Is concurrent chemotherapy/IMRT too toxic and dangerous for use in H&N cancer?

ABSTRACT: Some state that concurrent chemotherapy/IMRT is not beneficial due to high toxicity, but others maintain that toxicity can be controlled when delivered by experts with use of prophylactic measures.

SAN FRANCISCO-In a recent debate, both speakers agreed that IMRT with concurrent chemotherapy is toxic in patients with head and neck cancer, but disagreed on whether the risk/benefit ratio justifies its use. The event was held at the 2008 International Conference on Head and Neck Cancer, sponsored by the American Head & Neck Society.

Asked to argue the pro side-that IMRT [intensity-modulated radiation therapy] plus concurrent chemotherapy is too toxic and dangerous-Avraham Eisbruch, MD, professor of radiation oncology, University of Michigan, focused on the hazards of IMRT, compared with conventional radiation therapy, and concluded that IMRT is too toxic to combine with chemotherapy and has not been proved to be more effective than conventional RT.

Taking the con side, Vincent Gregoire, MD, PhD, professor of radiation oncology, Universite Catholique de Louvain, Brussels, Belgium, argued that the toxicity of concurrent chemotherapy/IMRT is manageable and such therapy offers patients the best outcome when performed by experienced physicians at high-volume centers. He expects further improvements in technology to lower the risks of toxicity.

Selection bias

Dr. Eisbruch acknowledged that IMRT is effective in controlling oropharyngeal cancer. “All series have very good numbers [90% to 98% 2-year locoregional control], better than standard radiation,” he said. “However, there is obviously a selection bias in these IMRT series.”

He said that the studies offered no details on how many patients were treated at the same time period with conventional RT, and that patients with poor performance status, advanced tumors, and difficulties with prolonged treatment times were most likely excluded. “When IMRT is compared to conventional RT from the same era, there is no difference in outcome,” he said, citing Hodge et al (IJROBP 69:1032-1041, 2007).

Furthermore, Dr. Eisbruch said, the recent improvement in outcomes for oropharyngeal cancer may be due to a change in the disease rather than improved treatments. An increase in HPV (human papillomavirus)-related cases has driven a worldwide increase in the disease, but disease-specific survival is significantly better in HPV-positive than in HPV-negative patients.

In-field recurrences

Although IMRT clearly has a dosimetric advantage, Dr. Eisbruch suggested that this is “irrelevant,” since in IMRT-treated patients, the disease recurs more often at the center of the target rather than the periphery. The solution to this problem of in-field recurrences, he said, has been to escalate the dose per fraction and the total biologically effective dose to the gross target volume (GTV).

He cited two studies that used this approach-the SMART trial from Baylor College of Medicine (Butler et al: IJROBP 45:21-32, 1999) and the Medical College of Virginia dose-escalation study (Lauve et al: IJROBP 60:374-387, 2004). But in both of these studies, he pointed out, the combination of large fraction doses and high normalized total dose led to “hot spots” that, depending on their location, increased the risk of late complications.

In patients with advanced disease who require concurrent chemotherapy, such high-dose IMRT regimens may not be feasible, Dr. Eisbruch said. For example, the SMART regimen (60 Gy at 2.5 Gy/fraction) given with chemotherapy was not tolerable due to excessive mucositis. So, he said, “we need to choose between high fraction doses to the GTV or lower dose fractions with concurrent chemotherapy. We can’t do both.”

Given that concurrent chemotherapy has an established benefit in these patients, while the benefit/risk ratio for high-dose IMRT is unknown, Dr. Eisbruch said he would choose concurrent chemotherapy with conventional RT over high-dose IMRT alone.

As for the practice of boosting the dose to part of the GTV (dose painting), he noted that very high doses at the high fraction doses suggested for the boosts may be detrimental even for smaller volumes.

While one can plan such boosts so as to spare “important organs” (the parotids, spinal cord, etc), he said, mucosa, submucosa, nerves, and blood vessels are embedded within the tumor and will be adversely affected by the higher doses.

Further, he said, there is no difference in the incidence of severe xerostomia between patients treated with conventional RT and those treated with parotid-sparing IMRT. This is probably because mucins, which help retain wetness of the mucosa, are produced primarily by mucinous cells in the submandibular and minor salivary glands, and not the parotid glands.

Efforts to spare the submandibular glands by IMRT, however, may compromise tumor targets nearby, he added.

Similarly, he said, efficacy may be compromised when IMRT plans spare the pharyngeal constrictors in an attempt to avoid late dysphagia/aspiration, and attempts to reduce high dysphagia rates associated with whole-neck IMRT by using IMRT only in the upper neck can lead to a high recurrence rate in the lower neck.

Dr. Gregoire responds

Dr. Gregoire said that Dr. Eisbruch, who focused on the toxicity and dangers of IMRT, “did not debate the issue at hand,” ie, the risks and benefits of concurrent chemotherapy/IMRT.

“I am not here to convince you that concurrent chemotherapy/IMRT is not toxic or not dangerous, but to convince you that it is not too toxic in light of the benefits to patients,” he said.

Dr. Gregoire pointed out that from 25% to 30% of head and neck squamous cell cancer (HNSCC) patients still die from local recurrences. With T1 patients, local control is good with conventional RT (about 85%), but falls to 77% for T2 patients, 61% for T3 patients, and 47% for T4 patients.

“Obviously, we need to improve. How do we do it? What are the options?” he asked. Studies show that concurrent chemotherapy/RT does improve outcomes: A meta-analysis (MACH-NC) of more than 17,000 nonmetastatic HNSCC patients, he said, showed an absolute benefit in survival of up to 8% in those treated with concomitant chemotherapy/RT, whereas those given adjuvant or neoadjuvant chemotherapy only had a 1% to 2% improvement.

Dr. Gregoire also pointed to better survival in the Intergroup R-91-11 trial of laryngeal cancer in patients receiving concurrent chemotherapy, compared with those receiving induction chemotherapy or RT alone.

No other options?

Dr. Gregoire looked at two possible alternatives to concurrent chemotherapy: accelerated RT without chemotherapy and new targeted agents, such as cetuximab (Erbitux).

The ESSAI GORTEC 99-02 study of patients with stage III-IV HNSCC showed that accelerated RT alone was just as good as chemotherapy/RT or chemotherapy/accelerated RT in terms of overall survival. But, Dr. Gregoire pointed out, patients receiving accelerated RT alone had a higher rate of grade 3-4 mucositis (86% vs 69% for chemo/RT) and feeding tubes were required in 70% of patients on accelerated RT vs 60% on chemo/RT.

Take safety measures

As for targeted agents, although the EGFR inhibitor cetuximab produced overall survival rates similar to standard concurrent chemotherapy and did not increase the typical side effects when added to RT, the agent does carry a risk of skin rash that may interrupt RT (Bonner et al: N Engl J Med 354:567-578, 2006), including cases of severe rash that require interruption of therapy. “Every day you interrupt radiation, you are losing local control,” Dr. Gregoire said. “What is my message? Using a treatment that appears to be very safe and nontoxic, you may see severe toxicity in 10% to 15% of your patients.”

Dr. Gregoire acknowledged the acute toxicity of concomitant chemotherapy (which must include a platin) and IMRT, but emphasized that “we all know what to do” to reduce toxicity, including pre- and post-IMRT prophylactic dental care, and placing patients in the hospital for a few days or weeks.

“You know it will be demanding for the patient and the medical staff, but if you know what to do, if you do what you should do, patients will tolerate the therapy,” he said.

As for IMRT vs conventional RT, the dose distribution is clearly better with IMRT, Dr. Gregoire said, and in his practice, he noted, “I don’t get hot spots.”

Concurrent chemotherapy/IMRT also increases late toxicity, particularly in the mandible, Dr. Gregoire acknowledged. But if you take prophylactic measures, he said, “you don’t see any cases of osteoradionecrosis” (Ben-David et al: IJROBP 68:396-402, 2007).

Finally, Dr. Gregoire stressed that institutional expertise is the key to safe delivery of concomitant chemotherapy/IMRT and encouraged physicians to refer their patients to high-volume centers. n