy with fluoropyrimidines and Oxaliplatin is the current worldwide standard of care for stage III colorectal cancer (CRC). This regimen leads to significant cost, toxicity, and patient inconvenience. Oxaliplatin induces two distinct forms of neuropathy: a common acute syndrome that is transient (dysesthesia, contractures and numbness) and a dose-limiting chronic sensory neurotoxicity that is cumulative. Neurotoxicity is common; it affects 80% of patients and becomes chronic in 15-20% of cases, sometimes irreversibly. Chronic neurotoxicity can severely affect everyday life activities. To date, neuromodulators agents have failed to prevent neurotoxicity and Stop & Go strategies, intended to decrease the cumulative dose of Oxaliplatin administrated, are more appropriate for palliative treatment of advanced CRC. Recent data support the plausibility of a shorter duration of adjuvant treatment without loss of efficacy. This hypothesis is tested in several international trials.
Cytotoxic chemotherapy is usually scaled to the body surface area (BSA), and is currently not adjusted to the body proportions of lean and fat (i.e. body composition) of individual patients. The impact of body composition on drug metabolism is however well known: i.e. anesthetics accumulate in adipose tissue and specific precautions are essential to avoid overdose. Concerning chemotherapies, the lean body mass (LBM) may be the salient feature defining drug metabolism. A theme is emerging from recent studies: in patients with breast cancer and treated with 5-FU (whose dosage was calculated from the body surface), severe depletion of the LBM is a powerful predictor of excessive toxicity. Indeed, depletion of the LBM, as precisely defined by computed tomography, is a unique predictor of clinically unacceptable toxicity. Low LBM was shown to be a significant predictor of dose-limiting toxicity (DLT) in CRC patients administered 5-FU using a conventional BSA-based dosing and DLT was concentrated in patients receiving >20 mg 5FU/kg LBM. Two cohorts of CRC patients treated with Oxaliplatin showed that overall DLTs, and specifically Oxaliplatin-due neuropathy, occurred mostly in patients who receive > 3.09 mg/Oxaliplatin/kg LBM. Although, preliminary findings are available in hepatocellular carcinoma, the area under the concentration time curve (AUC) of Sorafenib cancer therapy was doubled in patients with depleted LBM (102.4 vs. 53.7ng/mL.h), which seem of interest. Patients with low muscle mass behave like patients "overdosed" with chemotherapy resulted in dose-limiting toxicities (e.g. dose reductions, treatment delays or permanent treatment discontinuation), independently of the patient's weight.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Folfox 4 | Active Comparator | Standard FOLFOX4: Oxaliplatin and simplified LV5FU2 Dose of oxaliplatin 85mg/m² |
|
| Folfox 4 LBM | Experimental | Adapted FOLFOX4: Oxaliplatin and simplified LV5FU2 Dose of oxaliplatin allocated according to lean body mass (LBM) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Oxaliplatin | Drug | Simplified FOLFOX 4 regimen: Association of Oxaliplatin (85 mg/m² ) + simplified LV5FU2 Length of a cycle : 2 days Interval between 2 cycles : 2 weeks (D1=D15) Expected number of cycles: 12 |
| Measure | Description | Time Frame |
|---|---|---|
| Evaluation of neurotoxicity associated with Oxaliplatin | Neurotoxicity assessment | through study completion, an average of 5 years |
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Inclusion Criteria:
WBC ≥ 3000/mm3; ANC ≥1500/mm3; PLT ≥100,000/mm3; HgB ≥10.0g/dl; Total bilirubin ≤1.5 x upper normal limit (UNL); Serum creatinine ≤1.5 x UNL; Serum calcium ≤ 1.2 x UNL; Serum magnesium ≤ 1.2 x UNL.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| marc YCHOU | Institut régional du Cancer de Montpellier | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hôpital Européen | Marseille | Bouches Du Rhône | 13003 | France | ||
| Centre hospitalier régional et universitaire de Montpellier |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40540704 | Derived | Assenat E, Ben Abdelghani M, Gourgou S, Perrier H, Akouz FK, Desgrippes R, Galais MP, Janiszewski C, Mazard T, Rinaldi Y, Lepage C, Tetreau R, Senesse P. Impact of Lean Body Mass-Based Oxaliplatin Dose Calculation on Neurotoxicity in Adjuvant Treatment of Stage III Colon Cancer: Results of the Phase II Randomized LEANOX Trial. J Clin Oncol. 2025 Aug 10;43(23):2616-2627. doi: 10.1200/JCO-24-02754. Epub 2025 Jun 20. |
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| ID | Term |
|---|---|
| D003110 | Colonic Neoplasms |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
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| ID | Term |
|---|---|
| D000077150 | Oxaliplatin |
| ID | Term |
|---|---|
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |
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| Oxaliplatin LBM | Drug | Simplified FOLFOX 4 regimen: Association of Oxaliplatin (LBM) + simplified LV5FU2 |
|
|
| Montpellier |
| Hérault |
| 34000 |
| France |
| CHU de Nancy | Vandœuvre-lès-Nancy | Lorraine | 54511 | France |
| Insitut de Cancérologie de Lorraine | Vandœuvre-lès-Nancy | Meurthe-et-Moselle, | 54519 | France |
| Hôpital Saint-Jean | Perpignan | Pyrénées-orientales | 66000 | France |
| Centre François Baclesse | Caen | 14076 | France |
| CHU La TIMONE | Marseille | 13 | France |
| Institut regional du Cancer - Val d Aurelle | Montpellier | 34298 | France |
| AP-HP Hôpital Saint-Louis | Paris | France |
| Centre Eugène Marquis | Rennes | 35042 | France |
| Centre Paul Strauss | Strasbourg | France |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |