What is the preferred platinum agent for concurrent chemoradiation in patients with locally advanced head and neck cancer, cisplatin or carboplatin?

Cisplatin Remains the Preferred Platinum Agent for Concurrent Chemoradiation in Locally Advanced Head and Neck Cancer

Cisplatin at 100 mg/m² every 3 weeks for 3 cycles is the evidence-based standard of care for concurrent chemoradiation in locally advanced head and neck cancer, and should be used unless specific contraindications exist. 1, 2

Standard Cisplatin Regimen

The National Comprehensive Cancer Network (NCCN) explicitly recommends concurrent single-agent cisplatin at 100 mg/m² every 3 weeks as the standard regimen for both definitive and postoperative chemoradiation. 1 This recommendation is based on landmark trials (EORTC #22931 and RTOG #9501) that established this as the gold standard, demonstrating significant improvements in locoregional control and overall survival. 1

The cumulative cisplatin dose of ≥200 mg/m² is critical for efficacy, with post-hoc analyses showing that patients receiving less than this threshold have significantly worse overall survival. 2 The high-dose triweekly regimen achieves this target in 89% of patients compared to only 86% with weekly cisplatin at 40 mg/m² and 25% with lower weekly doses. 3

When to Consider Carboplatin

Carboplatin should be reserved for patients with specific contraindications to cisplatin, primarily:

• Impaired renal function (creatinine >1.5 mg/100 mL or creatinine clearance inadequate for cisplatin) 4
• Significant cardiac dysfunction 4
• Pre-existing hearing impairment where cisplatin's ototoxicity is unacceptable 2

When carboplatin is used, the recommended regimen is carboplatin AUC 2 weekly plus paclitaxel 45 mg/m² weekly during radiation, or carboplatin AUC 5-6 every 3 weeks as monotherapy. 2, 4

Evidence Comparing Cisplatin and Carboplatin

While carboplatin-based regimens show equivalent locoregional control and overall survival in matched-pair analyses, these studies have significant limitations. 5 A 2013 matched-pair study of 130 patients found no significant difference in 3-year locoregional control (87% vs 79%, p=0.54) or overall survival (59% vs 68%, p=0.24) between carboplatin and cisplatin cohorts. 5 However, these are retrospective comparisons in selected populations, not the randomized controlled trials that established cisplatin's efficacy. 5

The toxicity profiles differ substantially: cisplatin causes more nephrotoxicity and emesis, while carboplatin causes more hematologic toxicity (anemia and thrombocytopenia). 4, 5 In one institutional series, 95.2% of patients who switched from cisplatin to carboplatin did so due to nephrotoxicity. 4

Alternative Cisplatin Dosing

Weekly cisplatin at 40 mg/m² for 6-7 weeks is an acceptable alternative when the standard triweekly regimen is not tolerated, though it remains inferior to high-dose cisplatin. 2, 6, 3 Recent evidence suggests weekly cisplatin may be non-inferior for disease control with reduced toxicity, but this remains controversial. 6 A 2021 retrospective study showed that high-dose cisplatin achieved superior 2-year overall survival (87% vs 77%) and disease-free survival (75% vs 68%) compared to weekly cisplatin at 40 mg/m². 3

The ASCO/CSCO nasopharyngeal carcinoma guideline found no significant survival differences between weekly and triweekly schedules, with weekly regimens showing improved quality of life, but this applies specifically to nasopharyngeal cancer and may not generalize to other head and neck sites. 2

Clinical Algorithm for Platinum Selection

1. First-line: Cisplatin 100 mg/m² every 3 weeks × 3 cycles 1, 2

   • Requires: Creatinine <1.5 mg/100 mL, adequate cardiac function, acceptable hearing 2
   • Mandatory prehydration with 1-2 liters over 8-12 hours 2

2. If nephrotoxicity develops during treatment: Switch to carboplatin AUC 2 + paclitaxel 45 mg/m² weekly 4

   • This strategy allows 61.9% of patients to complete ≥5 chemotherapy courses 4

3. If cisplatin contraindicated from outset: Carboplatin AUC 5-6 every 3 weeks or carboplatin AUC 2 + paclitaxel 45 mg/m² weekly 2, 4

4. If high-dose cisplatin not tolerated: Weekly cisplatin 40 mg/m² × 6-7 weeks 2, 6

Critical Pitfalls to Avoid

Do not use carboplatin as first-line therapy in cisplatin-eligible patients. The NCCN guidelines are unequivocal that cisplatin is the recommended agent, and carboplatin lacks the same level of prospective randomized evidence. 1 While retrospective data suggest equivalence, this reflects selection bias and does not justify substituting carboplatin in patients who can tolerate cisplatin. 5

Do not accept cumulative cisplatin doses <200 mg/m² without attempting dose optimization or alternative scheduling. Compliance with planned dosing is frequently suboptimal (median 84% of intended dose in some trials), but achieving the 200 mg/m² threshold is critical for efficacy. 2, 3

Ensure adequate supportive care infrastructure before initiating any concurrent chemoradiation regimen. The NCCN emphasizes that these treatments carry high toxicity burdens and should only be administered by experienced multidisciplinary teams with substantial supportive care. 1, 7