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Reduced-dose IMRT appropriate for induction chemotherapy responders with HPV-associated oropharyngeal cancer
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Complete clinical response to induction chemotherapy may serve as a biomarker to identify patients with HPV–associated oropharyngeal squamous cell carcinoma who could benefit from radiation deintensification, according to prospective study results.
A previous study demonstrated that patients with HPV–positive oropharyngeal squamous cell carcinoma (OPSCC) are more responsive to treatment than those with HPV–negative disease. However, patients with HPV–associated disease tend to be younger with lower comorbidity indexes.
As a result, these patients “may carry radiation sequelae for decades,” Barbara Burtness, MD, a HemOnc Today Editorial Board member, professor of medicine and co-director of the developmental therapeutics research program at Yale Cancer Center, and colleagues wrote.
The researchers hypothesized that a subgroup of patients with HPV–associated OPSCC may be suitable for radiation dose reduction to spare them from late sequelae.
In this phase 2 trial, patients with HPV16– or p16–positive, stage III to stage IV OPSCC received three cycles of induction chemotherapy with cisplatin, paclitaxel and cetuximab (Erbitux, Eli Lilly). Induction chemotherapy consisted of 75 mg/m² cisplatin on day 1; 90 mg/m² paclitaxel on days 1, 8 and 15; and 400 mg/m² cetuximab on day 1 of cycle 1, followed by 250 mg/m² cetuximab weekly. Cycles repeated every 21 days for three cycles.
Patients who achieved primary site clinical complete response to induction chemotherapy received 54 Gy of intensity-modulated radiation therapy with weekly cetuximab. Those with less than a clinical complete response to induction chemotherapy at the primary site or nodes received 69.3 Gy with cetuximab to those regions.
Two-year PFS served as the primary endpoint. The researchers also evaluated 2-year OS, clinical and radiologic responses at the primary and nodal sites after induction chemotherapy and after overall treatment, and safety and toxicity profiles.
Of the 80 eligible patients (median age, 57 years) identified among the 16 ECOG-ACRIN centers, the majority had stage T1 to T3 (89%) and N0 to N2b (69%) disease, and were not current smokers (85%).
Seventy-seven patients received three cycles of induction chemotherapy.
Fifty-six patients (70%; 95% CI, 59-80) achieved a primary-site clinical complete response to induction chemotherapy. Of those, 51 patients continued to cetuximab with 54 Gy IMRT and five received 69.3 Gy, which was a protocol deviation.
Eleven patients died during a median follow-up of 35.4 months (range, 3.9-41.6).
Of the patients who continued to cetuximab with 54 Gy IMRT, 80% (95% CI, 65-89) achieved 2-year PFS and 94% (95% CI, 82-98) achieved 2-year OS. For all 80 patients, rate of 2-year PFS was 78%( 95% CI, 67-86) and 2-year OS was 91% (95% CI, 82-96).
A subset analysis that combined tumor and nodal status with smoking history showed 2-year PFS and OS rates of 96% for both in 27 patients with a 10 pack-year history or less, and stage T4 and N2c disease or less.
Nine of the 51 patients treated with 54 Gy IMRT experienced treatment failure.
The most common grade 3 and grade 4 adverse events during induction chemotherapy included acneiform rash (28%), neutropenia (12%) and lymphopenia (6%).
The most common grade 3 adverse events among patients who underwent 54 Gy IMRT included mucositis (30%), dysphagia (15%), acneiform rash (12%), lymphopenia (12%) and radiation dermatitis (7%). Grade 3 adverse events among those treated with 69.3 Gy IMRT included mucositis (47%), dysphagia (29%), lymphopenia (29%), acneiform rash (24%), radiation dermatitis (12%) and thromboembolism (6%).
Further, fewer patients who received a reduced dose of IMRT reported difficulty swallowing solids (40% vs. 89%; P = .011) or had impaired nutrition (10% vs. 44%; P = .025) at 12 months.
“This finding provides justification for further study of radiation deintensification but requires validation in a larger comparative trial,” the researchers wrote. “Patient selection will be critical to optimal implementation of this strategy in future trials, because we observed that patients with minimal smoking history and low-volume tumors achieved the best disease control with de-escalation of definitive treatment.”
The researchers recommended phase 3 testing be conducted in favorable-risk patients.
However, patient selection may become “increasingly granular,” Sue S. Yom, MD, PhD, associate professor in the department of radiation oncology at the UCSF Helen Diller Family Comprehensive Cancer Center, wrote in an accompanying editorial.
“It will take another generation of studies before the subtle consequences of deintensification — or intensification — in finer subsets can be thoroughly understood,” she added.
Therefore, physicians may face a continually growing gap between everyday practice and treatments offered in clinical trials.
“Ideally, all patients with HPV–positive OPSCC should be enrolled in clinical trials,” Yom wrote. “For those who practicably cannot, it is at least reassuring that the standard of care, on the basis of upfront surgically or radiation-based therapy, remains highly effective for the great majority of patients with locoregionally advanced HPV–positive OPSCC. For these patients, their personal preferences will decide therapy more than findings from what remains an immature evidence base for deintensification.” – by Kristie L. Kahl
Disclosure: Burtness reports consultant roles with Amgen, Bayer, Boehringer Ingelheim, MedImmune, Merck and VentiRx; research funding from Merck; and has offered expert testimony for Johnson & Johnson. Please see the full study for a list of all other researchers’ relevant financial disclosures. Yom reports honoraria from AstraZeneca, research funding from Genentech, royalties from UpToDate, and travel accommodations from Abbott Laboratories and Varian Medical Systems.
Perspective
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David J. Adelstein
More than 3 decades of clinical trials exploring the use of induction chemotherapy prior to definitive management in squamous cell carcinoma of the head and neck have failed to demonstrate any clear impact on either locoregional control or survival. The use of induction chemotherapy as a treatment intensification strategy has generally been abandoned. Concurrent chemotherapy and radiation has emerged as a more successful multimodality approach with the consistent demonstration of improvement in both locoregional control and survival, albeit with a cost of a significant increase in both acute and long-term toxicity.
Marur and colleagues from the ECOG-ACRIN Cancer Research Group report results from E1308, a phase 2 clinical trial using induction chemotherapy, not as an attempt to intensify treatment but, instead, to deintensify treatment, with the goal of reducing the overall toxicity burden for patients without compromising treatment efficacy. This is of particular importance given the very high OS rate now achieved after treatment by patients with HPV–positive oropharynx cancer and the significant concern about late treatment-related functional compromise that long-term survivors may experience.
Focusing on these HPV–positive patients, the investigators demonstrated very acceptable PFS and OS rates after radiation dose reduction from 69.3 Gy to 54 Gy with concurrent cetuximab (Erbitux, Eli Lilly) in primary site complete responders after a 9-week course of induction chemotherapy. In an even more carefully selected subset of these primary site complete responders — less than 10 pack-year smokers and less than T4N2c disease — researchers observed a 96% rate of 2-year PFS and OS. Preliminary data also were presented suggesting that this modest radiation dose reduction was associated with a clinically meaningful improvement in both swallowing and nutrition at 12 months.
This use of induction chemotherapy as a biomarker of radiation responsiveness, in an effort to treatment deintensify, is not entirely new. It was also the rationale behind the landmark Veterans Affairs Laryngeal Cancer Study Group trial of laryngeal preservation, in which induction chemotherapy responders were spared laryngectomy and treated with radiation alone, without adversely impacting their survival. It has since been further explored by a number of clinical trials at University of Michigan. The idea of treatment deintensification in very good–risk patients with HPV–positive oropharynx cancer is being actively studied by many other investigators. The substitution of less toxic systemic agents, further reduction in radiation doses, the use of tighter radiation therapy fields and the incorporation of minimally invasive surgery all aim to reduce the overall toxicity burden and maintain treatment success.
Another unanswered question is how best to define the optimal patient population for deintensification strategies. Several risk stratification proposals have been suggested. How much can treatment be safely de-escalated and how much de-escalation is required to meaningfully impact late toxicity? Particularly relevant to this trial is the question of whether the added time, cost and acute toxicity of 9 weeks of induction chemotherapy will leave patients better off than the additional treatment week and the higher total dose of radiation.
References:
The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med. 1991;324:1685-1690.
Worden FP, et al. J Clin Oncol. 2008;26:3138-3146.
Urba S, et al. J Clin Oncol. 2006;24:593-598.
Disclosure: Adelstein reports no relevant financial disclosures.
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