Jin-hong Park

Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial.

BACKGROUNDnThe role of adjuvant chemotherapy for patients with rectal cancer is controversial, especially when used after preoperative chemoradiotherapy. Fluoropyrimidine-based adjuvant chemotherapy, including fluorouracil and leucovorin, has been widely used; however, the addition of oxaliplatin to fluorouracil and leucovorin (FOLFOX), a standard adjuvant regimen for colon cancer, has not been tested in rectal cancer. We aimed to compare the efficacy and safety of adjuvant fluorouracil and leucovorin with that of FOLFOX in patients with locally advanced rectal cancer after preoperative chemoradiotherapy.nnnMETHODSnIn this open-label, multicentre, phase 2, randomised trial, patients with postoperative pathological stage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision were recruited and randomly assigned (1:1) via a web-based software platform to receive adjuvant chemotherapy with either four cycles of fluorouracil and leucovorin (fluorouracil 380 mg/m(2) and leucovorin 20 mg/m(2) on days 1-5, every 4 weeks) or eight cycles of FOLFOX (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil bolus 400 mg/m(2) on day 1, and fluorouracil infusion 2400 mg/m(2) for 46 h, every 2 weeks). Stratification factors were pathological stage (II vs III) and centre. Neither patients nor investigators were masked to group assignment. The primary endpoint was 3-year disease-free survival, analysed by intention to treat. This study is fully enrolled, is in long-term follow-up, and is registered with ClinicalTrials.gov, number NCT00807911.nnnFINDINGSnBetween Nov 19, 2008, and June 12, 2012, 321 patients were randomly assigned to fluorouracil and leucovorin (n=161) and FOLFOX (n=160). 141 (95%) of 149 patients in the fluorouracil plus leucovorin group and 141 (97%) of 146 in the FOLFOX group completed all planned cycles of adjuvant treatment. Median follow-up was 38·2 months (IQR 26·4-50·6). 3-year disease-free survival was 71·6% (95% CI 64·6-78·6) in the FOLFOX group and 62·9% (55·4-70·4) in the fluorouracil plus leucovorin group (hazard ratio 0·657, 95% CI 0·434-0·994; p=0·047). Any grade neutropenia, thrombocytopenia, fatigue, nausea, and sensory neuropathy were significantly more common in the FOLFOX group than in the fluorouracil plus leucovorin group; however, we noted no significant difference in the frequency of these events at grade 3 or 4. The most common grade 3 or worse adverse events were neutropenia (38 [26%] of 149 patients in the fluorouracil plus leucovorin group vs 52 [36%] of 146 patients in the FOLFOX group), leucopenia (eight [5%] vs 12 [8%]), febrile neutropenia (four [3%] vs one [<1%]), diarrhoea (four [3%] vs two [1%]), and nausea (one [<1%] vs two [1%]).nnnINTERPRETATIONnAdjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation.nnnFUNDINGnKorea Healthcare Technology R&D Project (South Korean Ministry of Health and Welfare).

Radiotherapy Plus Transarterial Chemoembolization for Hepatocellular Carcinoma Invading the Portal Vein: Long-Term Patient Outcomes

PURPOSEnWe have evaluated the clinical outcomes of patients after transarterial chemoembolization (TACE) and 3-dimensional conformal radiotherapy for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT).nnnMETHODS AND MATERIALSnA registry database of 412 patients treated with TACE and three-dimensional conformal radiotherapy for HCC with PVTT between August 2002 and August 2008 were analyzed retrospectively. The radiotherapy volume included the PVTT, with a 2- to 3-cm margin to cover adjacent HCC. Intrahepatic primary HCC was managed by TACE before or after radiotherapy.nnnRESULTSnMedian patient age was 52 years old, and 88.1% of patients were male. Main or bilateral PVTT was observed in 200 (48.5%) patients. Median radiation dose was 40 Gy (range, 21-60 Gy) delivered in 2- to 5-Gy fractions. We found that 3.6% of patients achieved a complete response and that 24.3% of patients achieved a partial response. The response and progression-free rates of PVTT were 39.6% and 85.6%, respectively. Median patient survival was 10.6 months, and the 1- and 2-year survival rates were 42.5% and 22.8%, respectively. Significant independent variables associated with overall survival included advanced tumor stage, alpha-fetoprotein level, degree of PVTT, and response to radiotherapy. Forty-one patients (10.0%) showed grade 3-4 hepatic toxicity during or 3 months after completion of radiotherapy. Grades 2-3 gastroduodenal complications were observed in 15 patients (3.6%).nnnCONCLUSIONSnRadiotherapy is a safe and effective treatment for PVTT in patients with HCC. These results suggested that the combination of TACE and radiotherapy is a treatment option for relieving and/or stabilizing PVTT in patients with advanced HCC.

Pathologic complete response of primary tumor following preoperative chemoradiotherapy for locally advanced rectal cancer: long-term outcomes and prognostic significance of pathologic nodal status (KROG 09-01).

Objective: To investigate long-term outcomes of locally advanced rectal cancer (LARC) patients with postchemoradiotherapy (post-CRT) pathologic complete response of primary tumor (ypT0) and determine prognostic significance of post-CRT pathologic nodal (ypN) status. Background: LARC patients with post-CRT pathologic complete response were suggested to have favorable long-term outcomes, but prognostic significance of ypN status has never been specifically defined in ypT0 patients. Methods: The Korean Radiation Oncology Group collected clinical data for 333 LARC patients with ypT0 following preoperative CRT and curative radical resections between 1993 and 2007. Sphincter preservation surgery and abdominoperineal resection were performed in 283 (85.0%) and 50 (15.0%) patients, respectively. Postoperative chemotherapy was given to 285 (85.6%) patients. Survival was estimated by the Kaplan-Meier method, and the Cox proportional hazard model was used in multivariate analyses. Results: After median follow-up of 43 (range = 14–172) months, 5-year disease-free survival (DFS) was 84.6% and overall survival (OS) was 92.8%. The ypN status was ypT0N0 in 304 (91.3%), ypT0N1 in 22 (6.6%), and ypT0N2 in 7 (2.1%) patients. The ypN status was the most relevant independent prognostic factor for both DFS and OS in ypT0 patients. The 5-year DFS and OS was 88.5% and 94.8% in ypT0N0 patients, and 45.2% and 72.8% in ypT0N+ patients (both, P < 0.001). Conclusions: LARC patients achieving ypT0N0 after preoperative CRT had favorable long-term outcomes, whereas positive ypN status had a poor prognosis even after total regression of primary tumor.

Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma.

Background Even with early stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult location. Stereotactic body radiation therapy (SBRT) has been established as a standard treatment option for patients with stage I lung cancer, who are not eligible for surgery, and may be a promising alternative treatment for patients with small HCC who are not eligible for curative treatment. Materials and Methods A registry database of 93 patients who were treated with SBRT for HCC between 2007 and 2009 was analyzed. A dose of 10-20 Gy per fraction was given over 3-4 consecutive days, resulting in a total dose of 30-60 Gy. The tumor response was determined using dynamic computed tomography or magnetic resonance imaging, which was performed 3 months after completion of SBRT. Results The median follow-up period was 25.6 months. Median size of tumors was 2 cm (range: 1-6 cm). Overall patients’ survival rates at 1 and 3 years were 86.0% and 53.8%, respectively. Complete and partial tumor response were achieved in 15.5% and 45.7% of patients, respectively. Local recurrence-free survival rate was 92.1% at 3 years. Most local failures were found in patients with HCCs > 3 cm, and local control rate at 3 years was 76.3% in patients with HCC > 3 cm, 93.3% in patients with tumors between 2.1-3 cm, and 100% in patients with tumors ≤ 2 cm, respectively. Out-of-field intrahepatic recurrence-free survival rates at 1 and 3 years were 51.9% and 32.4%, respectively. Grade ≥ 3 hepatic toxicity was observed in 6 (6.5%). Conclusions SBRT was effective in local control of small HCC. SBRT may be a promising alternative treatment for patients with small HCC which is unsuitable for other curative therapy.

Prospective efficacy and safety study of neoadjuvant gemcitabine with capecitabine combination chemotherapy for borderline-resectable or unresectable locally advanced pancreatic adenocarcinoma

BACKGROUNDnTo determine the safety and efficacy of neoadjuvant gemcitabine/capecitabine followed by surgery for the treatment of locally advanced pancreatic adenocarcinoma (LAPC).nnnMETHODSnPatients with histologically confirmed LAPC were given 3-6 cycles of fixed-dose rate gemcitabine/capecitabine every 3 weeks. At the end of chemotherapy, patients were restaged and underwent surgery if the disease was not classified as unresectable. Our institutional criteria were used to classify respectability, which was recategorized on the basis of National Comprehensive Cancer Network (NCCN) criteria retroactively. The primary end point was rate of microscopic curative resection.nnnRESULTSnForty-three eligible patients (18 with borderline resectable disease and 25 with unresectable disease on the basis of NCCN criteria) were enrolled. The radiologic response rate was 18.6%. Grade three or worse adverse events were mainly hand-foot syndrome (11%), and there were no grade four adverse events. Surgery was performed in 17 patients (39.5%); pathologic curative resection (R0) was achieved in 14 patients (32.5%) among total 43 patients, and 82.3% (14/17) among the 17 resected patients. With 43-month follow-up, the median overall was 16.6 months with a median progression-free survival of 10.0 months. Median overall survival was 23.1 months in patients who underwent surgery and 13.2 months in patients who could not complete the surgery (P = .017).nnnCONCLUSIONnA subset of patients with borderline or unresectable pancreatic cancer could be performed curative tumor resection after neoadjuvant chemotherapy. Some patients might be benefit on survival from neoadjuvant chemotherapy after surgical resection.

Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer

Although many trials have shown the efficacy of preoperative chemoradiotherapy (CRT) or postoperative CRT compared with surgery alone, the optimal sequence of radiotherapy and surgery is unclear. The authors reported the final results of this single institution prospective randomized phase 3 trial comparing preoperative CRT with postoperative CRT using capecitabine in survival, local control, sphincter preservation, and toxicity for the treatment of locally advanced rectal cancer.

Radiation-induced liver disease after stereotactic body radiotherapy for small hepatocellular carcinoma: clinical and dose-volumetric parameters

BackgroundTo investigate the clinical and dose–volumetric parameters that predict the risk of radiation-induced liver disease (RILD) for patients with small, unresectable hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT).MethodsBetween March 2007 and December 2009, 92 patients with HCC treated with SBRT were reviewed for RILD within 3xa0months of completing treatment. RILD was evaluated according to the Common Terminology Criteria for Adverse Events, version 3.0. A dose of 10–20xa0Gy (median, 15xa0Gy) per fraction was given over 3–4 consecutive days for a total dose of 30–60xa0Gy (median, 45xa0Gy). The following clinical and dose–volumetric parameters were examined: age, gender, Child-Pugh class, presence of hepatitis B virus, gross tumor volume, normal liver volume, radiation dose, fraction size, mean dose to the normal liver, and normal liver volumes receiving fromu2009<u20095xa0Gy tou2009<u200960xa0Gy (in increments of 5xa0Gy).ResultsSeventeen (18.5%) of the 92 patients developed grade 2 or worse RILD after SBRT (49 patients in grade 1, 11 in grade 2, and 6 inu2009≥u2009grade 3). On univariate analysis, Child-Pugh class was identified as a significant clinical parameter, while normal liver volume and normal liver volumes receiving fromu2009<u200915xa0Gy tou2009<u200960xa0Gy were the significant dose–volumetric parameters. Upon multivariate analysis, only Child-Pugh class was a significant parameter for predicting grade 2 or worse RILD.ConclusionsThe Child-Pugh B cirrhosis was found to have a significantly greater susceptibility to the development of grade 2 or worse RILD after SBRT in patients with small, unresectable HCC. Additional efforts aimed at testing other models to predict the risk of RILD in a large series of HCC patients treated with SBRT are needed.

Postoperative Chemoradiotherapy for Extrahepatic Bile Duct Cancer

PURPOSEnTo evaluate the effect of postoperative concurrent chemoradiotherapy using three-dimensional conformal radiotherapy and to identify the prognostic factors that influence survival in patients with extrahepatic bile duct cancer.nnnMETHODS AND MATERIALSnWe retrospectively analyzed the data from 101 patients with extrahepatic bile duct cancer who had undergone postoperative concurrent chemoradiotherapy using three-dimensional conformal radiotherapy. Of the 101 patients, 52 (51%) had undergone complete resection (R0 resection) and 49 (49%) had microscopic or macroscopic residual tumors (R1 or R2 resection). The median radiation dose was 50 Gy. Also, 85 patients (84%) underwent concurrent chemotherapy with 5-fluorouracil.nnnRESULTSnThe median follow-up period was 47 months for the surviving patients. The 5-year overall survival rate was 34% for all patients. A comparison between patients with R0 and R1 resection indicated no significant difference in the 5-year overall survival (44% vs. 33%, p=.2779), progression-free survival (35% vs. 22%, p=.3107), or locoregional progression-free survival (75% vs. 63%, p=.2784) rates. An analysis of the first failure site in the 89 patients with R0 or R1 resection indicated isolated locoregional recurrence in 7 patients. Elevated postoperative carbohydrate antigen 19-9 level was an independent prognostic factor for overall survival (p=.001) and progression-free survival (p=.033). A total of 3 patients developed Grade 3 or greater late toxicity.nnnCONCLUSIONnAdjuvant concurrent chemoradiotherapy using three-dimensional conformal radiotherapy appears to improve locoregional control and survival in extrahepatic bile duct cancer patients with R1 resection. The postoperative carbohydrate antigen 19-9 level might be a useful prognostic marker to select patients for more intensified adjuvant therapy.

Characteristics and prognosis of patients with colorectal cancer-associated brain metastases in the era of modern systemic chemotherapy

Brain metastases (BM) occur in approximately 20–40% of cancer patients. The present study investigated the clinical outcomes of patients with BM from colorectal cancer (CRC) to assess the benefit of systemic chemotherapy (CT) administered after surgical or radiotherapeutic control of BM and to identify independent prognostic factors associated with survival after BM. Between August 2001 and July 2009, 118 patients with symptomatic BM from CRC received either cranial irradiation or craniotomy at two large cancer centers in South Korea. Retrospective review and statistical analysis of clinical characteristics and outcomes were performed for all patients. Median time from diagnosis of metastatic CRC to detection of BM was 12.2xa0months (range 0–76.2xa0months). Thirteen patients (11%) exhibited brain involvement at initial presentation. Median survival after BM development was 4.1xa0months [95% confidence interval (CI) 3.3–4.9xa0months]. Forty-six patients (40%) had been treated previously with the chemotherapeutic agents fluoropyrimidine, oxaliplatin, and irinotecan. Patients who received CT after BM exhibited significantly improved survival compared with those who did not (12.4 versus 3.1xa0months, respectively; Pxa0<xa00.001). Multivariate analysis revealed that CT intervention after presentation with BM was significantly associated with survival after BM, and the adjusted hazard ratio was 0.30 (95% CI 0.17–0.51, Pxa0<xa00.001). Although BM is a late-stage phenomenon in CRC, approximately two-thirds of patients were still unexposed to irinotecan or oxaliplatin at the development of BM in our study. Thus, additional chemotherapeutic intervention after BM associated with CRC may be beneficial for selected patients.

Four‐dimensional dose evaluation using deformable image registration in radiotherapy for liver cancer

PURPOSEnIn order to evaluate the dosimetric impact of respiratory motion on the dose delivered to the target volume and critical organs during free-breathing radiotherapy, a four-dimensional dose was evaluated using deformable image registration (DIR).nnnMETHODSnFour-dimensional computed tomography (4DCT) images were acquired for 11 patients who were treated for liver cancer. Internal target volume-based treatment planning and dose calculation (3D dose) were performed using the end-exhalation phase images. The four-dimensional dose (4D dose) was calculated based on DIR of all phase images from 4DCT to the planned image. Dosimetric parameters from the 4D dose, were calculated and compared with those from the 3D dose.nnnRESULTSnThere was no significant change of the dosimetric parameters for gross tumor volume (p > 0.05). The increase D(mean) and generalized equivalent uniform dose (gEUD) for liver were by 3.1% ± 3.3% (p = 0.003) and 2.8% ± 3.3% (p = 0.008), respectively, and for duodenum, they were decreased by 15.7% ± 11.2% (p = 0.003) and 15.1% ± 11.0% (p = 0.003), respectively. The D(max) and gEUD for stomach was decreased by 5.3% ± 5.8% (p = 0.003) and 9.7% ± 8.7% (p = 0.003), respectively. The D(max) and gEUD for right kidney was decreased by 11.2% ± 16.2% (p = 0.003) and 14.9% ± 16.8% (p = 0.005), respectively. For left kidney, D(max) and gEUD were decreased by 11.4% ± 11.0% (p = 0.003) and 12.8% ± 12.1% (p = 0.005), respectively. The NTCP values for duodenum and stomach were decreased by 8.4% ± 5.8% (p = 0.003) and 17.2% ± 13.7% (p = 0.003), respectively.nnnCONCLUSIONSnThe four-dimensional dose with a more realistic dose calculation accounting for respiratory motion revealed no significant difference in target coverage and potentially significant change in the physical and biological dosimetric parameters in normal organs during free-breathing treatment.