Publications by authors named "Andrew Bayley"

112 Publications

Transitions in oral and gut microbiome of HPV+ oropharyngeal squamous cell carcinoma following definitive chemoradiotherapy (ROMA LA-OPSCC study).

Br J Cancer 2021 Mar 10. Epub 2021 Mar 10.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.

Background: Oral and gut microbiomes have emerged as potential biomarkers in cancer. We characterised the oral and gut microbiomes in a prospective observational cohort of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) patients and evaluated the impact of chemoradiotherapy (CRT).

Methods: Saliva, oropharyngeal swabs over the tumour site and stool were collected at baseline and post-CRT. 16S RNA and shotgun metagenomic sequencing were used to generate taxonomic profiles, including relative abundance (RA), bacterial density, α-diversity and β-diversity.

Results: A total of 132 samples from 22 patients were analysed. Baseline saliva and swabs had similar taxonomic composition (R = 0.006; p = 0.827). Oropharyngeal swabs and stool taxonomic composition varied significantly by stage, with increased oral RA of Fusobacterium nucleatum observed in stage III disease (p < 0.05). CRT significantly reduced the species richness and increased the RA of gut-associated taxa in oropharyngeal swabs (p < 0.05), while it had no effect in stool samples. These findings remained significant when adjusted by stage, smoking status and antibiotic use.

Conclusions: Baseline oral and gut microbiomes differ by stage in this HPV+ cohort. CRT caused a shift towards a gut-like microbiome composition in oropharyngeal swabs. Stage-specific features and the transitions in oral microbiome might have prognostic and therapeutic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-020-01253-1DOI Listing
March 2021

Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis.

Eur Urol 2021 Mar 5. Epub 2021 Mar 5.

University of Toronto, Department of Radiation Oncology, 149 College Street, Unit 504, Toronto, Ontario, M5T 1P5, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, 700 University Avenue, 7th floor, Toronto, Ontario, M5G 1Z5, Canada; TECHNA Institute, University Health Network, University of Toronto, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada. Electronic address:

Background: The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches.

Objective: We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT).

Design/setting/participants: Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible.

Interventions: All patients underwent [F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT.

Outcome Measurements/statistical Analysis: Primary endpoint was biochemical response (complete, i.e. biochemical 'no evidence of disease' [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon's two-stage design was employed (null and alternate hypotheses <5% and >20% response rate, respectively), with α and β of 0.1.

Results: Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed.

Conclusions: PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/- systemic agents can expand the curative therapeutic armamentarium for PCa.

Patient Summary: We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2021.02.031DOI Listing
March 2021

Prognostic value of clinical and radiologic extranodal extension and their role in the 8th edition TNM cN classification for HPV-negative oropharyngeal carcinoma.

Oral Oncol 2021 Mar 25;114:105167. Epub 2021 Jan 25.

Department of Radiation Oncology, The Princess Margaret Cancer Centre/University of Toronto, Canada; Department of Otolaryngology-Head & Neck Surgery, The Princess Margaret Cancer Centre/University of Toronto, Canada. Electronic address:

Background/objectives: We evaluate the performance between the TNM-8 versus TNM-7 cN-classification and explore the relative prognostic contribution of radiologic extranodal extension (rENE) for HPV-negative oropharyngeal cancer (HPV-OPC).

Materials/methods: All HPV- OPC treated with IMRT between 2005 and 2016 were included. cENE was defined as unambiguous "fixation" of a neck mass or "skin involvement" on clinical examination. rENE was recorded by re-reviewing pre-treatment CT/MR. Disease-free survival (DFS) stratified by cENE or rENE were compared. Multivariable analyses (MVA) calculated the adjusted hazard ratio (aHR) for the separate cENE and rENE attributes and their combination. A refined cN-category incorporating both cENE and rENE parameters was proposed. The performance of the revision was compared to TNM-8 and TNM-7.

Results: Of 361 HPV- OPC, 97 were cN0 and 264 were cN+ with 48 cENE+ and 72 rENE+ respectively. Median follow-up was 5.4 years. The 3-year DFS was lower in cENE+ vs cENE-negative (cENE-) (23% vs 45%; aHR = 1.68, p = 0.008) and rENE+ vs rENE-negative (rENE-) patients (29% vs 45%; aHR = 1.44, p = 0.037). The cENE+/rENE+ subset had the worse DFS vs cENE-/rENE+ or cENE-/rENE- (24%/37%/46%, p = 0.005). We propose a refined cN-category wherein any cENE-/rENE+ case is reclassified one N-stratum higher while any cENE+ case remains cN3b. The stage schema with the refined N-categorization outperformed TNM-8, and both outperformed TNM-7.

Conclusions: cENE and rENE are both prognostic but the cENE+/rENE+ subset has the worst outcome. The TNM-8 cN-categories improves outcome prediction compared to the TNM-7. Incorporation of rENE into TNM-8 cN-categories may further augment performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oraloncology.2020.105167DOI Listing
March 2021

Healthcare resource utilization following unilateral versus bilateral radiation therapy for oropharyngeal carcinoma.

Radiother Oncol 2021 Mar 29;156:95-101. Epub 2020 Nov 29.

Department of Otolaryngology-Head & Neck Surgery/Surgical Oncology, Princess Margaret Cancer Centre/University of Toronto, Canada.

Purpose: To describe differences in healthcare resource utilization between patients treated with bilateral vs. unilateral neck radiation therapy (RT) for lateralized oropharyngeal cancer.

Methods: A propensity score matching strategy was used to identify two otherwise clinically similar cohorts of tonsillar cancer patients treated with either bilateral or unilateral neck RT. Cohorts were matched based on similar propensity scores for age, sex, ECOG performance status, pack-year smoking history, cT-category, cN-category, HPV-status, and use of concurrent chemotherapy. Short term (from start of RT to 3 months following end of RT) resource utilization included: 1) outpatient supportive care visits, 2) hospital admission, and 3) interventions (feeding tube insertion and outpatient intravenous hydration). Long-term resource utilization included feeding tube dependency at 1-year.

Results: Among 559 patients with tonsillar cancer treated between 2004-2017, propensity score matching identified a unilateral neck RT cohort (n = 81) and bilateral neck RT cohort (n = 81) with similar clinical and treatment characteristics. Bilateral neck RT was associated with a higher likelihood of hospitalization (33% vs 12%, p < 0.01), outpatient IV hydration (33% vs 17%, p = 0.03), and feeding tube insertion (33% vs 10%, p < 0.001); a greater number of total days of hospitalization (110 vs 47 days, p < 0.01) and outpatient IV hydration (135 vs 72 days, p = 0.02); and higher total number of supportive clinic visits (1226 vs 1053 days, p = 0.04). In the long-term, bilateral RT was associated with higher rate of feeding tube dependency at 1-year (7% vs 0%, p < 0.001).

Conclusion: Bilateral RT for tonsillar cancer resulted in significant increase in health resource utilization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2020.11.028DOI Listing
March 2021

Prostate or bone? Comparing the efficacy of image guidance surrogates for pelvis and prostate radiotherapy using accumulated delivered dose.

J Med Imaging Radiat Sci 2021 03 1;52(1):14-21. Epub 2020 Nov 1.

Radiation Medicine Program, Princess Margaret Cancer Centre, Department of Radiation Oncology, University of Toronto, Toronto, Canada.

Introduction: This study assessed the impact of dosimetry to both the target and normal tissue when either bony anatomy (BA) or prostate (PRO) was used as surrogates for image guidance for pelvis and prostate radiotherapy using a dose accumulation process.

Methods: Thirty patients who were prescribed 50-54Gy to the pelvic lymph nodes (PLN) and 78Gy to the prostate/seminal vesicles were included. Daily acquired CBCTs were rigidly registered to the CT using BA and PRO to simulate two different treatment positions. The accumulated delivered dose (D) of PLN, prostate, bladder and rectum for each surrogate were compared with the planned dose. Deviation from the planned dose (ΔD) of >5% was considered clinically significant.

Results: Prostate was displaced from bony anatomy by > 5 mm in 96/755 fractions (12.7%). Deviation between the mean D and the planned dose for PLN and prostate was <2% when either BA or PRO was used. No significant deviation from planned dose was observed for bladder (p > 0.2). In contrary, D for rectum D was significantly greater than the planned dose when BA was used (Mean ΔD = 6%). When examining individual patient, deviation from the planned dose for rectum D was clinically significant for 18 patients for BA (Range: 5-21%) and only 8 patients for PRO (Range: 5-8%).

Conclusions: The use of either BA or PRO for image guidance could deliver dose to PLN and prostate with minimal deviation from the plan using existing PTV margins. However, deviation for rectum was greater when BA was used.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmir.2020.10.001DOI Listing
March 2021

Short-term and long-term unstimulated saliva flow following unilateral vs bilateral radiotherapy for oropharyngeal carcinoma.

Head Neck 2021 Feb 15;43(2):456-466. Epub 2020 Oct 15.

Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada.

Background: We aimed to compare unstimulated saliva flow using 3-minute modified Schirmer test (MST) following bilateral vs unilateral radiotherapy (RT) in oropharyngeal carcinoma (OPC).

Methods: We reviewed OPC patients treated with definitive intensity-modulated radiation therapy (IMRT) between 2011 and 2017. MST was measured at baseline, 1-/6-/12-/24-month post-RT. MST values were compared between bilateral-RT vs unilateral-RT groups. Multivariable logistic regression analysis (MVA) identified predictors of hyposalivation (MST < 25 mm).

Results: Total 498 bilateral-RT and 36 unilateral-RT patients were eligible. The MST values at 1-/6-/12-/24-month post-RT were all significantly reduced from baseline for the entire cohort. Baseline unilateral-RT and bilateral-RT MST values (in mm) were similar (P = .2), but much higher for unilateral-RT 1-month (mean: 19.1 vs 13.0, P = .03), 6-month (20.5 vs 9.3, P < .001), 12-month (20.1 vs 11.9, P < .01), and 24-month post-RT (22.2 vs 13.9, P = .04). MVA confirmed that unilateral RT reduced the likelihood of hyposalivation vs bilateral RT (OR 2.36, P = .006).

Conclusion: Unilateral RT reduces unstimulated salivary flow in OPC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hed.26496DOI Listing
February 2021

Non-operative management for oral cavity carcinoma: Definitive radiation therapy as a potential alternative treatment approach.

Radiother Oncol 2021 01 28;154:70-75. Epub 2020 Aug 28.

Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Canada. Electronic address:

Purpose: To determine the outcomes of oral cavity squamous cell cancer (OSCC) patients treated with non-surgical approach i.e. definitive intensity-modulated radiation therapy (IMRT).

Methods: All OSCC patients treated radically with IMRT (without primary surgery) between 2005-2014 were reviewed in a prospectively collected database. OSCC patients treated with definitive RT received concurrent chemotherapy except for early stage patients or those who declined or were unfit for chemotherapy. The 5-year local, and regional, distant control rates, disease-free, overall, and cancer-specific survival, and late toxicity were analyzed.

Results: Among 1316 OSCC patients treated with curative-intent; 108 patients (8%) received non-operative management due to: medical inoperability (n = 14, 13%), surgical unresectability (n = 8, 7%), patient declined surgery (n = 15, 14%), attempted preservation of oral structure/function in view of required extensive surgery (n = 53, 49%) or extensive oropharyngeal involvement (n = 18, 17%). Sixty-eight (63%) were cT3-4, 38 (35%) were cN2-3, and 38 (35%) received concurrent chemotherapy. With a median follow-up of 52 months, the 5-year local, regional, distant control rate, disease-free, overall, and cancer-specific survival were 78%, 92%, 90%, 42%, 50%, and 76% respectively. Patients with cN2-3 had higher rate of 5-year distant metastasis (24% vs 3%, p = 0.001), with detrimental impact on DFS (p = 0.03) and OS (p < 0.02) on multivariable analysis. Grade ≥ 3 late toxicity was reported in 9% of patients (most common: grade 3 osteoradionecrosis in 6%).

Conclusions: Non-operative management of OSCC resulted in a meaningful rate of locoregional control, and could be an alternative curative approach when primary surgery would be declined, unsuitable or unacceptably delayed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453211PMC
January 2021

Sexual satisfaction in nasopharyngeal carcinoma survivors: Rates and determinants.

Oral Oncol 2020 Jul 14;109:104865. Epub 2020 Jul 14.

Department of Radiation Oncology, Princess Margaret Cancer Centre / University of Toronto, Toronto, ON, Canada. Electronic address:

Objectives: Sexual health problems have been identified as an unmet need in head and neck cancer (HNC) survivors. In particular, little is known about such outcomes in survivors of nasopharyngeal cancer (NPC).

Materials And Methods: A cross-sectional study of NPC survivors with ≥4y follow-up was undertaken. Sexual satisfaction was assessed using the optional "I am satisfied with my sex life" item of the FACT-H&N. Other patient-reported outcomes measures were also captured including fatigue (FACIT-F), HNC symptom burden (MDASI-HN), emotional distress (HADS) and frontal function (FrSBE). Univariate and multivariate analyses were performed to determine factors influencing sexual satisfaction.

Results: The sexual satisfaction item was answered by 85/103 (83%) enrollees. Female (p < 0.001) and non-partnered (p = 0.0045) patients were more likely to abstain from answering. The distribution of responses were: "very much" (26%), "quite a bit" (21%), "somewhat" (20%), "a little bit" (13%) and "not at all" (20%). Sexual satisfaction was associated with multiple patient-reported measures on univariate analysis, including quality of life, fatigue, a priori selected HNC symptoms (pain, taste), emotional distress, frontal lobe function, body image and relationship strength. On multivariate analysis, only relationship strength and emotional distress remained significant. Sociodemographic factors (age, sex, marital status) and other selected orofacial toxicities were not significant.

Conclusions: Nearly half (47%) of our sample reported being in the higher satisfaction range. While reassuring in the context of comparative population level data, a number of factors including toxicity, psychological and social factors were associated with sexual satisfaction responses. Prospective evaluation of this unmet need is required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oraloncology.2020.104865DOI Listing
July 2020

Hypofractionated radiotherapy alone with 2.4 Gy per fraction for head and neck cancer during the COVID-19 pandemic: The Princess Margaret experience and proposal.

Cancer 2020 08 1;126(15):3426-3437. Epub 2020 Jun 1.

Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada.

Background: The objective of this study was to identify a subgroup of patients with head and neck squamous cell carcinoma (HNSCC) who might be suitable for hypofractionated radiotherapy (RT-hypo) during the COVID-19 pandemic.

Methods: HNSCC cases (oropharynx/larynx/hypopharynx) treated with definitive RT-hypo (60 Gy in 25 fractions over 5 weeks), moderately accelerated radiotherapy (RT-acc) alone (70 Gy in 35 fractions over 6 weeks), or concurrent chemoradiotherapy (CCRT) during 2005-2017 were included. Locoregional control (LRC) and distant control (DC) after RT-hypo, RT-acc, and CCRT were compared for various subgroups.

Results: The study identified 994 human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma cases (with 61, 254, and 679 receiving RT-hypo, RT-acc, and CCRT, respectively) and 1045 HPV- HNSCC cases (with 263, 451, and 331 receiving RT-hypo, RT-acc, and CCRT, respectively). The CCRT cohort had higher T/N categories, whereas the radiotherapy-alone patients were older. The median follow-up was 4.6 years. RT-hypo, RT-acc, and CCRT produced comparable 3-year LRC and DC for HPV+ T1-2N0-N2a disease (seventh edition of the TNM system [TNM-7]; LRC, 94%, 100%, and 94%; P = .769; DC, 94%, 100%, and 94%; P = .272), T1-T2N2b disease (LRC, 90%, 94%, and 97%; P = .445; DC, 100%, 96%, and 95%; P = .697), and T1-2N2c/T3N0-N2c disease (LRC, 89%, 93%, and 95%; P = .494; DC, 89%, 90%, and 87%; P = .838). Although LRC was also similar for T4/N3 disease (78%, 84%, and 88%; P = .677), DC was significantly lower with RT-hypo or RT-acc versus CCRT (67%, 65%, and 87%; P = .005). For HPV- HNSCC, 3-year LRC and DC were similar with RT-hypo, RT-acc, and CCRT in stages I and II (LRC, 85%, 89%, and 100%; P = .320; DC, 99%, 98%, and 100%; P = .446); however, RT-hypo and RT-acc had significantly lower LRC in stage III (76%, 69%, and 91%; P = .006), whereas DC rates were similar (92%, 85%, and 90%; P = .410). Lower LRC in stage III predominated in patients with laryngeal squamous cell carcinoma receiving RT-acc (62%) but not RT-hypo (80%) or CCRT (92%; RT-hypo vs CCRT: P = .270; RT-acc vs CCRT: P = .004). CCRT had numerically higher LRC in comparison with RT-hypo or RT-acc in stage IV (73%, 65%, and 66%; P = .336).

Conclusions: It is proposed that RT-hypo be considered in place of CCRT for HPV+ T1-T3N0-N2c (TNM-7) HNSCCs, HPV- T1-T2N0 HNSCCs, and select stage III HNSCCs during the COVID-19 outbreak.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300809PMC
August 2020

Tumor-targeted dose escalation for localized prostate cancer using MR-guided HDR brachytherapy (HDR) or integrated VMAT (IB-VMAT) boost: Dosimetry, toxicity and health related quality of life.

Radiother Oncol 2020 08 22;149:240-245. Epub 2020 May 22.

Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Canada.

Purpose: To report dosimetry, preliminary toxicity and health-related quality of life (HRQoL) outcomes of tumor-targeted dose-escalation delivered by integrated boost volumetric arc therapy (IB-VMAT) or MR-guided HDR brachytherapy (HDR) boost for prostate cancer.

Materials And Methods: Patients diagnosed with localized prostate cancer, with at least 1 identifiable intraprostatic lesion on multiparametric MRI (mpMRI) were enrolled in a prospective non-randomized phase II study. All patients received VMAT to the prostate alone (76 Gy in 38 fractions) plus a GTV boost: IB-VMAT (95 Gy in 38 fractions) or MR-guided HDR (10 Gy single fraction). GTV was delineated on mpMRI and deformably registered to planning CT scans. Comparative dosimetry using EQD2 assuming α/β 3 Gy was performed. Toxicity and health-related quality of life data (HRQoL) data were collected using CTCAE v.4.0, International Prostate Symptom Score (IPSS) and the Expanded Prostate Index Composite (EPIC).

Results: Forty patients received IB-VMAT and 40 HDR boost. Organs at risk and target minimal doses were comparable between the two arms. HDR achieved higher mean and maximal tumor doses (p < 0.05). Median follow-up was 31 months (range 25-48); Acute grade G2 genitourinary (GU) toxicity was 30% and 37.5% in IB-VMAT and HDR boost, while gastrointestinal (GI) toxicity was 7.5% and 10%, respectively. Three patients developed acute G3 events, two GU toxicity (one IB-VMAT and one HDR boost) and one GI (IB-VMAT). Late G2 GU toxicity was 25% and 17.5% in the IB-VMAT and HDR boost arm and G2 GI was 5% and 7.5%, respectively. Two patients, both on the IB-VMAT arm, developed late G3 toxicity: one GI and one GU. No statistically significant difference was found in HRQoL between radiotherapy techniques (p > 0.2). Urinary and bowel HRQoL domains in both groups declined significantly by week 6 of treatment in both arms (p < 0.05) and recovered baseline scores at 6 months.

Conclusion: Intraprostatic tumor dose escalation using IB-VMAT or MR-guided HDR boost achieved comparable OAR dosimetry, toxicity and HRQOL outcomes, but higher mean and maximal tumor dose were achieved with the HDR technique. Further follow-up will determine long-term outcomes including disease control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2020.05.029DOI Listing
August 2020

[F]DCFPyL PET-MRI/CT for unveiling a molecularly defined oligorecurrent prostate cancer state amenable for curative-intent ablative therapy: study protocol for a phase II trial.

BMJ Open 2020 04 22;10(4):e035959. Epub 2020 Apr 22.

Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada

Introduction: The oligometastatic (OM) disease hypothesis of an intermediate metastatic state with limited distant disease deposits amenable for curative therapies remains debatable. Over a third of prostate cancer (PCa) patients treated with radical prostatectomy and postoperative radiotherapy experience disease recurrence; these patients are considered incurable by current standards. Often the recurrence cannot be localised by conventional imaging (CT and bone scan). Combined anatomical imaging with CT and/or MR with positron emission tomography (PET) using a novel second-generation prostate-specific membrane antigen (PSMA) probe, [F]DCFPyL, is a promising imaging modality to unveil disease deposits in these patients. A new and earlier molecularly defined oligorecurrent (OR) state may be amenable to focal-targeted ablative curative-intent therapies, such as stereotactic ablative radiotherapy (SABR) or surgery, thereby significantly delaying or completely avoiding the need for palliative therapies in men with recurrent PCa after maximal local treatments.

Methods And Analysis: This ongoing single-institution phase II study will enrol up to 75 patients total, to include up to 37 patients with response-evaluable disease, who have rising prostate-specific antigen (range 0.4-3.0 ng/mL) following maximal local therapies with no evidence of disease on conventional imaging. These patients will undergo [F]DCFPyL PET-MR/CT imaging to detect disease deposits, which will then be treated with SABR or surgery. The primary endpoints are performance of [F]DCFPyL PET-MR/CT, and treatment response rates following SABR or surgery. Demographics and disease characteristics will be summarised and analysed descriptively. Response rates will be described with waterfall plots and proportions.

Ethics And Dissemination: Ethics approval was obtained from the institutional Research Ethics Board. All patients will provide written informed consent. [F]DCFPyL has approval from Health Canada. The results of the study will be disseminated by the principal investigator. Patients will not be identifiable as individuals in any publication or presentation of this study.

Trial Registration Numbers: NCT03160794.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2019-035959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204865PMC
April 2020

Impact of cumulative cisplatin dose and adjuvant chemotherapy in locally-advanced nasopharyngeal carcinoma treated with definitive chemoradiotherapy.

Oral Oncol 2020 06 6;105:104666. Epub 2020 Apr 6.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada. Electronic address:

Background: Both adjuvant chemotherapy and higher cumulative cisplatin dose (CDDP-D) given as part of multimodality therapy for locally-advanced nasopharyngeal carcinoma (LA-NPC) have improved survival in Asian series. We evaluated their impact in a contemporary single-institution Canadian cohort of LA-NPC.

Methods: Patients with EBV-related stage II-IV LA-NPC by 7th edition TNM (TNM-7) treated with IMRT plus high-dose CDDP followed by adjuvant chemotherapy with CDDP/Carboplatin - 5-FU (maximum total/adjuvant CDDP-D = 540/240 mg/m) between 2003 and 2016 were analyzed. 5-year overall survival (OS) and recurrence-free survival (RFS) were calculated and compared using log-rank test by stage, adjuvant chemotherapy (yes/no) and total CDDP-D (>300 vs ≤300 mg/m). Multivariable analysis (MVA) was performed to identify survival predictors.

Results: A total of 312 patients were evaluated: TNM-7 stage II/III/IV = 2%/51%/47%; T4 = 36%; N3 = 17%; adjuvant chemotherapy = 83% (79% 21% CDDP/carboplatin); median total/adjuvant CDDP-D = 380/160 mg/m; median follow-up 76 years (range 06-149). 5-year OS differed by stage II-III vs IV (95% vs 80%, p < 0.001) and by total CDDP-D >300 (n = 210) vs ≤300 (n = 102) mg/m (89% vs 83%, p = 0.02). Adjuvant chemotherapy and total CDDP-D impacted on 5-year OS in stage IV but not stage II-III. 5-year RFS was higher in stage IV patients with total CDDP-D >300 vs ≤300 mg/m (74% vs 59%, p = 0.03), with a trend seen in locoregional (LRC) (91% vs 80%, p = 0.05) but not distant control (DC) (78% vs 72%, p = 0.36).

Conclusions: Adjuvant chemotherapy and total CDDP-D >300 mg/m improved OS and RFS in stage IV but not stage II-III LA-NPC, mainly due to effect on LRC rather than DC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oraloncology.2020.104666DOI Listing
June 2020

Cannabis and Radiation Therapy: A Scoping Review of Human Clinical Trials.

J Med Imaging Radiat Sci 2020 06 3;51(2):342-349. Epub 2020 Apr 3.

Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.

Introduction: It is estimated that at least 20% of Canadian patients with cancer use cannabis to alleviate symptoms of their disease and/or cope with the side effects of their treatment. Most patients want to learn more about cannabis from their healthcare team, but most oncology professionals feel too uninformed to make recommendations. The purpose of this scoping review was to address this oncology professionals' knowledge gap, by summarizing the literature on evaluations of the benefits and harms of cannabis use before, during, or after radiation therapy (RT).

Methods And Materials: A literature search was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines, using multiple electronic databases and combinations of key terms. To be included, studies must address the use of cannabis in patients undergoing RT. In vitro and in vivo evaluations, reviews, and editorials were excluded. Eligible full text manuscripts were then subjected to a formal risk of bias assessment using the Cochrane RoB 2.0 or ROBINS-I frameworks.

Results: A total of 48 records were identified, and 8 articles were included after vetting. These 8 studies suggest that the use of cannabinoids may calm anxious patients about to start RT, reduce nausea and vomiting consistent with the contemporary standard of care, reduce the symptoms of relapse for patients with glioma, and provide symptom relief >3 years after head and neck RT but not during or immediately. Six of these studies contained a high risk of bias (eg lack of randomization, poor blinding, and subjective outcome assessments). Most studies reported mild episodes of drowsiness and dry mouth with Δtetrahydrocannabinol, but substantial rates of dizziness, fatigue, and disorientation were also seen. It is important to note that these studies did not measure the impact of long-term cannabis consumption.

Conclusions: The existing body of literature evaluating the use of cannabinoids by patients undergoing RT is very limited. Well-designed randomized controlled trials are urgently needed, which address the significant design flaws of previous studies and evaluate the impact of phytocannabinoids in patients undergoing RT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmir.2020.01.007DOI Listing
June 2020

Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial.

BMC Cancer 2020 Feb 14;20(1):125. Epub 2020 Feb 14.

Department of Radiation Oncology, London Health Sciences Centre, Western University, 800 Commissioners Rd. E, London, Ontario, N6A 5W9, Canada.

Background: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches.

Methods: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity.

Discussion: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials.

Trial Registration: Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-6607-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023689PMC
February 2020

Prognostic importance of radiologic extranodal extension in HPV-positive oropharyngeal carcinoma and its potential role in refining TNM-8 cN-classification.

Radiother Oncol 2020 03 8;144:13-22. Epub 2019 Nov 8.

Department of Neuroradiology and Head and Neck Imaging, Princess Margaret Cancer Centre/University of Toronto, Canada.

Purpose: This study examines outcome heterogeneity and potential to refine the TNM-8 cN-classification using radiologic extranodal extension (rENE) in a contemporary HPV-positive (HPV+) oropharyngeal carcinoma (OPC) cohort.

Methods: All HPV+ OPC treated with definitive IMRT from 2010-2015 were included. Pre-treatment CT/MR of cN+ cases were reviewed by a head-neck radiologist for rENE. Overall survival (OS) and disease-free survival (DFS) were compared between rENE-positive (rENE+) vs rENE-negative (rENE-). Multivariable analysis (MVA) for OS confirmed the prognostic value of rENE. Refined cN-classifications for new TNM staging proposals were evaluated against TNM-8 using established criteria.

Results: A total of 517 cN+ (rENE+: 97; rENE-: 420) and 41 cN0 cases were identified. The rENE+ proportion increased with rising N-category (N1/N2/N3: 11%/19%/84%, p < 0.001). Median follow-up was 5.1 years. Compared to rENE-, rENE+ patients had a lower 5-year OS (56% vs 85%) and DFS (46% vs 83%) overall, and in N1 (OS: 57% vs 89%; DFS: 51% vs 87%) and N2 subsets (OS: 45% and 76%; DFS: 33% vs 74%) (all p < 0.001). MVA confirmed the prognostic value of rENE for OS (HR = 3.86, p < 0.001) and DFS (HR = 3.89, p < 0.001). We proposed two new cN-classifications: Schema1 reclassified any N_rENE+ as New_N3; Schema2 reclassified N1_rENE+ as New_N2 and N2_rENE+ as New_N3. Stage incorporating either Schema1 (ranked 1st) or Schema2 (ranked 2nd) cN-categories outperformed TNM-8.

Conclusion: This study confirms that rENE is prognostically important and facilitates understanding of known outcome heterogeneity within TNM-8 in HPV+ OPC patients. rENE is a promising parameter to refine the TNM-8 cN-classifications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2019.10.011DOI Listing
March 2020

The Prevalence and Determinants of Return to Work in Nasopharyngeal Carcinoma Survivors.

Int J Radiat Oncol Biol Phys 2020 01 27;106(1):134-145. Epub 2019 Sep 27.

Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada.

Purpose: To assess the employment status in working-age survivors of nasopharyngeal carcinoma (NPC) and explore clinical, treatment, and sociodemographic factors that may facilitate or impede successful return to work (RTW).

Methods And Materials: This Canadian study was part of a larger cross-sectional study assessing late toxicities in 107 disease-free survivors of NPC who received curative-intent intensity modulated radiation therapy ≥4 years earlier. For this substudy, eligible participants were employed at diagnosis and were of working age (<65 years) at study enrollment. Patient-reported work status (modified Radiation Therapy Oncology Group Work Status Questionnaire), quality of life (Functional Assessment of Cancer Therapy-Head and Neck questionnaire), symptom burden (MD Anderson Symptom Inventory for head and neck cancer), anxiety and depression (Hospital Anxiety and Depression Scale), neurobehavioral functioning (Frontal Systems Behavior Scale), and neurocognitive function (Montreal Cognitive Assessment) were assessed. Univariable and multivariable logistic regression models were used to explore the impact of variables on RTW status.

Results: Among 73 eligible patients, the median age was 53 years (range, 32-64) and median time from intensity modulated radiation therapy completion was 7.3 years (range, 4.2-11.1). At enrollment, 45 (62%) were working, of whom 14 (31%) had reduced work hours from diagnosis by a median of 12 h/wk (range, 4-30). Overall, mean work hours decreased from 41.6 to 37.8 h/wk (P = .005). Currently employed (vs unemployed) patients were younger (P = .017) and reported better performance status (P = .013). They had higher quality of life (P = .044), lower symptom burden (P = .03), less significant change from their baseline neurobehavioral function (P = .008), and disability (P = .0025) or private health benefits (P = .035). Anxiety, depression, occupation type, income, and Montreal Cognitive Assessment score were not significantly associated with RTW in the univariable analysis. Age, change in baseline neurobehavioral function, and having private health benefits were all independent predictors of RTW.

Conclusions: The majority of long-term survivors of NPC do RTW, although almost one-third report working fewer hours. Prospective research is needed to better understand and facilitate successful RTW in survivors of NPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2019.09.008DOI Listing
January 2020

Treatment outcomes in oropharynx cancer patients who did not complete planned curative radiotherapy.

Oral Oncol 2019 10 11;97:124-130. Epub 2019 Sep 11.

Department of Radiation Oncology, University of Toronto, 106-150 College St, Toronto, ON M5S 3E2, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, 610 University Ave, Toronto, ON M5G 2M9, Canada. Electronic address:

Purpose: To evaluate outcomes in oropharyngeal cancer (OPC) patients who did not complete their planned curative radiation therapy (RT).

Methods: OPC Patients who received less than planned curative RT dose between 2002 and 2016 were identified for analysis. HPV status was assessed. Radiation dose was normalized for fractionation variations using biological effective doses assuming tumor α/β = 10 Gy [BED10]. Outcomes were compared using BED10. Multivariable and univariable analysis identified OS predictors.

Results: From a total of 80 patients who did not complete therapy, 64 patients were eligible for analysis. RT incompletion was due to: RT side effects (n = 23), patients' decision (n = 21), disease progression or metastases (n = 3), and other causes (n = 7). Median BED10 (Gy) was 56.2 for the HPV-positive and 58 for the HPV-negative. Three-year OS was 74% vs 13% (p < 0.001) for the HPV-positive (n = 29) and HPV-negative (n = 24), respectively. HPV-positive patients who received BED10 ≥55 had higher OS than those received BED10 <55 (94% vs 47%, p = 0.002) while no difference in OS by BED10 ≥55 vs <55 for the HPV-negative (12 vs 13%, p = NS). HPV-positive status was associated with a higher OS (HR 12.5, 95% CI, 4.54 to 33.3, p < 0.001). A total of 37 patients were available to estimate TD for local control assessment. TD (BED10) was estimated at 60.5 Gy for HPV-negative patients compared to 27.2 Gy for HPV-positive patients.

Conclusion: Overall, in patients with incomplete treatment, HPV-positive OPC patients demonstrated a better OS compared to HPV-negative patients. HPV-positive patients who received BED10 ≥55 have higher rates of OS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oraloncology.2019.05.012DOI Listing
October 2019

Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial.

Lancet Oncol 2019 10 12;20(10):1349-1359. Epub 2019 Aug 12.

Department of Radiation Oncology, Western University, London, ON, Canada.

Background: Transoral robotic surgery (TORS) with concurrent neck dissection has supplanted radiotherapy in the USA as the most common treatment for oropharyngeal squamous cell carcinoma (OPSCC), yet no randomised trials have compared these modalities. We aimed to evaluate differences in quality of life (QOL) 1 year after treatment.

Methods: The ORATOR trial was an investigator-initiated, multicentre, international, open-label, parallel-group, phase 2, randomised study. Patients were enrolled at six hospitals in Canada and Australia. We randomly assigned (1:1) patients aged 18 years or older, with Eastern Cooperative Oncology Group scores of 0-2, and with T1-T2, N0-2 (≤4 cm) OPSCC tumour types to radiotherapy (70 Gy, with chemotherapy if N1-2) or TORS plus neck dissection (with or without adjuvant chemoradiotherapy, based on pathology). Following stratification by p16 status, patients were randomly assigned using a computer-generated randomisation list with permuted blocks of four. The primary endpoint was swallowing-related QOL at 1 year as established using the MD Anderson Dysphagia Inventory (MDADI) score, powered to detect a 10-point improvement (a clinically meaningful change) in the TORS plus neck dissection group. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov (NCT01590355) and is active, but not currently recruiting.

Findings: 68 patients were randomly assigned (34 per group) between Aug 10, 2012, and June 9, 2017. Median follow-up was 25 months (IQR 20-33) for the radiotherapy group and 29 months (23-43) for the TORS plus neck dissection group. MDADI total scores at 1 year were mean 86·9 (SD 11·4) in the radiotherapy group versus 80·1 (13·0) in the TORS plus neck dissection group (p=0·042). There were more cases of neutropenia (six [18%] of 34 patients vs none of 34), hearing loss (13 [38%] vs five [15%]), and tinnitus (12 [35%] vs two [6%]) reported in the radiotherapy group than in the TORS plus neck dissection group, and more cases of trismus in the TORS plus neck dissection group (nine [26%] vs one [3%]). The most common adverse events in the radiotherapy group were dysphagia (n=6), hearing loss (n=6), and mucositis (n=4), all grade 3, and in the TORS plus neck dissection group, dysphagia (n=9, all grade 3) and there was one death caused by bleeding after TORS.

Interpretation: Patients treated with radiotherapy showed superior swallowing-related QOL scores 1 year after treatment, although the difference did not represent a clinically meaningful change. Toxicity patterns differed between the groups. Patients with OPSCC should be informed about both treatment options.

Funding: Canadian Cancer Society Research Institute Grant (#701842), Ontario Institute for Cancer Research Clinician-Scientist research grant, and the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers grant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(19)30410-3DOI Listing
October 2019

Impact of cisplatin dose and smoking pack-years in human papillomavirus-positive oropharyngeal squamous cell carcinoma treated with chemoradiotherapy.

Eur J Cancer 2019 09 19;118:112-120. Epub 2019 Jul 19.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada. Electronic address:

Background: To evaluate the impact of cisplatin cumulative dose (CDDP-D) and smoking pack-years (PYs) on cause-specific survival (CSS) and overall survival (OS) in human papillomavirus-positive (HPV+) oropharyngeal carcinoma (OPSCC) using the eighth edition tumour-node-metastasis (TNM) staging classification (TNM8).

Patients And Methods: We reviewed patients with HPV+ OPSCC treated with high-dose CDDP and intensity-modulated radiotherapy between 2005 and 2015 at Princess Margaret Cancer Centre. CSS and OS were compared according to CDDP-D <200/=200/>200 mg/m stratified by TNM8.

Results: A total of 482 consecutive patients were evaluated (stage I/II/III: N = 189/174/119; CDDP-D <200/=200/>200 mg/m: N = 112/220/150). Median follow-up duration was 5.1 years (range: 0.6-12.8). Five-year CSS and OS differed by stages I/II/III: 96%/85%/88% (p=0.005) and 93%/84%/78% (p = 0.001), respectively. Five-year CSS by CDDP-D <200/=200/>200 mg/m was similar in stage I (98%/95%/95%, p = 0.74) and stage II (88%/84%/84%, p = 0.86) but different in stage III (76%/98%/84%, p = 0.02). Five-year OS by CDDP-D <200/=200/>200 mg/m did not differ significantly among stages. In the multivariable analysis, CDDP-D <200 mg/m did not influence CSS in the whole cohort versus = 200/>200 mg/m (p=0.53/0.79, respectively) but was associated with reduced CSS in stage III subgroup versus =200 mg/m (=200 mg/m versus < 200 mg/m hazard ratio [HR] = 0.08; 95% confidence interval [CI]: 0.01-0.67; p = 0.02). Higher smoking PYs had no effect on CSS (p = 0.34) but reduced OS in the whole cohort (HR = 1.14 [95% CI: 1.02-1.27], p=0.01).

Conclusion: CDDP-D correlated with neither survival nor disease-specific outcomes in this large and homogeneous HPV+ cohort, although reduced CSS was observed in stageIII HPV+ OPSCC receiving CDDP-D <200 mg/m. Smoking PYs were negatively associated with OS but not with CSS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2019.06.019DOI Listing
September 2019

Validation of distant metastases risk-groups in oral cavity squamous cell carcinoma patients treated with postoperative intensity-modulated radiotherapy.

Radiother Oncol 2019 05 31;134:10-16. Epub 2019 Jan 31.

Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Canada. Electronic address:

Background: This study aimed to derive distant metastases (DM) risk-groups in oral cavity squamous cell carcinoma (OSCC) patients treated with postoperative intensity-modulated radiation therapy (PO-IMRT).

Methods: OSCC patients treated with PO-IMRT were divided into discovery (2005-2012) and validation (2013-2014) cohorts. DM predictors were identified from multivariable analysis (MVA) to derive low- and high-risk groups in the discovery-cohort. The result was subsequently evaluated in validation-cohort.

Results: Overall 447 patients were included (discovery-cohort: n = 300, and validation-cohort: n = 147). Between the two cohorts, there were no significant differences in DM (p = 0.16) or OS (p = 0.26). MVA identified pN2-3 and histological grade 2-3 (G2-3) as DM predictors. High-risk group included patients who had both poor predictors (pN2-3 and G2-3), while low-risk group included patients with no or only one poor predictor. In discovery-cohort, 3-year distant control (DC) was 78% and 97% in high- and low-risk groups respectively (p < 0.001, concordance index = 0.72). In validation-cohort, risk-group classification performed similarly (concordance index = 0.73). The 3-year OS for high- versus low-risk group was 85% versus 95% in discovery-cohort (p < 0.001), and 74% versus 93% in validation-cohort (p < 0.001).

Conclusion: A model (G2-3/pN2-3) which identifies high DM risk was validated internally. This model might be used to design future prospective studies investigating treatment intensification and/or DM surveillance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2019.01.014DOI Listing
May 2019

Radiologic Extranodal Extension Portends Worse Outcome in cN+ TNM-8 Stage I Human Papillomavirus-Mediated Oropharyngeal Cancer.

Int J Radiat Oncol Biol Phys 2019 08 4;104(5):1017-1027. Epub 2019 Apr 4.

Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada. Electronic address:

Purpose: To identify adverse radiologic nodal features in cN+ TNM-8 stage I human papillomavirus-related (HPV+) oropharyngeal cancer (OPC).

Methods And Materials: All patients with HPV+ cT1-T2cN1 OPC treated with definitive intensity modulated radiation therapy from 2008 to 2015 were included. Radiologically involved lymph node number (LN), radiologic extranodal extension (rENE), retropharyngeal LN (RPLN), and lower neck (level 4 or 5b) LN involvement were assessed on pre-treatment computed tomography/magnetic resonance imaging by a specialized head and neck neuroradiologist. Disease-free survival (DFS), locoregional control, and distant control were compared between those with versus without rENE. Univariable and multivariable analysis with stepwise modal selection were applied to identify prognostic factors for DFS.

Results: A total of 45 rENE+ and 234 rENE- were identified. The rENE+ cohort had a higher number of LNs per patient (median: 6 vs 2, P < .001) and was more likely to have necrotic LNs (33 [73%] vs 132 [56%], P = .046). Median follow-up was 4.8 years. Although locoregional control was high in both cohorts (93% vs 97%, P = .34), the rENE+ group had inferior 5-year distant control (78% [59-88] vs 95% [91-97], P < .001) and DFS (58% [43-77] vs 90% [86-94], P < .001). In multivariable analysis, rENE+ (HR [hazard ratio] 4.3 [2.3-8.1], P < .001], T2 (vs T1) category (HR 2.1 [1.0-4.2], P = .039), smoking pack-years (HR 1.02 [1.0-1.03], P = .013), and the addition of systemic agents (HR 0.4 [0.2-0.8], P = .005) were prognostic for DFS. RPLN was prognostic for distant metastasis (HR 3.2, P = .013) but not for DFS after adjusting for rENE.

Conclusions: Data from this contemporaneously treated cT1-T2N1 HPV+ OPC cohort suggest that the presence of rENE is an independent prognostic factor within stage I HPV+ OPC. RPLN is also associated with DM risk but not with DFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2019.03.047DOI Listing
August 2019

Impact of high dose volumetric CT on PTV margin reduction in VMAT prostate radiotherapy.

Phys Med Biol 2019 03 14;64(6):065017. Epub 2019 Mar 14.

Radiation Medicine Program, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada. Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada. Author to whom any correspondence should be addressed.

The aim of the study is to determine PTV margin for inter-observer variability in the volumetric modulated arc therapy (VMAT) prostate radiotherapy with high-dose volumetric CT (HDVCT) and conventional helical CT (CCT) for planning. Secondly to investigate the impact of geometric (PTV expansion) and dosimetric (conformity) imperfection of planning process on the PTV margin analysis. Prostate gland of ten patients were scanned with CCT and HDVCT techniques consecutively on a 320 slice volumetric CT scanner with wide field detector of 16 cm. Five radiation oncologists delineated CTV of the prostate. VMAT plans were developed with PTV margin of 4 mm and 6 mm (totaling 200 plans) and target coverage of each plan was evaluated on the target volume in agreement determined by shared voxels with three or more from 5 observers. Dosimetry on 200 VMAT plans showed that PTV margin for inter-observer variability were 6 mm and 4 mm for CCT and HDVCT techniques, respectively. It is about 3 mm smaller than our estimation from the previous study (8.8 mm and 7.3 mm) based on the inter-observer variability. This difference is mainly due to the accuracy of PTV volume expansion and limited dose conformity to guarantee target coverage. PTVs were measured 2 mm larger on average than the assigned margin. Planning iso-dose volume was found to be 2 mm larger than PTV. Regardless these limitations, enhanced image quality of HDVCT reduces PTV margin by 2 mm compared to CCT. PTV reduction of 2 mm potentially leads to 15% reduction in D30% of rectal and bladder wall maintaining the same target coverage. Inter-observer variability remains a source of systematic uncertainty. HDVCT for treatment planning demonstrated reduction of the uncertainty and the PTV margin by 2 mm. It is important to consider the over-expanded PTV volume and generous iso-dose volume after optimization in the process of radiotherapy planning in the determination of PTV margin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1361-6560/ab050fDOI Listing
March 2019

A cross sectional study in cognitive and neurobehavioral impairment in long-term nasopharyngeal cancer survivors treated with intensity-modulated radiotherapy.

Radiother Oncol 2019 02 29;131:179-185. Epub 2018 Sep 29.

Department of Supportive Care, Princess Margaret Cancer Centre, University of Toronto, Canada. Electronic address:

Purpose/objectives: To determine neurocognitive and neurobehavioral impairment in long-term nasopharyngeal cancer survivors (NPC) treated with intensity-modulated radiotherapy (IMRT).

Materials/methods: A cross-sectional cohort of NPC ≥4 years (y) following IMRT was assessed. Objective cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and patient-reported memory was assessed with the MDASI-HN problems remembering item. Patient and family ratings of patients' neurobehavioral symptoms of apathy, disinhibition and executive dysfunction were assessed with the Frontal Systems Behavior Scale (FrSBe). Other patient-reported symptoms (MDASI-HN), mood (HADS), and quality of life (FACT-H&N) were also collected.

Results: Among 102 participants: M:F = 66:36; median age 56y (32-77); median time since IMRT 7.5y (4.2-11.1). Impaired MoCA scores (<23) were observed in 33 (32%). Patient and family ratings of pre-illness neurobehavioral symptoms were in the normal range (total FrSBe T-scores 53.3 and 59.0 respectively). In contrast, post-treatment patient and family T-scores were clinically impaired (64.7, 71.3 respectively), with apathy, disinhibition and executive dysfunction post-treatment ratings all significantly worse than pre-treatment (p < 0.001). Prevalence of clinically significant post-treatment disturbance was high by patient and family ratings (48%/66% apathy, 35%/53% disinhibition, 39%/56% executive dysfunction). Post-treatment neurobehavioral symptoms strongly correlated with lower quality of life (r = -0.62) and higher anxiety (r = 0.62) and depression scores (r = 0.67, all p < 0.001). Total MoCA scores did not correlate with RT dose. However, greater declines in apathy, disinhibition and executive dysfunction were associated with receiving >75 Gy to temporal lobes.

Conclusion: NPC treated with IMRT had moderate to high rates of neurocognitive impairment and clinically significant apathy, disinhibition, and executive dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2018.09.012DOI Listing
February 2019

Predictors of Early Recurrence Prior to Planned Postoperative Radiation Therapy for Oral Cavity Squamous Cell Carcinoma and Outcomes Following Salvage Intensified Radiation Therapy.

Int J Radiat Oncol Biol Phys 2019 02 21;103(2):363-373. Epub 2018 Sep 21.

Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.

Purpose: To determine predictors and outcomes for oral squamous cell carcinoma (OSCC) patients who had early recurrence before commencement of postoperative radiation therapy (PORT).

Methods: Retrospective review was performed for patients with OSCC treated with PORT between 2003 and 2015 after curative-intent surgery. Early recurrence was defined as tumor recurrence after surgical resection and before initiating planned PORT. Patients were classified into the following groups: (1) adjuvant PORT group (no early recurrence), (2) salvage PORT group (locoregional early recurrence), and (3) palliative PORT group (locoregional and distant early recurrence). For the whole cohort, multivariable analysis (MVA) was applied to identify predictors of early recurrence. In the salvage group, the post-PORT recurrence-free rate was estimated, and MVA was used to identify predictors of recurrence-free rate, disease-free survival, and overall survival (OS).

Results: Six hundred and one patients were identified, of whom 513 (85%) were treated with adjuvant PORT. Eighty-eight patients (15%) had early recurrence (28 of 88; 32% were biopsy proven) before PORT (70 in the salvage group and 18 in the palliative group). On MVA, oral tongue subsite, microscopic positive resection margin, pT3-4, and pN2-3 were associated with the development of early recurrence (P < .05 for all). The 3-year OS rates for patients with OSCC treated with adjuvant and salvage PORT were 71% (95% confidence interval [CI], 67%-75%) and 41% (95% CI, 30%-56%), respectively (P < .001; median follow-up was 3.4 and 2.9 years, respectively). After salvage PORT, the 3-year recurrence-free rate was 36% (95% CI, 23%-47%). On MVA, extranodal extension and volume of early recurrent gross disease were associated with poor recurrence-free rate, disease-free survival, and OS (P < .05 for all).

Conclusion: Early recurrences are not uncommon in patients with high-risk features, Further study is required to improve prediction and outcomes of this very high-risk group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2018.09.013DOI Listing
February 2019

Long-Term Late Toxicity, Quality of Life, and Emotional Distress in Patients With Nasopharyngeal Carcinoma Treated With Intensity Modulated Radiation Therapy.

Int J Radiat Oncol Biol Phys 2018 10 4;102(2):340-352. Epub 2018 Jun 4.

Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada. Electronic address:

Purpose: To report long-term (>4 years) toxicity and quality of life (QoL) among patients with nasopharyngeal carcinoma (NPC) treated with intensity modulated radiation therapy (IMRT) in a nonendemic center.

Methods And Materials: A cross-sectional cohort study enrolled patients with NPC who were disease-free and ≥4 years after IMRT ± chemotherapy. Physician-reported adverse events (Common Terminology Criteria for Adverse Events, version 4.03) and patient-reported QoL (Functional Assessment of Cancer Therapy-Head and Neck, Functional Assessment of Chronic Illness Therapy-Fatigue), utilities (EuroQOL-5D), head and neck symptoms (MD Anderson Symptom Inventory-Head and Neck), and emotional distress (Hospital Anxiety and Depression Scale) were collected. Consenting patients also underwent endocrine screening and audiometry.

Results: Among 107 patients enrolled, median age at enrollment and time since treatment were 57 (32-81) and 7.5 years (4.2-11.1), respectively. Most patients (99%) received 70 Gy in 35 fractions; the majority (93%) received concurrent chemotherapy. Mean scores for the Functional Assessment of Cancer Therapy-Head and Neck, Functional Assessment of Chronic Illness Therapy-Fatigue, and EuroQOL-5D were 105.0 (46-148), 116.6 (44-160), and 0.85 (0.29-1.00), respectively. Dry mouth, mucus, swallowing/chewing, memory, and teeth/gum problems were scored highest on the MD Anderson Symptom Inventory-Head and Neck; mean symptom severity and symptom interference scores were 2.3 and 2.4, respectively. Grade 3 or higher physician-reported adverse events were noted in 50 patients (47%), most frequently hearing problems (46, 43%). Audiometry revealed significant bilateral hearing loss (grade ≥3) in 68 patients (72%). Depression (25%), anxiety (37%), and fatigue (28%) were common and strongly correlated with QoL. Most patients (69%) developed hypothyroidism; 1 patient (1%) developed pituitary dysfunction requiring hormone replacement. V50 >90 and V45 >99 to the thyroid correlated with significantly higher rates of hypothyroidism.

Conclusions: Despite the implementation of IMRT, survivors of NPC still experience many physical symptoms that affect long-term QoL many years after treatment. Depression, anxiety, and fatigue remain common in long-term survivors and are highly correlated with QoL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2018.05.060DOI Listing
October 2018

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

Oral Oncol 2018 07 1;82:162-167. Epub 2018 Jun 1.

Department of Otolaryngology, Head and Neck Surgery/Surgical Oncology, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oraloncology.2018.05.023DOI Listing
July 2018

Partial Laryngeal IMRT for T2N0 Glottic Cancer: Impact of Image Guidance and Radiation Therapy Intensification.

Int J Radiat Oncol Biol Phys 2018 11 30;102(4):941-949. Epub 2018 Mar 30.

Department of Radiation Oncology, Princess Margaret Cancer Centre-University of Toronto, Toronto, Ontario, Canada. Electronic address:

Purpose: To assess the impact of the radiation therapy (RT) regimen and image guidance (image guided radiation therapy [IGRT]) protocol on local control (LC) for T2N0 glottic cancer treated with partial laryngeal intensity modulated radiation therapy (IMRT).

Methods And Materials: All patients with T2N0 glottic cancer treated with IMRT from 2006 to 2013 at a single institution were retrospectively reviewed. The gross tumor volume (GTV), delineated from endoscopic and/or radiologic findings, was expanded 0.5 cm for the high-dose clinical target volume and an additional 0.5 cm for the lower-dose clinical target volume (total of 1.0 cm from GTV). The planning target volume margin was 0.5 cm radially and 1 cm superiorly and inferiorly. RT regimens evolved from hypofractionated IMRT (RT-hypo, 60 Gy in 25 fractions over a period of 5 weeks) to moderately accelerated IMRT (RT-acc, 66-70 Gy in 33-35 fractions over a period of 5.5-6 weeks) since 2010. The IGRT matching surrogate changed from cervical vertebral bone (IGRT-bone) to laryngeal soft tissue (IGRT-larynx) in 2008. LC was compared between 3 sequential cohorts: RT-hypo/IGRT-bone, RT-hypo/IGRT-larynx, and RT-acc/IGRT-larynx. Multivariable analysis assessed the relative impact of RT regimen and IGRT technique on local failure separately.

Results: Among 139 eligible patients (median follow-up period, 5.03 years [range, 0.8-10.5 years]), we identified 28 local, 6 regional, and 2 distant failures. A higher 3-year LC rate was observed for RT-acc/IGRT-larynx (89% [95% CI: 78%-95%]) versus RT-hypo/IGRT-larynx (80% [95% CI: 54%-91%]) and RT-hypo/IGRT-bone (70% [95% CI: 53%-80%]) (P = .02). Multivariable analysis adjusted for GTV (in cubic centimeters) and smoking status confirmed that IGRT-larynx versus IGRT-bone (hazard ratio, 0.40; P = .019) and RT-acc versus RT-hypo (hazard ratio, 0.34; P = .012) both reduced the risk of local failure.

Conclusions: This single-institution cohort study shows a high LC rate (89%) for T2N0 glottic cancer following moderately accelerated partial laryngeal IMRT with daily laryngeal soft tissue matching IGRT. These results appear to represent an improvement attributable to changes in both IGRT matching and dose delivered, but their independent significance is unknown and further confirmation in a larger cohort is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2018.03.034DOI Listing
November 2018

Radiomic Biomarkers to Refine Risk Models for Distant Metastasis in HPV-related Oropharyngeal Carcinoma.

Int J Radiat Oncol Biol Phys 2018 11 1;102(4):1107-1116. Epub 2018 Feb 1.

Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Purpose: Distant metastasis (DM) is the main cause of death for patients with human papillomavirus (HPV)-related oropharyngeal cancers (OPCs); yet, there are few reliable predictors of DM in this disease. The role of quantitative imaging (ie, radiomic) analysis was examined to determine whether there are primary tumor features discernible on imaging studies that are associated with a higher risk of DM developing.

Methods And Materials: Radiation therapy planning computed tomography scans were retrieved for all nonmetastatic p16-positive OPC patients treated with radiation therapy or chemoradiation therapy at a single institution between 2005 and 2010. Radiomic biomarkers were derived from each gross tumor volume. The biomarkers included 4 representative radiomic features from tumor first-order statistics, shape, texture, and wavelet groups, as well as a combined 4-feature signature. Univariable Cox proportional hazards models for DM risk were identified. The discriminative performance of prognostic univariable and multivariable models was compared using the concordance index (C-index). Subgroup analyses were performed.

Results: There were 300 HPV-related OPC patients who were eligible for the analysis. A total of 36 DM events occurred within a median follow-up period of 5 years. On univariable analysis, top results included the 4 representative radiomic features (C-index, 0.670-0.686; P < .001), the radiomic signature (C-index, 0.670; P < .001), tumor stage (C-index, 0.633; P < .001), tumor diameter (C-index, 0.653; P < .001), and tumor volume (C-index, 0.674; P < .001), which demonstrated moderate discrimination of DM risk. Combined clinical-radiomic models yielded significantly improved performance (C-index, 0.701-0.714; P < .05). In subgroup analyses, the radiomic biomarkers consistently stratified patients for DM risk, particularly for those cohorts with greater risks (C-index, 0.663-0.796), such as patients with stage III disease.

Conclusions: Radiomic biomarkers appear to classify DM risk for patients with nonmetastatic HPV-related OPC. Radiomic biomarkers could be used either alone or with other clinical characteristics in the assignment of DM risk in future HPV-related OPC clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2018.01.057DOI Listing
November 2018

Use of hydrogel spacer for improved rectal dose-sparing in patients undergoing radical radiotherapy for localized prostate cancer: First Canadian experience.

Can Urol Assoc J 2017 Dec 1;11(12):373-375. Epub 2017 Nov 1.

Radiation Medicine Program, Princess Margaret Cancer Centre, Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.

We describe the initial experience using a hydrogel spacer (SpaceOAR) to separate the prostate-rectum interspace in patients planned to undergo radical hypofractionated, image-guided, intensity-modulated radiotherapy (IG-IMRT). We depict and discuss the impact of SpaceOAR in the context of hypofractionated IG-IMRT, and the particular considerations for its applications in the Canadian setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5489/cuaj.4681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962942PMC
December 2017

Evaluation of high dose volumetric CT to reduce inter-observer delineation variability and PTV margins for prostate cancer radiotherapy.

Radiother Oncol 2017 10 28;125(1):118-123. Epub 2017 Aug 28.

Radiation Medicine Program, Princess Margaret Hospital, University Health Network, Canada; Department of Radiation Oncology, University of Toronto, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Canada; Department of Medical Biophysics, University of Toronto, Canada.

Purpose: The aim was to determine whether the enhanced soft tissue contrast provided by high-dose volumetric CT (HDVCT) can reduce inter-observer variability in delineating prostate compared to helical conventional CT (CCT) scans and 3T MRI scans for patients undergoing radical prostate cancer radiotherapy. Secondly, to quantify the potential PTV reduction with decreased inter-observer variability.

Materials And Methods: A 320 slice volumetric CT scanner was used. The wide-detector coverage of 16cm enabled volumetric image acquisition of prostate gland in one rotation. Three imaging studies were performed on ten patients. CCT and HDVCT were performed consecutively at the same coordinate system followed by MRI. Five radiation oncologists delineated the prostate.

Results: The inter-observer variability is 2.0±0.6, 1.9±0.4 and 1.8±0.4mm for CCT, HDVCT and MR respectively with the maximum at the apex region. Comparing inter-observer difference variability between CCT and HDVCT with MR indicates that observers have larger variations in contouring using CCT than HDVCT especially at apex. Jaccard index of HDVCT is significantly higher than CCT with a mean difference of 0.03 (p=0.011). Both MRI and HDVCT provide the opportunity for a 2mm PTV margin reduction at the apex compared to CCT.

Conclusion: Inter-observer variability in delineation remains an important source of systematic error. HDCTV for treatment planning reduces this error without recourse to MRI and permits a PTV reduction of 2mm at the apex. The margins required to account for residual error with any imaging modality are still greater than are used in typical current practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2017.08.012DOI Listing
October 2017