Patients with human papillomavirus (HPV)-positive (HPV+) head and neck cancers who respond to induction chemotherapy can subsequently be treated safely and effectively with a substantially lower radiation dose, show new results from the OPTIMA trial.
Radiation therapy (RT) or chemoradiation therapy could be de-escalated by 30% to 35%, the researchers report. These patients still achieved excellent pathologic complete response (pCR) and excellent survival and progression-free survival (PFS). Overall survival ranged between 97% and 100% for these patients.
Moreover, adverse event rates were lower for patients who received de-escalated RT or chemoradiation therapy (CRT) than for patients who received standard CRT, with significantly fewer patients dependent on a feeding tube.
“This degree of de-escalation with high-risk patients is novel, as is selection using induction as the key component to reduce radiation doses and subsequent toxicities to such low levels,” said Tanguy Seiwert, MD, lead author of the study and an assistant professor of medicine at University of Chicago Medicine, Illinois.
“In my opinion, treatment for HPV-positive disease should be de-escalated when possible, and induction is an ideal method to identify HPV-related head and neck cancer biology,” he added.
Seiwert was speaking at a press briefing before the 2018 Multidisciplinary Head and Neck Cancers Symposium, to be held in Scottsdale, Arizona, on February 15 to 17, at which these new data will be presented.
Response to Indication Therapy
OPTIMA (NCT02258659) is the University of Chicago’s de-escalation approach to stratify patients according to response to induction chemotherapy with carboplatin and nab-paclitaxel (Abraxane, Celgene). The purpose of induction therapy is to lower the risk for distant failure and to identify adverse tumor biology, Seiwert explained at a press conference.
The study was conducted in patients with HPV+ oropharyngeal cancer, of whom 28 were classed as low risk (≤T3, ≤N2b, ≤10 pack-year smoking history) and 34 were high-risk (T4, ≥N2c, >10 pack-year smoking history).
All patients received three cycles of induction chemotherapy with carboplatin, area under the curve of 6, given on day 1 and nab-paclitaxel, 100 mg/m2, given on days 1, 8, and 15 every 3 weeks.
Patients were assigned to RT doses on the basis of their response to induction chemotherapy. Low-risk patients with at least 50% reduction in tumor size received low-dose RT alone to 50 Gy (RT50). Low-risk patients with 30% to 50% reduction in tumor size and high-risk patients with at least 50% reduction in tumor size received low-dose CRT to 45 Gy (CRT45). All other patients were considered poor responders and received standard CRT to 75 Gy (CRT75).
RT50 was delivered over 5 weeks in 2-Gy daily fractions. Patients in the CRT groups received systemic therapy with paclitaxel, 5-fluorouracil, and hydroxyurea, as well as 1.5-Gy twice-daily RT given every other week.
“The majority of patients received de-escalated treatment with limited field 50-Gy RT or 45-Gy CRT, including patients with high-risk nodal stages of disease,” Seiwert said.
Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pCR rate and toxicity.
OPTIMA Results
After induction chemotherapy, in the second stage of the study, 19 patients received RT50, 28 patients received CRT45, and 15 patients received CRT75.
The median follow-up was 22.3 months.
Seiwert reported that all low-risk patients and 32 of 34 (94%) high-risk patients were progression free at 2 years. Two-year overall survival rates were 100% and 97% for low-risk and high-risk patients, respectively; 2.5-year overall survival rates were 97.0% and 85.7%, respectively.
The pCR rate was 94.7% (18 of 19) for patients receiving low-dose RT and 89.3% (25 of 26) for patients receiving low-dose CRT (100% for low-risk patients [6 of 6] and 86.4% [19 of 22] for high-risk patients).
Side effects from de-escalated therapy were significantly improved compared with standard treatment (CRT75), Seiwert noted. Grade 3 or higher mucositis was reported for 15.0%, 46.7%, and 63.6% of patients in the RT50, CRT45, and CRT75 groups, respectively (P = .01). Correspondingly, grade 3 or higher dermatitis was reported for 0%, 10.0%, and 45.5% of patients in those three groups, respectively (P = .002).
Dependency on a feeding tube is a long-term side effect in these patients, and this was significantly reduced in the de-escalated therapy groups. After 12 months of treatment, no patient in the RT50 group and 3.5% of patients in the CRT45 group experienced long-term dependency on a feeding tube compared with 9.1% of patients in the CRT75 group (P < .001)
“With our approach of using induction chemotherapy to identify candidates for de-escalated radiation therapy, we achieved excellent treatment outcomes with giving 30% to 35% smaller radiation doses, even for patients with advanced nodal stages, such as N2c. Patients experienced less toxicity and survival rates exceeded historic data, although more follow-up is needed to confirm these findings,” Seiwert said in a statement.
De-escalation May Be Considered a Standard Option
When asked how this study would translate to routine clinical practice, Seiwert explained that the de-escalation approach has been the subject of several studies and each approach works differently. In one approach, surgery is used in de-escalation. In another approach, cetuximab is used instead of cisplatin and radiation is untouched, he told Medscape Medical News.
“All approaches show that de-escalation is feasible, safe, and effective, and outcomes are better,” he said.
De-escalation should be considered for all patients, Seiwert noted. However, he cautioned that de-escalation should be performed at large academic centers, which have experience with this patient population. “This is not a cookbook approach and may be risky if one does not know how to de-escalate,” he said. “For example, if one uses one third of the radiation, the field has to be perfect,” Seiwert said.
In addition, he indicated that de-escalation is not for all patients. “Most tumors do well, but there are a few bad players not served well by de-escalation,” Seiwert said.
Seiwert prefers the University of Chicago method for de-escalation to other approaches because the induction therapy accounts for adverse biology, selects appropriate patients, and reduces the radiation dose; the outcomes are truly exceptional; and it includes high-risk patients with nodal disease.
At his institution, Seiwert and his colleagues use the de-escalation approach broadly in routine clinical management of patients outside clinical trials. “Indeed, we have set up OPTIMA 2, which essentially uses the same approach as OPTIMA 1, but induction therapy incorporates immunotherapy and a surgical option is included for de-escalation,” he said.
Seiwert receives honoraria from AstraZeneca, Bristol-Myers Squibb, Innate, Oncolys, Merck, and Nanobiotix. He also receives research funding from Bristol-Myers Squibb, Jounce, and Merck.
2018 Multidisciplinary Head and Neck Cancers Symposium. Abstract 5. To be presented February 15, 2018.
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