Average Cumulative Relative Adjuvant Chemo Dose Linked With Survival in CRC

Average cumulative relative dose (ACRD) was found to be associated with survival over average relative dose intensity (ARDI) in patients with colorectal cancer (CRC), highlighting that obese patients receive lower cumulative doses of adjuvant chemotherapy and therefore may be attributed to their poorer survival outcomes, according to results from the OCTOPUS consortium that were presented at the 2021 European Society of Medical Oncology Virtual World Congress on Gastrointestinal Cancer and subsequently published in Annals of Oncology.^1,2

Results showed that 5% increments in ACRD were significantly associated with improvements in disease-free survival (DFS; HR, 0.953; 95% CI, 0926-0.980; P = .001). While overall survival (OS) was also associated with ACRD (HR, 0.931; 95% CI, 0.908-0.955; P <.001), as was cancer-specific survival (CCS; HR, 0.941; 95% CI, 0.924-0.959; P <.001), there was no significant association with ARDI with regards to DFS (HR, 1.015; 95% CI, 0.967-1.065; P = .552), OS (HR, 1.035; 95% CI, 0.990-1.081; P = .134) or CCS (HR, 1.022; 95% CI, 0.982-1.064; P = .282).

Researchers suggested that the lack of association could be because ARDI is a less sensitive measure of reductions in cumulative dose of chemotherapy.

“Our study has demonstrated an association between increasing body mass index and modest reductions in the cumulative relative dose of adjuvant chemotherapy in patients with colorectal cancer. And we also saw an association between increased cumulative relative dose and improved survival,” said lead author Corinna Slawinski, MD, of the Division of Cancer Sciences, University of Manchester, in the United Kingdom.³ “This supports the recently published ASCO guidance that full, weight-based chemotherapy doses should be used to treat obese adult patients.”

Prior findings have demonstrated that obese patients with CRC tend to have worse survival outcomes vs those who are not obese. Moreover, adjuvant chemotherapy is often capped at a body surface area of 2.2 m2 or higher. However, because of study limitations, researchers have been unable to determine whether a higher BMI is directly linked with survival, or whether dose administration of therapy, specifically calculation of chemotherapy doses, is another factor.

“Adjuvant chemotherapy is dosed according to a person’s body surface area, which is calculated from their height and weight,” said Slawinski. “But in obese patients [with a high BMI], and who are more likely to have high body surface areas], doses are often capped, or based on an idealized weight, because of concern that large doses might increase side effects. This means that obese patients may receive proportionately lower doses of chemotherapy.”

In the OCTOPUS meta-analysis, investigators sought to better understand the relationship between BMI and chemotherapy dosing, as well as chemotherapy dosing and OS in CRC. Data were analyzed of 7269 patients receiving adjuvant chemotherapy following curative surgery for CRC from 4 randomized trials: MOSAIC (NCT00275210), SCOT, PROCTORSCRIPT, and CHRONICLE (CRC-ACT; NCT00427713). Chemotherapy dosage was analyzed to see if patients received treatment measured by ACRD or ARDI.

ACRD is defined as the proportion of total expected standard dose—per unit of body surface area—over the entire chemotherapy course that was received. ARDI, which also takes the duration of treatment into account, is the proportion of the expected standard dose intensity—the total dose per unit of body surface area, divided by the number of weeks of treatment— that was received. Furthermore, 2-stage, random-effects, meta-analyses of linear or Cox proportional hazards regression models were implemented to evaluate BMI-ARDI/-ACRD and ARDI-/ACRD-survival relationships, respectively.

The primary end point was DFS; secondary end points were OS, CCS, ARDI, and ACRD. All models were also adjusted for sex, age, performance status, T stage, and N stage.

Additional results showed that each BMI increase of 5 kg/m2 was linked with a 2.04% reduction in the relative chemotherapy dose in the first cycle of chemotherapy (95% CI, -2.45 to -1.64) and 1% reductions in both ACRD and ARDI. These data suggest that an obese patient with a BMI of 37.5 kg/m2 would have a 3% reduction of ACRD and ARDI vs a non-obese patient with a BMI of 22.5 kg/m2.

“Our results so far support giving obese patients a full dose of chemotherapy based on their body weight. But we are still exploring toxicity data, examining the relationship between BMI, dose capping, toxicity, and survival,” Slawinski said. “Toxicity has the potential to reduce quality of life and can be life threatening. There may also be other reasons for reducing chemotherapy doses, such as comorbidities, so it is important that dosing and treatment decisions are individualized to the patient.”

Elizabeth Smyth, MD, Addenbrooke’s Hospital in Cambridge, United Kingdom, and member of the ESMO Faculty for Gastrointestinal Tumors, commented on the findings and suggested that further similar analyses are necessary before having implications on clinical practice.

“Dose reductions for high BMI may be associated with lower cure rates in resected colon cancer treated with adjuvant chemotherapy,” Smyth said. “Adjuvant chemotherapy has the potential to cure patients with residual micrometastatic disease following curative surgery, so it is important that we maximize the benefits for all patients.”

References

1. Slawinski C, Malcomson L, Barriuso J, et al. Average cumulative relative dose (ACRD) of adjuvant chemotherapy is more important than average relative dose intensity (ARDI) for colorectal cancer survival, with implications for treating obese patients: the OCTOPUS consortium. Presented at: 2021 European Society of Medical Oncology Virtual World Congress on Gastrointestinal Cancer; June 30-July 3, 2021; virtual. Abstract O-4.
2. Slawinski C, Malcomson L, Barriuso J, et al. Average cumulative relative dose of adjuvant chemotherapy is more important than average relative dose intensity for colorectal cancer survival, with implications for treating obese patients: the OCTOPUS consortium. Ann Oncol. 2021;32(S3):S218-S219. doi:10.1016/j.annonc.2021.05.008
3. Poorer Survival in Obese Colorectal Cancer Patients Possibly Linked to Lower Chemotherapy Doses [ESM World GI 2021 Press Release]. News release. European Scoeity for Medical Oncology. July 2, 2021. Accessed August 13, 2021. https://bit.ly/3jWmi4R