As treatments for head and neck cancers improve, many of the experts contacted by HemOnc Today said that they have shifted their practice not only to include the latest therapies, but they also consider how best to combine modalities and target therapy to minimize toxicities.

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“There is great, great interest and enthusiasm in increasingly targeting therapy to the cancer and trying to minimize therapy and toxicity to normal organs,” said Louis B. Harrison, MD, chairman of radiation oncology at Beth Israel Medical Center and editor of HemOnc Today’s Head and Neck Cancer Section. “This is particularly true in radiation oncology and medical oncology, but it’s also becoming true in surgery.”

The evolving role of induction chemotherapy, targeted biologic agents and advances in surgery and imaging are all playing a part in helping oncologists craft an individualized mix of radiation, surgery and chemotherapy for each patient while maximizing cure rates and minimizing organ damage.

In the past few years, research has confirmed the causes of head and neck cancer: environmental — smoking, drinking or exposure to toxic materials — and those related to exposure to human papillomavirus, particularly HPV-16. Research published last year estimated that 26% of more than 500,000 annual diagnoses of head and neck cancers are related to HPV exposure.

D’Souza et al published results in 2005 showing a correlation between oropharyngeal cancer and a high lifetime number of oral sex partners (OR=3.4; 95% CI, 1.3-8.8) or vaginal sex partners (OR=3.1; 95% CI, 1.5-6.5).

That study also found a strong correlation between the presence of HPV-16 and oropharyngeal cancer (OR=14.6; 95% CI, 6.3-36.6) and determined that the association was “greatly increased among those without a history of smoking or drinking,” with an OR of 44.8 (95% CI, 5.9-338.5).

Patients with HPV-related disease, usually expressed as squamous cell carcinoma of the oropharynx or larynx, tend to be younger, healthier, and have better prognosis than those with environmentally-caused head and neck cancers. Fakhry et al concluded in results published earlier this year that patients with HPV-related disease had better response to treatment, better overall survival, lower risk for progression and lower risk for all-cause mortality.

“Understanding the role of HPV and what it may mean prognostically could well have an impact on how you treat those patients,” said Wesley Hicks Jr., MD, a professor of otolaryngology and head and neck surgery at Roswell Park Cancer Institute in Buffalo, NY. “The standard of care for patients’ head and neck malignancies, especially with advanced disease, is often surgery followed by concurrent chemoradiation therapy. That has shown an improvement in terms of locoregional control that doesn’t necessarily translate into an improvement in survival. However, that treatment itself has morbidities, so if you can tailor treatments for your head and neck malignancies, you may in fact decrease morbidity while improving locoregional control and potentially survival.”

The HPV vaccine (Gardasil, Merck) has been approved to prevent gynecologic cancers. Many of the oncologists contacted for this story hope that something similar could eventually emerge for HPV-related head and neck cancers.

“I certainly see that the vaccine has potential to be effective, but it’s not going to help patients that are already infected,” said Marshall Posner, MD, medical director of the Head and Neck Oncology Program at Dana-Farber Cancer Institute. “This is something that will take three generations. The 10- to 18-year-old boys should be treated and they may well benefit. The problem with vaccinating people for a disease they may get 30 or 40 years later is that you don’t have good answers in the short term. There’s no model to predict this.”

Induction chemotherapy

Posner has been a staunch advocate for induction chemotherapy throughout his career. Patients with HPV-related disease have 60% to 70% survival rates in chemoradiation trials and up to 90% in induction chemotherapy trials, he said. He has no doubt that induction chemotherapy provides more benefit to some patients than adjuvant chemotherapy.

“This regimen is effective for organ preservation and for improving survival in patients, and there is compelling, suggestive evidence that it might be better than chemoradiotherapy,” Posner told HemOnc Today. “In conjunction with chemoradiotherapy, it’s quite possible that taxotere-platinum 5-FU-based induction chemotherapy may actually prove to be substantially better than chemoradiotherapy or induction alone. We’re moving toward improvements in survival in patients with locally advanced diseases that are unprecedented in our literature.”

The data on induction chemotherapy are mixed and trials are still ongoing. The University of Chicago is recruiting patients for the DeCIDE trial, a phase-III study of induction therapy with docetaxel followed by chemoradiotherapy vs. chemoradiotherapy alone in patients with nodal stage N2 or N3 disease. Dana-Farber and the University of Medicine and Dentistry of New Jersey are recruiting for the PARADIGM trial. That study compares induction chemotherapy with radiation vs. chemotherapy plus radiation.

Results published by the Journal of Clinical Oncology in 2001 by Posner et al evaluated 43 patients with previously untreated phase I-II SCCHN assigned to 75 mg/g2 daily docetaxel, either 75 mg/m2 daily cisplatin or 100 mg/m2 daily cisplatin and continuous infusion 1,000 mg/g2 fluorouracil.

The researchers found a complete clinical response rate of 40% (95% CI, 25%-56%) and a partial response rate of 54%; they concluded that the regimen was safe and effective.

However, results of a 2003 study published in The New England Journal of Medicine showed that radiotherapy with concurrent cisplatin was superior to induction cisplatin plus fluorouracil followed by radiotherapy in patients with advanced laryngeal cancer. After a median follow-up of 3.8 years, the researchers concluded that patients assigned to concurrent cisplatin were more likely to have intact larynx (84% vs. 72%) and had better estimates for two- and five-year survival.

James A. Bonner, MD, chair of radiation oncology at the University of Alabama-Birmingham Health System, said induction chemotherapy combined with chemoradiation is promising but has not yet been proven more effective than chemoradiation.

“Right now, there are several ongoing trials looking at the three-drug induction chemotherapy followed by chemoradiotherapy vs. just starting with chemoradiotherapy alone,” he said. “If we’re going to continue to pursue induction chemotherapy, we need to show that it’s better than chemoradiotherapy without induction. That has not been done.

“If those (trials) show that induction is better, that will be a hot area of investigation for many years because then we’ll start looking at various combinations in the induction mode and giving targeted therapies during the induction regimen as well as during the radiation treatment,” Bonner said.

Hicks is more skeptical and said he and Posner have had some frank discussions about the issue as members of the National Comprehensive Cancer Network Head and Neck Cancers – Occult Primary Panel.

“There are no conclusive data presently codifying that induction chemotherapy is going to produce better clinical outcomes,” Hicks said. “There are data that strongly supports the fact that concurrent chemoradiation given to patients after surgery does improve locoregional control. I know that Marshall is doing some very innovative things, and hope that his data will eventually lead to definitive evidence that in defined clinical settings induction chemotherapy will prove to be the treatment of choice.

“I’m a conservative man by nature. I do believe there will be role for induction chemotherapy, but that role presently is not clear. Though I would support induction chemotherapy under protocols or specified clinical settings, I can’t say I’m going to recommend it for all of my patients because we don’t know in which setting it would be of the most benefit.”

Pinpoint precision

Increasingly, Harrison said, oncologists are looking for ways to more tightly control treatment in an effort to spare normal tissues and decrease morbidities. He cited intensity-modulated radiation therapy, image-guided radiotherapy and adaptive radiotherapy as new ways radiation oncologists are trying to target tumors with greater precision.

“All of these things are works in progress and all these concepts are under significant evaluation and investigation, but the evolution in the continuum from IMRT, to IGRT added to that and ART even added to that, is allowing radiation therapy to become increasingly targeted and increasingly focused,” he said. “Along with that in head and neck cancer, improvements in brachytherapy and the selective use of intraoperative radiation therapy to deliver radiation right to the tumor bed, adds even further to this concept of being very, very targeted.”

Cetuximab (Erbitux, Bristol-Myers Squibb, ImClone), an EFGR-inhibitor first approved for use in metastatic colorectal cancer, is the only targeted agent approved for use in head and neck cancers.

Bonner, who has studied cetuximab extensively, mentioned bevacizumab (Avastin, Genentech), erlotinib (Tarceva, OSI Pharms) and panitumumab (Vectibix, Amgen) as biologic agents being evaluated for use in patients with head and neck cancers.

“There are certainly a lot of other promising ones in the pipeline,” he said. “Bevacizumab is being explored. A group at Duke University led by Dave Brizel, MD, is performing a trial where they’re combining bevacizumab with an anti-VEGF agent. They’re combining Avastin with erlotinib, an anti-EGFR agent, and radiation. The Dana-Farber group, Marshall Posner and Lori Wirth, MD, presented a promising trial at ASCO this year combining carboplaxin with paclitaxel and another anti-EGFR antibody called panitumumab.

“That’s a fully humanized antibody,” Bonner said. “The advantage of a fully humanized antibody is that it would have less of a chance of causing an allergic reaction. Cetuximab is a chimeric antibody – it’s part mouse and part human. It has a little higher chance of causing an allergic reaction.”

There are other antiangiogenic compounds targeting VEGF receptors, platelet-derived growth factor and fibroblast growth factor agents being tested. A group based at Seattle’s Fred Hutchinson Cancer Research Center is enrolling patients for a study comparing erlotinib, cisplatin and radiotherapy vs. cisplatin and radiotherapy in patients with advanced squamous cell carcinoma of the head and neck.

Renato Martins, MD, MPH, medical director of the Thoracic/Head & Neck Cancer Program at the University of Washington and one of the study’s principal investigators, hopes to have results late next year.

“A standard of care for patients with head and neck cancer that have locally advanced disease is full-dose cisplatin in combination with radiation therapy. What our trial is trying to look at is, what if you add erlotinib to this strategy? Does that lead to an increased cure rate?” Martins asked. “Our trial has as its primary objective obtaining complete response. That is frequently an adequate surrogate for ultimate improved outcome.”

“The future is how to integrate the targeted agents into what is basically highly effective chemotherapy,” Posner said. “There’s little evidence that targeted agents by themselves are active. It’s quite possible that by adding these new targeted agents to what is really quite effective chemotherapy, we’re going to end up with much better treatments for our patients.”

Surgery

Ernest M. Myers, MD, chief of otolaryngology at Howard University Medical School, said major surgery and resections are becoming less common in the treatment of head and neck cancers. For the most part, he said, surgeons are now focused on salvage.

“The collaboration between the medical oncologist and the radiation oncologist has allowed the patient to have organ-sparing treatment,” he said. “As a result, the patients aren’t having massive resections or oblations; however, there are still some functional problems after having these therapies. Many of these patients are treated and they are cured, but some of them do have some problems as a result of the side effects of these treatments.”

Harrison said both the training and technology, such as free-flap reconstruction and the advent of osseointegrated implants, have made surgery more effective.

“If you look at organ preservation surgery, the advent of microsurgery in the repair of surgical defects has been a huge boon to the surgical treatment of head and neck disease,” Hicks said. “With the advent of skull base surgery, tumors that were once considered unresectable and incurable have now, with the combined modalities of both head and neck surgeons and neurosurgeons, saved lives and cured a lot of these tumors that even 20 years ago were considered untreatable.”

Putting the pieces together

No oncologist works in a vacuum; a new advance or breakthrough discovery in chemotherapy, for instance, has ramifications for surgeons and radiation oncologists. The trick is finding the right mix of therapies for each patient.

“Surgeons like to operate,” Hicks said. “Medical oncologists like to give antineoplastic agents. The fact is it’s the melding of the two techniques that’s made the most advances. The proper implementation of those techniques — right time, right site, right disease — is what makes the advances in care.”

The goal, of course, is to create an entirely unique treatment program to address the specific disease of a specific patient, while causing as little damage to the patient as possible.

“All of these advancements, when taken together, open up aggressive multidisciplinary therapy that is increasingly intensive for the tumor and increasingly respectful to the surrounding normal tissues by either sparing them or reconstructing them,” Harrison said. – by Jason Harris

As head and neck cancer treatments have improved, have they become unacceptably toxic?

For more information:

• Chamberlin J. Role of induction chemotherapy in the treatment of head and neck cancer — An ongoing debate: An expert interview with Dr. Marshall R. Posner. Medscape. March 29, 2007. Available at http://www.medscape.com/viewarticle/552491. Accessed Oct. 9, 2008.
• Cmelak AJ, LI S, Goldwasser M, et al. Phase II trial of chemoradiation for organ preservation in resectable stage III or IV squamous cell carcinomas of the larynx or oropharynx: Results of Eastern Cooperative Oncology Group Study E2399. J Natl. Cancer Inst. 2007;25:3971-3977.
• D’Souza G, Kreimer A, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944-1956.
• Fakhry C, Westra W, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl. Cancer Inst. 2008;100:261-269.
• Forastier AA, Goepfer H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:2091-2098.
• Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med. 2008;359:1143-1154.
• Hashibe M, Brennan P, Benhamou S, et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers and the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst. 2007;99:777-789.
• Khuri FR, Shin DM. Head and neck cancer chemoprevention gets a shot in the arm [Editorial]. J Clin Oncol. 2008;26;345-347.
• Posner MR, Glisson B, Frennette, et al. Multicenter phase I-II trial of docetaxel, cisplatin and fluorouracil induction chemotherapy for patients with locally advanced squamous cell cancer of the head and neck. J Clin Oncol. 2001;19:1096-1104.
• Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357:1705-1715.
• Seiwert TY, Cohen EFW. State-of-the-art management of locally advanced head and neck cancer. British Journal of Cancer. 2005;92:1341-1348.
• Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116-1127.
• Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357:1695-1674.