J. Tey

Outcomes of Adjuvant Chemoradiotherapy After a Radical Gastrectomy and a D2 Node Dissection for Gastric Adenocarcinoma

Purpose:Intergroup 0116 (INT-0116) established adjuvant chemoradiation as the standard of care for resected high-risk adenocarcinoma of the stomach in the United States. However, adjuvant chemoradiation remains controversial in many parts of Asia and Europe, where patients tend to undergo a more thorough D2 dissection. In INT-0116, 90% of patients had a limited or inadequate node dissection (D0 or D1). Also, 17% of patients in the chemoradiation arm had to discontinue treatment because of toxicities. The objectives of this retrospective study are to report the clinical outcomes of a cohort of patients who were mostly treated with a D2 node dissection and received adjuvant chemoradiation as per INT-0116, and the toxicities of chemoradiation in the context of more aggressive surgery. Methods:After the results of INT-0116 became apparent, we adopted an institutional policy whereby patients who would otherwise fit the inclusion criteria of INT-0116 received adjuvant chemoradiation. Between March 1999 and November 2004, 70 consecutive patients with pathologic stage T3, T4, or node-positive disease were treated according to the chemoradiation arm of INT-0116. Patients received intravenous 5-fluorouracil 425 mg/m2 and leucovorin 20 mg/m2 in cycles 1, 3, and 4. Concurrent chemoradiation was given in cycle 2 and consisted of bolus 5-fluorouracil and leucovorin and radiotherapy (45 Gy over 25 fractions in 5 weeks). All patients were operated on by dedicated Japan-trained Surgical Oncologists. Results:Sixty-seven patients (96%) had a D2 nodal dissection. Sixty-five patients (93%) had negative pathologic margins (R0 resection) and 5 (7%) had microscopically involved margins (R1 resection). The median follow-up was 27 months (range, 10.1–60.3). The 3-year overall survival, disease-free survival, and local control were 60.6%, 54.1%, and 84.3%, respectively. Of the 30 patients who relapsed, 5 (17%) had isolated locoregional recurrences only. The National Cancer Institute – Common Terminology Criteria version 3.0 acute grade 3 or 4 gastrointestinal and hematological toxicity rates were 15.7% and 4.3%, respectively. Toxicities led to chemotherapy dose-reductions in 18 patients and dose-delay in 19 patients. Including chemotherapy dose-reductions and delays, 66 patients (94%) completed the entire chemoradiation regimen. There were no toxicity-related deaths. Conclusion:In our cohort of 70 patients who had a more thorough D2 node dissection, adjuvant chemoradiation was well tolerated with acceptable toxicities and reasonable tumor control.

Clinical outcome of palliative radiotherapy for locally advanced symptomatic gastric cancer in the modern era.

AbstractThe purpose of this study was to report the outcomes of patients with symptomatic locally advanced/recurrent gastric cancer treated with radiotherapy (RT) using modern 3-dimensional conformal techniques.We retrospectively reviewed patients who had palliative RT for index symptoms of gastric bleeding, pain, and obstruction. Study endpoints included symptom response, median survival, and treatment toxicity.Of 115 patients with median age of 77 years, 78 (67.8%) patients had metastatic disease at the time of treatment. Index symptoms were gastric bleeding, pain, and obstruction in 89.6%, 9.2%, and 14.3% of patients, respectively. Dose fractionation regimen ranged from 8-Gy single fraction to 40 Gy in 16 fractions. One hundred eleven patients (93.3%) were computed tomography (CT) planned. Median follow-up was 85 days. Response rates for bleeding, pain, and obstruction were 80.6% (83/103), 45.5% (5/11), and 52.9% (9/17), respectively, and median duration of response was 99 days, 233 days, and 97 days, respectively. Median survival was 85 days. Actuarial 12-month survival was 15.3%. There was no difference in response rates between low (⩽39 Gy) and high (>39 Gy) biologically effective dose (BED) regimens (&agr;/&bgr; ratio = 10). Median survival was significantly longer in patients who responded to RT compared with patients who did not (113.5 vs 47 days, P < 0.001). Three patients (2.6%) had grade 3 Common Toxicity Criteria equivalent toxicity (nausea/vomiting/anorexia).External beam RT delivered using 3-dimensional conformal techniques is highly effective and well tolerated in the local palliation of gastric cancer, with palliation lasting the majority of patient’s lives. Short (⩽39 Gy BED) RT schedules are adequate for effective symptom palliation. A phase II study of palliative gastric RT is ongoing.

Adjuvant chemoradiotherapy with or without intraoperative radiotherapy for the treatment of resectable locally advanced gastric adenocarcinoma.

PURPOSE To document the long-term efficacy of intraoperative electron radiotherapy (IOERT) followed by concurrent chemotherapy and external-beam radiotherapy (EBRT) in the management of locally advanced gastric cancer. MATERIALS AND METHODS A total of 97 consecutive patients with T3/4 or N+ gastric adenocarcinoma were enrolled. Fifty-one patients received adjuvant chemoradiotherapy (EBRT group) and 46 received IOERT (dose range, 12-15 Gy) followed by chemoradiotherapy (EBRT+IOERT group). RESULTS The 5-year locoregional control rates were 50% and 35% in the two groups with or without IOERT, respectively (p=0.04). Two patients had recurrence within the IOERT field in the EBRT+IOERT group and 14 patients recurred in the same area in the EBRT group (p=0.02). Multivariate analyses revealed that adjuvant IOERT was an independent prognosticator for both local-regional control (p=0.02) and disease-free survival (p=0.05). G3/4 late toxicity was observed in 5 patients in the EBRT+IOERT group, but none in the EBRT group (p=0.02). CONCLUSIONS Higher radiation dose may contribute to the improvement of local control, especially in the field encompassed by IOERT. The addition of IOERT to surgery and adjuvant chemoradiation deserves further investigation in a randomized trial.

Palliative radiotherapy for gastric cancer: a systematic review and meta-analysis

Background/Purpose To review the efficacy and toxicity of palliative radiotherapy (RT) for symptomatic locally advanced gastric cancer (GC) and to determine the optimal RT schedule for symptom palliation. Methods We searched MEDLINE and CENTRAL for eligible studies published from 1995 to 2015. Outcomes of interest were relief of bleeding, pain and obstruction. RESULTS Seven non-comparative observational studies were included. There were large variations in RT dose and fractionation. The pooled overall response rates for bleeding, pain and obstruction symptoms were 74%, 67% and 68% respectively. There was no difference in response rate of bleeding between regimens with high biological equivalent dose (BED) of = 39Gy versus regimens with low BED<39Gy regimens (p value =0.39). Grade 3 to 4 toxicities occurred in up to 15% of patients for patients treated with RT alone and up to 25% of patients treated with chemoradiotherapy. Health-related quality of life (HRQL) outcomes were not reported. Conclusion More than two-thirds of patients receiving RT would have a clinical benefit. Low BED regimens appear to be adequate for symptom palliation. Toxicity rates appear acceptable for patients treated with RT alone. The optimal dose fractionation regimen for symptom palliation remains unclear. Prospective studies to determine the effects of palliative gastric RT on HRQL outcomes are warranted.

Efficacy of palliative radiation therapy for symptomatic rectal cancer

99 patients with symptomatic locally advanced rectal cancer who were treated with palliative radiation alone were reviewed. Dose-fractionation ranged from 18 to 54Gy. Response rate ranged from 62.5 to 86.7%, with a median response duration ranging 4.2-5.4months. Median survival was 6.9months. Using a BED cut-off of 39Gy10, no dose-response relationship was found.

Adjuvant chemoradiation plus intraoperative radiotherapy versus adjuvant chemoradiation alone in patients with locally advanced rectal cancer.

Objectives:To document the efficacy of intraoperative radiotherapy (IORT) followed by adjuvant chemoradiation in the management of locally advanced rectal cancer. Materials and Methods:A total of 148 patients with pT4N0/T1-4N+ rectal adenocarcinoma were enrolled. Seventy-seven patients received total mesorectal excision surgery followed by adjuvant chemoradiation alone, 71 patients received total mesorectal excision surgery followed by IORT (range, 10 to 20 Gy) and adjuvant chemoradiation. Results:The 5-year local control (LC) and disease-free survival were 79.2% versus 89.7% (P=0.032), 58.5% versus 69.0% (P=0.049) for external-beam radiation (EBRT) and IORT+EBRT groups, respectively. Multivariate analysis revealed that adjuvant IORT has a trend toward improvement of LC (P=0.079); 5 (3%) patients (EBRT n=2; IORT n=3) experienced incomplete intestinal obstruction and 3 patients had chronic diarrhea. There was no clinically relevant neuropathy or sacral osteoradionecrosis. Hydronephrosis occurred in 13 patients (EBRT n=8; IORT+EBRT n=5), 8 of whom had documented concomitant disease recurrence. Conclusions:For patients with locally advanced rectal cancer, higher radiation dose may contribute to the improvement of both LC and disease-free survival, without significantly increasing the incidence of acute and long-term complications compared with adjuvant chemoradiotherapy alone.

Intraoperative radiotherapy in the combination of adjuvant chemotherapy for the treatment of pT3N0M0 rectal cancer after radical surgery.

Objectives:The role of chemoradiotherapy in patients with pT3N0M0 rectal cancer is controversial. Intraoperative radiotherapy (IORT) has the ability to deliver a high, single-fraction radiation dose to tumor bed with minimal exposure of surrounding tissues. On the basis of the literature, the local failure pattern occurs mostly in the presacral-perineal space rather than the regional lymph node after adjuvant chemoradiation for T3N0 rectal adenocarcinoma. Our aim was to evaluate the efficacy of IORT followed by adjuvant chemotherapy in the treatment of pT3N0M0 rectal adenocarcinoma. Materials and Methods:A total of 91 consecutive patients with newly diagnosed pT3N0M0 well-differentiated and moderately differentiated rectal adenocarcinoma were enrolled: 46 patients received adjuvant concurrent chemoradiotherapy (external beam radiotherapy [EBRT group]) and 45 patients received IORT (dose range, 15 to 25 Gy), followed by identical systemic chemotherapy (IORT group). Results:The 5-year locoregional control rate, overall survival, and disease-free survival were 86%, 86%%, and 73% in the EBRT group versus 84%, 84%, and 71% in the IORT group, respectively (P>0.05). Compared with the EBRT group, the incidence of acute grade 3 toxicity was significantly lower in the IORT group than in the EBRT group (P<0.05). There were no severe late complications observed in the IORT group. Conclusions:IORT followed by adjuvant chemotherapy for pT3N0M0 rectal adenocarcinoma provided a similar outcome in terms of local control, overall survival, and disease-free survival, as compared with concurrent chemoradiotherapy after surgery. However, no significant acute or late complications were observed in patients treated with IORT. Further investigation, preferably in a prospective manner, is warranted to confirm the efficacy of IORT in the treatment of nonmetastatic T3 rectal cancer.

Induction chemotherapy for locally advanced nasopharyngeal carcinoma treated with concurrent chemoradiation: A systematic review and meta-analysis

PURPOSE To determine if the addition of induction chemotherapy (IC) to concurrent chemoradiation (CCRT) in locally advanced nasopharyngeal carcinoma (LA-NPC) can improve survival. METHODS We performed a meta-analysis of both randomized controlled trials (RCTs) and observational studies (OBS) to compare the effects of addition of IC to CCRT versus (vs) CCRT alone on overall survival (OS), progression free survival (PFS), distant metastasis-free survival (DMFS) and adverse events (AE) in LA-NPC. We searched MEDLINE for eligible studies comparing IC plus CCRT vs CCRT for LA-NPC from Jan 1996 to May 2017. We selected RCTs and OBS that included patients with non-metastatic, LA-NPC who received IC followed by CCRT or CCRT alone. Three reviewers independently assessed the abstracts for eligibility. We assessed the methodological quality of the included studies using the MERGE criteria. We performed the meta-analysis with random effects model. We used the GRADE approach to appraise the quality of evidence from RCTs. The primary outcome was OS; secondary outcomes included PFS, DMFS and AE. RESULTS We found six RCTs and five OBS including 2802 patients with low to moderate risk of bias in their methodological quality. There was high quality evidence from the RCTs that IC improved PFS (HR 0.69, 95% CI 0.57-0.84, P = 0.0003, I2 = 0%) and OS (HR 0.77, 95% CI 0.60-0.98, P = 0.03, I2 = 0%) significantly and was associated with more frequent AE. The estimates of IC effects from RCTs and OBS were similar (PFS HR 0.69 vs 0.71, interaction P (IP) = 0.92; OS HR 0.77 vs 0.58, IP = 0.27). CONCLUSIONS IC delays disease progression and improves survival significantly for LA-NPC treated with CCRT, and was associated with more toxicity. There were no divergent results between RCTs and OBS. IC followed by CCRT can be considered one of the standard treatment options for LA-NPC.

Outcomes of Asian patients with localized prostate cancer treated with combined intensity modulated radiation therapy (IMRT) and high dose rate (HDR) brachytherapy: A single institution experience

External beam radiotherapy (EBRT) followed by high dose rate (HDR) brachytherapy boost has demonstrated minimal toxicities and improved disease control rate compared with EBRT alone in observational and randomized studies with predominantly Caucasian patients. This study aims to report the outcomes of patients treated with this approach in our predominantly Asian population.

A phase II trial of preoperative concurrent chemotherapy and dose escalated intensity modulated radiotherapy (IMRT) for locally advanced rectal cancer

Objectives: To determine the pathological response rates and toxicity and in patients with locally advanced rectal cancer treated with concurrent capecitabine and dose escalated intensity modulated radiotherapy (IMRT) Methods: Patients with stage II or III adenocarcinoma of the rectum were treated with preoperative concurrent capecitabine and IMRT. Dose of capecitabine was 825mg/m2, 5 days a week for 5 weeks. IMRT was used to deliver a dose of 45Gy in 25 fractions (1.8Gy per fraction daily, 5 days a week over 5 weeks) to the regional lymphatics and areas at risk of harbouring microscopic disease. A concomitant synchronous integrated boost (SIB) to the gross tumour with a margin to a total dose of 55Gy in 25 fractions was also delivered in the same period. TME surgery was performed 8 weeks after preoperative therapy. The primary endpoint is pathological complete response rate (pCR) and the secondary endpoint was downstaging rates, Sphincter preservation rates (SPR), disease free survival (DFS) at 2 years and toxicity graded using the CTCAE v3.0. Results: Twenty three patients were enrolled. Three were not evaluable; one did not complete treatment due to logistic issues and two declined surgery. The remaining 20 patients completed preoperative chemoIMRT followed by TME surgery. At a median follow-up of 38.2 months (17.5-53.2 months), 90% (18 of 20) patients were alive. The 2 year overall survival and DFS were 90% and 90% respectively. 35%(7/20) of patients had a pCR. 65% (13 of 20) patients had successful downstaging of their rectal tumours. There was no local recurrence. Sphincter preservation rate was 85%. Treatment was well tolerated with only one patient (5%) having Grade 3 radiation proctitis. Conclusions: Preoperative concurrent capecitabine and dose escalated IMRT is well tolerated and results in high rates of pCR. A randomized trial comparing this regimen with standard 3D conformal chemoradiotherapy is warranted.