Muscling in on body surface area to reduce oxaliplatin-induced peripheral neuropathy in colon cancer

The practice of dosing cytotoxic chemotherapy by body surface area (BSA) emerged in the 1950s, based on physiological observations that parameters such as blood volume, metabolic rate, and drug toxicity scaled more consistently with surface area than body weight across species (1). This approach was reinforced in the 1960s, with the observation that maximum tolerated doses (MTDs) of cytotoxic drugs aligned more closely when expressed per m² rather than per kg, bolstering the use of BSA for translating drug doses from animals to humans (2). However, this historical foundation for BSA-based dosing began to be questioned in the 1980s–2000s as population pharmacokinetic (PK) methods emerged, demonstrating that BSA accounts for a small fraction of inter-patient variability in drug clearance, often explaining 10−30% of PK variability for common cytotoxic drugs (3-5).

The consequences of a BSA-based approach to dosing become most evident from drugs or regimens with narrow therapeutic windows, such as oxaliplatin-based adjuvant therapy for stage III colon cancer. Oxaliplatin remains a cornerstone of adjuvant therapy for stage III colon cancer, yet its use is constrained by oxaliplatin-induced peripheral neuropathy (OIPN) (6), a toxicity that often interrupts treatment continuity and erodes patient-reported quality of life (7). Against this backdrop, LEANOX, a phase II randomized trial, evaluated the hypothesis that rather than relying on the BSA, dosing tailored to a patient’s lean body mass (LBM) might meaningfully reduce OIPN in patients with stage III colon cancer who are receiving adjuvant oxaliplatin-based chemotherapy (8). This Editorial Commentary for the Journal of Gastrointestinal Oncology evaluates the implications of the LEANOX trial (8), contextualizes the findings with the International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration (9), and discusses how body composition assessment may refine future drug dosing paradigms across oncology.

LBM, also known as fat-free mass, is the estimated mass of all nonfat molecules in the body, regardless of where they occur (here “fat” refers to nonpolar lipids, mainly triglycerides) (10). Two patients can have a similar BSA but substantially different LBM because BSA captures external dimensions, whereas LBM depends on internal body composition. For example, two patients, both weighing 80 kg and standing 1.83 m, have the same BSA (≈2 m²), but patient #1 has 60 kg LBM, whereas patient #2 has 40 kg LBM. In the paradigm of BSA-based dosing, both patients would receive a similar oxaliplatin dose, which may contribute to heterogeneity in toxicity risk. In the foundational study that provided preliminary data to inform the design of LEANOX, among 58 colon cancer patients administered oxaliplatin based on BSA, values of oxaliplatin per kg of LBM ranged from 2.55 to 6.60 mg/kg (11). Colon cancer patients with low LBM may therefore be at an increased risk of oxaliplatin-related toxicity, necessitating treatment delays or treatment discontinuation (12). This creates the premise that reducing the oxaliplatin dose in patients with low-LBM may not be underdosing per se, but correcting an implicit overdose obscured by the BSA-based paradigm, paving the way for the LEANOX trial.

The LEANOX trial was a multicenter, phase II, randomized trial conducted in France. The trial enrolled patients with curatively resected colon cancer who planned to initiate adjuvant leucovorin, fluorouracil, and oxaliplatin (FOLFOX) administered every 2 weeks for up to 12 cycles. Computed tomography (CT) images recorded within 30 days before treatment initiation were used to measure LBM. LBM was quantified using standardized and validated equations within 72 hours. Patients with a low-LBM (defined as ≥3.09 mg oxaliplatin per kg of LBM) were randomized in a 1:1 ratio to receive BSA-based oxaliplatin dosing (85 mg/m²) or LBM-based oxaliplatin dosing (3.09 mg per kg of LBM). Patients with a high-LBM were not randomized, but followed longitudinally, completing the same assessments as the randomized groups. The fluorouracil bolus (400 mg/m²) and continuous infusion (2,400 mg/m²) were BSA-based for all patients. The primary endpoint was the percentage of patients without grade ≥2 OIPN during the first six cycles of therapy, assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.

Between December 2017 and December 2021, 160 patients were enrolled across 18 centers, and 127 (79%) patients with low LBM were randomized. The median age was 63 years (range, 29−77 years), and the median LBM of randomized patients was 41.5 kg (range, 29−65 kg). The primary endpoint, the percentage of patients who remained free from grade ≥2 OIPN during the first six cycles of chemotherapy, was statistically significantly higher in the LBM-based group compared to the BSA-based group (67.2% vs. 42.1%; P=0.01). The median time to grade ≥2 OIPN was 5.7 months in the LBM-based group, as compared with 2.3 months in the BSA-based group [hazard ratio (HR): 0.53; 95% confidence interval (CI): 0.34–0.84; P=0.01]. Despite experiencing less OIPN, a 34% higher cumulative dose of oxaliplatin was delivered in the LBM-based group compared to the BSA-based group (P=0.04).

Patients also perceived a higher quality of life in the LBM-based group compared to the BSA-based group, as quantified using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20) questionnaire, particularly in terms of motor function in later treatment cycles. Among patients with incident grade ≥2 OIPN, the time to resolution was not different between randomized groups (P=0.65). Recurrence-free survival and overall survival rates were similar between groups; however, this comparison is statistically underpowered for definitive conclusions.

The LEANOX trial represents a biologically informed strategy for reconsidering the optimal dose of oxaliplatin. LBM-based oxaliplatin dosing is one of the first scalable alternatives to BSA in oncology. It is not perfect—body composition is one of many variables that influence PK—but it is an excellent foundation on which to build. The key strengths of this trial include its randomized design, the integration of a validated radiologic workflow to quantify LBM, and the use of clinically relevant endpoints that are representative of how patients feel, function, and survive. Enrollment of patients from multiple centers reduces site-specific bias and provides a framework for high-throughput, centralized radiologic workflows using routine CT imaging, which can efficiently provide measurement results to inform treatment planning.

However, there are important limitations that are relevant to this trial. LEANOX did not quantify oxaliplatin PK parameters. Although altered PK related to LBM is hypothesized to be the mechanism underlying the dosing strategy, this was not directly investigated by LEANOX. LBM may be associated with oxaliplatin PK (13), but prospective studies that examine oxaliplatin PK with LBM-based dosing will be critical to corroborate the hypothesized mechanism of action. LBM was quantified only at baseline, which, although practical, does not account for longitudinal changes that may occur in LBM (14). Uncertainty persists regarding whether the radiologic workflow is generalizable to diverse cancer care environments, such as community oncology settings, where barriers to implementation may include limited access to validated software, short turnaround times, inter-reader variability, and reimbursement considerations. The trial was not blinded; however, the neurotoxicity grading was standardized and supplemented by patient-reported outcomes. Importantly, the use of LBM-based dosing in patients with normal or high LBM was not addressed in LEANOX; additional research is needed to determine if LBM-based oxaliplatin dosing might risk overdosing in patients with normal or high LBM. Despite limitations, the pre-specified rationale and biological and clinical consistency of the results make LEANOX compelling.

The LEANOX trial opened to accrual prior to the publication of the results from the IDEA collaboration (9), in an era when most patients were treated with 6 months of adjuvant chemotherapy. The data from the IDEA collaboration suggested that the choice of fluoropyrimidine (5-fluorouracil or capecitabine), the duration of therapy (3 or 6 months), and patient characteristics may be used to optimally balance disease control and toxicity. LEANOX adds a new dimension to IDEA. Specifically, IDEA acknowledged that oxaliplatin toxicity is a critical barrier to completing 6 months of therapy. LEANOX now suggests that tailoring the oxaliplatin dose based on LBM could maintain or increase cumulative oxaliplatin exposure without increasing OIPN. The two strategies—de-escalating duration (IDEA) and optimizing dose per biological mass (LEANOX)—are complementary rather than competing.

The bridge between IDEA and LEANOX creates an opportunity to explore other avenues for synergizing these studies in a manner that is clinically valuable and more personalized. For example, among higher-risk patients treated with a 6-month duration of therapy, LBM-based dosing may provide a pathway to deliver more oxaliplatin throughout the full duration, potentially with fewer toxicity-related treatment interruptions. Conversely, among lower-risk patients treated with a 3-month duration of capecitabine and oxaliplatin (often at a higher initial dose than that used in FOLFOX, 130 vs. 85 mg/m²), could tailoring the oxaliplatin dose based on LBM mitigate early OIPN, helping patients complete the planned duration of therapy? Together, IDEA and LEANOX create a paradigm where duration of therapy is guided by tumor risk biology, and dosing is guided by patient biology. This precision-based risk stratification paradigm may reduce chronic OIPN that often persists long after the completion of therapy and enhance overall quality of life during cancer survivorship.

While the LEANOX trial was focused on the adjuvant setting, oxaliplatin remains critical in the management of metastatic colorectal cancer (15). Opportunities exist for future research to better understand the effects of LBM-based dosing in the setting of advanced colorectal cancer, where time to first progression may exceed 10 months, and the median overall survival is 30 months (16). As patients with advanced disease live longer, it is also accompanied by prolonged exposure to the toxicities of systemic therapy. It is uncertain how LBM-based dosing compares to stop-and-go or intermittent treatment strategies in terms of optimizing the balance of quality of life and clinical efficacy (17). LBM-based dosing might be thought to reduce early dose-limiting OIPN and extend the utility of oxaliplatin in long-term disease management; however, this is speculative and would need to be evaluated.

The LEANOX trial provides compelling justification for investigating the effects of LBM-based dosing on other cytotoxic therapies and body composition compartments. For example, in an observational study of patients with metastatic colorectal cancer, patients with grade ≥3 toxicity had a higher dose of 5-fluorouracil per kg of LBM, particularly for hematologic toxicities (110 vs. 94 mg/kg; P=0.002) (18). Moreover, other body composition compartments, such as adipose tissue, may be relevant to treatment tolerability. In a cohort of 26 older adults with various types of gastrointestinal cancers, LBM and total adipose tissue explained 11% and 14% of the variability in oxaliplatin PK, respectively, and patients with low LBM and excess adipose tissue had a 45% higher risk of grade ≥3 toxicity (13). In addition to the absolute quantity of lean mass, the quality of that mass may also be relevant. Among 533 patients with stage II–III colorectal cancer, fatty infiltration into the skeletal muscle—a phenotype known as myosteatosis—was associated with a nearly three-fold increase in the risk of prematurely discontinuing adjuvant FOLFOX (19).

LBM and other body composition compartments are modifiable. The American Society for Clinical Oncology recommends that patients engage in regular aerobic and resistance exercise during active treatment (20). However, it is currently uncertain if the magnitude of exercise-induced change in LBM and other body composition compartments during cancer therapy is sufficient to meaningfully improve treatment tolerability (21,22). The National Cancer Institute recently launched the consortium of “Exercise and Nutrition to Improve Cancer Treatment-Related Outcomes (ENICTO)” to better understand how lifestyle programs impact chemotherapy dose intensity and patient-reported toxicities (23).

The LEANOX trial provides the best evidence to date that LBM-based oxaliplatin dosing reduces neurotoxicity in patients with stage III colon cancer (8). The French Scientific Society for Diseases of the Digestive Tract now recommends considering LBM-based dosing in the management of early colon cancer. The LEANOX trial demonstrates the following: one-size-fits-all dosing strategies are more of a historical artifact than a biological necessity; chemotherapy toxicity is not random, but rather predictable; body composition matters; and imaging-derived biomarkers can strategically inform therapy decisions. Combined with the risk-stratified treatment duration principles from the IDEA collaboration (9), the LEANOX trial points toward a future where chemotherapy is delivered with far greater biological precision. The LEANOX trial is an exemplar for future personalization efforts.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1007/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1007/coif). J.C.B. discloses grants from the National Institutes of Health and the American Institute for Cancer Research, which are paid to his employer. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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