The use of CRT in the definitive management of HNSCC frequently mandates feeding tube placement. It remains unclear whether nasogastric (NG) or percutaneous gastrostomy (PEG) enteral feeding is superior. Prior short-term studies suggest that PEG feeding prevents acute weight loss and is more convenient for patients while NG feeding is associated with a shorter duration of tube dependence and reduced rates of persistent dysphagia. Long-term follow-up is necessary to evaluate late effects when comparing PEG to NG feeding. To address these late toxicities we reviewed our IRB approved registry with improved follow-up compared to our previously reported patient series. In contrast to previous work, we identified all patients with stage III-IV tumors of the larynx, hypopharynx and HPV-negative oropharynx treated between 1995-2012 with definitive CRT who acutely required a feeding tube during therapy. Patients with less than one year of follow-up and those who failed therapy within two years were excluded. CTCAE v4.0 criteria were used to evaluate for severe (Grade 3) late pharyngeal toxicity defined as the need for stricture dilation or chronic enteral feeding dependence. Logistic regression was used to control for treatment parameters. Seventy-eight survivors who acutely required a feeding tube and met the strict criteria above were identified. Median follow-up was 61.7 months (range 11.0-197.80 months). In 3 patients feeding was necessary prior to radiation (2 PEG, 1 NG). The primary tumor was located in the larynx in 40 (51.3%), hypopharynx in 25 (32.1%) and (HPV-negative) oropharynx in 13 (16.7%) and 75.6% of tumors were locally-advanced (T3-T4). 3D-Conformal Radiation therapy (3D-CRT) was used in 84.6% and Intensity-Modulated Radiation therapy (IMRT) in 15.4%. A temporary small-bore NG tube was used in 29 patients (37.2%) and a PEG in 49 (62.8%). 31.0% of the NG patients experienced late pharyngeal toxicity compared to 57.1% of the PEG patients. On univariate analysis the use of PEG feeding was the only factor significantly associated with an increased risk of this severe toxicity (OR 2.96, 95% CI 1.12-7.81; p = 0.028). Age, T-stage, N-stage, adjuvant neck dissection, multiagent chemotherapy, hyperfractionated radiation therapy or the use of IMRT were not associated, although there was a trend towards increased toxicity in patients with hypopharynx primaries (p = 0.058). On multivariate analysis, when controlling for location of the primary tumor, the use of a PEG tube remained independently associated with late pharyngeal toxicity (OR 2.83, 95% CI 1.04-7.69, p = 0.042). Our updated series with long-term follow-up shows that PEG tubes are associated with significantly higher rates of severe late pharyngeal toxicity as opposed to NG tubes. Routine PEG use should be avoided when possible to encourage pharyngeal exercise and prevent late strictures.

Late toxicity is a common concern after the definitive treatment of HNSCC. Randomized trials have shown improvement in xerostomia and overall quality-of-life after IMRT compared to 3D-Conformal Radiation Therapy (3D-CRT), but the value of IMRT likely extends beyond improvement in xerostomia. We compared other late toxicities after IMRT, with those encountered after 3D-CRT in patients (pts) with Non-HPV associated tumors who are at higher-risk for late dysfunction. We reviewed our IRB-approved database and identified stage III-IV pts with HPV-negative oropharynx, larynx and hypopharynx SCC treated between 1989-2013 using definitive concurrent chemoradiation. Late toxicities which occurred more than three months from treatment were graded according to CTCAE 4.0 criteria. Late grade 3 dysphagia, stricture, feeding tube use, osteonecrosis, trismus, tracheostomy, aspiration and fibrosis were considered severe. Taste changes and xerostomia were not included. Differences in the development of toxicities were analyzed using logistic regression. Survival statistics were computed using the Kaplan-Meier technique and compared using the Log-Rank test. 167 pts were identified, 133 treated with 3D-CRT and 34 who were treated with IMRT. Disease was located in the supraglottis in 66 patients (39.5%), hypopharynx in 54 (32.3%), glottis in 20 (12.0%) and HPV-negative oropharynx in 25 (15.0%). Two pts had unknown primaries (1%). Multiagent cisplatin/5-FU was used in 82.6%, cisplatin alone in 13.8% and cetuximab alone in 1.8%. Two-year overall survival (84.7% vs 86.4%, p = 0.91) and disease-free survival (77.6% vs 72.4%, p = 0.46) did not differ between the IMRT and the 3D-CRT groups, with a median follow-up of 16.8 and 55.9 months, respectively. On univariate analysis, the rate of severe toxicity was markedly reduced with the use of IMRT (17.6% vs 38.9%, OR 0.226; p = 0.0023) and single-agent chemotherapy (OR 0.098; p = 0.0023) but was not impacted by tumor site, T-stage, age, smoking during therapy, adjuvant neck dissection, the use of hyperfractionated radiation therapy or medical comorbidities. On multivariate analysis both single-agent chemotherapy (OR 0.156, p = 0.018) and the use of IMRT (OR 0.233; p = 0.014) were independently associated with less frequent late grade 3 toxicity. The use of IMRT for pts with Non-HPV associated HNSCC treated with CRT is associated with significant reductions in severe late effects more likely to impact long term function than xerostomia.

Patients (pts) with oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiation therapy (CRT) have historically had significant long term toxicity. We hypothesize that HPV + patients treated with chemoIMRT have more favorable long term toxicity profiles and quality of life than historical data suggests. Pts with stage III-IVb OPSCC and known tumor HPV status treated with CRT between 2002 and 2012 and rendered disease free were identified from an IRB approved registry. HPV + disease included pts who tested positive for HPV DNA by in-situ hybridization, or had diffuse and strong (>75%) staining for p16 by immunohistochemistry. Radiation therapy (RT) was administered once (79%) or twice daily (21%) to a total dose of 70-74.4 Gy, with a 3-field approach (3D-RT) in the earlier years (65%) and IMRT (35%) more recently. Most patients were treated with Cisplatin and 5-Fluorouracil (62%), while more recently patients were treated with Cisplatin (26%), or Cetuximab (9%) at standard dosing. Toxicity was scored according to CTCAE v4.0. Significant late toxicity was defined as any grade ≥3, or any persistent grade 2 fibrosis, dysphagia, osteoradionecrosis, trismus, pain, hoarseness, or hearing loss that occurred >3 months after the completion of treatment. Xerostomia, taste and skin changes were excluded from this combined endpoint. Logistic regression analysis was performed to identify pt, tumor, and treatment related variables associated with significant late toxicity. Of the 197 pts included in this study, the majority were Caucasian (95%) and male (91%), and 32% were never smokers. The median age was 56, median KPS 90, and median f/u was 39.4 months (range: 3.1-137.8). At last follow-up, 91% of patients returned to a normal diet, while 6.5% had a limited oral diet and 2.5% were feeding tube dependent. Of the 41 pts (20%) who required dilation for a stricture, 21 pts had their dysphagia resolve. The use of 5-FU based chemotherapy (76% vs 37%; p<0.0001) and the use of 3D-RT (70% vs 44%; p=0.0005) were independently associated with the need for a feeding tube. Similarly, 5-FU based chemotherapy (43% vs 16%; p=<0.0001) and 3D-RT (44% vs 13%; p<0.0001) were significantly associated with higher rates of significant late toxicity. In patients treated with once daily IMRT and non-5-FU based chemotherapy, the rate of significant late toxicity was 5.7%. Not using IMRT was associated with the highest risk of late toxicity on MVA (OR 3.4; p=0.005). Pts with HPV + OPSCC treated with IMRT and non 5-FU based chemotherapy have excellent long term functional recovery and low rates of significant late toxicity. .

Evidence about the benefit of IMRT to reduce serious late effects specifically in pts with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) treated with CRT is sparse. We investigated the impact of IMRT vs standard 3-field radiation therapy (3D-RT) on late effects outcomes in this pt cohort. Pts with HPV + stage III-IVb OPSCC treated with CRT between 2002 and 2012 and rendered disease free were identified from an IRB approved registry. Pts who tested positive for HPV DNA by in-situ hybridization, or had diffuse and strong (>75%) staining for p16 by immunohistochemistry were included. Radiation therapy (RT) was administered once (79%) or twice daily (21%) to a total dose of 70-74.4 Gy. 3D-RT was used in the earlier years (65%) while IMRT with daily cone beam CT and 2-3 mm CTV and PTV expansions, respectively, was used more recently (35%). Most patients were treated with Cisplatin and 5-Fluorouracil (62%), while more recently patients were treated with Cisplatin (26%), or Cetuximab (9%) at standard dosing. Toxicity was scored according to CTCAE v4.0. Significant late toxicity was defined as any grade ≥3, or any persistent grade 2 fibrosis, dysphagia, osteoradionecrosis, trismus, pain, hoarseness, or hearing loss that occurred >3 months after the completion of treatment. Xerostomia, taste and skin changes were excluded from this combined endpoint. Logistic regression analysis was performed to identify factors associated with significant late toxicity. Of the 197 pts included in this study, the majority were white (95%), men (91%), and 32% were never smokers. The median age was 56, median KPS 90, and median f/u was 39.4 months. At last follow-up, 91% of patients returned to a normal diet, while 6.5% had a limited oral diet and 2.5% were feeding tube dependent. 5-FU based chemotherapy (43% vs 16%; p = <0.0001) and 3D-RT (44% vs 13%; p<0.0001) were significantly associated with higher rates of significant late toxicity. In patients treated with once daily IMRT and non-5-FU based chemotherapy, the rate of significant late toxicity was only 5.7%. On MVA, not using IMRT was associated with the highest risk of significant late toxicity (OR 3.4; p = 0.005), overshadowing smoking status, T stage, neck dissection and chemotherapy type. Pts with HPV + OPSCC treated with IMRT have fewer significant late effects than those treated with 3D-RT. Nearly all pts treated with IMRT and non 5-FU based chemotherapy have minimal significant late effects and excellent long term pharyngeal function.