Vokes Charts a New Course in Head and Neck Cancer Treatment

The “Giants of Cancer Care” awards program, which OncLive launched last year, honors oncology specialists whose work has made a significant impact on the lives of patients with cancer. Everett E. Vokes, MD, was recognized for groundbreaking research into head and neck cancers, yet he also has helped advance the field of lung cancer therapies.

In 2007, when Everett E. Vokes, MD, first saw Grant Achatz, the 33-year-old patient already had stage IV squamous cell carcinoma of the tongue, and the assurance of two eminent doctors that amputation was his only hope to survive more than a few months.

That surgery would hinder speech and nearly eliminate all sense of taste–a hardship for anyone but a nightmare for this particular patient, who happened to be one of the world’s most celebrated chefs. Even if he was one of the “lucky” 31% of patients who was alive three years after the surgery, he’d have a life he couldn’t imagine wanting to live.

Luckily for Achatz–and the foodies who have circumnavigated the globe to visit his Chicago restaurant, Alinea–Vokes was then running a clinical trial, one based on previous work that had boosted survival rates to the 70% range and minimized the need for surgery with a combination of three drugs, and then two months later, chemoradiation.

Discovering Medical Oncology

Vokes was able to save both the patient and his tongue. It was another victory for the various combinations of chemotherapy and radiation that Vokes has helped to develop, test, and implement as standards of care for locally advanced head and neck cancer (HNC).Vokes was born in New York City to parents who were both studying at The Juilliard School. His parents divorced when he was 4, and his mother took him to live in West Germany.

Vokes, though an American citizen, grew up entirely in West Germany and attended medical school in Bonn, which Vokes describes as a “small and fairly sedate city,” despite being the nation’s capital during his time there. One thing that Vokes did not encounter at medical school in Bonn was medical oncology. It was not common in Germany, even in the 1970s, and so Vokes had no experience with it until a three-month exchange rotation in Sydney, Australia.

Seeing the Need to Enhance Chemotherapy

“After graduating from medical school I ‘returned’ to the United States without knowing whether I’d stay,” Vokes said. “I started my postgraduate education at Ravenswood Hospital in Chicago–which was a small community hospital at the time but no longer exists–and where I again encountered medical oncology and became fascinated by the concept of treating malignancies with systemic therapy as opposed to surgery or radiation therapy. I had a feeling that there was much work to do in cancer care.”“I was a first-year fellow the first time I saw chemotherapy used to treat a head and neck cancer tumor. It was part of a trial. The tumor shrank dramatically, but the study found no survival benefits,” Vokes said. “None of the early individual studies did, indicating cross-resistance with radiotherapy.”

Many doctors inferred that chemotherapy’s lackluster performance in those early trials indicated its irrelevance to HNC treatment. As a result, many forgot all about the tumor shrinkage and continued the status quo: surgery followed by radiation in most cases, or, sometimes, just one or the other.

Vokes, on the other hand, remembered the dramatic shrinkage and wondered how to enhance chemotherapy’s obvious effect, how to augment something that was already strong enough to kill most of the cancer to the point that it could kill all of the cancer. By the mid-1980s, when he was working his way up the ladder at the oncology-hematology section at the University of Chicago Medical Center, Vokes believed the answer might lie in giving patients chemotherapy and radiation simultaneously.

He secured both permission and funding, and then began testing concomitant chemoradiation, along with several other protocols that used different timetables to combine chemotherapy with radiation and surgery. Concomitant chemoradiation therapy was the runaway winner. It produced highly encouraging results from the start, curing patients with many of the late-stage tumors that almost always eluded existing standards of care and killed patients.

Chemoradiation Becomes the New Standard of Care

“The early trials were small and they lacked randomized control groups, but the results were dramatic,” said Vokes, who, based on his institutional experience, thought that chemoradiation had proved its value by the early 1990s and hoped that other HNC specialists would also adopt it. “There were a number of factors that made people reluctant to begin the regular use of radiation and chemotherapy at the same time, including the very intensive nature of such a program,” Vokes said.Indeed, the chemoradiation programs that fared best in Vokes’ studies were far harder on patients than existing standards of care. That said, the numbers showed that such harsh programs offered huge rewards– rewards that went beyond higher cure rates–to patients who endured the exhaustion, nausea, and other miseries.

“Chemoradiation attacks cancerous tissues, but it can be also toxic to the healthy tissues that neighbor the tumors. It shrinks them, causing fibrosis, leads to mucosal ulcerations and pain on swallowing, and can lead to serious long-term functional deficiencies. But in the end, if the cancer is eliminated, many of the toxicities will improve,” Vokes said. “Surgically removing cancerous tissue, on the other hand, is permanent, and reconstruction efforts can’t compensate for the loss, especially following large surgical procedures.”

In order to definitively prove all of the benefits suggested by Vokes’ smaller studies, skeptics demanded national and international trials based on the gold standard of medical research: large, double-blind trials that compared chemoradiation with established treatments at multiple facilities. Vokes did not lead those trials–the dramatic results he had already achieved with chemoradiation made him deeply uncomfortable with the idea of assigning patients to the nonchemotherapy arm of any trial– but the trials were conducted.

Current Research

It took the better part of a decade for other researchers around the globe to conduct sufficiently large trials, follow patients for sufficiently long periods, and assemble the data in sufficiently compelling form to convince everyone, but the results of these trials did ultimately make chemoradiation the new standard of care for most advanced HNC. The breakthroughs discovered by Vokes and his colleagues have thus saved many lives. These discoveries also provided today’s relatively large cohort of HNC survivors with a far higher quality of life than that experienced by the very small group that beat the disease in the recent past.Vokes’ research today focuses on several different areas, including lung cancer. He has long carried out lung cancer work in parallel with his HNC studies and, to some degree, worked along the same lines: testing combinations of radiation and chemotherapy.

Lung cancer has turned out to be a much harder-to-treat malignancy, and the results have been less striking. Still, progress does continue, and new trials offer the opportunity for more.

“A very intensive form of radiation called stereotactic ablative radiation is increasingly producing exciting data,” he said. “It’s currently used to treat inoperable patients who have early stages of disease. We are investigating a similar approach in stage III disease.”

Among patients with HNC, where chemoradiation has already established itself as the standard of care, Vokes and his team continue to look for improved treatments that will increase survival rates, ease the pain of treatment, or both. The technique that first got Vokes interested in using medicine to combat HNC, induction chemotherapy, has begun to make a comeback after its original failure to increase survival times banished it from favor.

The introduction of new and improved chemotherapies such as paclitaxel in the 1990s has induced Vokes and his colleagues to revisit the idea and test it with a new twist: using combination chemotherapy to shrink tumors before further treating them with chemoradiation (rather than radiation alone), and reserving surgery for those patients who have remaining disease in the head and neck after completion of therapy. This type of trial began after observations that patients whose tumors involved several lymph nodes frequently had later recurrences outside of the head and neck area, an observation that indicated a possible need for more systemic therapy.

Hope for Less Aggressive Treatments

Vokes was running just such a trial of induction chemotherapy in 2007, when chef Achatz came to visit. That experimental induction chemotherapy consisted of paclitaxel, carboplatin, and the antibody cetuximab. A full course of chemoradiation followed several weeks later. (Achatz also had several lymph nodes removed.) It was an extremely intense regimen for patients with very serious disease. Although the survival data exceeded 70%, the results still did not specifically justify the added administration of induction chemotherapy. Nonetheless, testing of this approach for patients with extensive lymph node involvement continues to be of interest–as do far less intensive treatment options for different types of patients.Indeed, despite spending some of his research time examining more aggressive treatments for the sickest patients, Vokes sees much reason to hope that many patients with HNC will soon experience far milder treatments that work just as well as current standards. “It’s not just that our tools and our skill at using them keep improving–though obviously they do–it’s also that the patient population in HNC is undergoing a transformation that may well have a big impact on treatment.”

The transformation in question stems from a huge increase in HNC caused by human papillomavirus (HPV) that is happening at the same time as a huge decrease in HNC caused by a sharp drop in tobacco and alcohol use. Overall, the incidence of HNC is rising despite the lower rates of tobacco use, but the tumors created by HPV seem far less aggressive and far less resilient than those created by cigarettes and snuff.

Establishing a Work-Life Balance

“Tobacco damages DNA over decades and thus creates tumors that are not only genetically complicated but also highly variable from one to the next. HPV, on the other hand, creates a simpler tumor in a very standardized way,” Vokes said. “Yet despite all the differences between tobacco tumors and HPV tumors, we still treat everything with protocols developed to beat tobacco tumors. There’s no guarantee we’ll be able to treat tumors arising from HPV with less intensive treatment protocols, but it is certainly a plausible enough theory that it merits investigation and represents a major hope for patients.”Vokes’ time at Ravenswood Hospital in Chicago introduced him to something even more fascinating than medical oncology: the woman who was to become his wife. Now the father of two adult daughters, Vokes enjoys vacations with the family, including recent biking trips to Provence, Tuscany, and Canada

Putting Vokes’ Research Into Context

But he also delights in his work, particularly his work with patients. “I find taking care of patients to be one of the most rewarding activities, as it keeps me grounded in reality and focused on the need to advance the field through giving the best possible care today and improving treatment options for tomorrow,” he said.Leading oncology researchers described the contributions that Everett E. Vokes, MD, has made to the field of head and neck cancer therapy in interviews with OncologyLive.

Richard L. Schilsky, MD

Chief Medical Officer, American Society of Clinical Oncology

“Everett Vokes is among the most innovative investigators in head and neck cancer. The regimen he devised that combined two radiation-sensitizing drugs (5-FU and hydroxyurea) with a unique schedule of radiation delivery has produced remarkable results even in patients with locally far advanced head and neck cancers.

“This ‘backbone’ regimen has also formed the basis for many other clinical trials attempting to improve results by adding novel agents when appropriate. His large clinical experience, coupled with biospecimen collection and rigorous quality-of-life assessment, has enabled his program to develop new insights into the biology of head and neck cancer as well as into patient preferences in the care they receive.

“Although his treatment program has not been universally adopted, his results have set the bar very high for what can be achieved in treatment of patients with head and neck cancer through careful clinical investigation and meticulous care.”

Robert L. Ferris, MD, PhD

Vice Chair, Clinical Operations, Chief, Division of Head and Neck Surgery, Departments of Otolaryngology, Radiation Oncology, and Immunology, University of Pittsburgh Cancer Institute

“Dr Vokes revolutionized the way we think about the use of chemotherapy in head and neck cancer treatment. He showed that nearly all head and neck cancers are chemosensitive, and that a subset can actually be cured with chemotherapy, in combination with radiation.

“Mainly, he advocated for giving chemotherapy combinations as the initial treatment, to sensitize the tumor cells to further treatment with chemo/radiation, all the while avoiding the need for major surgery. He did all this in a very collaborative, yet persistent, manner that made him a respected and revered international leader.”

Barbara Ann Burtness, MD

Clinical Research Program Leader, Head and Neck Cancers Program, Smilow Cancer Hospital at Yale-New Haven, Co-Director, Developmental Therapeutics Research Program, Yale Cancer Center

“Dr Vokes has been a pioneer in the use of chemotherapy to improve outcomes in head and neck cancer. He studied the use of combination chemotherapy in patients with metastatic/recurrent disease, and developed a cisplatin-free chemoradiation approach that has served as the backbone for numerous studies of targeted therapy incorporated with chemoradiation, as well as of some important studies of natural history in treated head and neck cancer.

“His group was able to identify that as local control improved with better radiation approaches and more active chemotherapy schedules, distant recurrence became a more prominent feature of the natural history of head and neck cancer, emphasizing the importance of active systemic therapy in combined modality treatment regimens.

Dr Vokes’ Selected Publications

• Kawada I, Hasina R, Arif Q, et al. Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer [published online December 4, 2013]. Cancer Res. 2014;73(3):884-895.
• Cohen EE, Subramanian J, Gao F, et al. Targeted and cytotoxic therapy in coordinated sequence (TACTICS): erlotinib, bevacizumab, and standard chemotherapy for non-small cell lung cancer (NSCLC), a phase II trial [published online November 18, 2011]. Clin Lung Cancer. 2012;13(2):123-128.
• Pederson AW, Salama JK, Witt ME, et al. Concurrent chemotherapy and intensity-modulated radiotherapy for organ preservation of locoregionally advanced oral cavity cancer. Am J Clin Oncol. 2011;34(4):356-361.
• Langerman A, Plein C, Vokes EE, et al. Neck response to chemoradiotherapy: complete radiographic response correlates with pathologic complete response in locoregionally advanced head and neck cancer. Arch Otolaryngol Head Neck Surg. 2009;135(11):1133-1136.
• Vokes EE, Stenson K, Rosen FR, et al. Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol. 2003;21(2):320-326.
• Vokes EE, Herndon JE 2nd, Crawford J, et al. Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB nonsmall cell lung cancer: Cancer and Leukemia Group B study 9431. J Clin Oncol. 2002;20:4191-4198.
• Vokes EE, Kies MS, Haraf DJ, et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol. 2000;18(8):1652-1661.
• Vokes EE, Weichselbaum RR, Mick R, et al. Favorable long-term survival following induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin and concomitant chemoradiotherapy for locally advanced head and neck cancer. J Natl Cancer Inst.1992;84(11):877-882.
• Vokes EE, Schilsky RL, Weichselbaum RR, et al. Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for locally advanced head and neck cancer: a clinical and pharmacologic analysis. J Clin Oncol. 1990; 8(2):241—247.
• Vokes EE, Choi KE, Schilsky RL, et al. Cisplatin, fluorouracil, and high-dose leucovorin for recurrent or metastatic head and neck cancer. J Clin Oncol. 1988;6(4):618—626.

“Dr Vokes is also a notable mentor, and among the faculty who began their careers with him are several of the most important thought leaders in head and neck oncology today.”