Jannet C. Beukema

Patterns of Recurrence After Surgery Alone Versus Preoperative Chemoradiotherapy and Surgery in the CROSS Trials

PURPOSE To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone. PATIENTS AND METHODS Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin. RESULTS Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery. CONCLUSION Preoperative CRT in patients with esophageal cancer reduced LRR and peritoneal carcinomatosis. Recurrence within the radiation target volume occurred in only 5%, mostly combined with outfield failures.

Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer – the RAPIDO trial

BackgroundCurrent standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer.Methods and designPatients with rectal cancer with high risk features for local or systemic failure on magnetic resonance imaging are randomized to either a standard arm or an experimental arm. The standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine) preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative chemotherapy is optional and may be omitted by participating institutions. The experimental arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy (capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no postoperative chemotherapy is prescribed. Surgery is performed according to TME principles in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant chemotherapy increases disease-free and overall survival without compromising local control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include overall survival, local control, toxicity profile, and treatment completion rate, rate of pathological complete response and microscopically radical resection, and quality of life.DiscussionFollowing the advances in rectal cancer management, increased focus on survival rather than only on local control is now justified. In an experimental arm, short-course radiotherapy is combined with full-dose chemotherapy preoperatively, an alternative that offers advantages compared to concomitant chemoradiotherapy with or without postoperative chemotherapy. In a multi-centre setting this regimen is compared to current standard with the aim of improving survival for patients with locally advanced rectal cancer.Trial registrationClinicalTrials.gov NCT01558921

A systematic review on the role of FDG-PET/CT in tumour delineation and radiotherapy planning in patients with esophageal cancer

PURPOSE FDG-PET/CT has proven to be useful in the staging process of esophageal tumours. This review analysed the role of FDG-PET/CT in tumour delineation and radiotherapy planning in comparison with CT alone among patients with esophageal cancer. Thereby we focused on the detection of the primary tumour and lymph nodes by FDG-PET/CT, changes in target volume (TV) delineation based on FDG-PET/CT and its validity, changes in inter- and intra-observer variability in TV delineation, consequences for radiotherapy treatment planning with regard to either target volumes or organs at risk and finally on the validation of FDG-PET/CT-based TVs in terms of treatment outcome. METHODS A literature search was performed in MEDLINE and Cochrane library databases for studies concerning the current value of FDG-PET/CT in tumour detection and delineation and radiotherapy-planning procedures among patients with esophageal cancer. Both prospective and retrospective studies were included. RESULTS Fifty publications met the eligibility criteria, of which 19 were review papers and one was a case report. The remaining 30 publications reported on the results of original studies. FDG-PET was able to identify most primary tumours, with a sensitivity and specificity for the detection of metastatic lymph nodes of 30-93% and 79-100%. The use of FDG-PET/CT resulted in changes of target volumes, and consequently in changes in treatment planning. However, evidence supporting the validity of the use of FDG-PET/CT in the tumour delineation process is very limited. Only three studies reported a significant positive correlation between FDG-PET-based tumour lengths and pathological findings. There were two studies that tested the influence of FDG-PET/CT to the inter- and intra-observer variability. One of them found a significant decrease in inter- and intra-observer variability, while the others did not. Furthermore, there are no studies demonstrating the use of PET/CT in terms of improved locoregional control or survival. CONCLUSION Since the literature is very limited standard implementation of FDG-PET/CT into the tumour delineation process for radiation treatment seems unjustified and needs further clinical validation first.

Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: prognostic and therapeutic impact on survival.

Objectives:We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT. Background:Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently “sterilize” regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. Methods:Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups. Results:One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12–27) and 14 (9–21), with 2 (1–6) and 0 (0–1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P = 0.007), but not in the multimodality arm (hazard ratio 1.00; P = 0.98). Conclusions:The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

Consequences of additional use of PET information for target volume delineation and radiotherapy dose distribution for esophageal cancer

BACKGROUND AND PURPOSE To determine the consequences of target volume (TV) modifications, based on the additional use of PET information, on radiation planning, assuming PET/CT-imaging represents the true extent of the tumour. MATERIALS AND METHODS For 21 patients with esophageal cancer, two separate TVs were retrospectively defined based on CT (CT-TV) and co-registered PET/CT images (PET/CT-TV). Two 3D-CRT plans (prescribed dose 50.4 Gy) were constructed to cover the corresponding TVs. Subsequently, these plans were compared for target coverage, normal tissue dose-volume histograms and the corresponding normal tissue complication probability (NTCP) values. RESULTS The addition of PET led to the modification of CT-TV with at least 10% in 12 of 21 patients (57%) (reduction in 9, enlargement in 3). PET/CT-TV was inadequately covered by the CT-based treatment plan in 8 patients (36%). Treatment plan modifications resulted in significant changes (p<0.05) in dose distributions to heart and lungs. Corresponding changes in NTCP values ranged from -3% to +2% for radiation pneumonitis and from -0.2% to +1.2% for cardiac mortality. CONCLUSIONS This study demonstrated that TVs based on CT might exclude PET-avid disease. Consequences are under dosing and thereby possibly ineffective treatment. Moreover, the addition of PET in radiation planning might result in clinical important changes in NTCP.

A comparison of carboplatin and paclitaxel with cisplatinum and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients

BACKGROUND In esophageal cancer (EC) patients who are not eligible for surgery, definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard chemotherapy regimen. Nowadays carboplatin/paclitaxel is also often used. In this study, we compared survival and toxicity rates between both regimens. PATIENTS AND METHODS This multicenter study included 102 patients treated in five centers in the Northeast Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU (75 mg/m(2) and 1 g/m(2)) and 55 patients carboplatin/paclitaxel (AUC2 and 50 mg/m(2)). RESULTS Overall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group {[P = 0.879, hazard ratio (HR) 0.97 [confidence interval (CI) 0.62-1.51]}, with a median survival of 16.1 (CI 11.8-20.5) and 13.8 months (CI 10.8-16.9). Median disease-free survival (DFS) was comparable [P = 0.760, HR 0.93 (CI 0.60-1.45)] between the cisplatinum/5-FU group [11.1 months (CI 6.9-15.3)] and the carboplatin/paclitaxel group [9.7 months (CI 5.1-14.4)]. Groups were comparable except clinical T stage was higher in the carboplatin/paclitaxel group (P = 0.008). High clinical T stage (cT4) was not related to OS and DFS in a univariate analysis (P = 0.250 and P = 0.201). A higher percentage of patients completed the carboplatin/paclitaxel regimen (82% versus 57%, P = 0.010). Hematological and nonhematological toxicity (≥grade 3) in the carboplatin/paclitaxel group (4% and 18%) was significantly lower than in the cisplatinum/5-FU (19% and 38%, P = 0.001). CONCLUSIONS In this study, we showed comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared with cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment of cisplatinum/5-FU is a good candidate regimen for further evaluation.BACKGROUND In esophageal cancer (EC) patients who are not eligible for surgery, definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard chemotherapy regimen. Nowadays carboplatin/paclitaxel is also often used. In this study, we compared survival and toxicity rates between both regimens. PATIENTS AND METHODS This multicenter study included 102 patients treated in five centers in the Northeast Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU (75 mg/m2 and 1 g/m2) and 55 patients carboplatin/paclitaxel (AUC2 and 50 mg/m2). RESULTS Overall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group {[P = 0.879, hazard ratio (HR) 0.97 [confidence interval (CI) 0.62-1.51]}, with a median survival of 16.1 (CI 11.8-20.5) and 13.8 months (CI 10.8-16.9). Median disease-free survival (DFS) was comparable [P = 0.760, HR 0.93 (CI 0.60-1.45)] between the cisplatinum/5-FU group [11.1 months (CI 6.9-15.3)] and the carboplatin/paclitaxel group [9.7 months (CI 5.1-14.4)]. Groups were comparable except clinical T stage was higher in the carboplatin/paclitaxel group (P = 0.008). High clinical T stage (cT4) was not related to OS and DFS in a univariate analysis (P = 0.250 and P = 0.201). A higher percentage of patients completed the carboplatin/paclitaxel regimen (82% versus 57%, P = 0.010). Hematological and nonhematological toxicity (≥grade 3) in the carboplatin/paclitaxel group (4% and 18%) was significantly lower than in the cisplatinum/5-FU (19% and 38%, P = 0.001). CONCLUSIONS In this study, we showed comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared with cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment of cisplatinum/5-FU is a good candidate regimen for further evaluation.

Target volume delineation variation in radiotherapy for early stage rectal cancer in the Netherlands

PURPOSE The aim of this study was to measure and improve the quality of target volume delineation by means of national consensus on target volume definition in early-stage rectal cancer. METHODS AND MATERIALS The CTVs for eight patients were delineated by 11 radiation oncologists in 10 institutes according to local guidelines (phase 1). After observer variation analysis a workshop was organized to establish delineation guidelines and a digital atlas, with which the same observers re-delineated the dataset (phase 2). Variation in volume, most caudal and cranial slice and local surface distance variation were analyzed. RESULTS The average delineated CTV volume decreased from 620 to 460 cc (p<0.001) in phase 2. Variation in the caudal CTV border was reduced significantly from 1.8 to 1.2 cm SD (p=0.01), while it remained 0.7 cm SD for the cranial border. The local surface distance variation (cm SD) reduced from 1.02 to 0.74 for anterior, 0.63 to 0.54 for lateral, 0.33 to 0.25 for posterior and 1.22 to 0.46 for the sphincter region, respectively. CONCLUSIONS The large variation in target volume delineation could significantly be reduced by use of consensus guidelines and a digital delineation atlas. Despite the significant reduction there is still a need for further improvement.

Systematic review of the role of a belly board device in radiotherapy delivery in patients with pelvic malignancies

PURPOSE This review analyses the literature concerning the influence of the patient position (supine, prone and prone on a belly board device (BB) on the irradiated small-bowel-volume (SB-V)) and the resulting morbidity of radiation therapy (RT) in pelvic malignancies. METHODS A literature search was performed in MEDLINE, web of science and Scopus. RESULTS Forty-six full papers were found, of which 33 met the eligibility criteria. Fifteen articles focussed on the irradiated SB-V using dose volume histograms (DVHs). Twenty-seven articles studied the patient setup in different patient positions. This review showed that a prone treatment position can result in a lower irradiated SB-V as compared to a supine position, but a more significant reduction of the SB-V can be reached by the additional use of a BB in prone position, for both 3D-CRT and IMRT treatment plans. This reduction of the irradiated SB-V might result in a reduced GI-morbidity. The patient position did not influence the required PTV margins for prostate and rectum. CONCLUSIONS The irradiated SB-V can be maximally reduced by the use of a prone treatment position combined with a BB for both 3D-CRT and IMRT, which might individually result in a reduction of GI-morbidity.

Is cardiac toxicity a relevant issue in the radiation treatment of esophageal cancer

PURPOSE In recent years several papers have been published on radiation-induced cardiac toxicity, especially in breast cancer patients. However, in esophageal cancer patients the radiation dose to the heart is usually markedly higher. To determine whether radiation-induced cardiac toxicity is also a relevant issue for this group, we conducted a review of the current literature. METHODS A literature search was performed in Medline for papers concerning cardiac toxicity in esophageal cancer patients treated with radiotherapy with or without chemotherapy. RESULTS The overall crude incidence of symptomatic cardiac toxicity was as high as 10.8%. Toxicities corresponded with several dose-volume parameters of the heart. The most frequently reported complications were pericardial effusion, ischemic heart disease and heart failure. CONCLUSION Cardiac toxicity is a relevant issue in the treatment of esophageal cancer. However, valid Normal Tissue Complication Probability models for esophageal cancer are not available at present.

Prolonged time to surgery after neoadjuvant chemoradiotherapy increases histopathological response without affecting survival in patients with esophageal or junctional cancer

Objective:To determine the relation between time to surgery (TTS) after neoadjuvant chemoradiotherapy (nCRT) and pathologically complete response (pCR), surgical outcome, and survival in patients with esophageal cancer. Background:Standard treatment for potentially curable esophageal cancer is nCRT plus surgery after 4 to 6 weeks. In rectal cancer patients, evidence suggests that prolonged TTS is associated with a higher pCR rate and possibly with better survival. Methods:We identified patients treated with nCRT plus surgery for esophageal cancer between 2001 and 2011. TTS (last day of radiotherapy to day of surgery) varied mainly for logistical reasons. Minimal follow-up was 24 months. The effect of TTS on pCR rate, postoperative complications, and survival was determined with (ordinal) logistic, linear, and Cox regression, respectively. Results:In total, 325 patients were included. Median TTS was 48 days (p25–p75 = 40–60). After 45 days, TTS was associated with an increased probability of pCR [odds ratio (OR) = 1.35 per additional week of TSS, P = 0.0004] and a small increased risk of postoperative complications (OR = 1.20, P < 0.001). Prolonged TTS had no effect on disease-free and overall survivals (HR = 1.00 and HR = 1.06 per additional week of TSS, P = 0.976 and P = 0.139, respectively). Conclusions:Prolonged TTS after nCRT increases the probability of pCR and is associated with a slightly increased probability of postoperative complications, without affecting disease-free and overall survivals. We conclude that TTS can be safely prolonged from the usual 4 to 6 weeks up to at least 12 weeks, which facilitates a more conservative wait-and-see strategy after neoadjuvant chemoradiotherapy to be tested.