In the past, locoregionally advanced head and neck cancer routinely was treated by surgery followed by adjuvant radiation therapy, unless the disease was too extensive to be resected and treatment defaulted to radiation therapy alone. We simply didn't have effective alternatives, and in the words of Bernard Baruch, “If all you have is a hammer, everything looks like a nail.”
In this issue of ONCOLOGY, Drs. Culliney and colleagues review the rapidly growing options of care for advanced head and neck cancers and comment that now “it is difficult to recommend a ‘one size fits all’ approach.” Drs. Culliney et al begin their review by reminding us that “historically, 50% to 60% of patients with locoregionally advanced head and neck cancer treated with radiation therapy (RT), surgery, or both have developed locoregional recurrence in 2 years” and “20% to 30% … developed distant metastases.” They add, “for unresectable head and neck cancer, the 5-year survival rate with RT alone is less than 25%.”
However, it must be remembered that not all of these deaths are attributable to the primary tumor: independent second malignancies are detected in 3% to 4% of head and neck cancer survivors every year, and the comorbidities associated with the use of alcohol(Drug information on alcohol) and tobacco (that likely promoted the original tumor) account for deaths as well. Hence, our focus traditionally has been on locoregional control as the principal measure of treatment efficacy. Perhaps this explains, in part, the continued use of the term “unresectable,” a traditional proxy for a more difficult tumor to control.
I agree with the authors that the definition of “unresectable” is difficult. But, I would rather focus on the reality that unresectable tumors today are not the same as unresectable tumors of the past. Just as anal cancer no longer requires ablative surgery and breast cancer can now often be treated with conservative surgery, laryngeal preservation strategies are commonplace, and the key surgical question has become, “When must surgery remain an indispensible part of the regimen?” Another way to ask the same question is “Can the biologic effect of radiation therapy be intensified sufficiently in the tumor (without irreparably damaging normal tissues) to replace surgery?” This question has driven the quest to explore altered-fractionation radiation therapy.
It is not yet possible to measure in real time the exact kinetics of a tumor and its surrounding normal tissues. Consequently, class solutions that attempt to maximize the difference in treatment effect between tumor and normal tissues for different models of tumor/normal tissue behavior have been tested. Altered (ie, not the conventional 2 Gy per day, 5 days per week) fractionation schemes all seek to improve the therapeutic ratio, but may differ in the ways they attempt to do so.
Accelerated fractionation—either by giving more than 2 Gy per fraction (often requiring a decrease in the total dose to protect normal tissues) or by shortening the number of weeks of treatment (without decreasing the total dose; by treating more than 5 days per week and/or by treating more than once per day with a dose close to 2 Gy)—seeks to improve the therapeutic ratio by overcoming the ability of tumor cells to repopulate faster than the radiation can kill them. Concomitant boost therapy is a variant in which the treatment begins with once a day “standard therapy” and after some of the tumor cells are killed (freeing the oxygen and nutrients they would otherwise consume), thereby allowing the surviving tumor cells to accelerate their cell cycle (so-called accelerated repopulation), treatment accelerates to twice daily (with a minimum interfraction interval of 6 hours to allow normal tissue repair).
In contrast, hyperfractionation involves treatment more than once daily, but with a dose per fraction that is just slightly greater than half the “standard” 2 Gy. This appears to preferentially spare normal tissues, thereby allowing greater total doses to be given, killing more tumor cells without simultaneously causing increased normal tissue damage. Both accelerated fractionation and hyperfractionation appear to improve the therapeutic ratio of radiation compared to standard fractionation, permitting more aggressive treatment of tumors and leading to an increase in locoregional control. Sadly, despite the reality that locoregional recurrence is the most common type of treatment failure, the other causes of death in this population have thus far prevented the incremental improvements in locoregional control attributable to altered fractionation from translating into clinically meaningful improvements in survival.
The biologic effect of radiotherapy also appears to be enhanced by some drugs. As described by Dr. Culliney and colleagues, cisplatin(Drug information on cisplatin) (100 mg/m2 concurrently on days 1, 22, and 43) is the gold standard for such chemotherapy-enhanced radiation therapy (CERT). In numerous phase III trials and by meta-analysis, the concurrent administration of cisplatin and radiation therapy for advanced head and neck cancer resulted in better locoregional control than radiotherapy alone, but at the cost of increased toxicity.
Surely cisplatin is not the only drug with this ability; in other trials, mitomycin, bleomycin(Drug information on bleomycin), and fluorouracil(Drug information on fluorouracil) appeared to act similarly. Furthermore, the noncytotoxic, anti–epidermal growth factor receptor (EGFR)-targeted antibody cetuximab(Drug information on cetuximab) (Erbitux) appeared to be a radiosensitizer in the Bonner trial discussed by Dr. Culliney et al. However, it may be important to reserve judgment about cetuximab because (1) it is only one trial, (2) most (56%) of the patients in that trial received concomitant boost–style accelerated radiation therapy, and (3) the effect of the drug differed by anatomic site (it produced a much more modest effect for laryngeal or hypopharyngeal tumors than it did for oropharyngeal tumors, raising the possibility that the outcome was influenced by an unexpected influence of human papillomavirus (HPV) infection–related oropharyngeal cancers).
Yet, the improvement in locoregional control produced by concurrent drug-modulated radiation therapy is, in fact, already sufficient that the subsequent appearance of distant metastases (a previously less important mode of treatment failure) is now beginning to rival locoregional failure.
Role of Induction Therapy
Because it is generally believed that the amount of chemotherapy that can be administered as part of concurrent CERT is insufficient to control subclinical distant disease, several phase II trials are trying to refine regimens that would graft additional chemotherapy to CERT. As Dr. Culliney et al state, although “the vast majority of the earlier induction trials did not support this approach as the optimal treatment strategy,” perhaps the concept would work if multidrug “induction chemotherapy” is administered prior to CERT. My bias is that this approach makes sense, but only if the induction therapy does not compromise subsequent CERT and the toxicity is tolerable.
Before the reader should consider adopting such induction therapy as a standard of care, it is critical to remember that the leading researchers in this field are still investigating it in institutional review board–approved clinical trials, and there are no completed head-to-head phase III comparison trials of induction plus CERT vs CERT on which to base conclusions. As Dr. Culliney et al state, “With the potential added toxicities of induction chemotherapy as well as a prolongation in the time it takes to complete therapy, an important concern is that a proportion of patients may not complete the chemoradiotherapy portion of treatment as planned.” Moreover, induction therapy may not control distant metastases (in the TAX 324 trial, there was no statistically significant difference in the incidence of distant metastases), and without a very precise risk allocation strategy, ensuring that only the most refractory tumors are treated in this fashion, the increase in control may be overwhelmed by the increase in toxicity.
I would urge readers first to familiarize themselves with the work of Trotti et al, looking at the far more rapidly escalating cost of toxicity than improved locoregional control as chemotherapy is added to radiation therapy before prescribing CERT, and absolutely before prescribing induction chemotherapy plus CERT.
In the end, I agree with Dr. Culliney et al that one size no longer fits all. For suitably chosen relatively healthy patients who have large tumors, selecting treatments that are more biologically aggressive than once per day, standard-fractionation radiotherapy is clearly appropriate. But that does not mean that such aggressive therapies are appropriate for everyone, nor that if more is good, even more is better.
—Jay S. Cooper, MD, FACR, FACRO, FASTRO