Partnering of chemotherapy and radiation yields great response rates in H&N ca, but has not improved survival

One of the long-term debates in the head and neck cancer community is whether chemotherapy provides greater benefit when administered in the induction setting or concomitantly with radiation therapy. For some time, the discussion fell along party lines, so to speak: Radiation oncologists cited randomized trial data demonstrating that induction chemotherapy was not more effective than chemotherapy given along with radiation treatment and that what benefits there were did not outweigh the toxicities. On the other hand, medical oncologists cited preliminary data comparing one regimen of induction chemotherapy to another and inferring a survival advantage.

JONATHAN J. BEITLER, MD, MBA

At an American Society of Clinical Oncology (ASCO) 2010 education session, Jonathan J. Beitler, MD, MBA, highlighted current thinking on the role of induction therapy in head and neck cancer from the radiation oncology standpoint: Results from numerous clinical trials have reshaped the radiation oncology perspective on the role of chemotherapy in locally advanced squamous cell cancer of the head and neck. Dr. Beitler is a professor of radiation oncology, otolaryngology and hematology and medical oncology at Emory University in Atlanta.

Dr. Beitler's presentation started with an overview of radiation oncology in head and neck cancer patients, including fractionation. One of the seminal studies in head and neck radiation therapy was a Radiation Therapy Oncology Group trial (9003) that tested the efficacy of hyperfractionation and two types of accelerated fractionation against standard fractionation (Int J Radiat Oncol Biol Phys 48:7-16, 2000).

Tumor HPV status: Strong predictor of H&N cancer survival

Human papillomavirus status is one of four factors that influence a head and neck cancer patient's survival chances. Investigators at Houston's M.D. Anderson Cancer Center and other institutions performed a retrospective analysis of the association between tumor HPV status and survival among 323 patients with stage III or IV oropharyngeal squamous cell carcinoma enrolled in the RTOG 0129 trial.

The authors found the three-year overall survival rate was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy. The median follow-up period was 4.8 years.

A total of 63.8% of patients with oropharyngeal cancer had HPV-positive tumors and these patients had better three-year overall survival rates (82.4%, vs 57.1% for patients with HPV-negative tumors; P < .001), the authors reported. Pack-years of tobacco smoking, tumor stage, and nodal stage also played a part in the level of risk (N Engl J Med 363:24-35, 2010).

"RTOG 9003 was the best radiobiology ever done. Compared with standard fractionation, hyperfractionation improved local control," he explained.

Another study, out of Yugoslavia, assessed whether the addition of cisplatin-based chemotherapy to hyperfractionation radiation therapy offered an advantage over hyperfractionation radiation alone in locally advanced stage III and IV squamous cell carcinoma of the head and neck. In another study, RTOG 9111, patients with laryngeal cancer benefited from radiotherapy with concurrent administration of cisplatin vs induction chemotherapy followed by radiotherapy or radiotherapy alone (J Clin Oncol 18:1458-1464, 2000; N Engl J Med 349:2091-2098, 2003).

In both studies, local control was improved, but the addition of chemotherapy brought very little change in the rate of distant metastases. "My first conclusion is that distant metastases are relatively unchanged, and that concurrent chemotherapy is working as a radiation sensitizer. That's what is increasing our local control," Dr. Beitler said, adding that his conclusion is backed up by a meta-analysis of RTOG 9111 and other major trials (Radiother Oncol 92:4-14, 2009).

This trend continued in subsequent studies, such as RTOG 9914, which looked at the feasibility of combining a concomitant boost-accelerated radiation regimen with cisplatin. While the combination was 95% successful at local control, there was still a 20% distant metastases rate and a 17% rate of the gastrostomy tube still being in place at four years. The increased toxicity of this treatment approach was confirmed in a meta-analysis of late toxicity (Int J Radiat Oncol Biol Phys 71:1351-1355, 2008; J Clin Oncol 26:3582-3589, 2008).

"So if conclusion number two is that concurrent chemotherapy adds toxicity, is the chemotherapy worth the increased toxicity?" Dr. Beitler asked. The answer is "yes," because the addition of chemotherapy allows for a radiation dose escalation.

Dr. Beitler highlighted a study by David Brizel, MD, and colleagues that evaluated the biologic equivalent dose (BED) of radiotherapy in nine trials of standard fractionated radiotherapy and five trials of modified fractionated radiotherapy with or without chemotherapy. The investigators found that chemotherapy increases BED by approximately 10 Gy in standard and modified fractionated radiotherapy, which was equivalent to a dose escalation of 12 Gy in doses of 2 Gy daily or 1.2 Gy twice daily. "Such an escalation could not be safely achieved by increasing radiation dose alone," they stated (Int J Radiat Oncol Biol Phys 68:1491-1495, 2007).

"The attraction of induction chemotherapy for the medical oncologists is the opportunity to give increased doses of chemotherapy without the side effects from concurrent radiation. Unfortunately, induction chemotherapy has not demonstrated a survival advantage, so the benefit of increased chemotherapy is theoretical."

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The addition of chemotherapy may overpower the results of hyperfractionation. The RTOG 0129 trial assessed the impact of radiation and cisplatin intensity on outcomes, specifically accelerated-fractionation radiotherapy vs standard-fractionation radiotherapy, each combined with cisplatin therapy (ASCO 2010 abstract 5507; see Related Reading).

In this trial adding accelerated radiation to cisplatin was not advantageous, Dr. Beitler said. The regimen also increased toxicity.

In fact, cisplatin-based induction chemotherapy has a consistently poor record in terms of curing more patients, he said, so taxane-based therapy may offer a better option-but the emphasis is on "may."

Led by Marshall R. Posner, MD, the TAX 324 study was a randomized phase III trial of induction chemotherapy with docetaxel (Taxotere) plus cisplatin and 5-fluorouracil or cisplatin and 5-FU alone followed by chemoradiotherapy. While the first regimen turned in better results than the second in terms of survival, Dr. Beitler said that the high dropout rate in both arms was troubling (N Engl J Med 357:1705-1715, 2007).

"What concerns me is, did the noncompletes receive the optimal care?" he said. "For patients who were trying to get chemoradiation after chemotherapy, there was a 21% drop-off rate and that may overshadow improvements in survival due to the incorporation of taxanes into the treatment mix."

Oncology News International

is pleased to present part two of a two-part series on the use of induction chemotherapy in head and neck cancer. Read part one, "

What is the clinical role of induction therapy in locally advanced squamous cell cancer of the head and neck?

" (August 2010, page 28).

However, a phase II, 105-patient Eastern Cooperative Oncology Group (E2399) trial indicated that IMRT plus induction therapy with paclitaxel and carboplatin was possible with 94% of the patients completing radiation, 91% receiving four or more cycles of docetaxel, and 89% completing the protocol therapy. In terms of toxicity, at three months, swallowing was markedly impaired in 17% to 21% of oropharynx and larynx patients; but by 12 to 24 months, less than 10% of patients had marked swallowing impairment (J Clin Oncol 25:3971-3977, 2007).

"We are improving IMRT and that is part of our learning process," Dr. Beitler said. "Induction chemotherapy plus radiation therapy is doable."

Dr. Beitler posed two questions for which the answers are still pending: Why not test the use of concurrent taxane and radiation vs concurrent cisplatin and radiation? If the completion rates for TAX 324 were acceptable, why not retain concurrent radiation and cisplatin (100 mg/m² q3 weeks) and see if the addition of induction docetaxel, cisplatin, and 5-FU improves survival?

Concurrent chemoradiation has improved local control, but distant disease is still a problem. Induction chemotherapy, despite great response rates, has not yet been shown to improve survival over the standard of care, concurrent chemoradiation. Radiation oncologists "want something that does not interfere with our success in local control," he said. "We, like our medical oncology colleagues, are desperate for something that significantly improves control of distant disease."

Additional reporting by Fran Lowry.