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

Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 18, 2006

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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?



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