J.F. Greskovich

Survival by radiation therapy oncology group recursive partitioning analysis class and treatment modality in patients with brain metastases from malignant melanoma: A retrospective study

In a population of patients with brain metastases from melanoma, the authors sought to determine whether various therapies provided any benefit at all, whether local therapy was better than whole brain radiotherapy (WBRT), and whether combined local therapy and WBRT provided any advantage over local therapy alone. They also analyzed survival according to a Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) to determine how well the RTOG RPA classes predicted survival in this patient population and whether treatments varied in effectiveness from category to category.

Esophageal Dose Tolerance to Hypofractionated Stereotactic Body Radiation Therapy: Risk Factors for Late Toxicity

PURPOSE To identify factors associated with grade ≥3 treatment related late esophageal toxicity after lung or liver stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS This was a retrospective review of 52 patients with a planning target volume within 2 cm of the esophagus from a prospective registry of 607 lung and liver SBRT patients treated between 2005 and 2011. Patients were treated using a risk-adapted dose regimen to a median dose of 50 Gy in 5 fractions (range, 37.5-60 Gy in 3-10 fractions). Normal structures were contoured using Radiation Therapy Oncology Group (RTOG) defined criteria. RESULTS The median esophageal point dose and 1-cc dose were 32.3 Gy (range, 8.9-55.4 Gy) and 24.0 Gy (range, 7.8-50.9 Gy), respectively. Two patients had an esophageal fistula at a median of 8.4 months after SBRT, with maximum esophageal point doses of 51.5 and 52 Gy, and 1-cc doses of 48.1 and 50 Gy, respectively. These point and 1-cc doses were exceeded by 9 and 2 patients, respectively, without a fistula. The risk of a fistula for point doses exceeding 40, 45, and 50 Gy was 9.5% (n=2/21), 10.5% (n=2/19), and 12.5% (n=2/16), respectively. The risk of fistula for 1-cc doses exceeding 40, 45, and 50 Gy was 25% (n=2/9), 50% (n=2/4), and 50% (n=2/4), respectively. Eighteen patients received systemic therapy after SBRT (11 systemic chemotherapy, and 6 biologic agents, and 1 both). Both patients with fistulas had received adjuvant anti-angiogenic (vascular endothelial growth factor) agents within 2 months of completing SBRT. No patient had a fistula in the absence of adjuvant VEGF-modulating agents. CONCLUSIONS Esophageal fistula is a rare complication of SBRT. In this series, fistula was seen with esophageal point doses exceeding 51 Gy and 1-cc doses greater than 48 Gy. Notably, however, fistula was seen only in those patients who also received adjuvant VEGF-modulating agents after SBRT. The potential interaction of dose and adjuvant therapy should be considered when delivering SBRT near the esophagus.

Effect of human papillomavirus on patterns of distant metastatic failure in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy.

IMPORTANCE Important differences exist in the pattern and timing of distant metastases between human papillomavirus-initiated (HPV+) and HPV- oropharyngeal squamous cell carcinoma (OPSCC). However, our understanding of the natural history of distant metastases in HPV+ OPSCC and its implications for surveillance is limited. OBJECTIVE To investigate the rate, pattern, and timing of distant metastases in advanced-stage OPSCC treated definitively with concomitant chemoradiotherapy. DESIGN, SETTING, AND PARTICIPANTS In a retrospective review, we identified 291 patients with pathologically diagnosed stages III to IVB OPSCC and known HPV status from a tumor registry at the Cleveland Clinic. Patients were treated from January 1, 1996, through December 31, 2013. Details of treatment failure and the natural history of the disease were retrieved from the electronic medical records. INTERVENTIONS All patients were treated with definitive concomitant chemoradiotherapy. MAIN OUTCOMES AND MEASURES The primary outcome was the rate and timing of distant metastases. Secondary outcomes included the pattern of distant failure and survival after distant metastases. RESULTS Thirty-seven patients developed distant metastatic disease after definitive treatment, including 28 of 252 patients with HPV+ disease and 9 of 39 patients with HPV- disease. The 3-year projected distant control rate was higher in the HPV+ group (88% vs 74%; P = .01). The median time to develop distant metastases was also longer after the completion of treatment for HPV+ disease compared with HPV- disease (16.4 vs 7.2 months; P = .008). We detected a trend in patients with HPV+ disease for more distant metastatic sites involved than in those with HPV- disease (2.04 vs 1.33 sites; P = .09). Although the lung was the most common distant site involved in HPV+ and HPV- disease (HPV+ group, 23 of 28 patients [82%]; HPV- group, 7 of 9 patients [78%]), the HPV+ group had metastases to several subsets atypical for head and neck squamous cell carcinoma, including the brain, kidney, skin, skeletal muscle, and axillary lymph nodes in 2 patients each and in the intra-abdominal lymph nodes in 3 patients. The rate of 3-year overall survival was higher in the HPV+ group (89.9% vs 62.0%; P < .001), as was the median survival after the occurrence of distant metastases regardless of additional treatment (25.6 vs 11.1 months; P < .001). CONCLUSIONS AND RELEVANCE This retrospective review suggests that distant metastases in patients with HPV+ OPSCC occurs significantly later after completion of chemoradiotherapy than in patients with HPV- disease. Human papillomavirus-initiated OPSCC also appears to involve a greater number of subsites and metastatic sites infrequently seen in head and neck squamous cell carcinoma. Distant metastatic disease in HPV+ OPSCC has unique characteristics and a natural history that may require alternative surveillance strategies.

Salvage Laryngectomy in Patients with Recurrent Laryngeal Cancer in the Setting of Nonoperative Treatment Failure

Objective To investigate the effectiveness of salvage partial and total laryngectomy in the treatment of recurrent laryngeal cancer in the setting of initial nonoperative treatment failure and to identify factors influencing long-term survival. Study Design Case series with planned chart review. Setting Tertiary medical center. Subjects and Methods Patients with recurrent squamous cell carcinoma of the larynx initially treated with either radiation or chemoradiation, who underwent salvage laryngectomy at the Cleveland Clinic Foundation from 1997 to 2011, were identified. The cohort was divided into an early-stage group and an advanced-stage group based on initial tumor staging. Survival outcome was evaluated separately in each group against tumor staging, methods of treatment, and nodal status. Secondary endpoints of speech and swallowing were also evaluated. Results A total of 100 patients were identified, with 72 patients in the early-stage group and 28 patients in the advanced-stage group. The overall postsalvage locoregional control rate was 70%, and the 5-year disease-specific survival was 70% and 55.2% in the early and advanced group, respectively (P = .39). The 5-year disease-specific survival was not significant in either group when compared with recurrent staging, initial treatment, salvage treatment, or nodal disease (P = ns). Using voice prostheses, good to excellent speech function was achieved postoperatively in most patients. Conclusion Tumor staging, methods of initial and salvage treatment, and nodal disease were not significant predictors of survival. Both salvage partial and total laryngectomy were effective methods in the treatment of recurrent laryngeal cancer in carefully selected patients.

Endoscopic and Open Surgical Approaches to Locally Advanced Sinonasal Melanoma: Comparing the Therapeutic Benefits

IMPORTANCE This study helps to elucidate the appropriate surgical treatment for sinonasal melanoma. OBJECTIVE To compare open resection (OR) and endoscopic resection (ER) as surgical approaches to sinonasal mucosal melanoma (SNM)and evaluate their associations with treatment-related outcomes. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of the medical records of 25 patients with sinonasal mucosal melanoma (SNM) treated by either OR or ER in an academic tertiary care medical center. INTERVENTIONS The patients underwent either OR or ER of their SNM tumors. MAIN OUTCOMES AND MEASURES Overall survival was the primary outcome measured; secondary outcomes were postoperative complications, lengths of hospital stay, patterns of failure, and disease-free survival. RESULTS Thirteen patients with SNM underwent an OR, while 12 had ER of their tumors. The OR and ER groups did not differ significantly in demographic and tumor characteristics. In the OR vs ER group comparisons, mean age (67.8 vs 65.5 years) (P = .63), the proportions of patients who received adjuvant radiotherapy (85% [n = 11] vs 92% [n = 11]) (P > .99), and the proportion who achieved negative surgical margins on resection (54% [n = 7] vs 58% [n = 7]) (P = .82) were similar. Overall all median survival (12.7 and 1.9 years) (P = .87) and disease-free survival (1.9 and 1.2 years) (P = .72) were modest and did not differ between OR and ER groups, respectively. Likewise, the OR and ER groups, respectively, showed comparable mean lengths of hospital stay (3.6 and 3.8 days) (P = .87), rates of postoperative bleeding (8% [n = 1] and 17% [n = 2]) (P = .59), and rates of cerebrospinal fluid leak (15% [n = 2] and 25% [n = 3]) (P = .64). In addition, the OR and ER groups, respectively, had high rates of local (23% [n = 3] and 8% [n = 1]) (P = .59), distant (15% [n = 2] and 25% [n = 3]) (P = .64), and multiple failures (15% [n = 2] and 25% [n = 3]) (P = .64). CONCLUSIONS AND RELEVANCE This retrospective study of a rare disease suggests that endoscopic resection of sinonasal melanoma offers an attractive, minimally invasive surgical option. In the hands of an experienced surgeon, an endoscopic approach yields survival and morbidity outcomes comparable to those of an open approach.

It is not just IMRT: Human papillomavirus related oropharynx squamous cell carcinoma is associated with better swallowing outcomes after definitive chemoradiotherapy

OBJECTIVES Long term swallowing dysfunction in patients with oropharynx squamous cell carcinoma (OPSCC) treated with concurrent chemoradiation (CRT) is declining. While the use of intensity modulated radiotherapy (IMRT) is commonly believed to be a potential cause, we hypothesize that the increasing incidence of human papillomavirus (HPV) related disease may also favorably impact this outcome. MATERIALS AND METHODS We reviewed 130 HPV+ and 17 HPV- patients with stage III-IV OPSCC treated exclusively with conventional 3-field radiotherapy with chemotherapy between 2002 and 2010. The rates of normal diet, limited diet (significant restrictions in the types of foods eaten, and/or requiring nutritional supplementation for weight maintenance) and feeding tube dependence (FTD) were compared between HPV+ and HPV- patients. Cox proportional hazards modeling were used to perform univariate analysis (UVA) to examine predictors of a combined endpoint of dietary limitation, which included limited diet and/or FTD. These outcomes were also compared to our previously reported cohort of OPSCC patients treated between 1989 and 2002 to assess changes in toxicity over time given the changing disease epidemiology, in the setting of identical treatment regimens. RESULTS With a median follow-up of 55 months, HPV+ patients more frequently had resumed a normal diet (87% vs. 65%) at last follow up and had lower rates of limited diet (9% vs. 18%) and FTD (4% vs. 18%) compared to HPV- patients (p=0.02). HPV status was the only significant predictor of reduced swallowing dysfunction on UVA (HR 0.19; p=0.008). When compared to our 1989-2002 cohort, patients treated between 2002 and 2010 had less FTD (7.5% vs. 34%, p<0.001) and dietary limitations (26% vs.46%, p<0.001) at 6 months post treatment. CONCLUSIONS HPV+ patients with OPSCC have reduced late swallowing dysfunction after chemoradiation compared to HPV- patients. The changing epidemiology of OPSCC may play a role in toxicity reduction in these patients, independent of the increasing use of IMRT.

Severe late dysphagia and cause of death after concurrent chemoradiation for larynx cancer in patients eligible for RTOG 91-11

PURPOSE The long-term results of RTOG 91-11 suggested increased deaths not attributed to larynx cancer after concomitant chemoradiotherapy (CRT) despite no apparent increase in late effects. Because the timing of events was not reported by RTOG 91-11, one possibility is that severe late dysphagia (SLD) develops beyond five years and leads to unreported treatment-related deaths. Here we explore the timing of SLD after CRT. METHODS Patients who would have met eligibility criteria for RTOG 91-11 and were treated with CRT between 1993 and 2013 were identified. Events occurring beyond 3months after treatment and suggestive of SLD were recorded including esophageal stricture dilations, hospital admissions for aspiration pneumonia or feeding-tube insertion. Feeding-tube dependence beyond one year was also considered SLD. The cumulative incidence of SLD and its components was quantified using Grays competing risk analysis with recurrence or death considered competing risks. RESULTS Eighty-four patients were included with a median follow-up of 43months. The 5-year overall survival was 70% (95% CI 58-80%). No death was directly a result of treatment-induced late dysphagia. The 5-year incidence of SLD was 26.5%. While 15 of 18 (83%) first stricture dilations occurred within 5years after CRT, 3 of 5 (60%) aspiration admissions and 5 of 8 late feeding tube insertions occurred beyond five years from CRT. CONCLUSIONS SLD is common after CRT for larynx cancer and can occur beyond 5years from the end of treatment, emphasizing the importance of survivorship follow-up. Despite the incidence of SLD, death related to dysphagia is uncommon.

Randomized phase III study of 2 cisplatin-based chemoradiation regimens in locally advanced head and neck squamous cell carcinoma: Impact of changing disease epidemiology on contemporary trial design

Chemoradiotherapy results in excellent outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC). This trial compared 2 chemoradiotherapy regimens.

Accelerated hyperfractionated radiation, concurrent paclitaxel/cisplatin chemotherapy and surgery for stage III non-small cell lung cancer.

The low surgical cure rate in patients with stage III non-small cell lung cancer has prompted an exploration of multimodality treatment strategies. Mature results are presented from a phase II trial of accelerated hyperfractionated radiation therapy, concurrent paclitaxel/cisplatin chemotherapy and surgery for these patients. Between 1994 and 1997, 45 patients with surgically demonstrated stage III non-small cell lung cancer underwent induction treatment with a 96 h continuous cisplatin infusion (20 mg/m(2) per day) and a 24 h infusion of paclitaxel (175 mg/m(2)) given concurrently with accelerated hyperfractionated radiation therapy (1.5 Gy twice daily) to a total dose of 30 Gy. Induction was completed in ten treatment (12 total) days. Surgical resection was scheduled 4 weeks later with a second identical course of chemoradiotherapy given 4-6 weeks post-operatively, to a total radiation dose of 60-63 Gy. Thirty-five patients had stage III(A) disease and ten had stage III(B) disease (eight with N(3) tumors). Induction toxicity included nausea in 89%, dysphagia in 89%, and neutropenia <1000/mm(3) in 84% which required hospitalization for fever in 40%. There were no toxic deaths during induction. About 40 of the 45 patients (89%) were operable and 32 (71%) were resectable for cure. A pathologic response was identified in 22 patients (49%); five patients (11%) had no residual disease. Fourteen patients (31%) were downstaged to mediastinal node negativity. With a median follow-up of 60 months, the Kaplan-Meier projected 5-year overall survival was 29%; locoregional control 79%; and distant metastatic disease control 38%. The projected 5-year survival for the 14 patients downstaged to mediastinal node negativity was 50%. For the 19 patients with residual ipsilateral mediastinal node involvement at surgery it was 32%. This short-course of paclitaxel and cisplatin chemotherapy and concurrent accelerated fractionation radiation is tolerable despite significant myelosuppression. Locoregional control is excellent and survival is better than historical expectations. Patients downstaged to mediastinal node negativity have a prognosis similar to those with de novo stage I(B) and II disease. Distant metastases are the major cause of treatment failure.

Modern Image-Guided Intensity-Modulated Radiotherapy for Oropharynx Cancer and Severe Late Toxic Effects: Implications for Clinical Trial Design

Importance Late toxic effects are common after definitive radiotherapy and chemoradiotherapy for oropharynx cancer and are considered a significant contributor to decreased quality of life for survivors. The incidence of severe late toxic effects may be reduced by modern narrow-margin image-guided intensity-modulated radiotherapy (IG-IMRT), current supportive care improvements, and the changing epidemiology of oropharynx cancer. Objective Assess the incidence of severe late toxic effects after modern definitive non-operative treatment for oropharynx cancer. Design, Setting, and Participants For this single-institution retrospective review, 156 patients with stage I-IVB squamous cell carcinoma of the oropharynx treated between April 2009 and February 2015 at a tertiary-referral academic multidisciplinary head and neck practice were recruited. Interventions Definitive narrow-margin IG-IMRT to a dose of 66 Gy (to convert milligray to rad, multiply by 0.1) or higher with or without concurrent cisplatin. Main Outcomes and Measures The primary outcome was the prospectively collected 2-year cumulative incidence of severe late toxic effects (Common Terminology Criteria for Adverse Events grade 3 or higher) occurring 3 months or more after radiotherapy. Toxic effect end points investigated included esophageal stricture requiring dilation, aspiration pneumonia hospitalization, vocal dysfunction, delayed feeding tube insertions, and osteoradionecrosis. Feeding tube dependence at 1 year was also considered a severe late toxic effect. Secondary outcomes collected include physician-reported grade 2 or higher neck fibrosis and xerostomia. The competing risks of recurrence and death were accounted for using the Gray method. Results One-hundred fifty-six patients (median [range] age, 58 [37-96] years) were identified; 130 patients (83%) were HPV positive. Concurrent cisplatin was delivered in 131 patients (84%) and 5 patients (3%) underwent an adjuvant neck dissection. The median (range) follow-up for survivors was 22 (4-73) months from diagnosis. The projected 2-year locoregional control was 93% (95% CI, 88.4%-97.6%) and overall survival was 88% (95% CI, 82.2%-94.0%). Thirty-eight patients (23%) required a feeding tube during treatment. The cumulative incidence of severe late toxic effects adjusted for competing risks at 2-year posttreatment was 2.3% (95% CI, 0%-5.6%). One patient required free-flap reconstruction for grade 3 osteoradionecrosis at 47 months. At 1 year, 2 patients (1%) experienced grade 2 neck fibrosis and 38 patients (23%) experienced grade 2 xerostomia. Conclusions and Relevance These results suggest that severe late toxic effects after modern definitive IG-IMRT, with or without cisplatin, for oropharynx cancer is likely uncommon. The importance of late toxic effect reduction in current and future investigational strategies, including clinical trials, should be considered.