What is the first-line systemic treatment for metastatic (mts) anal cancer?

First-Line Systemic Treatment for Metastatic Anal Cancer

Carboplatin plus paclitaxel is the preferred first-line systemic treatment regimen for metastatic anal cancer due to its superior efficacy and lower toxicity profile compared to other regimens. 1

Evidence-Based Recommendation

The recommendation for carboplatin plus paclitaxel as first-line therapy is based on the phase II International Multi-centre InterAACT study, which provides the highest quality evidence for treatment of metastatic anal cancer. This randomized controlled trial compared carboplatin plus paclitaxel to cisplatin plus 5-FU in patients with previously untreated, unresectable, locally recurrent or metastatic anal squamous cell carcinoma.

Key findings from the InterAACT study:

• Similar response rates between regimens (59% for carboplatin/paclitaxel vs 57% for cisplatin/5-FU)
• Significantly lower toxicity with carboplatin/paclitaxel (71% vs 76% grade ≥3 toxicity)
• Fewer serious adverse events with carboplatin/paclitaxel (36% vs 62%, p=0.016)
• Superior survival outcomes with carboplatin/paclitaxel:
  • Median PFS: 8.1 vs 5.7 months
  • Median OS: 20 vs 12.3 months (HR for OS, 2.0; 95% CI, 1.15–3.47; p=0.014) 1

Alternative First-Line Options

While carboplatin plus paclitaxel is preferred, several alternative regimens may be considered:

1. FOLFCIS (5-FU, leucovorin, cisplatin)

   • Demonstrated safety and efficacy in a retrospective study of 53 patients
   • Response rate: 48%
   • Median PFS: 7.1 months
   • Median OS: 22.1 months 1

2. FOLFOX (5-FU, leucovorin, oxaliplatin)

   • Added to NCCN guidelines based on consensus and use at major cancer centers
   • Consider discontinuing oxaliplatin after 3-4 months to minimize neurotoxicity 1

3. 5-FU plus cisplatin (Category 2B)

   • Historically used but has higher toxicity compared to carboplatin/paclitaxel 1

4. Modified DCF (docetaxel, cisplatin, 5-FU) (Category 2B)

   • Demonstrated efficacy but with significant toxicity concerns 1

Special Considerations

Local Control of Symptomatic Primary Tumor

• Palliative chemoradiotherapy to the primary site can be administered after upfront chemotherapy for symptomatic bulky primary tumors
• Analysis of the National Cancer Database showed improved median OS with the addition of definitive pelvic RT to chemotherapy (21.3 vs 15.9 months; HR, 0.70; p<0.001) 1

Management of Liver Metastases

• Retrospective data suggests resection or ablation of liver metastases may result in long-term survival in selected patients, though this approach is not currently included in NCCN guidelines 1

Second-Line Options

For patients who progress on first-line therapy, immune checkpoint inhibitors like nivolumab and pembrolizumab have shown activity and may be considered 1.

Common Pitfalls and Caveats

1. Delayed treatment decisions: Due to the rarity of metastatic anal cancer, clinicians may delay treatment while seeking additional opinions. Prompt initiation of systemic therapy is important for disease control.

2. Overlooking supportive care: Patients receiving platinum-based regimens require adequate hydration and antiemetic prophylaxis to manage toxicity.

3. Continuing oxaliplatin too long: Consider discontinuing oxaliplatin after 3-4 months (or sooner for unacceptable neurotoxicity) while maintaining other agents to minimize cumulative neurotoxicity 1.

4. Inadequate monitoring: Regular clinical and radiographic assessments are necessary to evaluate treatment response and manage toxicities promptly.

In conclusion, carboplatin plus paclitaxel represents the current standard of care for first-line treatment of metastatic anal cancer based on the most recent and highest quality evidence available.