Harm van Tinteren

Randomized Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Versus Systemic Chemotherapy and Palliative Surgery in Patients With Peritoneal Carcinomatosis of Colorectal Cancer

PURPOSE To confirm the findings from uncontrolled studies that aggressive cytoreduction in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is superior to standard treatment in patients with peritoneal carcinomatosis of colorectal cancer origin. PATIENTS AND METHODS Between February 1998 and August 2001, 105 patients were randomly assigned to receive either standard treatment consisting of systemic chemotherapy (fluorouracil-leucovorin) with or without palliative surgery, or experimental therapy consisting of aggressive cytoreduction with HIPEC, followed by the same systemic chemotherapy regime. The primary end point was survival. RESULTS After a median follow-up period of 21.6 months, the median survival was 12.6 months in the standard therapy arm and 22.3 months in the experimental therapy arm (log-rank test, P =.032). The treatment-related mortality in the aggressive therapy group was 8%. Most complications from HIPEC were related to bowel leakage. Subgroup analysis of the HIPEC group showed that patients with 0 to 5 of the 7 regions of the abdominal cavity involved by tumor at the time of the cytoreduction had a significantly better survival than patients with 6 or 7 affected regions (log-rank test, P <.0001). If the cytoreduction was macroscopically complete (R-1), the median survival was also significantly better than in patients with limited (R-2a), or extensive residual disease (R-2b; log-rank test, P <.0001). CONCLUSION Cytoreduction followed by HIPEC improves survival in patients with peritoneal carcinomatosis of colorectal origin. However, patients with involvement of six or more regions of the abdominal cavity, or grossly incomplete cytoreduction, had still a grave prognosis.

Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial

BACKGROUND Up to 50% of curative surgery for suspected non-small-cell lung cancer is unsuccessful. Accuracy of positron emission tomography (PET) with 18-fluorodeoxyglucose (18FDG) is thought to be better than conventional staging for diagnosis of this malignancy. Up to now however, there has been no evidence that PET leads to improved management of patients in routine clinical practice. We did a randomised controlled trial in patients with suspected non-small-cell lung cancer, who were scheduled for surgery after conventional workup, to test whether PET with 18FDG reduces number of futile thoracotomies. METHODS Before surgery (mediastinoscopy or thoracotomy), 188 patients from nine hospitals were randomly assigned to either conventional workup (CWU) or conventional workup and PET (CWU+PET). Patients were followed up for 1 year. Thoracotomy was regarded as futile if the patient had benign disease, explorative thoracotomy, pathological stage IIIA-N2/IIIB, or postoperative relapse or death within 12 months of randomisation. The primary outcome measure was futile thoracotomy. Analysis was by intention to treat. FINDINGS 96 patients were randomly assigned CWU and 92 CWU+PET. Two patients in the CWU+PET group did not undergo PET. 18 patients in the CWU group and 32 in the CWU+PET group did not have thoracotomy. In the CWU group, 39 (41%) patients had a futile thoracotomy, compared with 19 (21%) in the CWU+PET group (relative reduction 51%, 95% CI 32-80%; p=0.003). INTERPRETATION Addition of PET to conventional workup prevented unnecessary surgery in one out of five patients with suspected non-small-cell lung cancer.

Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial

BACKGROUND Colon cancer is curable by surgery, but cure rate depends on the extent of disease. We investigated whether adjuvant active specific immunotherapy (ASI) with an autologous tumour cell-BCG vaccine with surgical resection was more beneficial than resection alone in stage II and III colon cancer. METHODS In a prospective randomised trial, 254 patients with colon cancer were randomly assigned postoperative ASI or no adjuvant treatment. ASI was three weekly vaccinations starting 4 weeks after surgery, with a booster vaccination at 6 months with 10(7) irradiated autologous tumour cells. The first vaccinations contained 10(7) BCG organisms. We followed up patients for time to recurrence, and recurrence-free and overall survival. Analysis was by intention to treat. FINDINGS The 5.3 year median follow-up (range 8 months to 8 years 11 months) showed 44% (95% CI 7-66) risk reduction for recurrence in the recurrence-free period in all patients receiving ASI (p=0.023). Overall, there were 40 recurrences in the control group and 25 in the ASI group. Analysis by stage showed no significant benefit of ASI in stage III disease. The major impact of ASI was seen in patients with stage II disease, with a significantly longer recurrence-free period (p=0.011) and 61% (18-81) risk reduction for recurrences. Recurrence-free survival was significantly longer with ASI (42% risk reduction for recurrence or death [0-68], p=0.032) and there was a trend towards improved overall survival. INTERPRETATION ASI gave significant clinical benefit in surgically resected patients with stage II colon cancer. ASI has minimal adverse reactions and should be considered in the management of stage II colon cancer.

Prognostic Relevance of Response Evaluation Using [18F]-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography in Patients With Locally Advanced Non–Small-Cell Lung Cancer

PURPOSE The objective of this study was to determine the accuracy of (early) response measurements using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG PET) with respect to survival of patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC) undergoing induction chemotherapy (IC), with a comparative analysis of PET methods. PATIENTS AND METHODS In a prospective multicenter study, PET was performed in patients before IC and after one and three cycles. Computed tomography (CT) was performed before and after IC. Glucose consumption (metabolic rate of glucose [MRglu]) was measured using Patlak graphical analysis and correlated with simplified methods. Mediastinal lymph node (MLN) status was assessed visually. Cox proportional hazards analysis was used to determine the prognostic relevance of CT and PET measures of response with respect to survival. RESULTS Complete PET data sets were available in 47 patients. Median survival was 21 months. MLN status after IC by PET predicted survival (hazard ratio [HR], 2.33; 95% CI, 1.04 to 5.22; P = .04) in contrast with CT (HR, 1.87; 95% CI, 0.81 to 4.30; P = .14). Residual MRglu after IC proved to be the best prognostic factor (HR, 1.95; 95% CI, 1.28 to 2.97; P = .002). Multivariate stepwise analysis showed that PET identified prognostically different strata in patients considered responsive according to CT. Residual MRglu after one cycle selected patients with different outcomes (HR, 2.04; 95% CI, 1.18 to 3.52; P = .01). Simplified quantitative 18FDG PET methods were correlated with Patlak graphical analysis during and after therapy (r > or = 0.90). CONCLUSION 18FDG PET has additional value over CT in monitoring response to IC in patients with stage IIIA-N2 NSCLC, and it seems feasible to predict survival early during IC. Simple semiquantitative and complex PET methods perform equally well.

Squamous Cell Carcinoma of the Penis. IV. Prognostic Factors of Survival: Analysis of Tumor, Nodes and Metastasis Classification System

Various prognostic factors of survival were assessed in 118 patients with squamous cell carcinoma of the penis treated at The Netherlands Cancer Institute between 1956 and 1989. Using the clinical parameters of the tumor, nodes and metastasis classification system of the International Union Against Cancer (1978 version) and a differentiation system consisting of 3 grades the prognostic relevance for survival was analyzed. T category, N category and grade of differentiation showed statistical significance in the univariate analysis. Patients with small tumors, clinically negative nodes and well differentiated tumors showed a favorable prognosis. Only N category and grade were independent prognostic factors of survival using the Cox proportional hazards model. On the basis of the survival analysis a stage grouping consisting of 3 stages is proposed with 5-year survival probabilities for stages 1, 2 and 3 of 93%, 55% and 30%, respectively. A revised version of the tumor, nodes and metastasis system was introduced in 1987. This latest version was analyzed with the previous method, which was used in this report, and prognostically important and clinically useful parameters, such as the size of the primary tumor and evidence of fixation of the regional lymph nodes, have been discarded. The changes in the revised version seem to have little relevance to clinical staging. The revised version should be considered a histopathological classification only.

Squamous Cell Carcinoma of the Penis. III. Treatment of Regional Lymph Nodes

We analyzed the management of regional lymph nodes in 110 patients with squamous cell carcinoma of the penis treated at the Netherlands Cancer Institute between 1956 and 1989 with curative intent. Of 66 patients who presented with unsuspected nodes 57 were placed on a surveillance program, while lymph node dissection was performed in 5 (with adjuvant external radiation therapy in 1) and 4 were treated with external radiation therapy only. The management of 40 patients with clinically suspected nodes included surveillance in 5, lymph node dissection in 27 (with adjuvant radiotherapy in 11), biopsy in 4 and external radiation therapy in 4. Postoperative radiotherapy had been given if more than 2 nodes were involved or when extracapsular growth was observed. Overall, 25 patients had a regional recurrence, 5 of whom could be cured subsequently. All regional recurrences developed within 2 years after primary treatment. Analysis showed 100% survival in histologically proved node negative patients (stage pN0). The success of lymph node dissection was related to the extent of the metastatic spread and to the number of involved nodes. Patients with 1 positive node and unilateral inguinal involvement showed a statistically significant survival advantage compared to patients with more extensive spread. Considering the indications for node dissection we found a clear relationship among T category, grade and the probability of lymph node invasion. Patients with stage T1 tumors and stage T2, grades 1 and 2 tumors presented significantly less often with lymphatic invasion than those with other categories of disease and were less likely to have a regional recurrence after treatment of the primary tumor only. In these categories we recommend surveillance of the regional lymph nodes in patients who present with unsuspected nodes. However, patients with stage T2 grade 3, stage T3 and operable stage T4 tumors should undergo an immediate inguinal node dissection because of the high probability of clinically occult lymph node invasion (in our material more than 50%). With respect to the extent of the node dissection, we found that the likelihood of spread to the contralateral and/or pelvic regions was related to the number of invaded nodes in the inguinal region. We recommend contralateral node dissection and unilateral pelvic node dissection when 2 or more positive nodes are found in the dissected groin specimen. Primary pelvic node dissection should be performed in patients who present initially with cytologically or biopsy proved positive inguinal nodes.(ABSTRACT TRUNCATED AT 400 WORDS)

Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group

BACKGROUND The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. METHODS In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the studys primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637. FINDINGS Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36-57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56-0·81, p<0·0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 [23%] patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups. INTERPRETATION Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life. FUNDING Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis.

Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial

BACKGROUND Most patients with extensive stage small-cell lung cancer (ES-SCLC) who undergo chemotherapy, and prophylactic cranial irradiation, have persistent intrathoracic disease. We assessed thoracic radiotherapy for treatment of this patient group. METHODS We did this phase 3 randomised controlled trial at 42 hospitals: 16 in Netherlands, 22 in the UK, three in Norway, and one in Belgium. We enrolled patients with WHO performance score 0-2 and confirmed ES-SCLC who responded to chemotherapy. They were randomly assigned (1:1) to receive either thoracic radiotherapy (30 Gy in ten fractions) or no thoracic radiotherapy. All underwent prophylactic cranial irradiation. The primary endpoint was overall survival at 1 year in the intention-to-treat population. Secondary endpoints included progression-free survival. This study is registered with the Nederlands Trial Register, number NTR1527. FINDINGS We randomly assigned 498 patients between Feb 18, 2009, and Dec 21, 2012. Three withdrew informed consent, leaving 247 patients in the thoracic radiotherapy group and 248 in the control group. Mean interval between diagnosis and randomisation was 17 weeks. Median follow-up was 24 months. Overall survival at 1 year was not significantly different between groups: 33% (95% CI 27-39) for the thoracic radiotherapy group versus 28% (95% CI 22-34) for the control group (hazard ratio [HR] 0.84, 95% CI 0.69-1.01; p=0.066). However, in a secondary analysis, 2-year overall survival was 13% (95% CI 9-19) versus 3% (95% CI 2-8; p=0.004). Progression was less likely in the thoracic radiotherapy group than in the control group (HR 0.73, 95% CI 0.61-0.87; p=0.001). At 6 months, progression-free survival was 24% (95% CI 19-30) versus 7% (95% CI 4-11; p=0.001). We recorded no severe toxic effects. The most common grade 3 or higher toxic effects were fatigue (11 vs 9) and dyspnoea (three vs four). INTERPRETATION Thoracic radiotherapy in addition to prophylactic cranial irradiation should be considered for all patients with ES-SCLC who respond to chemotherapy. FUNDING Dutch Cancer Society (CKTO), Dutch Lung Cancer Research Group, Cancer Research UK, Manchester Academic Health Science Centre Trials Coordination Unit, and the UK National Cancer Research Network.

Angiosarcoma of the breast after conservation therapy for invasive cancer, the incidence and outcome. An unforeseen sequela

Purpose. In the past 15 years breast conserving therapy (BCT) has become an important treatment option for primary breast cancer. Thirty three angiosarcomas (AS) after BCT have been described in a total of 20 published reports. Limited follow-up data and the lack of information on incidence of AS prompted the authors to review the comprehensive experience in the Netherlands. Methods. Between 1987 and 1995 twenty-one patients with BCT-associated AS were diagnosed in the Netherlands. Follow-up after diagnosis of AS ranged from 6 to 82 months with a median of 24 months. Information on the total number of patients treated with BCT and on the numbers of angiosarcoma in the breast was obtained. Results. The median interval between BCT and AS was 74 months (range: 29–106) and appeared to decrease with higher age. Detection of skin changes followed by incisional biopsy provided the diagnosis. Two year overall (OS) and disease free survivals were 72% (s.e. 10.9) and 35% (s.e. 10.7), respectively. Two year OS after initial complete surgical resection was 86% (s.e. 9.3) compared to 0% after incomplete resection of the AS (P=0.04). The estimated incidence of AS after BCT is 0.16%. Conclusions. BCT-associated AS arises after a relatively short interval. Although the incidence of AS is low, the absolute number of patients at risk is increasing. This calls for vigilance concerning skin changes occurring after BCT. An incisional biopsy provides the only reliable diagnosis. The prognosis appears to be related to the completeness of surgical resection.

Overall survival and PD-L1 expression in metastasized malignant melanoma.

Cancers are known to elude the immune system, for example, by MHC loss, FAS up‐regulation, or increased secretion of TGF‐beta. Recently, ligands of coinhibitory receptors like programmed cell death ligand–1 (PD‐L1, B7‐H1) have come to attention for their role in tumor immune escape. Various tumors have been tested for PD‐L1 expression, and conflicting results were obtained regarding its correlative impact on patient survival. This study aimed to determine the prognostic relevance of PD‐L1 expression for the survival of melanoma patients.