Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer

Authors: Wolf, G.T. et al. (The Department of Veterans Affairs (VA) Laryngeal Cancer Study Group)
Source: NEJM. 1991 324(24):1685-90.
Affiliation: Ann Arbor VA Medical Center, Ann Arbor, MI.

Background

• Prior to this landmark study, standard treatment for locally advanced (Stage III or IV) laryngeal cancer consisted of total laryngectomy +/- post-operative radiation.
• Laryngectomy results in substantial functional morbidity (loss of voice, altered swallowing, permanent tracheostomy).
• Pilot studies using induction chemotherapy followed by radiation demonstrated feasibility of larynx preservation with this approach
• This study evaluated the ability to preserve the larynx without detriment to survival with induction chemotherapy and radiation instead of immediate laryngectomy.

Methods

• Design: Randomized Phase III design (n=332)
• Patients: VA patients with Stage III or IV squamous cell carcinoma of the larynx
  • Excluded: stage T1N1, unresectable disease, distant metastases, KPS<50, lab values that would preclude chemotherapy
• Randomized to:
  • Induction Chemotherapy followed by definitive radiation
    • Evaluated for response after 2 cycles of:
      • CDDP (100 mg/m2) + 5-FU (1000 mg/m2 x 5 d) every 3 weeks
    • If complete or partial remission (CR or PR), then received 3 rd cycle of CDDP/5-FU and definitive RT
    • If less than PR, then underwent total laryngectomy and post-op RT
  • Immediate Laryngectomy followed by post-op RT
• Stratification: performance status, stage (N0/1 vs. N2/3), glottic vs. supraglottic site
• Assessment of response:
  • Physical exam and indirect laryngoscopy after 2 nd chemotherapy cycle and 12 weeks after completion of definitive radiation
  • CR: complete disappearance of visible tumor
  • PR: 50% decrease in sum of the products of longest dimension and perpendicular
  • Biopsies taken after 3 rd cycle of chemotherapy
• Definitive radiation:
  • Primary: 66-70 Gy
  • Nodes: N0: 50 Gy; <2cm: 66 Gy; 2-4 cm: 70 Gy; >4 cm: 75 Gy
• Post-operative radiation:
  • Normal risk microscopic: 50 Gy
  • High risk: 60 Gy
  • Presumed residual: 65-73 Gy
• Surgery:
  • wide-field total laryngectomy except rare cases where a horizontal partial laryngectomy could be performed
  • neck dissection: all except T3N0 and midline supraglottic T4N0 where side could not be determined
  • Median follow-up was 33 months (range, 11 to 62 months)

Results

• Groups were well-balanced and represented typical VA population with larynx cancer (80% white, 97% male, 99% smokers, 85% drank alcohol)
• Responses after chemo:
  • CR 31% (2 cycles); 49% (3 cycles)
  • PR 54% (2 cycles); 49% (3 cycles)
• Pathologic complete responses after definitive RT
  • 88% of clinical CR, 45% of clinical PR
• Response did not predict overall survival
• Of the deaths, most died from cancer
  • 8 patients (2%) died during treatment
  • 3/8 surgical complications
  • 1/8 related to chemo (neutropenic septicemia)
• Overall survival was identical: 68% at 2 yr (p=0.98)
• Disease-free survival was non-significantly worse in induction chemo arm (p=0.12)
• Larynx preservation: 64% chemo arm, 0% surgery arm
• Relapse patterns differed, but overall rates did not:
  • Local: 2% surgery arm, 12% chemo arm
  • Distant: 17% surgery arm, 11% chemo arm
• Salvage laryngectomy:
  • 30 patients:
    • 19 for persistent disease at 12 week re-evaluation
    • 11 for recurrence
    • required more often in patients with Stage IV disease (p=0.048) and T4 disease (0.001)

Discussion

• Larynx preservation could be achieved in 64% via induction chemotherapy followed by definitive radiation in locally advanced larynx cancer
• This was accomplished without a decrement in overall survival
• Patterns of relapse differed: more local failures and fewer distant failures in chemo arm compared to surgery arm

Author's Conclusions

This was a landmark study that established the possibility of larynx preservation in locally advanced laryngeal squamous cell carcinoma

Epilogue:

• Overall survival at 5 and 10 years, chemotherapy-treated group was 5% less than the surgical arm (difference not statistically significant)
• Quality of life was better in chemo arm
• RTOG 91-11 showed that concurrent chemoradiation superceded induction in terms of laryngectomy-free survival and time-to-laryngectomy

Criticisms and Pertinent Questions:

• The concept of "organ preservation" is not as important as "functional organ preservation."
• The success rate of late salvage laryngectomy after induction chemo and RT was not described in this paper
• Does lack of response to chemotherapy predict a poor response to radiation?
• Could some of these patients have been cured with radiation alone?