Induction chemotherapy resulted in good disease control for patients with cancer at the base of the tongue, according to data from a small study at the University of Oklahoma. The value of induction chemotherapy in these patients remains controversial, however, and is the subject of four ongoing phase III clinical trials.
Physicians have traditionally treated patients with cancer at the base of the tongue (BOT) with surgery or, more recently, with concurrent chemoradiation. Several research groups hypothesize that treating these patients with chemotherapy before concurrent chemoradiation may reduce the mass of the tumor, decreasing the amount of chemoradiation necessary to cure the tumor and potentially improving overall survival.
To learn whether induction chemotherapy works in their own center, Jesus E. Medina, MD, Professor and Chairman of the Department of Otorhinolaryngology at the University of Oklahoma, and colleagues enrolled 18 patients with stage III or IV BOT cancer in a single-institution cohort study. Patients received up to three cycles of induction chemotherapy every 21 days, including 175 mg/m2 paclitaxel, 60 mg/m2 cisplatin, and 1000 mg/m2 ifosfamide. Following induction chemotherapy, patients received seven weeks of concurrent chemoradiation with paclitaxel and carboplatin. Patients who showed no response after two induction cycles were referred to surgery and adjuvant radiation. Patients who had a complete response after two cycles progressed immediately to concurrent chemoradiation, skipping the third induction cycle.
The preliminary results of the study, which the researchers presented at a 2008 Triological Society section meeting, indicate that 17 patients had at least a partial response to therapy. Eight patients had a complete response after two cycles, and four more showed a complete response after three cycles of induction chemotherapy. Five patients attained a complete response only after chemoradiation. One patient who did not respond to induction therapy refused surgery, went off-study, and subsequently died from the disease.
With a median follow-up of 29.6 months for the 17 patients who remained on-study, two patients have been lost to follow-up, fourteen are relapse-free, and one patient suffered a distant recurrence.
Three patients developed neuropathy during induction therapy, but the side effect resolved itself. Twelve patients required a temporary PEG tube, and three (17%) individuals required a permanent tube due to unresolved dysphagia.
It is not clear whether the addition of induction chemotherapy to concurrent chemoradiation increases long-term toxicities, according to Dr. Medina. We don’t have a basis for comparison. However, we really didn’t have any toxicities that occurred during the induction part. Granted, they did have nausea and a few other things such as fatigue and chronic hiccups. The real nitty-gritty of the toxicity of these regimens comes when you use radiation therapy, and especially if you combine it with chemotherapy. Mucositis and difficulty of swallowing are the main problems.
Not everyone agrees that the level of toxicity in this patient series is acceptable, however. I would say that the treatment result is not optimal if 17% of these patients are requiring a long-term feeding tube, said Arlene Forastiere, MD, Professor of Oncology and Otolaryngology-Head and Neck Surgery at Johns Hopkins University School of Medicine in Baltimore. The whole point of doing organ preservation therapy, instead of surgery, is to preserve patients’ speech and swallowing function. So if 17 percent of patients are alive but they can’t swallow, it indicates a level of late toxicity with this particular treatment that is counter to the overall goal. You’ve negated the effect on quality of life and everything else with this treatment.
Phase III Clinical Trials
Physicians shouldn’t decide, on the basis of an uncontrolled study, that they are going to treat all their patients in this fashion, Dr. Forastiere continued. They should be putting patients into clinical trials. There are several ongoing randomized phase III trials designed to tease out the value of induction chemotherapy in patients with BOT and other head and neck cancers. We need the answers from those trials, she said.
Such trials are important, according to Marshall Posner, MD, Associate Professor of Medicine at Harvard Medical School and the Dana-Farber Cancer Institute in Boston, who is leading the Paradigm trial (ClinicalTrials.gov Identifier NCT00095875). There are sufficient data from randomized trials to support the use of docetaxel-cisplatin-5-fluorouracil-based induction chemotherapy as a reasonable treatment for patients with locally advanced head and neck cancer. There is also suggestive evidence that it might even be better than chemoradiotherapy alone. The question now is whether induction chemotherapy offers a significant advantage over chemoradiotherapy for organ preservation or survival, he said.
Enrollment in at least one of the trials is going slowly, though. Despite having been open for enrollment since August 2004, the Paradigm trial has accrued only about one-third of the planned patients.
Part of the cause for the slow enrollment, in Dr. Posner’s view, is that the trial is complex, with different radiation doses depending on the trial arm and an individual patient’s response to induction chemotherapy. The induction-plus-chemoradiation arm is so radically different from the chemoradiation arm that it is hard for patients to understand it. It is hard for physicians to explain, he said.
It is hard to do this kind of study. It would be infinitely easier if the Radiation Therapy Oncology Group [RTOG] and ENT physicians were willing to participate in this kind of trial and accepted how important this study question was rather than focusing only on a radiation research agenda, Dr. Posner continued. If we can finish these trials, we can get answers in a timely fashion. Right now the resistance from the RTOG in favor of their research program has made it very difficult to get sites to participate and put patients on these studies. It has really been an impediment to moving forward. There are people, it seems, for whom no induction trial would ever be acceptable.
Despite Dr. Posner’s contention that enrollment is slow because of resistance by the US academic radiation oncology community, other researchers see more pragmatic reasons. Head and neck cancer is uncommon and many trials are competing for a limited population, said Andy M. Trotti, MD, Professor and Director of Radiation Oncology Clinical Research at H. Lee Moffitt Cancer Center at the University of South Florida in Tampa. Some patients are not eligible for an intensive or prolonged therapy program due to comorbidities. And it takes extraordinary coordination among the treatment team to deliver a timely and complete course of induction followed by full concurrent chemoradiation therapy. Some centers just cannot pull it off.
Finally, he pointed out, some physicians, like the Oklahoma group, have already started using induction therapy as their standard of care, and are thus not interested in enrolling patients in a trial where they may not get induction. Some groups are already believers in induction, while others think more data are needed to call it a new standard, he said.
When asked directly if he thinks there is a lack of enthusiasm among radiation oncologists for induction chemotherapy regimens, Dr. Trotti said that the big problem was that there were no data comparing the approach head-to-head with existing chemoradiation protocols. I think most radiation oncologists are very open to using induction if it is clearly proven better than concurrent chemoradiation. We will not be able to deny a patient induction if the current trials show a survival advantage. But there are no mature results on any of these at the moment, he said.
Impact of a Shifting Patient Population
Another complication for the field and for the ongoing clinical trials is the shifting profile of head and neck cancer patients. Previously, patients with head and neck cancer tended to be older, with a history of smoking and drinking. More recently, however, a growing fraction of patients are younger and develop the disease following infection with human papillomavirus (HPV). Some researchers estimate that as many as 60% to 70% of base of tongue and tonsil cancers, which are the susceptible sites, are now due to HPV infection. (Such cancers are not associated with tobacco or alcohol use, according to recent work from the Johns Hopkins University School of Medicine.)
Not only do these new patients tend to be healthier than individuals with tobacco- or alcohol-associated head and neck cancers, but the cancers themselves seem to be more responsive to therapy.
The shift in patient and disease profile means that comparing patient outcomes between single-institution trials or with historical studies can easily lead to faulty conclusions. Thus, the large phase III randomized trials become even more important. The studies are large enough that patient subgroups-including anatomical location of primary tumor and HPV-positive patients-can be examined separately to get a window into how they respond to therapy.
In one prospective study, investigators found that HPV-positive patients had a 70% lower risk of distant disease progression relative to individuals with tobacco- and alcohol-associated disease, according to Dr. Forastiere. Therefore it is hard to know what to make of small studies like the one from the Oklahoma group. The question is if you intensify treatment by adding induction chemotherapy to chemoradiation, are the patients really benefiting from that, or would they do as well with chemoradiation alone, because HPV-positive cancer is a different disease that has a much better prognosis and greater sensitivity to chemotherapy and radiation, she observed.
The HPV question will be the focus of a National Cancer Institute (NCI) State of the Science meeting in late 2008, according to Dr. Trotti, who, along with Dr. Forastiere, co-chairs the National Cancer Institute (NCI) Head and Neck Steering Committee that is responsible for approving NCI trials. HPV is perhaps the most important biologic question facing head and neck cancer today. We plan to gather the best minds in the field to design the next series of trials with a focus on how HPV status may impact response or prognosis. There is a lot changing at one time in head and neck cancer. It will take more planning and collaboration if we are going to answer these important biologic and clinical questions, he said.
As for the value of induction chemotherapy, only the results of the phase III trials, which are still years away, will answer that question. Until then, many investigators agree that induction chemotherapy should only be used within a clinical trial, though some researchers feel that there is already sufficient evidence to support using induction for patients with advanced stages of cancer.
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