Ali Hosni

Conditional Risk of Relapse in Surveillance for Clinical Stage I Testicular Cancer

BACKGROUND Patients on surveillance for clinical stage I (CSI) testicular cancer are counseled regarding their baseline risk of relapse. The conditional risk of relapse (cRR), which provides prognostic information on patients who have survived for a period of time without relapse, have not been determined for CSI testicular cancer. OBJECTIVE To determine cRR in CSI testicular cancer. DESIGN, SETTING, AND PARTICIPANTS We reviewed 1239 patients with CSI testicular cancer managed with surveillance at a tertiary academic centre between 1980 and 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: cRR estimates were calculated using the Kaplan-Meier method. We stratified patients according to validated risk factors for relapse. We used linear regression to determine cRR trends over time. RESULTS AND LIMITATIONS At orchiectomy, the risk of relapse within 5 yr was 42.4%, 17.3%, 20.3%, and 12.2% among patients with high-risk nonseminomatous germ cell tumor (NSGCT), low-risk NSGCT, seminoma with tumor size ≥3cm, and seminoma with tumor size <3cm, respectively. However, for patients without relapse within the first 2 yr of follow-up, the corresponding risk of relapse within the next 5 yr in the groups was 0.0%, 1.0% (95% confidence interval [CI] 0.3-1.7%), 5.6% (95% CI 3.1-8.2%), and 3.9% (95% CI 1.4-6.4%). Over time, cRR decreased (p≤0.021) in all models. Limitations include changes to surveillance protocols over time and few late relapses. CONCLUSIONS After 2 yr, the risk of relapse on surveillance for CSI testicular cancer is very low. Consideration should be given to adapting surveillance protocols to individualized risk of relapse based on cRR as opposed to static protocols based on baseline factors. This strategy could reduce the intensity of follow-up for the majority of patients. PATIENT SUMMARY Our study is the first to provide data on the future risk of relapse during surveillance for clinical stage I testicular cancer, given a patient has been without relapse for a specified period of time.

Outcomes and prognostic factors for major salivary gland carcinoma following postoperative radiotherapy.

PURPOSE To report outcomes of postoperative radiotherapy (PORT) for major salivary gland carcinoma (SGC) and identify patients at high risk of distant metastases (DM). METHODS AND MATERIALS Patients with major SGC treated between 2000-2012 were identified. All patients underwent initial primary resection, with neck dissection (ND) therapeutically (if N+) or electively in high risk N0 patients. PORT was delivered using 3D-CRT or IMRT. Multivariable analysis (MVA) assessed predictors for DM, cause-specific (CSS) and overall survival. RESULTS Overall 304 patients were identified: 48% stage III-IVB, 22% lymphovascular invasion (LVI), 50% involved margins and 64% high risk pathology. ND was performed in 154 patients (51%). Adjuvant chemotherapy was used in 10 patients (3%). IMRT was delivered in 171 patients (56%) and 3D-CRT in 133 (44%). With a median follow-up of 82 months, the 5-(10-) year local, regional, distant control, CSS and OS were 96% (96%), 95% (94%), 80% (77%), 83% (82%) and 78% (75%), respectively. DM was the most frequent treatment failure (n=62). On MVA, stage III-IVB and LVI significantly correlated with DM, CSS and OS, while positive margins predicted DM and CSS, and high risk pathology predicted DM. No grade ⩾ 4 RTOG late toxicity was reported; 9 patients had grade 3, including osteoradionecrosis (n=4), neck fibrosis (n=3), trismus (n=1) and dysphagia (n=1). CONCLUSIONS Surgery and PORT with 3D-CRT/IMRT produced excellent long-term outcomes. Further research is required for patients with stage III-IVB, LVI, positive margins and high risk pathology to determine the incremental benefit of systemic therapy in management of SGC.

Radiotherapy Characteristics and Outcomes for Head and Neck Carcinoma of Unknown Primary vs T1 Base-of-Tongue Carcinoma

Importance Transoral robotic surgery- or transoral laser microsurgery-assisted lingual tonsillectomy may improve the identification rate of hidden base-of-tongue (BOT) carcinoma presenting as head or neck carcinoma of unknown primary (CUP) site. Objective To evaluate the potential impact of lingual tonsillectomy in CUP site by comparing differences in radiotherapy volumes, dosimetry, and clinical outcomes for CUP site and T1-category BOT carcinoma. Design, Setting, and Participants Retrospective study of 115 patients treated at a tertiary cancer center between January 1, 2005, and December 31, 2013, that included patients with BOT carcinoma (category T1N1-3M0) and CUP site (category T0N1-3M0) with known p16 status. Fifty-four patients with T1-category BOT carcinoma (50 [92.6%] p16-positive) were treated with definitive intensity-modulated radiotherapy (IMRT), including 34 (63%) who received concurrent chemotherapy. Sixty-one patients with CUP site (38 [62.3%] p16-positive) received definitive (42 [68.9%]) or postoperative (19 [31.1%]) IMRT, including 22 (36%) who received concurrent chemotherapy. Interventions Definitive or postoperative IMRT, with or without concurrent chemotherapy. Main Outcomes and Measures Characteristics of mucosal clinical target volume (CTV-T), nodal CTV, and organ-at-risk dosimetry; local, regional, and distant control; cause-specific and overall survival; and Radiation Therapy Oncology Group grade 3 or higher late toxic effects. Results Of 115 participants, 104 (90.4%) were male; mean (SD) age was 59 (10) years. High-dose CTV-T was prescribed in all 54 patients with BOT carcinoma and 23 (37.7%) with CUP site (effect size [Δ], 62%; 95% CI, 50%-74%). Low-dose CTV-T included mucosal pharyngeal sites outside the oropharynx in no patients with BOT carcinoma and 26 (42.6%) (95% CI, 30%-54%) with CUP site, with greater low-dose CTV-T volume in CUP site than BOT carcinoma (113 vs 84 cm3; Δ, 30 cm3; 95% CI, 10-49 cm3). Bilateral neck irradiation was used in 53 of 54 patients (98.1%) with BOT carcinoma and 46 of 61 (75.4%) with CUP site (Δ, 23%; 95% CI, 12% to 34%). Patients with BOT carcinoma received a higher maximum dose to the mandible (71 vs 67.2 Gy; Δ, 3.8 Gy; 95% CI, 1.6 to 6 Gy), with a nonsignificantly higher maximum dose (66.1 vs 62.8 Gy; 3.2 Gy; 95% CI, -0.1 to 6.5 Gy) and lower mean dose to the larynx (43.8 vs 47.1 Gy; 3.3 Gy; 95% CI, -0.3 to 6.9 Gy). There were no significant differences in local control, regional control, distant control, cause-specific survival, and overall survival between the BOT carcinoma and CUP site groups stratified by p16 status. Grade 3 Radiation Therapy Oncology Group late toxic effects occurred in 2 patients (3.3%) with CUP site (both neck fibrosis) and 5 (9.3%) with BOT carcinoma (2 neck fibrosis, 2 osteoradionecrosis, and 1 dysphagia). Conclusions and Relevance Intensity-modulated radiotherapy for CUP site or T1-category BOT carcinoma had similar clinical outcomes. Identifying hidden BOT primary carcinoma with novel approaches (eg, transoral robotic surgery and transoral laser microsurgery) may lead to changes in the radiotherapy target volume and dose prescription. Studies are needed to investigate the effect of these differences on quality of life and functional outcomes.

Dosimetric feasibility of ablative dose escalated focal monotherapy with MRI-guided high-dose-rate (HDR) brachytherapy for prostate cancer

PURPOSE To determine the dosimetric feasibility of dose-escalated MRI-guided high-dose-rate brachytherapy (HDR-BT) focal monotherapy for prostate cancer (PCa). METHODS In all patients, GTV was defined with mpMRI, and deformably registered onto post-catheter insertion planning MRI. PTV included the GTV plus 9mm craniocaudal and 5mm in every other direction. In discovery-cohort, plans were obtained for each PTV independently aiming to deliver ⩾16.5Gy/fraction (two fraction schedule) while respecting predefined organs-at-risk (OAR) constraints or halted when achieved equivalent single-dose plan (24Gy). Dosimetric results of original and focal HDR-BT plans were evaluated to develop a planning protocol for the validation-cohort. RESULTS In discovery-cohort (20-patients, 32-GTVs): PTV D95% ⩾16.5Gy could not be reached in a single plan (3%) and was accomplished (range 16.5-23.8Gy) in 15 GTVs (47%). Single-dose schedule was feasible in 16 (50%) plans. In the validation-cohort (10-patients, 10-GTVs, two separate implants each): plans met acceptable and ideal criteria in 100% and 43-100% respectively. Migration to single-dose treatment schedule was feasible in 7 implants (35%), without relaxing OARs constraints or increasing the dose (D100% and D35%) to mpMRI-normal prostate (p>0.05). CONCLUSION Focal ablative dose-escalated radiation is feasible with the proposed protocol. Prospective studies are warranted to determine the clinical outcomes.

Lymph node ratio relationship to regional failure and distant metastases in oral cavity cancer

BACKGROUND We aimed to investigate the impact of lymph node ratio (LNR, number of positive nodes/total number of excised nodes) on regional-only-failure, distant-only-failure and overall survival (OS) in oral squamous cell carcinoma (OSCC). METHODS Retrospective review of pN0-2 OSCC-patients (1994-2012) treated with curative-surgery with neck dissection±postoperative radiotherapy (PORT)±concurrent chemotherapy. LNR was subjected to multivariable analysis (MVA) of regional-only-failure, distant-only-failure and OS. RESULTS Overall 914 patients were identified; median follow-up: 51months (1-189); pN0: 482 (52.7%), pN1: 128 (14%), pN2a: 6 (0.7%); pN2b: 225 (24.6%); pN2c: 73 (8%); median number of dissected nodes: 36 (6-125); median number of pN+: 2 (1-49); median LNR for pN+ patients: 6%; extranodal extension: 187 (20.5%). Bilateral neck dissection: 368 (40.3%); PORT: 452 (49.5%); and concurrent chemotherapy: 80 (8.8%). High grade, lymphovascular invasion perineural invasion and pT3-4 were associated with high LNR. On MVA, LNR was associated with regional-only-failure (HR=1.06; 95%CI: 1.04-1.08; p<0.001), distant-only-failure (HR=1.03; 95%CI: 1.02-1.05; p=0.004) and lower OS (HR=1.03; 95%CI: 1.02-1.05; p<0.001). Similarly, in pN2-subgroup: LNR was associated with regional-only-failure (HR=1.04; 95%CI: 1.02-1.06; p<0.001), distant-only-failure (HR=1.03; 95%CI: 1.01-1.06; p=0.045) and lower OS (HR=1.03; 95%CI: 1.02-1.04; p<0.001). CONCLUSION High LNR is associated with higher regional-only-failure/distant-only-failure and lower OS. LNR should be assessed in future prospective trials for selection of adjuvant therapy.

Prevalence, prognosis, and treatment implications of retropharyngeal nodes in unknown primary head and neck carcinoma

OBJECTIVE (1) To estimate the prevalence of radiographically positive Retro-Pharyngeal Lymph Nodes (RPLN) in unknown primary carcinoma of the head and neck and (2) to determine the prognostic implications of radiographically positive RPLN and other radiographic features (3) to identify patients at low risk for retropharyngeal metastasis. MATERIALS AND METHODS The medical records of all 68 eligible patients treated at the Princess Margaret Cancer Centre between 2000 and 2014 were retrospectively reviewed for demographic, clinical, pathologic, and radiologic data. Radiologic data included: RPLN, extra capsular spread (ECS), neck staging and cystic/necrotic or matted neck nodes. LRR, DR, DFS and OS were estimated using the competing risk methods and the Kaplan-Meier method. RESULTS Seven patients had concerning RPLN (10.3%). Forty-four patients were p16 positive (65%). RPLN status did not have any effect on LRR, DFS, DR and OS. Radiological ECS and p16 (neg.) status were found to be significant predictors of LRR (p = 0.023; p = 0.014). Matted nodes, radiological ECS and p16 (neg.) status were found to be significant predictors of DFS (p = 0.012; p < 0.001; p = 0.014). Matted nodes and radiological ECS were found to be significant predictors of OS (p = 0.017; p = 0.0036). Only radiological ECS was found to be a significant predictor of distant recurrence (p = 0.0066). CONCLUSIONS 10% of CUP patients will harbor radiological positive RPLN. A large proportion of CUP patients are positive for p16. Radiologic features such as ECS and matted nodes can predict worse outcomes.

The ongoing challenge of large anal cancers: prospective long term outcomes of intensity-modulated radiation therapy with concurrent chemotherapy

Purpose Patterns of failure and long term outcomes were prospectively evaluated following tumor factors-stratified radiation dose for anal/perianal cancer. Methods Between 2008–2013, patients with anal/perianal squamous cell carcinoma were accrued to an institutional REB-approved prospective study. All patients were treated with image-guided intensity-modulated radiation therapy (IG-IMRT). Radiation dose selection (27–36 Gy for elective target, and 45–63 Gy for gross target) was based on tumor clinico-pathologic features. Chemotherapy regimen was 5-fluorouracil/mitomycin-C (weeks 1&5). Local [LF], regional failure [RF], distant metastasis [DM], overall- [OS], disease-free [DFS], colostomy-free survival [CFS] and late toxicity were analyzed. Results Overall, 101 patients were evaluated; median follow-up: 56.5 months; 49.5% male; 34.7% T3/4-category, and 35.6% N+. Median radiation dose was 63 Gy. The most common acute grade ≥3 toxicities were skin (41.6%) and hematological (30.7%). Five-year OS, DFS, CFS, LF, RF, DM rates were 83.4%, 75.7%, 74.7, 13.9%, 4.6% and 5% respectively. Five-year LF for patients with T1-2 and T3-4 disease were 0% and 39.2% respectively. All LF (n = 14, after 63 Gy, in tumors ≥5 cm) were in the high dose volume except one marginal to the high dose volume. All RF (n = 4) were within elective dose volume except one within the high dose volume. On multivariable analysis, T3/4-category predicted for poor DFS, CFS and OS. The overall late grade ≥3 toxicity was 36.2% (mainly anal [20%]). Conclusions Individualized radiation dose selection using IG-IMRT resulted in good long term outcomes. However, central failures remain a problem for locally advanced tumors even with high dose radiation (63 Gy/7weeks).

Distant Metastases Following Postoperative Intensity-Modulated Radiotherapy for Oral Cavity Squamous Cell Carcinoma

Importance Advances in surgical techniques, the advent of intensity-modulated radiotherapy (IMRT), and the use of concurrent chemotherapy in oral squamous cell carcinoma (OSCC) have led to improvement of locoregional control (LRC), but not distant control (DC). Moreover, the development of distant metastases (DM) in OSCC has a dismal prognosis. Objective To determine the characteristics and risk factors of DM following postoperative IMRT in OSCC, and to identify the clinicopathological features that could be associated with distant-only failure (DOF). Design, Setting, and Participants Retrospective study of 300 OSCC patients (192 [64%] men and 108 [36%] women) treated with surgery and postoperative IMRT between 2005-2012 in a tertiary cancer center. Interventions All patients underwent initial primary curative-intent resection with postoperative IMRT with or without concurrent chemotherapy based on predefined risk features. Main Outcomes and Measures Locoregional control, DC, overall survival (OS), and Radiation Therapy Oncology Group grade of 3 or higher late toxic effects. Multivariable analysis identified predictors for DM. Results Overall 300 patients were identified (histological grade 2-3 [G2-3], 285 [95%]; pT3-4, 121 [41%]; pN2-3, 141 [47%]). Positive resection margin was present in 64 of 300 (21%) patients and extracapsular extension in 89 of 281 (32%) neck dissections. Median IMRT dose was 66 Gy and concurrent chemotherapy was used in 73 patients (24%). Median follow-up was 41 months. The 5-year local, regional, and distant control and OS were 85%, 82%, 86%, and 69%, respectively. On multivariable analysis, pN2-3 (hazards ratio, 5.7; 95% CI, 2.2-14.7) and G2-3 (HR, 4.9; 95% CI, 2.8-8.9) were predictive of DM. Thirty-nine patients developed DM, of which 20 (51%) were DOF and 12 (31%) were oligometastatic (⩽5 lesions). The clinicopathological characteristics in DOF were similar to patients with DM subsequent to locoregional failure. In patients with G2-3, pN2-3, and extracapsullar extension (all together), the 5-year cumulative incidence of DOF was 22%. Conclusions and Relevance Surgery and postoperative IMRT with or without concurrent chemotherapy achieved encouraging outcomes. The clinicopathological characteristics of DOF and DM with locoregional failure were similar. Patients with G2-3, pN2-3, and extracapsullar extension (all together) have higher risk of DOF. Both pN2-3 and G2-3 were independent predictors of DM. Patients with these risk factors may be candidates for prospective clinical trials of intensified therapy or surveillance strategies.

Changes in prostate volume during neo-adjuvant hormone therapy and definitive radiotherapy.

e628 Background: Neo-adjuvant hormone therapy (NA-HT) produces profound changes in prostate vasculature and volume. There is little data available on how prostate volumes changes during radiotherapy (RT) after NA-HT. This is highly relevant in the context of adaptive RT and focal boosting. Methods: Eleven patients with intermediate- or high-risk prostate cancer, receiving 3 months NA-HT plus 60 Gy RT in 20 fractions, underwent four multiparametric MRI scans. These were performed before and after NA-HT, then during the third week of RT and 8 weeks after RT. The prostate was contoured on each scan by a radiation oncologist with experience in prostate MRI and reviewed by a second radiation oncologist. Statistical analysis was performed using Spearman correlation and the unpaired t-test with Welch’s correction. Results: One patient declined the post-treatment scan. NA-HT induced a dramatic mean volume reduction of 47%, range -27% to -64%. Volume changes during NA-HT inversely correlated with volume change dur...