Paul B. Romesser

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.

Telomere homolog oligonucleotides induce apoptosis in malignant but not in normal lymphoid cells: Mechanism and therapeutic potential

Human B‐ or T‐cell lymphoma lines and primary murine lymphomas were treated with DNA oligonucleotides homologous to the telomere (TTAGGG repeat; “T‐oligo”), either alone or in combination with standard, widely‐used anticancer chemotherapeutic agents. T‐oligo induces cell cycle arrest and apoptosis in cultured human or murine B or T‐lymphoma cell lines and primary tumor cells, but exerts no detectable toxicity on normal human or murine primary lymphocytes. Exposure to T‐oligo is hypothesized to mimic exposure of the 3′ telomere repeat sequence, activating the ataxia telangiectasia mutated kinase, which phosphorylates downstream effectors such as p53, but effects are not dependent solely on functional p53. T‐oligo causes early S‐phase arrest and cooperates well with G2‐ or M‐phase‐specific anticancer agents; when combined at 1/10th of the conventional dose, vincristine and T‐oligo produce greater‐than‐additive killing of human or murine lymphoma cells (78% of cells undergoing apoptosis after 6 hr vs. 5% of control cells). In mice, 1/10th of the conventional dose of a standard combination of cyclophosphamide, adriamycin, vincristine and prednisone is twice as effective when used in combination with low dose T‐oligo. Thus, T‐oligo sensitizes tumors to traditional anticancer agents and represents a potentially important new addition to the therapeutic arsenal for aggressive lymphomas.

Proton beam radiation therapy results in significantly reduced toxicity compared with intensity-modulated radiation therapy for head and neck tumors that require ipsilateral radiation

BACKGROUND As proton beam radiation therapy (PBRT) may allow greater normal tissue sparing when compared with intensity-modulated radiation therapy (IMRT), we compared the dosimetry and treatment-related toxicities between patients treated to the ipsilateral head and neck with either PBRT or IMRT. METHODS Between 01/2011 and 03/2014, 41 consecutive patients underwent ipsilateral irradiation for major salivary gland cancer or cutaneous squamous cell carcinoma. The availability of PBRT, during this period, resulted in an immediate shift in practice from IMRT to PBRT, without any change in target delineation. Acute toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. RESULTS Twenty-three (56.1%) patients were treated with IMRT and 18 (43.9%) with PBRT. The groups were balanced in terms of baseline, treatment, and target volume characteristics. IMRT plans had a greater median maximum brainstem (29.7 Gy vs. 0.62 Gy (RBE), ​P < 0.001), maximum spinal cord (36.3 Gy vs. 1.88 Gy (RBE), ​P < 0.001), mean oral cavity (20.6 Gy vs. 0.94 Gy (RBE), ​P < 0.001), mean contralateral parotid (1.4 Gy vs. 0.0 Gy (RBE), P<0.001), and mean contralateral submandibular (4.1 Gy vs. 0.0 Gy (RBE), ​P < 0.001) dose when compared to PBRT plans. PBRT had significantly lower rates of grade 2 or greater acute dysgeusia (5.6% vs. 65.2%, P<0.001), mucositis (16.7% vs. 52.2%, P=0.019), and nausea (11.1% vs. 56.5%, P=0.003). CONCLUSIONS The unique properties of PBRT allow greater normal tissue sparing without sacrificing target coverage when irradiating the ipsilateral head and neck. This dosimetric advantage seemingly translates into lower rates of acute treatment-related toxicity.

Proton Beam Reirradiation for Recurrent Head and Neck Cancer: Multi-institutional Report on Feasibility and Early Outcomes

PURPOSE Reirradiation therapy (re-RT) is the only potentially curative treatment option for patients with locally recurrent head and neck cancer (HNC). Given the significant morbidity with head and neck re-RT, interest in proton beam radiation therapy (PBRT) has increased. We report the first multi-institutional clinical experience using curative-intent PBRT for re-RT in recurrent HNC. METHODS AND MATERIALS A retrospective analysis of ongoing prospective data registries from 2 hybrid community practice and academic proton centers was conducted. Patients with recurrent HNC who underwent at least 1 prior course of definitive-intent external beam radiation therapy (RT) were included. Acute and late toxicities were assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and the Radiation Therapy Oncology Group late radiation morbidity scoring system, respectively. The cumulative incidence of locoregional failure was calculated with death as a competing risk. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were calculated with the Kaplan-Meier method. RESULTS Ninety-two consecutive patients were treated with curative-intent re-RT with PBRT between 2011 and 2014. Median follow-up among surviving patients was 13.3 months and among all patients was 10.4 months. The median time between last RT and PBRT was 34.4 months. There were 76 patients with 1 prior RT course and 16 with 2 or more courses. The median PBRT dose was 60.6 Gy (relative biological effectiveness, [RBE]). Eighty-five percent of patients underwent prior HNC RT for an oropharynx primary, and 39% underwent salvage surgery before re-RT. The cumulative incidence of locoregional failure at 12 months, with death as a competing risk, was 25.1%. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were 84.0% and 65.2%, respectively. Acute toxicities of grade 3 or greater included mucositis (9.9%), dysphagia (9.1%), esophagitis (9.1%), and dermatitis (3.3%). There was 1 death during PBRT due to disease progression. Grade 3 or greater late skin and dysphagia toxicities were noted in 6 patients (8.7%) and 4 patients (7.1%), respectively. Two patients had grade 5 toxicity due to treatment-related bleeding. CONCLUSIONS Proton beam re-RT of the head and neck can provide effective tumor control with acceptable acute and late toxicity profiles likely because of the decreased dose to the surrounding normal, albeit previously irradiated, tissue, although longer follow-up is needed to confirm these findings.

Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer

Colorectal cancer (CRC) is a leading cause of death in the developed world, yet facile preclinical models that mimic the natural stages of CRC progression are lacking. Through the orthotopic engraftment of colon organoids we describe a broadly usable immunocompetent CRC model that recapitulates the entire adenoma–adenocarcinoma–metastasis axis in vivo. The engraftment procedure takes less than 5 minutes, shows efficient tumor engraftment in two-thirds of mice, and can be achieved using organoids derived from genetically engineered mouse models (GEMMs), wild-type organoids engineered ex vivo, or from patient-derived human CRC organoids. In this model, we describe the genotype and time-dependent progression of CRCs from adenocarcinoma (6 weeks), to local disseminated disease (11–12 weeks), and spontaneous metastasis (>20 weeks). Further, we use the system to show that loss of dysregulated Wnt signaling is critical for the progression of disseminated CRCs. Thus, our approach provides a fast and flexible means to produce tailored CRC mouse models for genetic studies and pre-clinical investigation.

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.

External beam radiotherapy with or without concurrent chemotherapy in advanced or recurrent non‐anaplastic non‐medullary thyroid cancer

To review clinical outcomes and toxicities in locally advanced differentiated thyroid cancer patients treated with external beam radiotherapy (EBRT) with or without concurrent chemotherapy (CCRT).

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.

Radiation Dose to the Brachial Plexus in Head-and-Neck Intensity-Modulated Radiation Therapy and Its Relationship to Tumor and Nodal Stage

PURPOSE The purpose of this retrospective study was to determine tumor factors contributing to brachial plexus (BP) dose in head-and-neck cancer (HNC) patients treated with intensity-modulated radiotherapy (IMRT) when the BP is routinely contoured as an organ at risk (OAR) for IMRT optimization. METHODS AND MATERIALS From 2004 to 2011, a total of 114 HNC patients underwent IMRT to a total dose of 69.96 Gy in 33 fractions, with the right and left BP prospectively contoured as separate OARs in 111 patients and the ipsilateral BP contoured in 3 patients (total, 225 BP). Staging category T4 and N2/3 disease were present in 34 (29.8%) and 74 (64.9%) patients, respectively. During IMRT optimization, the intent was to keep the maximum BP dose to ≤60 Gy, but prioritizing tumor coverage over achieving the BP constraints. BP dose parameters were compared with tumor and nodal stage. RESULTS With a median follow-up of 16.2 months, 43 (37.7%) patients had ≥24 months of follow-up with no brachial plexopathy reported. Mean BP volume was 8.2 ± 4.5 cm(3). Mean BP maximum dose was 58.1 ± 12.2 Gy, and BP mean dose was 42.2 ± 11.3 Gy. The BP maximum dose was ≤60, ≤66, and ≤70 Gy in 122 (54.2%), 185 (82.2%), and 203 (90.2%) BP, respectively. For oropharynx, hypopharynx, and larynx sites, the mean BP maximum dose was 58.4 Gy and 63.4 Gy in T0-3 and T4 disease, respectively (p = 0.002). Mean BP maximum dose with N0/1 and N2/3 disease was 52.8 Gy and 60.9 Gy, respectively (p < 0.0001). CONCLUSIONS In head-and-neck IMRT, dose constraints for the BP are difficult to achieve to ≤60 to 66 Gy with T4 disease of the larynx, hypopharynx, and oropharynx or N2/3 disease. The risk of brachial plexopathy is likely very small in HNC patients undergoing IMRT, although longer follow-up is required.

A prognostic volumetric threshold of gross tumor volume in head and neck cancer patients treated with radiotherapy

Objectives:To determine the prognostic utility of a volumetric threshold for gross tumor volume (GTV) of the primary and nodal disease when accounting for the TNM classification in head and neck cancer (HNC) patients treated with definitive radiotherapy (RT). Materials and Methods:From 2004 to 2011, 79 HNC patients were treated to a median dose of 70 Gy, using intensity-modulated RT in 78.5% and 3-dimensional conformal RT in 21.5% with 83.5% receiving concurrent chemotherapy. Primary (GTV-P) and nodal (GTV-N) GTVs were derived from computed tomography (CT)-based contours for RT planning, of which 89.7% were aided by positron emission tomography-computed tomography. Local (LC), nodal (NC), distant (DC) control, and overall survival (OS) were assessed using the Kaplan-Meier product-limit method. Results:With a median follow-up of 27.1 months GTV-P, threshold of <32.9 mL (mean value) compared with ≥32.9 mL, correlated with improved 2-year LC (96.2% vs. 63.9%, P<0.0001), NC (100% vs. 69.2%, P<0.0001), DC (87.9% vs. 64.2%, P=0.001), and OS (88.4% vs. 58.6%, P=0.001). GTV-P demonstrated its prognostic utility in multivariate analyses when adjusted for tumor category, cancer site, and chemotherapy regimen. Nodal GTV (mean, 34.0 mL) was not predictive of nodal control and survival. Conclusions:A volumetric threshold of the primary tumor may be used as an independent prognostic factor in patients with HNC undergoing definitive RT.