Freedom From Distant Metastasis Research Articles

Pretreatment metabolic tumor volume as a prognostic factor in HPV-associated oropharyngeal cancer in the context of AJCC 8th edition staging.

This study evaluates the prognostic significance of 18 F-fluorodeoxyglucose-positron emission tomography ([F-18]FDG-PET)-derived metabolic tumor volume (MTV) in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCCs) in the context of AJCC 8th edition staging. We performed a retrospective study of HPV-associated OPSCCs treated with postoperative or definitive radiation. The prognostic significance of pretreatment MTV for freedom from recurrence (FFR), freedom from distant metastasis (FFDM), and overall survival (OS) was determined using Kaplan-Meier analysis. Multivariate analysis (MVA) was performed using Cox regression. In this 153-patient cohort, stratifying by the optimum MTV (24 cm3 ) was prognostic for FFR (P = .0002), FFDM (P = .001), and OS (P < .0001). Metabolic tumor volume (MTV) was prognostic of FFR in AJCC 8th edition stage I/II (P = .03), and stage III patients (P = .04). On multivariate analysis only MTV was a significant factor for OS. Metabolic tumor volume (MTV) is a significant prognostic factor in HPV-associated OPSCCs, independent of AJCC 8th edition stage.

Cardiac dose is associated with immunosuppression and poor survival in locally advanced non-small cell lung cancer

PurposeStudies have associated increased radiation therapy (RT) heart dose with cardiac toxicity. Others have correlated RT-related immunosuppression with worsened survival. Given the large vascular volumes irradiated during locally advanced non-small cell lung cancer (LA-NSCLC) treatment, we hypothesized an association between increased heart dose and immunosuppression. MethodsWe identified 400 LA-NSCLC patients treated with definitive RT ± chemotherapy between 2001 and 2016. Absolute lymphocyte counts (ALC), absolute neutrophil counts (ANC), and neutrophil-to-lymphocyte ratio (NLR = ANC/ALC) were analyzed pre-RT, during RT, and post-RT. Multivariable analysis (MVA) was performed to correlate Clinical factors with both hematologic toxicity and overall survival. An upper tertile threshold to increase specificity of NLR was chosen to dichotomize continuous hematologic variables. ResultsMedian follow up was 17 months (range 0.2–174 months) in all patients and 46 months (range 0.2–161 months) in survivors. A total of 94% of patients had stage III disease and 77% received concurrent chemo radiation. Two-year overall survival (OS), freedom from local recurrence (FFLR), and freedom from distant metastases (FFDM) was 42%, 60% and 45%, respectively. Median survival was 18 months. On MVA for OS (n = 207), male gender (Hazard Ratio [HR] 1.7; 95% CI 1.2–2.3), RT alone (HR 2.1; 95% CI 1.9–4.0), the percentage of heart receiving ≥50 Gy (V50) (HR 1.02; 95% CI 1.01–1.03), and higher NLR at 4 months (HR 1.02, 95% CI 1.01–1.03) were associated with reduced OS. ALC nadir was not associated with treatment outcomes. NLR >10.5 was associated with decreased OS (p < 0.001) and decreased FFDM (p = 0.04). On MVA evaluating factors associated with hematological toxicity (n = 247), adjuvant chemotherapy (HR 2.6; 95% CI 1.3–5.0; p = 0.006), RT alone (HR 3.6; 95% CI 1.1–12; p = 0.04), and heart V50 >25% (HR 2.0; 95% CI 1.1–3.5; p = 0.02) were associated with a NLR >10.5 4 months post-RT. ConclusionRT related immunosuppression is associated with worse patient outcomes, and may represent a source of increased mortality beyond cardiac toxicity alone.

(P37) Radiation-Induced Immunosuppression in Locally Advanced Non-Small Cell Lung Cancer: Another Cardiac Toxicity?

Recent reports have associated increased radiation therapy (RT) dose to the heart with higher rates of cardiac toxicity. Other reports have correlated RT-related immunosuppression with worsened survival in patients with solid malignancies. Given the large vascularized volumes exposed to RT during locally advanced non-small cell lung cancer (LA-NSCLC) treatment, we hypothesized that there is an association between increased heart dose and immunosuppression. A total of 400 LA-NSCLC patients with follow up laboratory values treated at a single institution with definitive intent RT +/- chemotherapy between 2001-2016 were identified. Organs at risk were reviewed and re-contoured according to the RTOG 0617 cardiac secondary analysis atlas. Absolute lymphocyte counts (ALC), absolute neutrophil counts (ANC), and neutrophil to lymphocyte ratio (NLR = ANC/ALC) were analyzed pre-RT, during RT, and at 2 and 4 months post-RT start. Patient, tumor, treatment, and dosimetric factors were correlated with hematologic toxicity and treatment outcomes. An upper tertile threshold to increase specificity of NLR was chosen to dichotomize continuous hematologic variables and identify cutpoints for hematologic values as a predictor of mortality. The median follow up was 17 (range 0.2-174) months in all patients and 46 (range 0.2-161) months in survivors. Patients received a median dose of 66 Gy (range 50-75.25 Gy) in median 2 Gy (range 1.8-2.5 Gy) fractions delivered with IMRT in 41% of patients. The estimated median overall survival (OS) was 17.9 months and progression free survival (PFS) 12.8 months. The estimated 5 year freedom from local recurrence (FFLR) and freedom from distant metastasis (FFDM) were 49% and 34%, respectively. There were 331/363 (91%) cases of ≥ grade 3 lymphopenia and 129/362 (36%) ≥ grade 4 lymphopenia at the nadir. At 4 months after RT start (290 patients), the median ALC, ANC, and NLR were 600 cells/mm3 (range: 100-4600), 4700 cells/mm3 (range: 300-113,600), and 7.2 (range: 0.60-259), respectively. On multivariable analysis, male gender (Hazard Ration [HR] 1.66; 95% CI 1.20-2.29; p=0.02), RT alone (HR 2.08; 95% CI 1.9-3.96; p=0.026), heart V50 (HR 1.02; 95% CI 1.01-1.03; p<0.001), and higher NLR at 4 months (HR 1.015, 95% CI 1.005-1.025; p=0.002) were significantly associated with worse OS. An upper tertile cutpoint of NLR > 10.5 at 4 months post RT, was associated with decreased OS (p<0.001) and decreased FFDM (p=0.04). The median OS stratified by NLR > 10.5 and NLR ≤ 10.5 was 11 months and 24 months, respectively (p < 0.001). NLR > 10.5 was associated with worse FFDM (p=0.04) and was borderline for PFS (p=0.08). On multivariable analysis, CRT with adjuvant chemotherapy (HR 2.55; 95% CI 1.30-4.98; p=0.006), RT alone (HR 3.56; 95% CI 1.07-11.88; P=0.039), and heart V50 > 25% (HR 1.98; 95% CI 1.11-3.54; p=0.021) were associated with an NLR>10.5 at 4 months post-RT. Higher RT dose to the heart is associated with increased immunosuppression and worse tumor control, and may represent an additional actionable cause of increased mortality beyond cardiac toxicity alone.

Postoperative Radiation Effects on Lymphopenia, Neutrophil to Lymphocyte Ratio, and Clinical Outcomes in Palatine Tonsil Cancers

Radiation-induced lymphopenia and pretreatment neutrophil to lymphocyte ratio (NLR) have been associated with head and neck cancer relapse. We hypothesized unilateral neck radiation could reduce rates of iatrogenic immunosuppression, and posttreatment NLR may be a useful prognostic clinical biomarker. Patients with palatine tonsil squamous cell cancer treated with postoperative radiation therapy (RT) at a single institution from 1997-2013 were reviewed retrospectively for grade 3-4 (ALC < 500 cells/mm3) and grade 4 (ALC < 200 cells/mm3) lymphopenia. Acute lymphopenia was evaluated at 3 weeks, 6 weeks, and 9 weeks after start of RT (60-70Gy). Prolonged lymphopenia was evaluated at 6 months and 12 months post-RT. Neutrophil counts were analyzed to calculate NLR. Receiver operating characteristic (ROC) analysis was used to determine NLR thresholds which were predictive of clinical outcomes. Logistic regression was used to determine clinical and treatment-related predictors of lymphopenia and elevated NLR. Kaplan-Meier and Cox analyses were done to show the association of lymphopenia and elevated NLR with locoregional control (LRC), freedom from distant metastases (FFDM), and overall survival (OS). Out of 154 patients treated with postoperative RT, 99 patients had ALC recorded at least at baseline and within 1 year of starting RT. Patients receiving bilateral neck RT (n = 70) and unilateral neck RT (n = 29) were predominantly stage IVA (79% vs 93%, respectively), p16+ (90% vs 96%, respectively), and received concurrent chemotherapy (69% vs 86%, respectively). Acute grade 3-4 lymphopenia occurred in 79% of bilateral neck RT patients and 58% of unilateral neck RT patients, P=.03. Acute grade 4 lymphopenia occurred in 15% of bilateral neck RT patients and none of the unilateral neck RT patients, P=.04. There were no significant differences in late grade 3-4 (21% vs 5%) or grade 4 (3% vs 0%) lymphopenia. Unilateral neck RT protected against acute grade 3-4 lymphopenia (OR = 0.322, 95% confidence interval [CI] 0.113-0.920) and acute NLR > 11.875 (OR = 0.156, 95% CI 0.043-0.568), but not late lymphopenia or late elevated NLR in logistic regression. Lymphopenia at any timepoint and pre-RT NLR was not associated with LRC, FFDM, or OS. Acute NLR > 11.875 correlated with worse OS (HR = 4.403, 95% CI 1.177-16.475). Late NLR > 6.875 independently correlated with significantly worse FFDM (HR = 15.942, 95% CI 1.852-137.190) and OS (HR = 12.020, 95% CI 3.024-47.778). Unilateral neck radiation for tonsil cancer reduces rates of acute grade 3-4 lymphopenia. Elevated acute and late NLR may help identify postoperative palatine tonsil patients who are at higher risk of metastasizing and subsequent mortality.

Treatment outcomes and HPV characteristics for an institutional cohort of patients with anal cancer receiving concurrent chemotherapy and intensity-modulated radiation therapy.

BackgroundIntensity-modulated radiation therapy (IMRT) has been used to limit treatment-related toxicity for patients with anal squamous cell carcinoma (SCC). The treatment outcomes and HPV characteristics for a cohort of patients receiving definitive concurrent chemotherapy and IMRT are reported.Materials and methods52 patients with anal SCC were treated with IMRT and concurrent chemotherapy. Radiation was delivered sequentially to the pelvis and inguinal lymph nodes (45 Gy) and anal tumor (median dose, 54 Gy). Multiplex real-time PCR for 7 high-risk HPV subtypes (n = 22) and p16 immunohistochemistry (n = 21, rated on a 0, 1, and 2+ scale) were performed on available specimens. Survival was estimated using Kaplan-Meier analysis, and toxicities were recorded.ResultsMedian follow-up was 33 months. Three-year freedom from locoregional failure (FFLRF), freedom from distant metastasis (FFDM), freedom from colostomy (FFC), and overall survival (OS) were 94%, 85%, 91%, and 90%, respectively. Acute grade 2+ skin, GI, and GU toxicities occurred in 83%, 71%, and 19% of evaluable patients, respectively. The rates of late grade 2+ GI and GU toxicities for evaluable patients (n = 32) were 28% and 9%, respectively. Of patients with available pathology, 91% and 71% were positive for HPV and p16 (2+), respectively. HPV genotypes included 16 (n = 17), 33 (n = 2), 18 (n = 1), and 45 (n = 1). HPV and p16 status were associated on Chi-square analysis (p = 0.07). Neither HPV nor p16 status was significantly associated with any clinical outcome. For HPV+ patients, 3-year FFLRF, FFDM, FFC, and OS were 100%, 69%, 100%, and 88%, respectively.ConclusionsIn this patient cohort, disease control was excellent for anal SCC treated with definitive concurrent chemotherapy and IMRT, and treatment was well tolerated. HPV and p16 status were not prognostic for treatment outcomes which may be related to our small sample size.

Optimal timing of post-prostatectomy radiotherapy for prostate cancer with high-risk pathologic features: A multi-institutional analysis.

24 Background: The use of radical prostatectomy (RP) as initial treatment of high-risk/locally-advanced prostate cancer is increasing but patients (pts) with adverse pathologic features such as positive surgical margins or T3 disease have up to 70% recurrence risk. These high-risk pts may be managed with adjuvant radiotherapy (ART) or early salvage radiotherapy (ESRT). The optimal timing of post-operative radiotherapy is unclear. Methods: Individual data from 1566 consecutive pts with pT2N0M0/R1 or pT3N0M0/R0-1 disease who underwent post-prostatectomy ART or ESRT (1987-2013) at 10 academic centers were pooled. Post-irradiation freedom from biochemical failure (FFBF), freedom from distant metastases (FFDM), prostate-cancer specific survival (PCSS), and overall survival (OS) were compared using Kaplan-Meier and multivariate competing-risks regression (MVA) analyses. Propensity score (PS) matching was used to account for covariates potentially associated with treatment allocation. All outcomes were measured from the date of surgery to address lead time bias. Results: After PS-matching, median follow-up after surgery was 66 vs. 73 months for the ART and ESRT groups, respectively, and baseline characteristics were well-matched. ART was associated with higher FFBF (12-yr: 69% vs. 43%; log-rank P &lt; 0.0001), FFDM (12-yr: 95% vs. 85%; log-rank P = 0.03), PCSS (12-yr: 99% vs. 94%; log-rank P = 0.048), and OS (12-yr: 91% vs. 79%; log-rank P = 0.01). ART, lower Gleason score, lower T-stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on MVA for BF. Sensitivity analysis demonstrated that the decreased risk of BF associated with ART remained significant unless more than 56% of ART pts were cured by surgery alone. This threshold is greater than the estimated 12-yr FFBF of 46% after RP alone as determined by a contemporary nomogram. Conclusions: To the best of our knowledge, this represents the largest multi-institutional study to date comparing ART to ESRT. ART was associated with reduced biochemical recurrence, distant metastases, and death compared to ESRT for high-risk pts, pending prospective validation.

Single-Arm Phase 2 Study of Stereotactic Body Radiation Therapy (SBRT) Concurrent with Nelfinavir for Solid Tumor Oligometastases

Patients (pts) with oligometastases (≤5 lesion sites) treated with SBRT have demonstrated evidence of long-term disease-free survival despite the overall poor prognosis of metastatic disease. Nelfinavir is a HIV protease inhibitor that may potentially act as a radiosensitizer. We performed a Phase II study of nelfinavir concurrent with SBRT in pts with solid tumor oligometastases to determine 6-month (6mo) freedom from local progression (FFLP). Secondary endpoints include safety, overall survival (OS), freedom from distant metastasis (FFDM) and progression-free survival (PFS). Pts with ≤5 histologic confirmed metastatic lesions (≤ 5.0 cm or ≤250 cm3) of lung, liver, lymph nodes, or bone, and good performance status (ECOG ≤ 2) were eligible. Pts were given 1250 mg of nelfinavir twice daily for 7 days prior to and after a single dose of 15 Gy SBRT per lesion. Responses were evaluated based on RECIST 1.1 criteria. A total of 38 pts were accrued between January 2014 and December 2015. One withdrew consent and 37 were included in the analysis, with a median follow-up of 18 months (range 5-31.5 months). The median patient age was 65 (range 35-81 years), 62% were men, and 51% and 22% had prostate and sarcoma as primary histologies, respectively. The majority of pts had ≤3 lesion sites (54% had 1 lesion, 22% had 2, and 16% had 3), and had recurrence sites at bone (57%) or lung (24%). The 6 mo FFLP rate was 78.4% (95% CI: 61.4-88.5%). Among the 68 treated lesions, the 6mo FFLP rate by lesion was 76.5% (95% CI: 64.5-84.9%). There were a total of 3 deaths due to disease progression. The 18 mo rates of OS, FFDM, and PFS were 90.7% (95% CI: 73.8-96.9), 62.4% (95% CI: 43.9-76.3), 57.6% (95% CI: 39.7-72.0), respectively. The 6 mo FFLP rate for patients with prostate cancer was 100% compared to 63% for patients with sarcoma (P < 0.0003). There were 4 grade 3 adverse events that may have been related to treatment (e.g., absolute lymphocyte decrease, anxiety, nausea, and cough). SBRT can be delivered safely with nelfinavir. Overall 6 mo FFLP rate for the entire cohort was not significantly higher than historical controls, although this may be secondary to tumor histology, treated site, and lesion number. Prostate cancer patients had significantly improved clinical outcomes relative to sarcoma patients and thus one may hypothesize that certain histologies may require a higher SBRT dose for local control. Further research should be conducted into the optimum patient cohort to benefit from the concurrent use of radiosensitizers with SBRT.

Natural history of 'second' biochemical failure after salvage radiation therapy for prostate cancer: a multi-institution study.

To describe the natural history of prostate cancer in men who experience a second biochemical recurrence (BCR) after salvage radiotherapy (SRT) after prostatectomy. After undergoing SRT at one of two institutions between 1986 and 2013, 286 patients experienced a second BCR, defined as two rises in prostate-specific antigen (PSA) of ≥0.2ng/mL above nadir. Event rates for distant metastasis (DM) or freedom from DM (FFDM), castration-resistant prostate cancer (CRPC), prostate cancer-specific survival (PCSS), and overall survival (OS) were estimated using the Kaplan-Meier method. Cox regression was used for comparative analyses. At a median of 6.1years after second BCR, DM, CRPC, PCSS and OS rates were 41%, 27%, 83% and 73%, respectively. On multivariable analysis, interval to second BCR <1year (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.71-4.14; P < 0.001], Gleason score 8-10 (HR 1.65, 95% CI 1.07-2.54; P = 0.022), and concurrent ADT during SRT (HR 1.76, 95% CI 1.08-2.88; P = 0.024) were associated with FFDM, while PCSS was associated with interval to second BCR <1year (HR 3.00, 95% CI 1.69-5.32; P < 0.001) and concurrent ADT during SRT (HR 2.15, CI 1.13-4.08; P = 0.019). These risk factors were used to stratify patients into three groups, with 6-year FFDM rates of 71%, 59% and 33%, and PCSS rates of 89%, 79%, and 65%, respectively. Following second BCR after SRT, clinical progression is enriched in a subgroup of patients with prostate cancer, while others remain without DM for long intervals. Stratifying patients into risk groups using prognostic factors may aid counselling and future trial design.

Influence of neoadjuvant chemotherapy on prognosis of patients with synovial sarcoma

BackgroundThis study aimed to explore the clinical efficacy of neoadjuvant chemotherapy combined with surgery in primary synovial sarcoma of the limbs and trunk through retrospective analysis of patients with primary synovial sarcoma of the limbs and trunk treated by this treatment in our hospital.MethodsA total of 89 patients diagnosed with synovial sarcoma were enrolled in this study between January 2005 and December 2011 in PLA General Hospital. Most of the patients received neoadjuvant chemotherapy combined with operative treatment (84.3%), 10.1% of them received adjuvant chemotherapy combined with operative treatment, and only 5.6% received merely operative treatment. The influence on the prognosis of patients with synovial sarcoma was analyzed by the statistics overall survival (OS), progression-free survival (PFS), local control (LC), and freedom from distant metastasis (FFDM).ResultsThe median follow-up time was 68.6 months. The 5-year OS, 5-year PFS, 5-year LC, and 5-year FFDM of the patients were 80.2, 60.5, 78.8, and 80.8%, respectively. The OS of the patients with a tumor size >5 cm was lower (91.4 vs 73.1%, P < 0.05). Besides, the OS and FFDM of neoadjuvant chemotherapy were better than those of adjuvant chemotherapy (84.5 vs 55.6%, P = 0.015, and 83.8 vs 55.6%, P = 0.028, respectively). However, there was no significant difference in the LC and PFS.ConclusionsNeoadjuvant chemotherapy was beneficial for patients with synovial sarcoma, and it could improve survival time and control distant metastasis. Tumor size was an important factor influencing patients’ prognosis.

Results of a Single Institution Experience with Dose-Escalated Chemoradiation for Locally Advanced Unresectable Non-Small Cell Lung Cancer.

We determined factors associated with morbidity and outcomes of a series of non-small cell lung cancer (NSCLC) patients treated with dose-escalated chemoradiotherapy at the University of Pittsburgh Lung Cancer Program. The records of 170 stage III NSCLC patients treated with definitive intent were retrospectively reviewed. All patients received four-dimensional CT simulation scan and had respiratory gating if tumor movement exceeded 5 mm. Overall survival (OS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated using log-rank and Cox regression analysis. For the present series of patients, median follow-up was 36.6 months, median survival 27.4 months, and the 2- and 4-year OS was 56.0 and 30.7%, respectively. The 4-year LRC and FFDM were 43.9 and 40.7%, respectively. No benefit was associated with irradiation doses above 66 Gy in OS (p = 0.586), LRC (p = 0.440), or FFDM (p = 0.230). On univariate analysis, variables associated with worse survival included: clinical stage IIIB (p = 0.037), planning target volume (PTV) over 450 cc (p < 0.001), heart V30 over 40% (p = -0.048), and esophageal mean dose over 20% (p = 0.024), V5 (p = -0.015), and V60 (p = -0.011). On multivariable analysis, PTV above 450 cc (52.2 vs. 25.3 months, p < 0.001) and esophageal V60 >20% (43.8 vs. 21.3 months, p = -0.01) were associated with lower survival. Grade 2 or higher acute lung toxicity and esophagitis were detected in 9.5 and 59.7%, respectively of patients. Grade 2 or higher acute lung toxicity was reduced if lung V5 was ≤65 (7.4 vs. 23.8%, p = 0.03). Grade 2 or higher acute esophagitis was reduced if V60 ≤ 20% (62 vs. 81.3%, p = 0.018). The use of intensity-modulated radiation therapy was more frequent in stage IIIB compared to stage IIIA patients (56.5 vs. 39.5%, p = 0.048) and was associated with a higher lung V5 and V10. The outcomes of a program of dose-escalated chemoradiotherapy for unresectable stage IIIA and IIIB NSCLC patients were consistent with other studies and showed no benefit to radiation doses above 66 Gy. Furthermore, maintaining low esophageal V60 and lung V5 were associated with lower morbidity and mortality.

Men’s health supplement use and outcomes in men receiving definitive intensity-modulated radiation therapy for localized prostate cancer

Background: Approximately 50% of newly diagnosed cancer patients start taking dietary supplements. Men’s health supplements (MHSs), which we define as supplements that are specifically marketed with the terms men’s health and prostate health (or similar permutations), are often mislabeled as having potential anticancer benefits.Objective: We evaluated the effects of MHSs on patient outcomes and toxicities in patients who were undergoing definitive intensity-modulated radiation therapy (IMRT) for localized prostate cancer.Design: This retrospective analysis included patients who were being treated at a National Cancer Institute–designated comprehensive cancer center and consented to have information stored in a prospective database. MHSs were queried online. Outcome measures were freedom from biochemical failure (FFBF) (biochemical failure was defined with the use of the prostate-specific antigen nadir + 2-ng/mL definition), freedom from distant metastasis (FFDM), cancer-specific survival (CSS), and overall survival (OS) as well as toxicities. Kaplan-Meier analysis, log-rank tests, Fine and Gray competing-risk regression (to adjust for patient and lifestyle factors), and Cox models were used.Results: From 2001 to 2012, 2207 patients were treated with IMRT with a median dose of 78 Gy, and a median follow-up of 46 mo. Of these patients, 43% were low risk, 37% were intermediate risk, and 20% were high risk; 10% used MHSs. MHSs contained a median of 3 identifiable ingredients (range: 0–78 ingredients). Patients who were taking an MHS compared with those who were not had improved 5-y OS (97% compared with 92%, respectively; P = 0.01), but there were no differences in the FFBF (94% compared with 89%, respectively; P = 0.12), FFDM (96% compared with 97%, respectively; P = 0.32), or CSS (100% compared with 99%, respectively; P = 0.22). The unadjusted association between MHS use and improved OS was attenuated after adjustment for patient lifestyle factors and comorbidities. There was no difference in toxicities between the 2 groups (late-grade 3–4 genitourinary <3%; gastrointestinal <4%).Conclusion: The use of MHSs is not associated with outcomes or toxicities.

Long-term results of adjuvant versus early salvage postprostatectomy radiation: A large single-institutional experience

PurposeThe purpose of this study was to evaluate freedom from biochemical failure (FFBF), freedom from androgen deprivation therapy (FFADT), freedom from distant metastases (FFDM), and overall survival (OS) after adjuvant radiation therapy (ART) versus early salvage radiation therapy (ESRT) in men with prostate cancer and adverse pathologic features (pT3 and/or positive surgical margins). Methods and materialsOf 718 patients consecutively treated with postoperative radiation therapy (RT) for prostate cancer between 1992 and 2013, we retrospectively identified 171 men receiving ART and 230 receiving ESRT (RT delivered at a prostate-specific antigen level ≤0.5 ng/mL) who had adverse pathologic features. Postirradiation FFBF (BF was defined as prostate-specific antigen level rise to ≥0.2 ng/mL), FFADT, FFDM, and OS were compared using Kaplan-Meier and Cox regression methods. Propensity score (PS)-matching was performed to estimate treatment effects while accounting for covariates predicting treatment allocation. ResultsMedian follow-up was 7.4 and 8.0 years for patients treated with ART and ESRT, respectively. Ten-year FFBF (69% vs 56%, P = .003) and 10-year FFADT (88% vs 81%, P = .046) rates were higher after ART; however, FFDM and OS did not significantly differ. After PS-matching, ART was associated with improved FFBF (P < .0001), FFADT (P = .0001), and FFDM (P = .02). Findings were confirmed in multivariable analyses in unmatched and PS-matched cohorts. Sensitivity analyses showed that FFBF benefit associated with ART lost statistical significance only after 38% of ART patients were assumed to have been cured by surgery and excluded from the model. This corresponds to the upper bound of patients with adverse pathologic features who did not recur after observation in prior randomized trials. ConclusionsPostoperative RT confers excellent long-term cancer control. These results suggest ART may be associated with improved FFBF, FFADT, and FFDM, but comparable OS. Given the retrospective study design, these findings should be interpreted with caution. Optimal timing of postoperative RT further awaits results of ongoing trials.

Results of a Single-Institution Experience With Dose-Escalated Chemoradiation for Locally Advanced Unresectable Non-Small Cell Lung Cancer

Abstract: Background: We determined factors associated with morbidity and outcomes of a series of non-small cell lung cancer (NSCLC) patients treated with dose escalated chemoradiotherapy at the University of Pittsburgh Lung Cancer Program. Methods and Materials: The records of 170 stage III NSCLC patients treated with definitive intent were retrospectively reviewed. All patients received 4D-CT simulation scan and had respiratory gating if tumor movement exceeded 5 mm. Overall survival (OS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated using log rank and Cox regression analysis. Results: For the present series of patients, median follow-up was 36.6 months, median survival 27.4 months, and the 2- and 4-year (OS) was 56.0 and 30.7%, respectively. The 4-year local regional control (LRC) and freedom from distant metastases (FFDM) were 43.9% and 40.7%, respectively. No benefit was associated with irradiation doses above 66 Gy in overall survival (OS) (p=0.586), LRC (p=0.440), or FFDM (p=0.230). On univariate analysis, variables associated with worse survival included: clinical stage IIIB (p=0.037), PTV over 450 cc (p 20% (43.8 vs. 21.3 months, p-0.01) were associated with lower survival. Grade 2 or higher acute lung toxicity and esophagitis were detected in 9.5% and 59.7%, respectively of patients. Grade 2 or higher acute lung toxicity was reduced if lung V5 was < 65 (7.4% vs. 23.8%, p=0.03). Grade 2 or higher acute esophagitis was reduced if V60 < 20% (62% vs. 81.3%, p=0.018). The use of Intensity Modulated Radiation Therapy (IMRT) was more frequent in stage IIIB compared to stage IIIA patients (56.5% vs. 39.5%, p=0.048), and was associated with a higher lung V5 and V10. Conclusions: The outcomes of a program of dose escalated chemoradiotherapy for unresectable stage IIIA and IIB NSCLC patients were consistent with other studies and showed no benefit to radiation doses above 66 Gy. Furthermore, maintaining low esophageal V60 and lung V5 were associated with lower morbidity and mortality.

Irradiation for Regionally Only Recurrent, Never-Irradiated Oral Cavity Cancers

The outcomes of patients (pts) after salvage radiation therapy (RT) for neck only recurrences of oral cavity cancers (OCC) are not well characterized. Therefore, we seek to report the treatment results and prognostic factors of pts who received RT as part of their salvage treatment for neck only recurrent disease (rT0 rN1-3) of initially node negative (T1-2 N0) OCC without upfront adjuvant RT. The records of consecutive pts who received salvage RT as part of their treatment for neck only recurrent OCC (rOCC) at our institution from 1989-2008 were reviewed. The Kaplan-Meier method was for overall survival (OS), disease specific survival (DSS), freedom from neck/regional failure (FFRF) and freedom from distant metastasis (FFDM). The Cox proportional hazards regression model was used to examine prognostic factors in univariate (UVA) and multivariate analysis (MVA). Time to event was calculated from start of RT. Out of 123 pts with rOCC treated with salvage RT, 44 pts were identified with neck only rOCC and compromised the study cohort. The median time to neck only recurrence from primary diagnosis was 15 mo. (range: 2 to 211 mos). From start of salvage RT, median follow-up for living pts was 125 mo. (range: 8 to 310 mo) and 24 mo. for all pts (4 to 310 mo). Thirty-nine pts (89%) had salvage neck dissection followed by RT, while the remaining 5 pts received definitive RT. Three pts who underwent salvage neck dissection had grossly invasive recurrent neck disease (e.g. large neck mass invading surrounding soft tissue/skeletal muscle, salivary gland, jugular vein, etc.) resulting in positive soft tissue margins on the nodal specimen. Fifteen pts (34%) received chemotherapy as part of their salvage therapy including 3 pts treated with definitive RT. Recurrent N stage was rN1, rN2, and rN3 in 17 (39%), 25 (57%), 2 (4%) pts, respectively. The 5-year OS, DSS, FFRF and FFDM were 32%, 52%, 80%, and 73%, respectively. On MVA of the entire cohort, disease resulting in a positive soft tissue margin after salvage neck dissection was independently associated with worse OS (HR 6.17, P = 0.009) as was lack of salvage surgery (HR: 3.45, P = 0.022). Disease resulting in positive margins was also independently associated with worse DSS (HR: 6.52, P = 0.005) while greater rN-stage (rN2/N3 vs. rN1) was independently associated with worse FFRF (HR: 8.2, P = 0.045). On MVA of the surgical pts subset, only negative surgical margin was independently associated with improved OS (HR: 4.97, P = 0.02) and DSS (HR: 4.92, P = 0.021). Neck only rOCC is a difficult to treat disease with poor outcomes. Pts who are able to undergo salvage neck dissection with disease amenable to achieving negative surgical margins attain the best clinical outcomes. We advocate for appropriate risk stratified treatment of initial disease to improve outcomes.

Proton Beam Radiation for Head and Neck Cancers: A Single-Institution Report on Feasibility and Early Outcomes

Definitive radiation of the head and neck has become a mainstay for locally advanced head and neck malignancies. This combined with initial surgery and/or adjuvant chemotherapy yields significant morbidity to the patients both short term and long term. This is a review of our prospective registry database of head and neck patients treated with proton beam radiation at our hybrid community practice/academic proton center to highlight our initial experience with relative long term follow up. All patients in our study were treated with the uniform scanning proton beam technology via the IBA system. Standard fractionation schemes with or without chemotherapy were delivered with curative intent. Acute and late toxicities were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and the by the Radiation Therapy Oncology Group late radiation morbidity scoring system, respectively. The cumulative incidence of locoregional failure (LRF) was calculated with death as a competing risk. The actuarial freedom from distant metastases (FFDM) and overall survival (OS) rates were calculated with the Kaplan-Meier method. A total of 66 patients were analyzed from our prospective registry. We focused on the 36 de-novo patients as our 30 re-irradiation patients are in process in upcoming literature. The scope of our patient population included patients with malignancies of the paranasal sinuses, nasopharynx, oropharynx, hypopharynx, and major salivary gland. Squamous Cell Carcinoma was the predominant histology, but others were Mucoepidermoid Carcinoma, Adenoid Cystic Carcinoma, Undifferentiated Carcinomas and Esthesioneuroblastomas. The median follow up was 33 months (9 – 53). The 2 and 5 year OS rates were 83% and 75%, respectively. The 2 and 5 year FFDM rates were 92% and 80%, respectively. There was 17% and 25% 2 and 5 year LRF rate. The mean time to failure was 17 months post initial proton beam treatment. Acute grade 3+ toxicity rate was 30.5% (mainly skin, mucositis, odynophagia, dysphagia, and anorexia), while the long term grade 3+ toxicity rate was 6% (anorexia and dysphagia). Ten patients had feeding tubes at some point during the radiation therapy, but none remained on tube feedings beyond 6 months post proton radiation therapy. Proton beam radiation of the head and neck can provide excellent disease control along with great sparing of the OARs. Longer follow up is needed with a less heterogeneous population to validate this modality. In addition, with the advent of intensity modulated proton beam radiation, even better conformality of proton beam will hopefully improve the toxicity profiles of even the acute toxicities.

Local radiotherapy alone following neoadjuvant chemotherapy and surgery in combined clinical stage II and III breast cancer.

PurposeThe outcomes and recurrence patterns for patients with combined clinical stage II and III breast cancer treated with local but not regional radiotherapy after neoadjuvant chemotherapy (NAC) and surgery are poorly documented.MethodsWe performed a retrospective review of a prospectively collected database comprised of breast cancer patients who received NAC at our institution. 172 patients met the specified criteria of receiving NAC, surgery inclusive of axillary nodal dissection and post-operative local (but not regional) radiotherapy.ResultsOne hundred eleven patients (64.5 %) were of combined clinical stage II and 61 (35.5 %) stage III at diagnosis. 103 patients (59.9 %) were clinically node positive with 101 cN1. On post-NAC pathology 29 (16.9 %) patients had a complete response, 30 (17.6 %) were combined yp stage I, 104 (60.5 %) yp stage II and 9 (5.2 %) yp stage III. 77 (44.8 %) were node positive on post-NAC pathology, all ypN1. 52.3 % were treated with breast conservation. At a median follow up of 67 months, 56 patients experienced breast cancer recurrence and 47 had died with breast cancer the dominant cause. Actuarial 5 and 10 year estimated freedom from locoregional recurrence (FFLRR), freedom from distant metastases (FFDM), disease free (DFS) and overall survival (OS) were 90 and 83.5, 74.5 and 64, 69.5 and 56, 79.5 and 65 % respectively. The most common pattern of failure was distant alone (without local or regional failure). Regional failure as the only site of first failure occurred in just three patients but was a component of first failure in a further twelve. Predictive factors on multivariate analysis for FFLRR were clinical stage II and estrogen receptor positivity. Prognostic factors were ypN0 stage and estrogen receptor positive status.ConclusionsLocal radiotherapy alone may be reasonable for selected patients. Isolated distant recurrence is the dominant mode of failure for breast cancer patients who have received local radiotherapy without regional coverage following NAC.

Resected pN1 non-small cell lung cancer: recurrence patterns and nodal risk factors may suggest selection criteria for post-operative radiotherapy.

To describe the pattern of recurrence in resected pN1 non-small cell lung cancer (NSCLC) and to identify factors predicting an increased risk of locoregional recurrence (LR) or distant metastasis (DM) to define a selected population who may benefit from postoperative radiotherapy (PORT). 285 patients with resected pN1 NSCLC were identified. Patients with positive surgical margins, undergoing neoadjuvant treatment or PORT, were excluded. LR was defined as first event of recurrence at the surgical bed, ipsilateral hilum or mediastinum, and other sites were considered as DM. Kaplan-Meier actuarial estimates of overall survival (OS), progression-free survival (PFS), freedom from LR (FFLR) and freedom from DM (FFDM) in different subgroups were compared with the log-rank test. Multivariate analysis was calculated. 202 patients met the inclusion criteria, 24% received adjuvant chemotherapy. The median follow-up was 39months. The total number of recurrences was 118 (64.4%): 44 (24%) and 74 (40.4%) for LR and DM, respectively. Five-year OS and PFS rates were 39.2 and 33.3%, respectively. Extra capsular extension (ECE) (RR 2.10, p=0.01) and lymph nodal ratio (LNR) >0:15 (RR 1.68, p=0.015) were associated with a worse PFS. ECE and LNR >0.15 were significantly related to a worst FFLR (RR 3.04 and 4.42, respectively), and adenocarcinoma to an unfavorable FFDM (RR 1.97, p=0.013). Nodal factors as high LNR and ECE can predict an increased risk of worse FFLR and PFS. Prospective data on selected patients, treated with modern radiotherapy techniques, need to be collected to re-evaluate the role of radiotherapy.

Final Results of a Randomized Phase 2 Trial Investigating the Addition of Cetuximab to Induction Chemotherapy and Accelerated or Hyperfractionated Chemoradiation Therapy for Locoregionally Advanced Head and Neck Cancer: HPV-negative Subset Analysis

detection of recurrence were abstracted. Patients either received definitive RT alone (nZ38, 15.4%) or concurrent systemic therapy and RT (nZ209, 84.6%). Outcomes, including local control (LC), regional control (RC), locoregional control (LRC), freedom from distant metastases (FFDM), and overall survival (OS) were calculated according to Kaplan-Meier method from the end of RT. Patients received a 3-month posttreatment positron emission tomographic/computed tomographic (PET/CT) scan and were seen every 3 months in the first year, every 4 months in Year 2, and every 6 months in Years 3 to 5. Results: Median follow-up of all patients was 36 months. LC was achieved in 239 of 245 patients, with a 3-year LC rate of 97.8%. Of the 6 local failures, all were detected by direct visualization (nZ2) or flexible laryngoscopy (nZ4). Three-year RC was 95.3%, where patients with 5 nodes or level 4 lymph nodes present were more likely to suffer regional failure (P<.05). Of the 9 regional recurrences, 89% (nZ8) were found by symptoms or 3-month posttreatment PET/CT. Three-year LRC was 94%. Of the 13 patients that suffered a locoregional failure, 92% (nZ12) presented with either symptoms or persistent disease on 3-month posttreatment PET/CT. Three-year FFDM rate was 91.4%, with increased risk of metastases occurring in patients with a lymph node greater than 6 cm, bilateral lymphadenopathy, 5 or more nodes, or if a lymph node was present in level 4 (P<.05). Of the 21 patients who suffered distant recurrence, 71% (nZ15) were found due to symptoms or 3-month posttreatment imaging. Three-year OS was 91% for all patients. Late grade 3 toxicity occurred in 21 patients (9%), with 19 being grade 3 toxicities and 2 grade 4 toxicities. The majority of toxicity and/or failure occurred within the first 6 months (64%), with only 4 events beyond 2 years. Conclusion: HPV-associated oropharyngeal cancer treated with definitive RT has excellent outcomes. Of the few patients that suffered a local failure, all were identified with physical exam. Symptoms and/or 3-month posttreatment PET/CT identified 92% of locoregional failures and 71% of distant failures. Given these findings, if posttreatment of PET/CT is negative, no further imaging is warranted. Follow-up should include history and physical exam with direct visualization. Author Disclosure: J.M. Frakes: None. A.O. Naghavi: None. T. Strom: None. A.R. Giuliano: None. L.B. Harrison: None. A. Trotti: None. J.J. Caudell: None.

Risk Factors for Local, Regional, or Distant Recurrence in Human Papillomavirus–Positive Oropharyngeal Cancer

Human papillomavirus (HPV)-associated squamous cell carcinomas of the oropharynx are increasingly seen as a separate disease entity from smoking-associated oropharyngeal cancers, with a much higher likelihood of cure. The current American Joint Commission on Cancer (AJCC) staging system for HPV-positive oropharyngeal cancer is not prognostic for outcome. We evaluated a variety of potential prognostic factors in order to propose potential new components for a staging system. After gaining institutional review board approval, we queried an institutional database for patients with HPV or p16-positive nonmetastatic oropharyngeal cancers treated with definitive radiation therapy (RT), and 245 cases were identified. Patient, tumor, and treatment factors were abstracted from the charts. In addition, pretreatment imaging was reviewed, including computed tomography (CT) in 99.6%, positron emission tomography/CT in 94.3%, and magnetic resonance imaging in 7.3% to obtain precise size, location, number, and extent of primary and nodes. Outcomes, including local control (LC), regional control (RC), locoregional control (LRC), and freedom from distant metastases (FFDM) were calculated from the end of RT and estimated via Kaplan-Meier method. Comparisons were made via log-rank test. Median follow-up of patients alive at last contact was 36 months. All patients were treated with definitive RT alone (n=38, 15.4%) or concurrent systemic therapy and RT (n=209, 84.6%). LC was seen in 239 of 245 patients, for a 3-year LC rate of 97.8%. There were no statistically significant prognostic factors for local control, including tumor size or invasion of adjacent structures. RC was achieved in 235 of 245 patients (95.3% at 3 years). RC was less likely if there were 5 or more nodes (1-4 vs ≥5, P=.05), or if a lymph node was present in level 4 (level 3 or above vs level 4, P=.005). Distant metastases occurred in 21 patients, for a 3-year FFDM rate of 91.4%. Lower rates of FFDM were associated with a lymph node greater than 6 cm (P=.02), bilateral lymphadenopathy (unilateral vs bilateral, P=.034), 5 or more nodes (1-4 vs ≥5, P<.001), or if a lymph node was present in level 4 (level 3 or above vs level 4, P<.001). Outcomes for patients with HPV-associated oropharyngeal cancer treated with definitive RT are excellent. The increasing burden of adenopathy, either by size, number, or bilateral involvement, or location in level 4 portended a higher risk of regional failure or metastasis. These factors may provide a basis for altering staging.

Early salvage versus adjuvant post-prostatectomy radiation therapy: Long-term results of a large institutional experience.

99 Background: Randomized trials and consensus statements support consideration of adjuvant radiation therapy (ART) after radical prostatectomy (RP) for adverse pathologic features (pT3, positive margins), although its use remains low. Whether early salvage radiation therapy (ESRT) is as effective as ART remains unknown. The objective of this study was to compare outcomes after ART and ESRT. Methods: We performed a retrospective institutional analysis of 719 consecutive patients receiving post-RP RT from 1992 to 2013. ESRT was defined as RT for biochemical failure (BF) with post-RP PSA ≤ 0.5 ng/ml. All included ART and ESRT patients had adverse surgical pathologic features. Outcomes examined were freedom from BF (FFBF; rising PSA ≥ 0.2 ng/ml with subsequent confirmation), freedom from subsequent androgen deprivation therapy (FFADT), freedom from distant metastases (FFDM), and overall survival (OS). ART and ESRT were compared using multivariable analyses (MVA) with propensity score (PS) matching for pre-RP PSA, age at RT, Gleason score, pT-stage, and margin status. Results: 537 patients received salvage RT, of whom 195 received ESRT; 181 patients received ART. Median follow-up from RP was 7.0 and 8.1 years in the ART and ESRT cohorts, respectively. Median time to BF after RT was 4.4 and 4.7 years in the ART and ESRT cohorts, respectively. On MVA, ART was associated with improved 10-year FFBF (74 vs 60%, HR 0.36 [95% CI: 0.23-0.58], P &lt; 0.0001) and 10-yr FFADT (91 vs 83%, HR 0.37 [95% CI: 0.18-0.76], P = 0.007). There were no significant differences in FFDM (96 vs 92%, HR 0.58 [95% CI: 0.19-1.7], P = 0.3), and OS (98 vs 95%, HR 1.24 [95% CI: 0.4-3.89], P = 0.7). After PS matching, ART (n = 169) remained significantly associated with improved FFBF (p &lt; 0.0001) and FFADT (p = 0.01), compared to ESRT (n = 176). Conclusions: Post-prostatectomy RT confers excellent long-term prostate cancer control, a finding supported by the long follow-up in this series. ART is associated with improved FFBF and FFADT compared to ESRT, although there were no statistically significant differences in FFDM and OS. Optimal timing of postoperative RT further awaits the results of ongoing randomized trials.