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