Jeremy Setton

Intensity-Modulated Radiotherapy in the Treatment of Oropharyngeal Cancer: An Update of the Memorial Sloan-Kettering Cancer Center Experience

PURPOSE To update the Memorial Sloan-Kettering Cancer Centers experience with intensity-modulated radiotherapy (IMRT) in the treatment of oropharyngeal cancer (OPC). METHODS AND MATERIALS Between September 1998 and April 2009, 442 patients with histologically confirmed OPC underwent IMRT at our center. There were 379 men and 63 women with a median age of 57 years (range, 27-91). The disease was Stage I in 2%, Stage II in 4%, Stage III in 21%, and Stage IV in 73% of patients. The primary tumor subsite was tonsil in 50%, base of tongue in 46%, pharyngeal wall in 3%, and soft palate in 2%. The median prescription dose to the planning target volume of the gross tumor was 70 Gy for definitive (n = 412) cases and 66 Gy for postoperative cases (n = 30). A total 404 patients (91%) received chemotherapy, including 389 (88%) who received concurrent chemotherapy, the majority of which was platinum-based. RESULTS Median follow-up among surviving patients was 36.8 months (range, 3-135). The 3-year cumulative incidence of local failure, regional failure, and distant metastasis was 5.4%, 5.6%, and 12.5%, respectively. The 3-year OS rate was 84.9%. The incidence of late dysphagia and late xerostomia ≥Grade 2 was 11% and 29%, respectively. CONCLUSIONS Our results confirm the feasibility of IMRT in achieving excellent locoregional control and low rates of xerostomia. According to our knowledge, this study is the largest report of patients treated with IMRT for OPC.

18F-FDG PET/CT Metabolic Tumor Volume and Total Lesion Glycolysis Predict Outcome in Oropharyngeal Squamous Cell Carcinoma

Treatment of oropharyngeal squamous cell carcinoma with chemoradiotherapy can now accomplish excellent locoregional disease control, but patient overall survival (OS) remains limited by development of distant metastases (DM). We investigated the prognostic value of staging 18F-FDG PET/CT, beyond clinical risk factors, for predicting DM and OS in 176 patients after definitive chemoradiotherapy. Methods: The PET parameters maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were recorded. Univariate Cox regression was used to examine the prognostic value of these variables and clinical prognosticators for local treatment failure (LTF), OS, and DM. Multivariate analysis examined the effect of SUVmax, TLG, and MTV in the presence of other covariates. Kaplan–Meier curves were used to evaluate prognostic values of PET/CT parameters. Results: Primary tumors were distributed across all stages. Most patients underwent chemoradiotherapy only, and 11 also underwent tonsillectomy. On univariate analysis, primary tumor MTV was predictive of LTF (P = 0.005, hazard ratio [HR] = 2.4 for a doubling of MTV), DM and OS (P < 0.001 for both, HR = 1.9 and 1.8, respectively). The primary tumor TLG was associated with DM and OS (P < 0.001, HR = 1.6 and 1.7, respectively, for a doubling of TLG). The primary tumor SUVmax was associated with death (P = 0.029, HR = 1.1 for a 1-unit increase in standardized uptake value) but had no relationship with LTF or DM. In multivariate analysis, TLG and MTV remained associated with death after correcting for T stage (P = 0.0125 and 0.0324, respectively) whereas no relationship was seen between standardized uptake value and death after adjusting for T stage (P = 0.158). Conclusion: Parameters capturing the volume of 18F-FDG–positive disease (MTV or TLG) provide important prognostic information in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy and should be considered for risk stratification in this disease.

A multi-institution pooled analysis of gastrostomy tube dependence in patients with oropharyngeal cancer treated with definitive intensity-modulated radiotherapy

Severe swallowing dysfunction necessitating enteral support is a well known late sequela of nonsurgical therapy for oropharyngeal cancer, but its incidence after intensity‐modulated radiotherapy has not been quantified comprehensively outside of small single‐institution series.

Intensity-modulated radiation therapy in oropharyngeal carcinoma: effect of tumor volume on clinical outcomes.

PURPOSE To analyze the effect of primary gross tumor volume (pGTV) and nodal gross tumor volume (nGTV) on treatment outcomes in patients treated with definitive intensity-modulated radiation therapy (IMRT) for oropharyngeal cancer (OPC). METHODS AND MATERIALS Between September 1998 and April 2009, a total of 442 patients with squamous cell carcinoma of the oropharynx were treated with IMRT with curative intent at our center. Thirty patients treated postoperatively and 2 additional patients who started treatment more than 6 months after diagnosis were excluded. A total of 340 patients with restorable treatment plans were included in this present study. The majority of the patients underwent concurrent platinum-based chemotherapy. The pGTV and nGTV were calculated using the original clinical treatment plans. Cox proportional hazards models and log-rank tests were used to evaluate the correlation between tumor volumes and overall survival (OS), and competing risks analysis tools were used to evaluate the correlation between local failure (LF), regional failure (RF), distant metastatic failure (DMF) vs. tumor volumes with death as a competing risk. RESULTS Median follow-up among surviving patients was 34 months (range, 5-67). The 2-year cumulative incidence of LF, RF and DF in this cohort of patients was 6.1%, 5.2%, and 12.2%, respectively. The 2-year OS rate was 88.6%. Univariate analysis determined pGTV and T-stage correlated with LF (p < 0.0001 and p = 0.004, respectively), whereas nGTV was not associated with RF. On multivariate analysis, pGTV and N-stage were independent risk factors for overall survival (p = 0.0003 and p = 0.0073, respectively) and distant control (p = 0.0008 and p = 0.002, respectively). CONCLUSIONS In this cohort of patients with OPC treated with IMRT, pGTV was found to be associated with overall survival, local failure, and distant metastatic failure.

Long-term regional control in the observed neck following definitive chemoradiation for node-positive oropharyngeal squamous cell cancer

Traditionally, patients treated with chemoradiotherapy for node‐positive oropharyngeal squamous cell carcinoma (N+ OPSCC) have undergone a planned neck dissection (ND) after treatment. Recently, negative post‐treatment positron‐emission tomography (PET)/computed tomography (CT) imaging has been found to have a high negative predictive value for the presence of residual disease in the neck. Here, we present the first comprehensive analysis of a large, uniform cohort of N+ OPSCC patients achieving a PET/CT‐based complete response (CR) after chemoradiotherapy, and undergoing observation, rather than ND. From 2002 to 2009, 302 patients with N+ OPSCC treated with 70 Gy intensity‐modulated radiation therapy and concurrent chemotherapy underwent post‐treatment clinical assessment including PET/CT. CR was defined as no evidence of disease on clinical examination and post‐treatment PET/CT. ND was reserved for patients with

Estimate of the impact of FDG-avidity on the dose required for head and neck radiotherapy local control

Background and purpose Although FDG-avid tumors are recognized as a potential target for dose escalation, there is no clear basis for selecting a boost dose to counter this apparent radioresistance. Using a novel analysis method, based on the new concept of an outcome-equivalent dose, we estimate the extra dose required to equalize local control between FDG-avid and non-avid head and neck tumors. Materials and methods Based on a literature review, five reports of head and neck cancer (423 patients in total), along with an internal validation dataset from our institution (135 oropharynx patients), were used in this analysis. To compensate for the heterogeneity among multi-institutional patient cohorts and corresponding treatment techniques, local control data of the cohorts were fit to a single dose–response curve with a clinically representative steepness (γ50 = 2), thereby defining an ‘outcome-equivalent dose’ (OED) for each institutional cohort. Separate dose–response curves were then determined for the FDG-avid and FDG-non-avid patient cohorts, and the ratio of TD50 (tumor dose required for 50% of control) values between the high- and low-FDG-uptake groups (TD50,high/TD50,low) was estimated, resulting in an estimated metabolic dose-modifying factor (mDMF) due to FDG-avidity. Results For individual datasets, the estimated mDMFs were found to be in the range of 1.07–1.62, decreasing if the assumed slope (γ50) increased. Weighted logistic regression for the six datasets resulted in a mDMF of 1.19 [95% CI: 1.04–1.34] for a γ50 value of 2, which translates to a needed dose increase of about 1.5 Gy per unit increase in the maximum standardized uptake value (SUVm) of FDG-PET [95% CI: 0.3–2.7]. Assumptions of lower or higher γ50 values (1.5 or 2.5) resulted in slightly different mDMFs: 1.26 or 1.15, respectively. A validation analysis with seven additional datasets, based on relaxed criteria, was consistent with the estimated mDMF. Conclusions We introduced a novel outcome-equivalent dose analysis method to estimate the dose– response modifying effect of FDG uptake variation. To reach equal response rates, FDG-avid tumors are likely to require 10% to 30% more dose than FDG-non-avid tumors. These estimates provide a rational starting point for selecting IMRT boosts for FDG-avid tumors. However, independent tests and refinements of the estimated dose-modifying effect, using high-quality prospective clinical trial data, are needed.

Definitive treatment of metastatic nasopharyngeal carcinoma: Report of 5 cases with review of literature†

To review the treatment outcomes of patients presenting to Memorial Sloan‐Kettering Cancer Center with metastatic nasopharyngeal carcinoma.

Percutaneous endoscopic gastrostomy in oropharyngeal cancer patients treated with intensity-modulated radiotherapy with concurrent chemotherapy†

The clinical benefit of routine placement of prophylactic percutaneous endoscopic gastrostomy (pPEG) tubes was assessed in patients with oropharyngeal cancer (OPC) who are undergoing intensity‐modulated radiotherapy (IMRT) with concurrent chemotherapy.

Efficacy of concurrent cetuximab vs. 5-fluorouracil/carboplatin or high-dose cisplatin with intensity-modulated radiation therapy (IMRT) for locally-advanced head and neck cancer (LAHNSCC)

OBJECTIVES We previously reported inferior outcomes for locally-advanced head and neck squamous cell carcinoma (LAHNSCC) patients treated with concurrent cetuximab vs. high-dose cisplatin with intensity-modulated radiation therapy (IMRT). Prior to FDA approval of cetuximab for LAHNSCC, non-cisplatin eligible patients at our institution received 5-fluorouracil (5FU)/carboplatin. We sought to compare concurrent cetuximab vs. 5FU/carboplatin vs. high-dose cisplatin with IMRT for LAHNSCC. MATERIALS AND METHODS Retrospective review was performed for LAHNSCC patients treated at Memorial Sloan-Kettering Cancer Center from 11/02 to 04/08 with concurrent cetuximab (n=49), 5FU/carboplatin (n=52), or cisplatin (n=259) and IMRT. Overall survival (OS), locoregional failure (LRF), distant metastasis-free survival, and late toxicity were analyzed using univariate and multivariate analyses. OS analysis was confirmed by propensity score adjustment. RESULTS Treatment groups were similar with regard to primary tumor site, overall stage, and alcohol and tobacco history. Cetuximab and 5FU/carboplatin patients were older, with lower performance status, more comorbidities, higher T classification, and worse renal function. On multivariate analysis, compared with cisplatin and 5FU/carboplatin, cetuximab was associated with inferior 4-year OS (86.9% vs. 70.2% vs. 40.9%; P<.0001) and 4-year LRF (6.3% vs. 9.7% vs. 40.2%; P<.0001). Late toxicity was highest with 5FU/carboplatin (25.0%) vs. cisplatin (8.0%) vs. cetuximab (7.7%). CONCLUSIONS Although 5FU/carboplatin patients were sicker and experienced greater toxicity than cisplatin patients, no significant difference was found in all endpoints. In contrast, despite similar pretreatment characteristics, outcomes for cetuximab vs. 5FU/carboplatin were significantly worse. We feel that caution should be used with routine use of cetuximab in the management of LAHNSCC.

The relative prognostic utility of standardized uptake value, gross tumor volume, and metabolic tumor volume in oropharyngeal cancer patients treated with platinum based concurrent chemoradiation with a pre-treatment [18F] fluorodeoxyglucose positron emission tomography scan

OBJECTIVES This study compared the relative prognostic utility of the Gross Tumor Volume (GTV), maximum Standardized Uptake Value (SUVmax), and Metabolic Tumor Volume (MTV) in a uniform cohort of oropharyngeal squamous cell carcinoma (OPSCC) patients treated with platinum-based concurrent chemoradiation therapy (CCRT). METHODS AND MATERIALS One-hundred OPSCC with a pretreatment [(18)F] fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) were treated with CCRT. Kaplan-Meier curves and Cox proportional hazard models were generated. RESULTS When dichotomized by the median, a smaller MTV correlated with improved 5year locoregional control (LRC) (98.0% versus 87.0%, p=0.049), freedom from distant metastasis (FDM) (91.7% versus 65.0%, p=0.005), progression-free survival (PFS) (80.3% versus 56.7%, p=0.015), and overall survival (OS) (84.1% versus 57.8%, p=0.008), whereas a smaller GTV correlated with improved PFS (80.3% versus 57.4%, p=0.040) and OS (82.1% versus 60.1%, p=0.025). SUVmax failed to correlate with any outcome. On multivariate analysis, when adjusted for GTV, T-stage, and N-stage a smaller MTV remained independently correlated with improved FDM, PFS, and OS. GTV failed to reach significance in the multivariate model. CONCLUSIONS A smaller MTV correlates with improved LRC, FDM, PFS, and OS in OPSCC patients undergoing platinum-based CCRT.