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BACKGROUND Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been associated with improved overall survival (OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre-NAC cT stage) on the OS of patients with MIBC treated with NAC. METHODS The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2-4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability-weighted regression adjustment. RESULTS Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P

Background Human Papillomavirus oropharyngeal carcinoma (HPVOPC) has better progression free (PFS) and overall survival (OS) than non-HPVOPC. Standard-dose chemoradiotherapy (sdCRT) results in significant acute toxicity and late morbidity. We hypothesized that after induction chemotherapy (IC), reduced dose chemoradiation (rdCRT) would result in equivalent PFS and OS compared to sdCRT plus IC in HPVOPC and would reduce toxicity. Methods Patients with p16+, previously untreated, locally advanced HPVOPC and ≤20 pack years smoking history received 3 cycles of IC with docetaxel, cisplatin and fluorouracil (TPF). Clinical responders who were HPV positive by type-specific PCR were randomized 1:2 to sdCRT (7000 cGy) or rdCRT (5600 cGy) with weekly carboplatin. The endpoints of the study were 3 year PFS and OS. Results 23 patients were enrolled, 22 were evaluable for TPF toxicity and 20 were randomized, 8 to sdCRT and 12 to rdCRT. Sixteen (80%) were HPV 16+ and 4 (20%) were other high risk (HR) variants. Fourteen (70%) had high risk features: T4, N2c, or N3. Median follow up was 56 months (range 42–70). Three-year PFS/OS for sdCRT and rdCRT are 87.5% vs 83.3% (log-rank test p = 0.85), respectively. All 3 failures are locoregional within 4 months of completion of CRT; 2 were in HR variants (50%). Conclusions rdCRT after IC resulted in similar PFS/OS compared sdCRT. These data support Phase 3 clinical trials of radiation dose reduction after IC as a treatment strategy in HPVOPC. Molecular HPV with variant testing and smoking history are necessary for de-escalation trials.

Background Although radical cystectomy (RC) is a standard treatment for muscle-invasive bladder cancer (MIBC), for many patients the risks versus benefits of RC may favor other approaches. We sought to define the landscape of early postcystectomy mortality in the United States and identify patients at high risk using pretreatment variables. Methods We identified patients with MIBC (cT2-T4aN0M0) who underwent RC without perioperative chemotherapy within the National Cancer Database (2003–2012). Using multistate multivariable modeling, we calculated time spent in three health states: hospitalized, discharged, and death more than 90 days postcystectomy. Cross-validation was performed by geographic region. Time spent in each state was weighted by utility to determine 90-day quality-adjusted life days (QALDs). Results Among 7922 patients, 90-day mortality was 7.6% (8.0% for lower and 6.7% for higher volume hospitals). Increasing age, clinical T stage, Charlson Comorbidity Index, and lower volume were associated with higher 90-day mortality and were included in the model. Cross-validation revealed appropriate performance (C-statistics of 0.53–0.74; calibration slopes of 0.50–1.67). The model predicted 25% of patients had a 90-day mortality risk higher than 10%, and observed 90-day mortality in this group was 14.0% (95% CI = 12.5% to 15.6%). Mean quality-adjusted life days (QALDs) was 63 (range = 44–68). Conclusions RC is associated with relatively high early mortality risk. Pretreatment variables may identify patients at particularly high risk, which may inform clinical trial design, facilitate shared decision making, and enhance quality improvement initiatives.

Purpose Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with a favorable prognosis. Patients with pathologic residual disease (pRD) generally have poor outcomes. However, prognosis after radical cystectomy (RC) improves with ongoing survivorship. Our objective was to determine whether the difference in prognosis of patients with pCR and pRD changes over time. Materials and Methods We queried the National Cancer Database for patients who received NAC and RC for localized MIBC (cT2-T4aN0M0) between 1998 and 2012. pCR was defined as ≤Tis disease. Kaplan-Meier analysis was used to estimate conditional survival to 5 years given survival to 1, 2, 3, and 4 years post-RC. Cox proportional hazard modeling was used to estimate the effect of pRD vs. pCR on overall survival. Results The cohort comprised 1,553 patients (pCR: 314 and pRD: 1,239). With median follow-up 2.65 years (range 0.01–9.97), median survival was 2.5 years (95% confidence interval 2.2–2.9) and not reached for pRD and pCR, respectively. All patients had improved conditional survival with each additional year of survivorship. Patients with pCR had improved overall survival relative to those with pRD. The effect of pRD vs. pCR on conditional survival did not differ over time (P = 0.7). Conclusions MIBC patients with pCR after NAC have improved conditional survival relative to those with pRD post-RC. This survival advantage does not significantly change over time. These findings may inform patient counseling, surveillance intensity, and novel adjuvant approaches for patients with pRD.

491 Background: Achieving a pathologic complete response (pCR) with neoadjuvat chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been correlated with improved survival. Such findings have served as justification for using pCR as an intermediate endpoint for clinical trials and perpetuated the notion that NAC only benefits patients achieving a pCR. The impact of downstaging (pDS) on outcomes of patients with MIBC treated with NAC has been underexplored. Methods: The National Cancer Database (NCDB) was queried to identify patients with MIBC (cT2-4N0M) treated with platinum-based NAC. A multivariable Cox model including either pDS or pCR and adjusted for potential confounders was generated and c-indices were computed to evaluate whether the inclusion of pDS or pCR was more informative in predicting overall survival (OS). Results: Overall 2,010 patients from NCDB met inclusion criteria. The median follow-up for survivors was 36 months with a 5-year OS of 47% (95% CI 44, 50%). Overall, 694 (43.5%) patients achieved pDS; 139, 201, 291, 49 and 14 downstaged of 1, 2, 3, 4 and 5 categories, respectively. The 5-year OS rate for patients who achieved pDS was 70%. A pCR was achieved by 306 (15%) of the patients, the 5-year OS rate in this group was 84%. In the NCDB, pDS and pCR emerged as predictors of OS: HR:0.36 (95% CI: 0.30,0.44, p

460 Background: Although RC is the standard treatment for MIBC, it is associated with non-negligible morbidity and mortality. Given the advanced age and prevalence of comorbidities in MIBC patients, many are suboptimal RC candidates. We sought to develop a prediction rule for determining high surgical risk using routinely available pre-surgical variables. Methods: We identified N=8,634 patients with MIBC (cT2-T4aN0M0) who underwent RC, without perioperative chemotherapy, within the National Cancer Database (2003-2012). Using multi-state modeling, we calculated time spent in 3 health states: hospitalized, discharged and death over 90 days post-RC. Predictors were selected in a stepwise manner. Cross validation was performed leaving one of 6 geographic regions out to assess model performance. Time spent in each state was weighted by utility (0=death, 1=full health) to determine 90d quality-adjusted survival (QAS) as a composite of morbidity and mortality. Results: Median age: 69y (IQR 62-78), mean length of stay: 10±12d, and 90d mortality: 654/8,634 (7.6%). Increasing age, cT stage, Charlson comorbidity index (CCI) and lower hospital RC volume were associated with greater 90d mortality (Table). C-statistics of 0.57-0.73 and calibration slopes of 0.54-1.37 (1=perfect) were sufficient across the regions. Our model predicted 25% of patients had a 90d mortality >10%; observed 90d mortality in this group was 14.0% (95% CI 12.5-15.5). Mean QAS was 63d (range 43-68). Conclusions: We developed a multi-state model to identify high post-RC risk that may ultimately help to identify patients for ‘prehabilitation’ strategies and/or inform standard definitions of ‘cystectomy ineligibility’ for clinical trials. [Table: see text]

520 Background: Achieving a pathologic complete response (pCR) with NAC for MIBC is associated with a favorable prognosis. Patients with pathologic residual disease (pRD) generally have poor outcomes. However, prognosis after radical cystectomy (RC) improves with ongoing survivorship. Whether the difference in prognosis of patients with pCR and pRD is sustained over time has not been explored. Methods: We queried the National Cancer Database for patients who received NAC and RC for clinically localized MIBC (cT2-T4aN0M0) between 2002-2010. We identified patients with pCR (15 RC/year: 61% vs. 49%). Patients with pCR had improved CS relative to those with pRD with survivorship up to 3 years, but the benefit associated with pCR becomes attenuated from 4 years post-RC (Table). Conclusions: MIBC patients with pRD after NAC have worse CS up to years 3 post-RC, but this difference diminishes after 4 years. These findings may inform patient counseling, surveillance intensity, and novel adjuvant approaches for patients with pRD, and are subject to confirmation with a forthcoming multivariable analysis. Probability of surviving to X years (95% CI). [Table: see text]

6069 Background: Locally advanced Human Papillomavirus (HPV) + oropharyngeal carcinoma (OPC) has a significantly better response, locoregional control and survival compared to non HPVOPC. Standard-dose chemoradiotherapy (sdCRT) results in significant side effects, leading to acute and life-threatening late morbidity. We studied whether reduced dose chemoradiation (rdCRT) after induction chemotherapy (IC) resulted in equivalent progression-free survival (PFS) compared to sdCRT + IC with decreased late morbidity. Methods: Patients with locally advanced OPC and < 20 pack years (py) smoking history were tested for p16 and then HPV by type-specific PCR. After 3 cycles of docetaxel, cisplatin and fluorouracil (TPF) IC all HPV+/p16+ subjects underwent clinical and radiographic evaluation. Clinical responders were randomized to either sdCRT (70Gy) or rdCRT (56Gy) with weekly carboplatin (AUC 1.5) at a 1:2 ratio. The primary endpoint was 2 year PFS; the secondary endpoint was 2 year overall survival (OS). Toxicity, late morbidity and swallowing were monitored. Results: 23 patients were enrolled and 20 randomized, 8 to sdCRT and 12 to rdCRT; 2 were HPV- and 1 refused further therapy after IC and were not randomized. Median age was 56.5 yrs (range 36-78); 30% were African-American, 10% were Hispanic, 5% were female; 16 were HPV 16+ and 4 were other high risk (HR) variants; 60% never smoked, 25% were < 10 py, and 15% were 10-20 py; 70% had high risk features: T4, N2c, or N3. Clinical response to TPF was 100%; 70% had a clinical complete response. As of February 1, patients have been followed for a median of 37.5 months (range 21.7 – 49.5). 2 year PFS/OS for sdCRT and rdCRT are 87.5% vs 83.3% (log-rank test p = 0.85), respectively. All 3 failures were local or regional and 2 of 3 occurred in non HPV16 HR variants. Conclusions: HPV+ OPC patients who received rdCRT after TPF IC had similar PFS/OS compared to those receiving sdCRT. These results uphold the potential clinical benefit of radiation dose reduction as a treatment option with comparable survival to the standard radiation dose. A Phase III trial comparing IC plus rdCRT to sdCRT alone or with IC is warranted in this population. Non-HPV16 HR variants may have a worse outcome. Clinical trial information: NCT01706939.

To determine a relationship between sexual functioning and health state among survivors of stage I endometrial cancer, and to examine whether adjuvant intravaginal radiotherapy (IVRT) affects these measures compared to hysterectomy alone. Two hundred five survivors (>1 year from surgery) completed questionnaires containing the EuroQol (EQ5D) and the Female Sexual Function Index (FSFI). A total of 136 (66.3 %) underwent surgery alone, and 69 (33.7 %) received IVRT. Pearson correlation was used to correlate FSFI and EQ5D–Health State scores. Multivariable regression was performed to measure the impact of IVRT on sexual functioning and health state. A majority of patients (80 %) met criteria for sexual dysfunction by FSFI

Background: Sexual dysfunction is reported after chemotherapy and endocrine therapies. However, the prevalence and severity of sexual dysfunction in premenopausal women undergoing therapy for both local and metastatic disease is not well defined. This study was performed in order to understand the impact of contemporary breast cancer treatment on the prevalence and severity of sexual health in premenopausal women. Methods: We developed a survey that includes a previously validated questionnaire, the Female Sexual Function Index (FSFI), as well as an established measure of health-related quality of life (the EuroQol EQ-5D), and disease-specific items to characterize sexual dysfunction and its causes based on literature review and expert consultations. Anonymous administration of the surveys was conducted in outpatient clinic waiting areas of the Breast Cancer Center at Memorial Sloan-Kettering Cancer Center (MSKCC), under an IRB waiver of consent. Results: 372 consecutively approached premenopausal women with breast cancer of any stage, undergoing treatment were each queried once. The mean age was 47. 87% reported current or past hormonal treatment, and 86% reported current or past chemotherapy (76% adjuvant; 24% for metastatic disease). Sexual dysfunction attributed to breast cancer or its treatment, defined as an FSFI score =5/10). In a multivariate analysis, metastatic disease, development of amenorrhea from cancer treatment, antidepressant use and poorer overall health were each significantly associated with worse FSFI scores. Lower FSFI scores were also significantly associated with worse health-related quality of life. Conclusion: Sexual dysfunction is prevalent in premenopausal women treated for breast cancer and should be discussed with patients as a potential adverse effect of therapy. Assessment of sexual symptoms throughout treatment and beyond may facilitate the use of potential interventions such as lubricants, dilators, treatment modification and counseling. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD04-03.

Background: Sexual dysfunction is reported after chemotherapy and endocrine therapies, and causes a substantial burden on women with breast cancer. However, the prevalence and severity of sexual dysfunction in women undergoing therapy for both local and metastatic disease is not well defined. Improved understanding of sexual dysfunction may facilitate enhanced treatment and interventions in patients with breast cancer undergoing active treatment, and in survivors of this disease.Methods: We developed a survey that includes a previously validated questionnaire, the female sexual function index (FSFI), as well as an established measure of health-related quality of life (the EuroQol EQ-5D), and disease-specific items to characterize sexual dysfunction and its causes based on literature review and expert consultations. Anonymous administration of the surveys was conducted in outpatient clinic waiting areas of the Breast Cancer Center at Memorial Sloan-Kettering Cancer Center (MSKCC) and two community centers, under an IRB waiver of consent.Results: During November 2008 through May 2009, 509 women undergoing treatment for breast cancer of all stages were each queried once. The mean age was 51 (range 26-91). 87% reported current or past hormonal treatment, and 82% reported current or past chemotherapy (76% adjuvant; 24% for metastatic disease). Sexual dysfunction attributed to breast cancer or its treatment, defined as an FSFI score =5/10). Patients attributed their sexual dysfunction to chemotherapy in 318/373 (85%) of cases; to hormonal therapy in 221/298 (74%) of cases; and to surgery in 331/442 (66%) of cases. Other reported contributors to sexual dysfunction include a new diagnosis of breast cancer by 81% of respondents, anxiety by 82% of respondents, and change in relationship with a partner by 55% of respondents.Conclusion: Sexual dysfunction is prevalent in women treated for breast cancer and should be discussed with patients as a potential adverse effect of therapy. Assessment of sexual symptoms throughout treatment and beyond may facilitate the use of potential interventions such as lubricants, dilators, treatment modification, topical estrogens, and counseling. Future work includes a longitudinal prospective trial to further characterize the etiologies of these symptoms and a randomized controlled trial to evaluate interventions for sexual dysfunction. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1056.