Transanal Local Excision for Patients With Rectal Cancer: Can Radiation Compensate for What Is Perceived as a Nondefinitive Surgical Approach?

BACKGROUND: Total mesorectal excision has long been the standard of care for patients with rectal cancer. However, in select patients, local excision is an appropriate alternative option. The role of adjuvant radiation therapy in patients treated with local excision is controversial and evidence is lacking. OBJECTIVE: The purpose of this study was to report oncological outcomes of patients with rectal cancer treated with local excision and adjuvant radiation. DESIGN: This study was a retrospective chart review. SETTINGS: The study was conducted at the BC Cancer Agency, a tertiary referral hospital. PATIENTS: A total of 93 patients with node-negative rectal cancer treated with local excision and adjuvant radiotherapy between 2001 and 2010 were included in the study. MAIN OUTCOME MEASURES: Patient and tumor characteristics are reported. Five-year local control, progression-free survival, and overall survival were analyzed using Kaplan-Meier methods. RESULTS: Five-year overall survival, local control, and progression-free survival for patients treated with local excision and adjuvant radiotherapy were 78.5%, 86.1%, and 83.8%. In T1 disease, local control was 92.5%. LIMITATIONS: Referral bias, selection bias, lack of uniform surveillance, and retrospective analysis are the study limitations. CONCLUSIONS: Local excision with adjuvant radiotherapy provides a good level of local control in T1 disease and remains a good treatment option for patients who are either medically not suitable for a more radical surgical approach or who refuse this procedure. Local excision and radiotherapy should not be advocated in T2/T3 disease; however, it can provide a good alternative in those patients who are not fit enough for a more radical operation.

Hyperfractionated or accelerated radiotherapy for head and neck cancer.

BACKGROUND: Several trials have studied the role of altered fractionation radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. OBJECTIVES: The aim of this individual patient data (IPD) meta-analysis was to assess whether this type of radiotherapy could improve survival. SEARCH STRATEGY: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; CENTRAL (2010, Issue 3); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN and additional sources for published and unpublished trials. The date of the most recent search was 8 August 2010. SELECTION CRITERIA: We identified randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic head and neck squamous cell carcinomas and grouped trials into three pre-specified treatment categories: hyperfractionated, accelerated and accelerated with total dose reduction. Trials were eligible if they began recruitment after 1969 and ended before 1998. DATA COLLECTION AND ANALYSIS: We obtained updated individual patient data. Overall survival was the main outcome measure. The secondary outcome measures were local or regional control rates (or both), distant control rates and cause-specific mortality. MAIN RESULTS: We included 15 trials with 6515 patients. The median follow up was six years. Tumour sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (UICC 2002). There was a significant survival benefit with altered fractionation radiotherapy, corresponding to an absolute benefit of 3.4% at five years (hazard ratio (HR) 0.92, 95% CI 0.86 to 0.97; P = 0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at five years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at five years, P = 0.02). There was a benefit in locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at five years; P < 0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (under 50 year old) (HR 0.78, 95% CI 0.65 to 0.94), 0.95 (95% CI 0.83 to 1.09) for 51 to 60 year olds, 0.92 (95% CI 0.81 to 1.06) for 61 to 70 year olds, and 1.08 (95% CI 0.89 to 1.30) for those over 70 years old; test for trends P = 0.007). AUTHORS' CONCLUSIONS: Altered fractionation radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation provides the greatest benefit. An update of this IPD meta-analysis (MARCH 2), which will increase the power of this analysis and allow for other comparisons, is currently in progress.

Effects of change in rectal cancer management on outcomes in British Columbia.

BACKGROUND: In a province-wide audit of patients undergoing treatment for rectal cancer in British Columbia in 1996, the 4-year rate of pelvic recurrence for stage 3 rectal cancer was 27%. The management guidelines were changed in 2002 to include adjuvant short-course preoperative radiation and total mesorectal excision surgical techniques. Education workshops were held to implement the protocol change. METHODS: We performed a provincial audit of rectal cancer cases for patients treated in the year after the protocol change, and we compared the pelvic recurrence rates with those from the audit performed in 1996. RESULTS: During a 12-month period beginning Oct. 1, 2003, a total of 367 patients underwent radical resection of rectal cancer with a curative intent. Preoperative adjuvant radiotherapy was used in 54% of cases (197/367). Median follow-up was 34.5 months, and 91% of patients were followed for at least 2 years. Relative to the 1996 cohort, there was a decreasing trend in 2-year overall pelvic recurrence rates in the 2003/04 cohort (9.6% v. 6.9%) and a significant decrease in recurrence among patients with stage 3 cancers (18.2% v. 9.2%; p = 0.020). Use of adjuvant radiation increased significantly (37% v. 65%; p < 0.001), and negative radial margins were achieved in 87% (319/367) of cases. CONCLUSION: The rates of pelvic recurrence were improved after changes in the management guidelines advocating increased use of total mesorectal excision surgery and preoperative radiation. Knowledge translation with an integrated strategy among surgeons and medical and radiation oncologists was successful in improving population outcomes among patients with rectal cancer.

Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis.

BACKGROUND: Several trials have studied the role of unconventional fractionated radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this meta-analysis was to assess whether this type of radiotherapy could improve survival. METHODS: Randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic HNSCC were identified and updated individual patient data were obtained. Overall survival was the main endpoint. Trials were grouped in three pre-specified categories: hyperfractionated, accelerated, and accelerated with total dose reduction. FINDINGS: 15 trials with 6515 patients were included. The median follow-up was 6 years. Tumours sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (International Union Against Cancer, 1987). There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3.4% at 5 years (hazard ratio 0.92, 95% CI 0.86-0.97; p=0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at 5 years, p=0.02). There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at 5 years; p<0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (hazard ratio 0.78 [0.65-0.94] for under 50 year olds, 0.95 [0.83-1.09] for 51-60 year olds, 0.92 [0.81-1.06] for 61-70 year olds, and 1.08 [0.89-1.30] for over 70 year olds; test for trends p=0.007). INTERPRETATION: Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit.

Quality of life and swallowing with standard chemoradiotherapy versus accelerated radiotherapy and panitumumab in locoregionally advanced carcinoma of the head and neck: A phase III randomised trial from the Canadian Cancer Trials Group (HN.6).

AIM: To compare quality of life (QOL) between standard (SFX) chemoradiotherapy (arm A) and altered fractionation radiotherapy (AFX) with panitumumab (PMab; arm B). METHODS: Patients with T any N + M0 or T3-4N0M0 squamous cell head-neck carcinoma were randomised to SFX (70 Gy/35/7 wks) plus cisplatin (100 mg/m2 IV × 3) versus AFX (70 Gy/35/6 wks) plus PMab (9 mg/kg IV × 3). QOL was collected at baseline, end of radiation therapy (RT) and 2, 4, 6, 12, 24 and 36 months post-RT using the Functional Assessment of Cancer Therapy Head and Neck (FACT-H&N), MD Anderson Dysphagia Index (MDADI) and SWAL-QOL. We hypothesised a 6-point more favourable change in FACT-H&N score from baseline to 1 year in arm B over arm A. RESULTS: Among 320 patients, median follow-up was 46 (range: 0.1-64.3) months, median age 56, 84% male, Eastern Cooperative Oncology Group PS 0 (71%), 1 (29%). Primary site was oropharynx in 81% (p16+ 68%, p16- 16%, missing 16%). Baseline scores did not differ by arm (A/B): FACT-H&N 116.5/115, MDADI Global 83/77, SWAL-QOL General 67/68. At 1 year, no difference was seen between arms in FACT-H&N change from baseline: A -1.70, B -4.81, p = 0.194. Subscale change scores by arm were (A/B): last week RT, FACT-Physical (-11.6, -10, p = 0.049), MDADI Physical (-40.4, -33.9, p = 0.045), and SWAL-QOL Eating Duration (-61.2, -51.2, p = 0.02), Eating Desire (-53.3, -43.9, p = 0.031) and Mental Health (-42, -32.6, p = 0.009); 4 months, HN subscale (-7.7, -10, p = 0.014). No clinically important differences by arm were seen post-treatment. CONCLUSIONS: PMab with AFX did not durably improve QOL or swallowing as compared with SFX with cisplatin. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00820248.

Effect of Standard Radiotherapy With Cisplatin vs Accelerated Radiotherapy With Panitumumab in Locoregionally Advanced Squamous Cell Head and Neck Carcinoma: A Randomized Clinical Trial.

IMPORTANCE: The Canadian Cancer Trials Group study HN.6 is the largest randomized clinical trial to date comparing the concurrent administration of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies with radiotherapy (RT) to standard chemoradiotherapy in locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). OBJECTIVE: To compare progression-free survival (PFS) in patients with LA-SCCHN treated with standard-fractionation RT plus high-dose cisplatin vs accelerated-fractionation RT plus the anti-EGFR antibody panitumumab. DESIGN, SETTING, AND PARTICIPANTS: A randomized phase 3 clinical trial in 17 Canadian centers. A total of 320 patients were randomized between December 2008 and November 2011. INTERVENTIONS: Patients with TanyN+M0 or T3-4N0M0 LA-SCCHN were randomized 1:1 to receive standard-fractionation RT (70 Gy/35 over 7 weeks) plus cisplatin at 100 mg/m2 intravenous for 3 doses (arm A) vs accelerated-fractionation RT (70 Gy/35 over 6 weeks) plus panitumumab at 9 mg/kg intravenous for 3 doses (arm B). MAIN OUTCOMES AND MEASURES: Primary end point was PFS. Due to an observed declining event rate, the protocol was amended to a time-based analysis. Secondary end points included overall survival, local and regional PFS, distant metastasis-free survival, quality of life, adverse events, and safety. RESULTS: Of 320 patients randomized (268 [84%] male; median age, 56 years), 156 received arm A and 159 arm B. A total of 93 PFS events occurred. By intention-to-treat, 2-year PFS was 73% (95% CI, 65%-79%) in arm A and 76% (95% CI, 68%-82%) in arm B (hazard ratio [HR], 0.95; 95% CI, 0.60-1.50; P = .83). The upper bound of the HR 95% CI exceeded the prespecified noninferiority margin. Two-year overall survival was 85% (95% CI, 78%-90%) in arm A and 88% (95% CI, 82%-92%) in arm B (HR, 0.89; 95% CI, 0.54-1.48; P = .66). Incidence of any grade 3 to 5 nonhematologic adverse event was 88% in arm A and 92% in arm B (P = .25). CONCLUSIONS AND RELEVANCE: With a median follow-up of 46 months, the PFS of panitumumab plus accelerated-fractionation RT was not superior to cisplatin plus standard-fractionation RT in LA-SCCHN and noninferiority was not proven. Despite having negative results, HN.6 has contributed important data regarding disease control and toxic effects of these treatment strategies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00820248.

Carotid artery stenosis in asymptomatic patients who have received unilateral head-and-neck irradiation.

PURPOSE: To determine the prevalence of carotid artery stenosis in patients who have received ipsilateral head-and-neck radiotherapy and have no symptoms of cerebrovascular disease. METHODS AND MATERIALS: Forty patients underwent ultrasound and computed tomography angiography of their carotid arteries. The vessels on the irradiated side were compared with those on the unirradiated side in a matched-pair analysis with regard to any stenosis, stenosis > or =60% in the internal carotid artery/carotid bulb, intima medial thickness (IMT), and grade of wall abnormalities. History, physical, and fasting blood levels were taken to detect risk factors for carotid disease. RESULTS: Fourteen irradiated carotid trees bore one or more stenosis vs. five in the unirradiated ones (p = 0.03). There were six bulb/internal carotid artery stenoses > or =60% in the irradiated carotids vs. one in the unirradiated (OR 6:1, p = 0.13). IMT and grade of vessel wall abnormality were higher in the irradiated carotids, but only at doses > or =50 Gy, and only at measurement points that lay within the radiation portals. CONCLUSION: Radiation appears to cause carotid artery stenosis. There may be a dose threshold for carotid wall changes, which has relevance for radiotherapy in several tumor sites.

Patterns of Relapse in Squamous Cell Carcinoma of the Tonsil - Unilateral vs. Bilateral Radiation in the HPV-Era.

OBJECTIVES:  In the pre-human papillomavirus (HPV) era, unilateral radiation therapy (URT) for tonsil cancer was associated with low contralateral failure rates and had less toxicity than bilateral radiation therapy (BRT). This study explores the validity of URT in HPV-positive tonsil cancers. METHODS:  Tonsil squamous cell carcinomas (SCC) treated (typically with 70 Gy radiation and Cisplatin-based chemotherapy) between 2001 and 2007 were reviewed. Retrospective p16 immunohistochemistry staining was undertaken. Baseline, treatment, and response data were collected. RESULTS:  Of 182 patients, 78% were p16-positive, were younger (predominantly male), mostly former or non-smokers, and had a more advanced nodal stage. With a median follow-up of 68 months, contralateral recurrence (CLR) rates were low (3.5% p16-positive versus 2.5% p16-negative, p=0.63). Overall survival (OS) was 74% for p16-positive versus 54% for p16-negative subjects (p=0.01), but all other outcomes were similar. Analysis amongst only p16-positive subjects revealed URT was delivered to 37%, with CLR rates of 7.5% versus 1.1% for those treated with BRT, p=0.05. Of the four p16-positive subjects treated with URT who developed contralateral recurrences, three were managed with neck dissection (two disease-free and one died of lung metastases) and one received palliative radiation to the neck and distant metastatic site. All disease control and survival outcomes were similar between those treated with URT versus BRT. CONCLUSION:  While CLRs remain rare overall, there appears to be a slightly increased rate among HPV-positive subjects treated with URT. However, overall outcomes do not appear to be impacted, suggesting that URT remains a reasonable approach in HPV-positive subjects.

Quantification of masticatory muscle atrophy after high-dose radiotherapy.

PURPOSE: To determine the rate of change in the cross-sectional area of the masticatory muscles after radiotherapy. METHODS AND MATERIALS: Eligible patients had undergone unilateral radiotherapy between 1993 and 2000 and had a baseline CT scan, a comparable follow-up CT scan a minimum of 1 year later, and no recurrence of cancer. Fourteen patients had their CT series scanned into digital image files. Two anatomically selected CT slices were bisected by the midline sagittal plane and stored under randomly assigned file names. Three observers measured the masseter and medial pterygoid areas on two occasions. RESULTS: The intraobserver reliability of the muscle area measurements was 96.3% for the masseter and 97.1% for the medial pterygoid. The interobserver reliability of the muscle area measurements was 96.7% for the masseter and 96.3% for the medial pterygoid. On the treated side, the muscles received a median dose of 56 Gy (range 47-63) in 2.0-0.4-Gy fractions. With a median follow-up of 2.9 years (range 1-7.6), mixed-effects regression analysis demonstrated a significant area of reduction of -0.17 cm(2)/y (p = 0.0001) for the masseter and -0.13 cm(2)/y (p = 0.001) for the medial pterygoid. The controlled rate of muscle atrophy was 3.9%/y (95% confidence interval 1.4-6.4) for the masseter and 2.3%/y (95% confidence interval -0.6 to 5.1) for the medial pterygoid. CONCLUSION: Standard therapeutic radiation doses appear to cause significant masticatory muscle atrophy.

Effects of positive resection margin and tumor distance from anus on rectal cancer treatment outcomes.

PURPOSE: Rectal cancer outcome depends on stage, technical aspects of surgical excision, and use of adjuvant chemoradiation. Here, we examine effects of positive resection margin and tumor distance from the anus in stage 2 and 3 cancers on 4-year disease-specific survival and recurrence. METHODS: We reviewed all 495 rectal cancer patients registered in British Columbia in 1996. RESULTS: There were 481 cases analyzed: 29 in situ, 134 stage 1, 107 stage 2, 100 stage 3, 83 stage 4, and 28 unknown stage. Survival was significantly affected by presence of positive resection margin in stage 2 and 3 cancers, P = 0.0001. Lower tumor distance from the anus for stage 2 and 3 cancers worsened survival, P = 0.0007, and overall recurrence, P =0.016, but not local recurrence, P = 0.11. Adjuvant postoperative combined radiation and chemotherapy in stage 2 and 3 cancers significantly improved survival, P = 0.070 and local recurrence, P = 0.018, but not overall recurrence, P = 0.19. CONCLUSIONS: Presence of positive resection margin and tumor distance from the anus affect survival, local recurrence, and overall recurrence. Adjuvant postoperative combined radiation and chemotherapy improved our outcomes. Our local recurrence rates for rectal cancers are worse than currently reported standards of less than 10%. Improved surgical excision and use of adjuvant preoperative radiation and chemotherapy may improve outcome.

Toxicity and outcomes in combined modality treatment of head and neck squamous cell carcinoma: cisplatin versus cetuximab.

AIMS: The standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC) is radiation therapy (RT) with concurrent cisplatin (CIS). Patients with renal or cardiac dysfunction, hearing loss or poor performance status (PS) may receive RT and cetuximab (CET) at our institution. This study compares treatment toxicities and outcomes. METHODS AND MATERIALS: All patients treated with curative intent RT and concurrent CIS (100 mg/m 2 Day 1, 22, 43) or CET (400 mg/m 2 Day -7, 250 mg/m 2 weekly during RT) between August 2007 and July 2010 were reviewed and toxicity and outcomes analyzed. RESULTS: Among 349 subjects (262 RT-CIS, 87 RT-CET) characteristics were similar except in age, head and neck subsite and RT fractionation. RT-CIS required more dose reductions, delays, and unplanned admissions and received less intended systemic therapy (ST). Weight loss and gastrostomy-tube use were similar. RT-CIS caused more nausea/vomiting, while RT-CET was associated with more dermatitis and acneiform rash. With mean follow-up of 20 months and 16 months, RT-CIS subjects experienced improved 1-year locoregional control (LRC) (90% vs. 72%, P < 0.01), disease-free survival (DFS) (83% vs. 67%, P < 0.01) and overall survival (OS) (90% vs. 80%, P = 0.04). On multivariate analysis type of ST was associated with LRC and DFS, but not OS. CONCLUSIONS: In patients with locally advanced HNSCC, CIS and CET were associated with different toxicity profiles. RT-CIS was associated with improved LRC and DFS, but similar OS compared to RT-CET.