Neoadjuvant FOLFOX Chemotherapy for Colon Cancer: Long-Term Chemotherapy-Induced Peripheral Neuropathy and Impact on Quality of Life

Introduction. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect experienced by many cancer patients receiving neurotoxic agents such as oxaliplatin. CIPN can manifest as numbness, tingling, and neuropathic pain, significantly impairing patients' quality of life (QoL). While the acute development of CIPN during chemotherapy treatment is well documented, the long-term persistence and severity of CIPN symptoms after completion of therapy is less understood.

The relatively new approach to treatment of patients with locally advanced colon cancer involves starting treatment with neoadjuvant (pre-operative) chemotherapy regimens containing oxaliplatin, such as FOLFOX, followed by definitive surgical resection and potentially additional adjuvant chemotherapy. This strategy has proven to be non-inferior to more established adjuvant (post-operative) chemotherapy, according to results of several clinical trials. However, the impact of this long-term CIPN on patient-reported outcomes and QoL in the setting of neoadjuvant chemotherapy has not been thoroughly investigated.

Additionally, there is interest in exploring whether modifying the sequence of neoadjuvant and adjuvant chemotherapy regimens could potentially mitigate the severity of CIPN. Specifically, a hypothesis can be made that delivering a reduced volume of oxaliplatin-containing chemotherapy (6 cycles of neoadjuvant FOLFOX) followed by a break for surgery, with only selective use of additional adjuvant chemotherapy based on response, may result in less cumulative neurotoxicity and improved long-term CIPN outcomes compared to the standard approach of administering the full course of chemotherapy after surgery.

The primary objective of this observational study was to characterize the long-term severity of CIPN symptoms and the associated impact on QoL in patients with locally advanced colon cancer who received neoadjuvant FOLFOX chemotherapy, followed by surgical resection and response-dependent adjuvant chemotherapy.

Study Design and Participants. This was a single-center, prospective observational study conducted at an academic medical center. Adult patients (≥18 years old) with histologically confirmed, locally advanced adenocarcinoma of the colon (clinical stage III or high-risk stage II) were eligible for enrollment. Key inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, adequate organ function, and no prior systemic chemotherapy or radiotherapy.

Eligible patients were enrolled and received 6 cycles of neoadjuvant FOLFOX chemotherapy. FOLFOX consisted of oxaliplatin 85 mg/m2 IV on day 1, leucovorin 400 mg/m2 IV on day 1, and 5-fluorouracil 400 mg/m2 IV bolus on day 1 followed by 2400 mg/m2 continuous IV infusion over 46 hours, every 2 weeks.

After completing six cycles of neoadjuvant FOLFOX chemotherapy, patients underwent definitive surgical resection of their primary tumor. For those who achieved a favorable pathologic response (defined as pT0-2N0M0 or pT3N0M0 without risk factors), no additional adjuvant chemotherapy was administered post-surgery. However, in cases of pT3N0M0 with the presence of risk factors, patients received 3 months of adjuvant capecitabine. Patients with a poor pathologic response were offered an additional six cycles of adjuvant FOLFOX chemotherapy.

Assessment of CIPN. Throughout the course of treatment, patients underwent clinical assessments for the development of CIPN. During treatment, a physician performed a neurological examination and graded the severity of CIPN using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. This standardized grading system classifies CIPN from grade 1 (mild) to grade 4 (life-threatening).

At a minimum of 3 months after the end of platinum-containing chemotherapy treatment, patients completed the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx) questionnaire. The FACT-GOG-Ntx is a validated, patient-reported outcome measure that evaluates the severity of CIPN symptoms and their impact on daily functioning and QoL.

The primary endpoint of this observational study was assessment of the long-term severity of CIPN and its impact on QoL, as measured by the FACT-GOG-Ntx questionnaire. The secondary target was assessment of correlation between various risk factors (older age (> 65 years), diabetes, Eastern Cooperative Oncology Group (ECOG) performance status, Body mass index (BMI) > 25, and higher cumulative oxaliplatin dose; cold temperatures during treatment) and severity of long-term CIPN.

Statistical Considerations. Descriptive statistics were used to summarize characteristics of patients. Associations between risk factors and ACIPN severity were evaluated using chi-squared tests. Two-tailed Mann-Whitney U tests were used to show significant differences in long-term CIPN outcomes and QoL scores between patient groups. Pearson and Spearman correlations were used to evaluate associations between risk factors and CIPN severity. Statistical significance was set at p < 0.05. Statistical analyses were performed using JASP (Version 0.18.3), an open-source statistical software package (JASP Team, 2024) or GraphPad Prism (GraphPad Software, San Diego, CA, USA).

Results. Between March 2021 and February 2024, a total of 54 patients were included and assessed by clinicians for acute CIPN during treatment. 45 of these patients provided complete FACT-GOG-Ntx questionnaire data for the long-term CIPN assessment, and 40 were included in the QoL analysis.

Inclusion criteria

• Patients with newly diagnosed, histologically confirmed, resectable colon cancer stage IIA - IIIC (cT3N0M0 [depth of invasion > 5 mm], cT4a-T4bN0M0, T1-4N1-2M0).
• Age < 75 years.
• ECOG performance status 0-1.
• Hemoglobin > 9 g/dL.
• Absolute neutrophil count > 1500/µL.
• Platelet count > 100,000/µL.
• Bilirubin level < 1.5 times the upper limit of normal.
• Creatinine clearance > 60 mL/min (calculated using the Cockcroft-Gault formula).
• ALT and AST levels < 2.5 times the upper limit of normal.

Exclusion criteria

• Presence of distant metastases.
• History of other oncological diseases, except for:

• Cured non-melanoma skin cancer without known signs of recurrence or progression for > 5 years.
• Cured carcinoma in situ without signs of recurrence or progression for > 5 years.
• Clinically significant concomitant cardiac pathology (chronic heart failure NYHA class > 1; hypertension with a risk of cardiovascular complications > 3; history of myocardial infarction, stroke, or transient ischemic attack; presence of other decompensated cardiovascular diseases).
• ECOG performance status > 1.
• Presence of viral or infectious diseases (human immunodeficiency virus, chronic viral hepatitis, other infectious diseases in the acute phase).
• History of clinically significant central nervous system disorders.
• Clinically significant peripheral polyneuropathy (> grade 2).
• Pregnancy or lactation.
• Individual intolerance to the components of the treatment.