Pivotal Trials in Head and Neck Cancers Yield Mixed Results

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The latest research in head and neck cancer reported at this year’s ASCO Annual Meeting presents a mixed picture, according to George R. Blumenschein, Jr, MD, Associate Professor at The Unviersity of Texas MD Anderson Cancer Center, Houston, who presented the data at the Best of ASCO San Diego meeting. Three trials attempting to improve on concurrent chemoradiation for locally advanced squamous cell carcinoma had disappointing results, meaning that chemoradiation remains the standard. But a trial of a new multitargeted tyrosine kinase inhibitor showed impressive efficacy in medullary thyroid cancer.

Induction Chemotherapy plus Chemoradiation

In the randomized phase III DeCIDE trial, patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck were assigned to two cycles of induction chemotherapy—docetaxel, cisplatin, and fluorouracil  (TPF)—followed by concurrent chemoradiation, or to chemoradiation alone.1 Although 400 patients were planned for the study, only 280 were accrued.

Compared with their counterparts who did not get induction chemotherapy, those who did showed trends toward better recurrence-free survival (P = .16) and distant failure–free survival (P = .37). Overall survival was statistically indistinguishable. Induction chemotherapy was associated with a lower rate of distant recurrence without locoregional recurrence (P = .04). Hematologic toxicity during chemoradiation was higher in the group who had received induction chemotherapy.

“This was a negative study, no overall survival difference with trends favoring the experimental arm in terms of disease-free survival,” Dr. Blumenschein said. He noted that a host of logistical issues, many seen in the next trial as well, may have played a role in the outcomes (see sidebar).

The randomized phase III PARADIGM trial also compared chemoradiation alone vs TPF induction chemotherapy followed by chemoradiation in patients with locally advanced stage III or IV squamous cell carcinoma of the head and neck.2 In the induction arm, the chemoradiation was tailored to the response to induction therapy.

This trial also struggled with accrual, enrolling just 145 of 330 planned patients, and was stopped early, at a median follow-up of 49 months.

The 3-year rate of overall survival was 73% with induction chemotherapy and 78% without it, a nonsignificant difference. The 3-year rate of progression-free survival was also similar (67% vs 69%), but tended to favor induction chemotherapy in patients with nonoropharynx tumors (66% vs 55%).

Within the induction chemotherapy group, the subset of patients who had a complete response and received less-intensive chemoradiation still had better outcomes than their counterparts who had lesser responses and received more intensive chemoradiation. Overall, the induction chemotherapy group had higher rates of grade 3/4 febrile neutropenia and early death.

Dr. Blumenschein concurred with the investigators’ conclusion that both treatment approaches are effective. “I think what it’s going to boil down to is selection—identifying which patient groups are really going to benefit more” from a given approach. “And this should be answered by the next generation of trials,” he said.

“Concurrent chemoradiation is still the standard of care for patients with locally advanced head and neck cancer,” he concluded. “In terms of induction chemotherapy, its role remains unclear, as these two trials failed to achieve their accrual goals to answer the question appropriately. I can tell you our preference is to give induction chemotherapy, especially for patients we feel are at higher risk for developing distant metastases.”

Panitumumab plus Chemoradiation

In the phase II randomized CONCERT-1 trial, patients with unresected, locally advanced squamous cell carcinoma of the head and neck were randomly assigned 2:3 to concurrent chemoradiation without or with added panitumumab (Vectibix), an antibody to epidermal growth factor receptor (EGFR).3

The panitumumab and control groups had statistically indistinguishable rates of locoregional control (61% vs 68%) and progression-free survival (60% vs 65%). There was a trend toward poorer overall survival in the panitumumab group (HR = 1.63, P = .12). Efficacy did not differ by tumor human papillomavirus status.

Rates of grade 3 or worse adverse events, especially mucosal and skin toxicity, were higher with panitumumab.

Dr. Blumenschein commented that the trend toward poorer survival with panitumumab may have been due in part to use of a lower dose of cisplatin in that arm’s chemoradiation regimen (75 vs 100 mg/m2). “Cisplatin is a fairy effective drug in head and neck cancer, and you want to maximize its dose, whether you are giving it every 3 weeks or weekly,” he asserted. “There were also more radiation therapy interruptions” in the panitumumab group.

“There is certainly a role for EGFR inhibitors in head and neck cancer,” he concluded. However, “we are still trying to figure out the best role [for them], … when to use them to maximize patient benefit, and identify the most effective combinations. I think future directions in this particular space are going to focus on how are we going to modify our treatment approaches and be a little bit smarter about how we design these studies, looking for predictive biomarkers of therapy benefit.”

Cabozantinib in Medullary Thyroid Cancer

The EXAM trial was the first randomized phase III trial of cabozantinib—a potent oral inhibitor of the MET, VEGFR2, and RET tyrosine kinases—in patients with medullary thyroid cancer.4 A total of 330 patients with progressive disease were randomly assigned 2:1 to cabozantinib or placebo.

For the primary endpoint of progression-free survival, this was a positive study, Dr. Blumenschein said, with a median of 11.2 months with cabozantinib vs 4.0 months with placebo (HR = 0.28; P < .0001). The 1-year rate of progression-free survival was 47% vs 7%, respectively.

There was benefit in nearly all patient subgroups. There was also a significantly better objective response rate with cabozantinib (28% vs 0%, P < .0001). Overall survival data are not yet mature.

As expected, adverse events, particularly gastrointestinal issues and hand-foot skin reaction, were more common with cabozantinib.

“We now have a new drug for medullary thyroid cancer—cabozantinib is something that’s going to be a therapeutic option. It’s not yet approved, but I anticipate it will be, based on these results,” Dr. Blumenschein predicted. “It offers activity, both for patients who have had prior lines of chemotherapy and prior tyrosine kinase inhibitors, with robust and durable responses, and improvement in progression-free survival.” ■

Disclosure: Dr. Blumenschein receives research funding from Exelixis.


1. Cohen EEW, Karrison T, Kocherginsky M, et al: DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). 2012 ASCO Annual Meeting. Abstract 550. Presented June 3, 2012.

2. Haddad RI, Rabinowits G, Tishler RB, et al: The PARADIGM trial: A phase III study comparing sequential therapy (ST) to concurrent chemoradiotherapy (CRT) in locally advanced head and neck cancer (LANHC). 2012 ASCO Annual Meeting. Abstract 5501. Presented June 3, 2012.

3. Giralt J, Fortin A, Mesia R, et al: A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients (pts) with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN). 2012 ASCO Annual Meeting. Abstract 5502. Presented June 3, 2012.

4. Schoffski P, Elisei R, Müller S, et al: An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. 2012 ASCO Annual Meeting. Abstract 5508. Presented June 4, 2012.

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SIDEBAR: Trials’ Shortcomings Leave Role of Induction Chemotherapy Unclear

Given certain shortcomings of the DeCIDE and PARADIGM trials, the true role of induction chemotherapy in head and neck cancer is still not clear, said George R. Blumenschein, Jr, MD, Associate Professor at The Unviersity of Texas MD Anderson Cancer Center, Houston, at the Best of ASCO San Diego...