The development of intensified treatment regimens has been a natural result, combining cytotoxic agents with high-dose radiation, accelerated regimens, and induction chemotherapy. Severe toxicities are a result, but the incidence, severity, and longevity of these have largely been given less attention than efficacy outcomes in attempts to improved tumor control and survival.
Over the past decade, HPV-driven oropharyngeal squamous cell carcinomas have risen dramatically. From 1996 to 2016, new cases in the United States have increased from roughly 29,000 to 48,000 per year(2). Retrospective analyses indicated an improved prognosis in HPV positive tumors, a finding that was later confirmed in the prospective Eastern Cooperative Oncology Group (ECOG) 2399 and Radiation Therapy Oncology Group (RTOG) 0129 trials, even when controlling for positive prognostic indicators such as age, performance status, and smoking (3),(4).(Figure 1)
These findings have resulted in a myriad of deintensification trials looking to improve on chronic toxicities that plague this otherwise generally healthy and younger population of patients. Hypotheses range from elimination of cytotoxic chemotherapy in the induction and/or concurrent setting, avoidance of trimodality approaches, radiation dose reduction such as was done in ECOG 1308 (5), and even elimination of prophylactic radiation to distant cervical lymph node regions. ( 6) These ongoing studies have appropriately targeted very specific patients with regards to disease site, performance, stage, and HPV status. While awaiting these data, clinicians can utilize radiation techniques that move the pendulum in the proper direction with regards to toxicity amelioration. Our large retrospective study addressed one possible approach. We analyzed a cohort of 209 sequentially treated patients at one large academic center who either received simultaneously-integrated boost IMRT technique (SIB) or sequential boost IMRT (SeqB) to determine how delivery technique may impact toxicity. Chemotherapy regimen was essentially the same for both cohorts, utilizing weekly paclitaxel and carboplatin. Induction chemotherapy use was equally used for very advanced patients, or those with initial weight loss or swallowing difficulties.
Study findings show there were no significant differences in local, regional, or distant RFS. At 3 years, OS was 69% for SeqB and 79% for SIB cohorts (p = 0.13). Three year DFS was not statistically different (63% vs. 73%; p = 0.27). Table 1 Figure 2. There were no differences in weight loss (p = 0.291), incidence of gastrostomy tube need (p = 0.494), or in prolonged gastrostomy tube dependence (p = 0.465). The rates of grade 3 or 4 dysphagia were higher for SIB than for SeqB (81% vs. 55%, < 0.001) as well as dermatitis (78% vs. 58%, p = 0.012). Fewer SIB patients received the total 69.3Gy IMRT dose due to acute toxicity compared to the SeqB patients (93% vs 100%; p = 0.03). Table 2
Dosimetry evaluation of IMRT mean dose, Dmax, and percent volumes of organs at risk (OARs) receiving 30Gy and 70Gy were not statistically different between the two cohorts, reflecting otherwise similar IMRT technique.
In conclusion, the SeqB IMRT technique resulted in lower grade 3 and 4 acute radiation dermatitis and dysphagia compared to SiB. More patients completed treatment with SeqB than did pts treated with SiB IMRT.
In patients with smoking-related head and neck cancer, tumor control and survival are still suboptimal and efficacy studies have largely been directed toward multi-agent chemotherapy, radiation intensification strategies, and novel biologic agents. Toxicities are dramatic and methods to minimize treatment breaks are elusive. In an HPV-positive patient population where numerous treatment modalities can obtain very high survival, it is QOL that will ultimately guide the decisions for best treatment approach for a given individual. We feel a re-initiation of sequential boost IMRT as a treatment approach can be a useful tool in treatment in both aggressive and deintensification strategies for both patient populations for toxicity amelioration while data from prospective clinical trials testing other approaches are pending.
Written by: Anthony J. Cmelak, MD, Mark J. Stavas MD and Greg Vlacich MD, Vanderbilt-Ingram Cancer Center, Nashville Tennessee
1. Bourhis J, Sire C, Graff P, etl.al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012 Feb;13(2):145-53.
2. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1996. CA Cancer J Clin. 1996 Jan 1;46(1):5–27.
3. Fakhry C, Zhang Q, Nguyen-Tan PF, Rosenthal D, El-Naggar A, Garden AS, et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. Journal of Clinical Oncology. 2014 Jun 23;32(30):3365–3373.
4. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. New England Journal of Medicine. 2010 Jun 7;363(1):24–35.
5. Marur S, Li S, Cmelak A, Zhao W, Westra WH, Chung CH, Gillison ML, Gilbert J, Bauman JE, Wagner LI, Ferris RL, Trevarthen DR, Colevas AD, Jahagirdar BN, Burtness B. E1308: Reduced-dose IMRT in human papilloma virus (HPV)-associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction chemotherapy (IC). J Clin Oncol. 2016 Dec 28.
6. Villaflor VM, Melotek JM, Karrison TG, Brisson RJ, Blair EA, Portugal L, et al. Response-adapted volume de-escalation (RAVD) in locally advanced head and neck cancer. Annals of Oncology. 2016 Feb 15;27(5):908–913.
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