In 1970, Ansfield and colleagues published the results of a randomized trial in head and neck cancer, which showed that giving fluorouracil(Drug information on fluorouracil) (5-FU) concomitantly with radiation decreased regional recurrences and improved overall survival over radiation alone. Publication of these results came 6 years before those of an Italian trial showing similar findings with adjuvant cyclophosphamide(Drug information on cyclophosphamide), methotrexate(Drug information on methotrexate), and 5-FU (CMF) in breast cancer. Yet, while adjuvant chemotherapy has rapidly become the norm in the management of early breast cancer, concomitant chemotherapy is still considered undefined in the treatment of head and neck cancer. This situation is elegantly described by Dr. Karen Fu, one of the most respected investigators in this area.
One might reasonably argue that breast cancer is much more common than head and neck cancer and that this has allowed for more definitive studies. However, meta-analyses have shown a similar survival impact from adding chemotherapy to radiation in head and neck cancer as from using adjuvant chemotherapy in breast cancer.[3,4]
Why is the Role of Chemotherapy So Different in the Two Cancers?
How has it happened that the defined role of chemotherapy has evolved so differently in these two diseases? I can enumerate a few reasons:
- Lack of Patient AdvocacyWhen trials of adjuvant chemotherapy in breast cancer were published in such well-read journals as The New England Journal of Medicine, the lay press rapidly disseminated this information to the public. Medical oncologists saw newly diagnosed breast cancer patients after surgery because women brought these articles to their surgeons and insisted on being referred for adjuvant therapy. What lay press picked up on the article by Merlano et al that found a disease-free and overall survival advantage from chemotherapy and radiation over radiation alone in head and neck cancer?
Physician CausesMedical oncologists, for the most part, do not know how to examine head and neck cancer patients, and thus, cannot accurately assess toxicity, response, or recurrence. Medical oncologists and their surgical colleagues do not understand the extraordinarily rapid proliferative rate of head and neck cancers, which have a labeling index of 24% ± 4% of cells and potential tumor doubling times of 47 ± 7 hours.
These cancers are highly sensitive to chemotherapy, with 80% or more of them showing a response. However, they are also remarkably able to develop resistant clones, with a very short time to progression seen with even the most active drug combinations. Given these characteristics of head and neck neoplasms, it is not surprising that induction chemotherapy has had no impact on survival. Also, sad to say, it is equally not surprising that physicians continue to use induction chemotherapy, despite its lack of benefit, because everyone feels good when the patient is responding.
- Failure to Accept Randomized Trial Results at Face ValueThe literature is full of explanations by medical oncologists of the inadequacies of randomized clinical trials that fail to show any benefit of induction chemotherapy. The literature is also replete with explanations by radiation oncologists as to why randomized clinical trials showing a benefit of combined chemotherapy and radiation are deficient. The most frequent comment is that the radiation given in the control arm was inadequate. If the trial was randomized, with the same radiation oncologist treating patients in both arms with similar techniques, how does this assessment invalidate the trial (or the meta-analysis)? If chemotherapy helps inadequate radiation oncologists, maybe it will help adequate radiation oncologists as well!
- Failure to Identify a Standard RegimenOnce defined, a standard regimen can be improved and refined (as, for example, 1 year of adjuvant CMF in breast cancer). However, investigators in head and neck cancer have diverted their energy into developing their own (better) regimen to treat their own limited patient population. How much further might we have come and how many more lives saved, with organ preservation achieved, if, for example, Ansfield and colleagues regimen of 5-FU had been adopted as a starting point, retested, and developed?
RTOG Trials May Help Set Standards
As decribed by Dr. Fu, ongoing trials by the Radiation Therapy Oncology Group (RTOG) that are evaluating cisplatin(Drug information on cisplatin) (Platinol) with radiation may lead the way in setting these badly needed standards. The recently reported RTOG trial in nasopharyngeal cancer showed an 80% 2-year survival rate in patients treated with radiation plus concomitant high-dose cisplatin, followed by adjuvant cisplatin and 5-FU infusion (at 80% of full dose) for 3 cycles, as compared with 55% survival in those given radiation alone (P = .0007).
This impressive result from a major cooperative group goes far in accomplishing the goal of setting standards. Although some skeptics might argue that the adjuvant cisplatin/5-FU caused the benefit, this seems unlikely. A recent nasopharyngeal cancer trial comparing radiation with two cycles of neoadjuvant cisplatin and 5-FU plus four cycles of adjuvant cisplatin and 5-FU, all at full dosage, showed no benefit at all.
Future directions that Dr. Fu has enumerated offer much promise. New drugs and biologic agents, coupled with a better understanding of the biology of this disease, offer the promise of more effective and less toxic treatment options in the future. Future trials, however, should also examine why head and neck cancer patients die. Deaths from other causes have always been a major source of mortality. We have recently found this to be highly correlated with T-stage but not N-stage or overall stage in our long-term analysis. Functional impairment at the primary site clearly is a long-term result of the original tumor and its treatment (with or without surgery). We cannot just assume that nonsurgical treatment is more functional and therefore better than surgical treatment. This requires more long-term study.