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Reduced-intensity chemoradiotherapy safe, effective for HPV-related oropharynx cancer
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Reduced-intensity radiation therapy and chemotherapy appeared as effective as the standard-dose combination among patients with HPV-related oropharynx cancer, according to results of a prospective multi-institutional phase 2 study presented at the ASTRO Annual Meeting.
Further, the reduced-intensity regimen led to fewer adverse events.
“With further study, this regimen may become the new standard of care for carefully selected patients with HPV-associated squamous cell carcinoma of the oropharynx,” Bhishamjit Chera, MD, associate professor of radiation oncology at University of North Carolina School of Medicine, said in a press release.
The standard treatment for HPV-related squamous cell carcinoma of the oropharynx includes a 7-week course of 70 Gy of radiation combined with 100 mg/m² cisplatin-based chemotherapy for 3 cycles. This treatment — although effective — often results in adverse effects such as chronic and acute difficulties in talking or swallowing, dry mouth, painful inflammation of the mucous membranes and/or digestive tract, tooth decay, and necrosis of the jawbone.
Chera and colleagues sought to assess the safety and efficacy of reduced-intensity chemoradiotherapy for 43 patients with favorable-risk HPV–associated oropharyngeal squamous cell carcinoma and a minimal smoking history. Researchers reduced the treatment to a 6-week course of 60 Gy of radiation therapy (a 16% reduction) and 30 mg/m² of cisplatin-based chemotherapy delivered concurrently (a 60% reduction).
Following the completion of this regimen, researchers biopsied the tumor site and removed originally positive lymph node regions to determine treatment efficacy.
Median follow-up was 20.7 months (range, 6-36 months) and all patients were alive and had no evidence of recurrence.
Eighty-six percent of the patients had no residual invasive tumor and no residual lymph node metastasis. The remaining 14% of the patients had microscopic cancer remaining.
“The results so far are certainly encouraging, and with longer follow-ups, we hope to confirm less long-term side effects as well,” Chera said.
The researchers also evaluated symptoms and quality of life by using patient-reported outcome questionnaires. They used modified barium swallow studies to assess swallowing outcomes.
Chera reported that reduced-intensity chemoradioherapy resulted in less toxicity and a reduction in adverse events such as mucositis, nausea, vomiting, difficulty swallowing and mouth dryness.
Further, feeding tube rates previously reported for the standard-dose regimen reached 80%, with 10% of patients required permanent feeding tubes. By contrast, 39% of the patients in this study needed a feeding tube at some point and none of them were permanent.
The swallowing studies showed patients’ swallowing function returned almost to normal compared with baseline.
Chera added that additional data are needed before any shift in standard treatment should be considered. He and his team are conducting a follow-up study of patients to evaluate biopsies of lymph node removal if a PET scan at 12 weeks post treatment is suspicious for persistent cancer. – by Anthony SanFilippo
For more information: Chera BS, et al. Abstract 3. Presented at: ASTRO Annual Meeting; Oct. 18-21, 2015; San Antonio, Texas.
Disclosure: HemOnc Today was unable to confirm the researchers’ relevant financial disclosures at the time of reporting.Perspective
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Bhupesh Parashar, MD
HPV-positive (or p16-positive) oropharynx cancer is defined by the presence of high-risk types of HPV in tumor cells, predominantly HPV type 16 (HPV-16). Several retrospective case series have shown that among patients with oropharyngeal squamous cell carcinoma, patients with HPV-positive tumors have a better prognosis than patients with HPV-negative tumors.A prospective study conducted by Fakhry and colleagues evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV head and neck squamous cell carcinoma of the oropharynx or larynx who participated in an ECOG phase 2 trial. Patients received two cycles of induction chemotherapy with IV paclitaxel and carboplatin followed by concomitant weekly IV paclitaxel and standard fractionation radiation therapy. Compared with patients with HPV-negative tumors, patients with HPV-positive tumors had higher response rates after induction chemotherapy (82% vs. 55%, P = .01) and after chemoradiation treatment (84% vs. 57%, P = .007). In addition, HPV-positive patients showed improved OS and, after adjustment for age, tumor stage and ECOG performance status, lower risks for progression and death from any cause (HR = 0.36, 95% CI, 0.15 to 0.85) than those with HPV-negative tumors.
The RTOG 0129 study addressed the question of whether accelerated-fractionation radiotherapy is superior to standard-fractionation radiotherapy in combination with concurrent cisplatin. A subset retrospective analysis was performed to assess association between HPV positivity and outcomes in this study. HPV-positive patients had better 3-year rates of OS (82.4%, vs. 57.1%; P < .001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure and treatment assignment, had a 58% reduction in the risk for death (HR = 0.42; 95% CI, 0.27-0.66).
Although these studies showed a better outcome in HPV-positive oropharynx cancers, it was not known if changing treatment paradigm to make it equally effective but less toxic is an option.
Chera and colleagues from University of North Carolina have finally tried to address this important issue through a phase 2 trial of radiation (RT) and chemotherapy dose de-escalation. RT included 60 Gy to gross tumor using intensity-modulated radiotherapy with concurrent weekly IV cisplatin (30 mg/m2). The primary study endpoint was pathologic complete response rate (pCR). Secondary endpoint measures included physician-reported toxicity (CTCAE), patient-reported symptoms (PRO-CTCAE), quality of life (EORTC QLQ-C30 & H&N35), and penetration aspiration scale (PAS) scores for modified barium swallow studies. The pCR rate was 86% (37/43). The incidence of CTCAE grade 3/4 toxicity and PRO-CTCAE severe/very-severe symptoms were: mucositis 34%/45%, pain 5%/48%, nausea 18%/52%, vomiting 5%/34%, dysphagia 39%/55% and xerostomia 2%/75%. Eleven percent of patients experienced grade 3/4 hematological toxicities. Thirty-nine percent of patients required a feeding tube (none permanent) for a median of 15 weeks (range, 5-22). There were no significant differences in PAS scores for thin, pureed and solid foods before and after CRT.
These are promising data but need to be tested in a phase 3 randomized trial comparing the regimen with standard RT fractionation and standard chemotherapy dosing. In addition, a longer follow-up is needed for accurate assessment of disease outcomes. Dose de-escalation will potentially benefit a number of toxicity outcomes, including xerostomia, rates of radiation necrosis, rates of renal dysfunction and hearing loss, and it also may help in faster recovery of taste after completion of RT. However, it is not known if relatively more aggressive cancers of the oropharynx — such as base of tongue, pharyngeal wall cancers — will respond in terms of tumor control to lower RT dose. In addition to local control, will chemotherapy dose reduction result in higher distant metastasis rates? These are important concerns that need to be addressed in a randomized fashion before we accept this dose reduction as the new standard in HPV-positive cancers.
References:
Ang KK, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa0912217.Fakhry C, et al. J Natl Cancer Inst. 2008;doi:10.1093/jnci/djn011.
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