EDITORIALS
Another Look at Induction Chemotherapy for
Organ Preservation in Patients With Head and
Neck Cancer
Arlene A. Forastiere*
Organ preservation as a primary end point in head and neck
cancer trials has been under investigation since the early 1980s.
Until now, the only site-specific large randomized trial was that
published by the Department of Veterans Affairs (VA) Laryngeal Cancer Study Group, which showed that laryngeal preservation could be achieved without jeopardizing survival with the
use of induction chemotherapy followed by radiotherapy (/).
Another logical site to attempt organ preservation is the
hypopharynx, since curative therapy requires laryngopharyngectomy and the survival of patients with locally advanced disease
so treated is particularly poor.
In this issue of the Journal, Lefebvre et al. (2) from the
European Organization for Research and Treatment of Cancer
(EORTC) Head and Neck Cooperative Group report the results
of another landmark trial of combined modality therapy for head
and neck cancer. Two hundred two patients with operable, locally advanced squamous cell cancer of the pyriform sinus or
the hypopharyngeal aspect of the aryepiglottic fold were randomly assigned to receive treatment with standard surgery and
postoperative radiotherapy or induction chemotherapy (cisplatin
and fluorouracil [5-FU]). Patients achieving a clinical complete
response (CR) at the primary site after two or three cycles of
chemotherapy received organ-sparing treatment with definitive
radiotherapy (70 Gy), while those with less than a CR were
treated surgically. At a median follow-up of 51 months (range,
3-106 months), the estimated survival outcomes for patients randomly assigned to receive the induction chemotherapy and the
surgery arms, respectively, were 3-year overall survival of 57%
versus 43%, 3-year disease-free survival of 43% versus 31%,
and median survival of 44 versus 25 months. These differences
reflected a trend for improved outcome from chemotherapy and
meet the statistical criteria for survival equivalence for the two
arms. The time to local or regional failure was similar for both
treatment groups, but a significant difference in time to distant
metastases was observed favoring the induction chemotherapy
arm (27% versus 40% failure rate at 3 years). Laryngeal preservation rate was estimated at 42% considering only deaths from
local disease as failure. On the basis of these results, the
European clinical research community has taken induction
Journal of the National Cancer Institute, Vol. 88, No. 13, July 3, 1996
chemotherapy followed by radiotherapy as its new standard for
comparison of future organ-sparing strategies.
The EORTC trial design differed from other induction
chemotherapy trials in some respects. First, only patients
achieving a CR on endoscopic evaluation were offered organsparing therapy. One could speculate that this resulted in better
local control (similar to surgically treated patients) than occurred in the VA Laryngeal Cancer Study that was less selective, allowing partial responders (PR) to receive radiotherapy. In
reality, it is quite difficult to obtain accurate bidimensional
measurements of a lesion visualized in the larynx or hypopharynx to document a PR. Second, endoscopy alone was used
to clinically evaluate response after each course of chemotherapy; computed tomographic imaging was recommended but
not required. Third, the decision to perform a neck dissection
before radiotherapy for patients with a CR at the primary but
residual disease in the neck was left to the treating physician,
not mandated. These variances served to streamline the study,
focusing on the main question of feasibility of organ preservation and survival, and do not detract from the results.
This protocol used a well-established chemotherapy regimen
(cisplatin at 100 mg/m2 on day 1 + infusional 5-FU at 1000
mg/m2 per day for 5 days repeated every 3 weeks). The 86%
response rate (54% CR + 32% PR) of the primary is in the expected range. Compliance was excellent: 95% of the patients
(89 of 94) in the surgery arm received the planned treatment as
did 93% of the patients (93 of 100) randomized to receive
chemotherapy. Only six patients randomized to receive induction chemotherapy for whom surgery was recommended refused
to undergo laryngopharyngectomy per protocol. There was one
treatment-related death during induction chemotherapy and no
increase in surgical complications after chemotherapy.
The EORTC trial was well designed and executed. A uniform
patient population with respect to site, stage, and operability was
studied with the use of an optimal drug regimen. Furthermore,
the sample size was adequate to formulate conclusions with
*Corrcspondence to: Arlene A. Forastiere, M.D., Johns Hopkins Oncology
Center, 600 N. Wolfe St., Baltimore, MD 21287-8936.
EDITORIALS
855
statistical confidence, even though the trial was closed early
after a Data Monitoring Committee review. This is important,
since so many other randomized trials are inconclusive because
of methodologic flaws (J). The results confirm the following
published findings for induction chemotherapy that have been
extensively reviewed (4-6). 1) Cisplatin and 5-FU produce high
response rates, 80%-90%, and CR in 40%-50% of the patients.
2) Induction chemotherapy affects micrometastatic disease as
shown by a decrease in the rate of distant metastases but does
not reduce local-regional recurrence or impact on cause of
death. 3) Chemotherapy does not increase the morbidity or mortality associated with surgery or radiotherapy. 4) Larynx preservation is feasible in a proportion of patients. 5) The survival of
patients whose surgery is delayed for a trial of chemotherapy
does not appear to be shortened. 6) Overall survival statistics are
neither improved nor worsened after induction chemotherapy
and surgical salvage compared with standard surgery and postoperative radiotherapy.
Given these conclusions and the results of this EORTC randomized trial, should patients with locally advanced, operable
cancer of the hypopharynx be offered this regimen for organ
preservation instead of laryngopharyngectomy? It would seem
that three criteria should be met. 1) The rate of organ preservation must be reasonably high to justify the morbidity and cost of
chemotherapy and the delay in definitive therapy for the whole
population. 2) The number of patients requiring salvage surgery
over time should be low. 3) Those who do fail locally or in the
neck should be salvageable with surgery.
The authors determined the organ-preservation rate for their
data in several ways. The 3-year survival rate with a functional
larynx for all 100 patients randomized to receive induction
chemotherapy was 28% (95% confidence interval [CI] = 17%37%). A total of 55 patients had died of local failure at the
time of the analysis; censoring deaths from other causes, the estimated 3-year laryngeal preservation rate was 42% (95% CI =
31%-53%). Performing the same analysis for the subset of 52
CRs treated with radiotherapy, the laryngeal preservation rate
was 64% (95% CI = 48%-80%). Thus far, only eight patients
have undergone salvage surgery after definitive radiotherapy,
suggesting a low failure rate. The 3-year data for laryngeal
preservation reported for the VA Laryngeal Cancer Study, with
a median follow-up of 60 months (range, 12-90 months), were as
follows. Survival with a functional larynx for all 166 patients
randomized to receive induction chemotherapy was 31% and the
percent of survivors at 3 years with a functional larynx was 66%
(52 of 79) (7). The percent of all patients randomized to receive
induction chemotherapy undergoing laryngectomy either before
or after radiotherapy at 3 years was 43% (43 of 100) in the
EORTC trial and 38% (63 of 166) in the VA trial. We do not
know how many patients failing locally or in the neck were no
longer resectable. Thus, the comparable analysis of results for
these two laryngeal preservation trials shows that 28% and 31%
of patients, respectively, were alive at 3 years with a functional
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EDITORIALS
larynx. This is the simplest and most generalizable way to view
the data, although admittedly there are multiple ways that one
could choose to calculate a laryngeal preservation rate.
Organ preservation alone is not a sufficient measure of success, particularly if a high percentage of patients ultimately fail
locally or do not achieve an adequate initial response to avoid
surgery. Clearly, a higher rate of survival with a functional
larynx must be achieved; induction chemotherapy alone will not
accomplish this. To that end, one can argue that, although these
trials represent a major step forward, neither provide results that
are compelling enough to warrant a change in the standard of
care to induction chemotherapy. Rather, this should be viewed
as an alternative therapy for the informed patient desiring voice
preservation and mandates enrollment in investigational protocols if feasible. We now have two excellent laryngeal preservation trials with comparable results. It is time to study
alternative strategies in controlled trials and to gain an understanding of the biology of head and neck cancer that leads some
tumors to respond so well to these therapies and others not.
The EORTC investigators are planning two successor trials
for patients with laryngeal and hypopharyngeal cancers comparing concurrent chemoradiotherapy with the induction chemotherapy approach in one trial and with radiotherapy alone in the
second trial. A three-arm randomized trial has been in progress
since 1992 in the U.S. intergroup for laryngeal cancer comparing the same strategies (8). Our European colleagues are to be
congratulated for successfully moving forward with large-scale
trials that address multimodality questions. Such trials are essential to ultimately change the standard of care that means improving survival in addition to quality of life.
References
(/) Induction chemotherapy plus radiation compared with surgery plus radiation
in patients with advanced laryngeal cancer. The Department of Veterans Affairs LaryngeaJ Cancer Study Group [see comment citation in Medline]. N
Engl J Med 1991:324:1685-90.
(2) Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud
T. Larynx preservation in pyriform sinus cancer: preliminary results of a
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trial. J Natl Cancer Inst 1996:88:890-9.
(J) Forastierc AA. Randomized trials of induction chemotherapy. A critical
review. Hematol Oncol Clin North Am 1991 ;5:725-36.
(4) Dimery IW, Hong WK. Overview of combined modality therapies for head
and neck cancer. J Natl Cancer Inst 1993:85:95-111.
(5) Schantz SP, Harrison LB, Hong WK. Cancer of the Head and Neck: Principles of Chemotherapy. In: DeVita VT Jr, Hellman S, Rosenberg SA,
editors. Cancer: Principles and Practice of Oncology. 4th ed. Philadelphia:
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(6) Tovorath R, Pfister DG. Chemotherapy for recurrent disease and combined
modality therapies for head and neck cancer. Curr Opin Oncol 1995;7:2427.
(7) Wolf G, Hong W, Fisher S, Spaulding M, Endicott J, Laramorc G, Hillman
R. et al. VA Laryngeal Cancer Study Group. Larynx preservation with induction chemotherapy (CT) and radiation (XRT) in advanced laryngeal cancer final results of the VA Laryngeal Cancer Study Group Cooperative
Trial. Proc ASCO 1993:12:277.
(S) Forastiere AA. Cisplatin and radiotherapy in the management of locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1993:27:465-70.
Journal of the National Cancer Institute. Vol. 88, No. 13. July 3, 1996