Zachary S. Zumsteg

Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality.

BACKGROUND In vitro data and early clinical results suggest that metformin has desirable antineoplastic effects and has a theoretical benefit on castration-resistant prostate cancer (CRPC). OBJECTIVE To determine whether the use of metformin would be associated with improved clinical outcomes and a reduction in the development of CRPC. DESIGN, SETTING, AND PARTICIPANTS Data from 2901 consecutive patients (157 metformin, 162 diabetic non-metformin, and 2582 nondiabetic) with localized prostate cancer treated with external-beam radiation therapy from 1992 to 2008 were collected from a single institution in the United States. INTERVENTION Use of metformin in localized prostate cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Univariate and multivariate regression models utilizing k-sample, Fine and Gray, Cox regression, log-rank, and Kaplan-Meier methods to assess prostate-specific antigen-recurrence-free survival (PSA-RFS), distant metastases-free survival (DMFS), prostate cancer-specific mortality (PCSM), overall survival (OS), and development of CRPC. RESULTS AND LIMITATIONS With a median follow-up of 8.7 yr, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic patients for PCSM were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 0.001), respectively. Metformin use independently predicted (correcting for PSA, T stage, Gleason score, age, diabetic status, and androgen-deprivation therapy use) improvement in all outcomes compared with the diabetic non-metformin group; PSA-RFS (hazard ratio [HR]: 1.99 [1.24-3.18]; p=0.004), DMFS (adjusted HR: 3.68 [1.78-7.62]; p<0.001), and PCSM (HR: 5.15 [1.53-17.35]; p=0.008). Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83-119.89]; p=0.01). The retrospective study design was the primary limitation of the study. CONCLUSIONS To our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC in prostate cancer patients. Further validation of metformins potential benefits is warranted.

Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer.

To compare tumour control and toxicity outcomes with the use of high‐dose intensity‐modulated radiation therapy (IMRT) alone or brachytherapy combined with IMRT (combo‐RT) for patients with intermediate‐risk prostate cancer.

The Natural History and Predictors of Outcome Following Biochemical Relapse in the Dose Escalation Era for Prostate Cancer Patients Undergoing Definitive External Beam Radiotherapy

BACKGROUND The management of biochemical failure (BF) following external beam radiotherapy (EBRT) for prostate cancer is controversial, due to both the heterogeneous disease course following a BF and a lack of clinical trials in this setting. OBJECTIVE We sought to characterize the natural history and predictors of outcome for patients experiencing BF in a large cohort of men with localized prostate cancer undergoing definitive dose-escalated EBRT. DESIGN, SETTING, AND PARTICIPANTS This retrospective analysis included 2694 patients with localized prostate cancer treated with EBRT at a large academic center. Of these, 609 experienced BF, defined as prostate-specific antigen (PSA) nadir + 2 ng/ml. The median follow-up was 83 mo for all patients and 122 mo for BF patients. INTERVENTION(S) All patients received EBRT at doses of 75.6-86.4 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary objective of this study was to determine predictors of distant progression at the time of BF. Cox proportional hazards models were used in univariate and multivariate analyses of distant metastases (DM), and a competing risks method was used to analyze prostate cancer-specific mortality (PCSM). RESULTS AND LIMITATIONS From the date of BF, the median times to DM and PCSM mortality were 5.4 yr and 10.5 yr, respectively. Shorter posttreatment PSA doubling time, a higher initial clinical tumor stage, a higher pretreatment Gleason score, and a shorter interval from the end of radiotherapy to BF were independent predictors for clinical progression following BF. Patients with two of these risk factors had a significantly higher incidence of DM and PCSM following BF than those with zero or one risk factor. The main limitations of this study are its retrospective nature and heterogeneous salvage interventions. CONCLUSIONS Clinical and pathologic factors can help identify patients at high risk of clinical progression following BF. PATIENT SUMMARY In this report, we look at predictors of outcome for patients with prostate cancer recurrence, as determined by prostate-specific antigen (PSA) levels, following radiation treatment. We found that the approximate median times to distant metastasis and death from prostate cancer for patients in this situation were 5 yr and 10 yr, respectively. Furthermore, we found that patients with a rapid increase in PSA levels following treatment, a short time to PSA recurrence, invasion of extraprostatic organs, or a high Gleason score had worse outcomes.

Short-term androgen-deprivation therapy improves prostate cancer-specific mortality in intermediate-risk prostate cancer patients undergoing dose-escalated external beam radiation therapy.

PURPOSE We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. METHODS AND MATERIALS The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. RESULTS The median follow-up was 7.9 years. Despite being more likely to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. CONCLUSIONS Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.

Short-term androgen deprivation therapy for patients with intermediate-risk prostate cancer undergoing dose-escalated radiotherapy: the standard of care?

What is the best way to manage patients with intermediate-risk prostate cancer? One of the most controversial aspects of treatment is the role of short-term androgen deprivation therapy in combination with definitive radiotherapy. In two randomised trials of patients with mostly intermediate-risk prostate cancer, increased overall survival was reported when short-term androgen deprivation therapy was added to radiotherapy. However, radiation doses in these studies were far below the current standard of care. This limitation, in combination with the heterogeneous nature of the cancers classified as intermediate risk, has complicated the application of these trial results to modern clinical practice. In this Review, we discuss clinical evidence for and against use of short-term androgen deprivation therapy with dose-escalated radiotherapy for patients with intermediate-risk prostate cancer.

Very Early Salvage Radiotherapy Improves Distant Metastasis-Free Survival

Purpose: Early salvage radiotherapy following radical prostatectomy for prostate cancer is commonly advocated in place of adjuvant radiotherapy. We aimed to determine the optimal definition of early salvage radiotherapy. Materials and Methods: We performed a multi‐institutional retrospective study of 657 men who underwent salvage radiotherapy between 1986 and 2013. Two comparisons were made to determine the optimal definition of early salvage radiotherapy, including 1) the time from radical prostatectomy to salvage radiotherapy (less than 9, 9 to 21, 22 to 47 or greater than 48 months) and 2) the level of detectable pre‐salvage radiotherapy prostate specific antigen (0.01 to 0.2, greater than 0.2 to 0.5 or greater than 0.5 ng/ml). Outcomes included freedom from salvage androgen deprivation therapy, and biochemical relapse‐free, distant metastases‐free and prostate cancer specific survival. Results: Median followup was 9.8 years. Time from radical prostatectomy to salvage radiotherapy did not correlate with 10‐year biochemical relapse‐free survival rates (R2 = 0.18). Increasing pre‐salvage radiotherapy prostate specific antigen strongly correlated with biochemical relapse‐free survival (R2 = 0.91). Increasing detectable pre‐salvage radiotherapy prostate specific antigen (0.01 to 0.2, greater than 0.2 to 0.5 and greater than 0.5 ng/ml) predicted worse 10‐year biochemical relapse‐free survival (62%, 44% and 27%), freedom from salvage androgen deprivation therapy (77%, 66% and 49%), distant metastases‐free survival (86%, 79% and 66%, each p <0.001) and prostate cancer specific survival (93%, 89% and 80%, respectively, p = 0.001). On multivariable analysis early salvage radiotherapy (prostate specific antigen greater than 0.2 to 0.5 ng/ml) was associated with a twofold increase in biochemical failure, use of salvage androgen deprivation therapy and distant metastases compared to very early salvage radiotherapy (prostate specific antigen 0.01 to 0.2 ng/ml). Conclusions: The duration from radical prostatectomy to salvage radiotherapy is not independently prognostic for outcomes after salvage radiotherapy and it should not be used to define early salvage radiotherapy. Grouping all patients with pre‐salvage radiotherapy prostate specific antigen 0.5 ng/ml or less may be inadequate to define early salvage radiotherapy and it has a relevant impact on ongoing and future clinical trials.

Incidence of Oropharyngeal Cancer Among Elderly Patients in the United States.

Importance An escalating incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has been reported predominantly among middle-aged adults. However, HPV infection is believed to occur many years before cancer develops, and tissue studies suggest that HPV DNA is found in the majority of OPSCC diagnosed in patients 65 years or older. Objective To update the trends in OPSCC incidence using US cancer registry data, with an emphasis on age-specific trends. Design, Setting, and Participants Data from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2012) were queried to compare changes in incidence and survival trends in OPSCC with selected tobacco-related cancers (larynx, oral cavity, hypopharynx, lung) and an HPV-related cancer (anus). A total of 40 264 patients who received a diagnosis of OPSCC from 2000 to 2012 were included. Elderly patients were defined as those 65 years or older. Main Outcomes and Measures The annual percentage change in OPSCC incidence from 2000 to 2012, stratified according to age group. Results Among the 40 264 patients who received a diagnosis of OPSCC from 2000 to 2012, 13 313 (33.1%) were aged 65 years or older and 80.3% were male. Significant increases in the age-adjusted incidence of OPSCC were observed during the study period for both younger adults aged 45 to 64 years (annual percentage change [APC], 2.31; 95% CI, 1.76-2.86; P < .001) and patients 65 years or older (APC, 2.92; 95% CI, 2.32-3.51; P < .001). These changes were driven predominantly by base-of-tongue and tonsil cancers in men. Concomitantly, the incidence of tobacco-associated head and neck cancers decreased for elderly patients (larynx: APC, -1.54; 95% CI, -2.00 to -1.08; P < .001; oral cavity: APC, -1.23; 95% CI, -1.84 to -0.62; P = .001; hypopharynx: APC, -2.44; 95% CI, -3.01 to -1.86; P < .001), whereas the incidence of anal cancer significantly increased (APC, 4.42; 95% CI, 3.28 to 5.57; P < .001). Furthermore, improved overall and cause-specific survival over time were observed for both younger and elderly patients with OPSCC. Nevertheless, absolute cause-specific survival remained worse for elderly patients (3-year CSS, 60.8%; 95% CI, 59.6%-61.9%) in comparison with those aged 45 to 64 years (75.7%; 95% CI, 75.1%-76.4%; P < .001). Conclusions and Relevance The incidence of OPSCC is increasing among elderly patients in the United States, likely driven by HPV-associated cancers. Given the unique challenges related to treating elderly patients with OPSCC, their limited enrollment in clinical trials, and the aging US population, clinical studies investigating improved therapeutic strategies for elderly patients with HPV-positive OPSCC should be performed.

Taselisib (GDC-0032), a Potent β-Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating PIK3CA Alterations

Purpose: Activating PIK3CA genomic alterations are frequent in head and neck squamous cell carcinoma (HNSCC), and there is an association between phosphoinositide 3-kinase (PI3K) signaling and radioresistance. Hence, we investigated the therapeutic efficacy of inhibiting PI3K with GDC-0032, a PI3K inhibitor with potent activity against p110α, in combination with radiation in HNSCC. Experimental Design: The efficacy of GDC-0032 was assessed in vitro in 26 HNSCC cell lines with crystal violet proliferation assays, and changes in PI3K signaling were measured by Western blot analysis. Cytotoxicity and radiosensitization were assessed with Annexin V staining via flow cytometry and clonogenic survival assays, respectively. DNA damage repair was assessed with immunofluorescence for γH2AX foci, and cell cycle analysis was performed with flow cytometry. In vivo efficacy of GDC-0032 and radiation was assessed in xenografts implanted into nude mice. Results: GDC-0032 inhibited potently PI3K signaling and displayed greater antiproliferative activity in HNSCC cell lines with PIK3CA mutations or amplification, whereas cell lines with PTEN alterations were relatively resistant to its effects. Pretreatment with GDC-0032 radiosensitized PIK3CA-mutant HNSCC cells, enhanced radiation-induced apoptosis, impaired DNA damage repair, and prolonged G2–M arrest following irradiation. Furthermore, combined GDC-0032 and radiation was more effective than either treatment alone in vivo in subcutaneous xenograft models. Conclusions: GDC-0032 has increased potency in HNSCC cell lines harboring PIK3CA-activating aberrations. Further, combined GDC-0032 and radiotherapy was more efficacious than either treatment alone in PIK3CA-altered HNSCC in vitro and in vivo. This strategy warrants further clinical investigation. Clin Cancer Res; 22(8); 2009–19. ©2015 AACR.

Carotid sparing intensity-modulated radiation therapy achieves comparable locoregional control to conventional radiotherapy in T1-2N0 laryngeal carcinoma

BACKGROUND Although intensity-modulated radiotherapy (IMRT) is a standard of care for many head and neck cancers, its use for carotid-sparing (CS) therapy in early-stage laryngeal carcinoma is controversial. METHODS 330 consecutive patients with early-stage laryngeal carcinoma were treated from 1/1989 to 5/2011, including 282 conventional radiotherapy (CRT) and 48 CS-IMRT patients. The median follow-up was 43 (CS-IMRT) and 66 (CRT) months. RESULTS There was no difference in local failure rates comparing patients undergoing CS-IMRT with CRT, with 3-year local control rates of 88% vs. 89%, respectively (p=0.938). Using a 1cm circumferential margin, the average dose to the left and right carotid arteries was 48.3 and 47.9 Gy, respectively. 88% of locoregional recurrences involved the ipsilateral true vocal cord, including all local recurrences in the IMRT group. CONCLUSIONS These results warrant further prospective evaluation of CS-IMRT for early-stage glottic larynx cancer.

Patterns of Lymph Node Failure after Dose-escalated Radiotherapy: Implications for Extended Pelvic Lymph Node Coverage

BACKGROUND Clinical trials evaluating the benefit of pelvic radiotherapy (PRT) in the radiotherapeutic management of patients with higher-risk prostate cancer have limited the superior field border to the S1/S2 or L5/S1 interspace. However, imaging and surgical series have demonstrated a high frequency of prostatic lymph node (LN) drainage beyond these landmarks. OBJECTIVE To determine the patterns of radiographically defined abdominopelvic LN failures and their potential implications for PRT field design. DESIGN, SETTING, AND PARTICIPANTS During 1992-2008, 2694 patients with localized prostate cancer were treated with prostate/seminal vesicle-only radiotherapy without PRT. Some 156 patients had their first failure within the abdominopelvic LNs, of whom 60 had isolated failures within the pelvic LNs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS A radiologist reviewed all imaging and mapped each LN failure to a template consisting of 34 abdominopelvic LN stations. RESULTS AND LIMITATIONS The median follow-up was 8.9 yr. Of patients who experienced first recurrence in the pelvic LNs (n=60), the common iliac station was involved in 55% (n=33) of patients, including 10% (n=6) who had isolated common iliac failures. Use of a PRT field superior border of L5/S1 would fully cover only 42% of the first recurrences among these patients. Extending the field to cover the common iliac stations would increase coverage to 93% of recurrences. The presence of T3/T4 disease and omission of androgen-deprivation therapy both independently conferred an approximate fivefold increase in the likelihood of having a common iliac LN failure. Use of imaging as a surrogate for LN involvement is the primary study limitation. CONCLUSIONS Pelvic LN failures frequently occur superior to the commonly used L5/S1 landmark for PRT coverage, and use of ADT may be protective of more superior LN failures. The current RTOG 0924 trial is evaluating the benefit of PRT with extended superior coverage to L4/5 when possible, which, according to our data, should significantly improve the coverage of potential sites of failure. PATIENT SUMMARY We looked at lymph node recurrence patterns after external beam radiotherapy of the prostate in men who did not have their lymph nodes treated. We found that there was a high incidence of pelvic lymph node recurrences above the internal and external iliac lymph node regions. Therefore, the current field recommendation for pelvic lymph nodes that stops at the superior border of the internal and external iliac vessels provides inadequate coverage of common sites of cancer recurrence, namely the common iliac lymph nodes.