G. van Tienhoven

Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer

BACKGROUND The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).

Prognosis after Treatment for Loco-regional Recurrence after Mastectomy or Breast Conserving Therapy in Two Randomised Trials (EORTC 10801 and DBCG-82TM)

The aim of this study was to investigate and compare the prognosis after treatment for loco-regional recurrences (LR) after (modified) radical mastectomy (MRM) or breast conserving therapy (BCT), in terms of overall survival and time to subsequent LR, in patients originally treated in two European randomised trials. In EORTC trial 10801 and DBCG trial 82-TM, 1,807 patients with stage I and II breast cancer were randomised to receive MRM or BCT from 1980 to 1989. All patients with a LR in these trials were analysed for survival and time to subsequent LR after salvage treatment. Of these, 133 patients had their LR as a first event, the majority within 5 years after initial treatment. The prognostic significance for survival and time to subsequent LR after salvage treatment was analysed in uni-, and multivariate analyses for a number of original tumour- and recurrence-related variables. After salvage treatment of LR after MRM or BCT, actuarial survival curves and the actuarial locoregional control curves were similar. The 5-year survival rates were 58% and 59% and the 5-year subsequent loco-regional control rates 62% and 63%, respectively. In a multivariate analysis, pN category (P = 0.03), pT category (P = 0.01) and vascular invasion (P = 0.02) of the primary tumour were the only independent prognostic factors for survival, whereas extensive LR (P < 0.001), interval < or = 2 years (P < 0.002) and pN+ at primary treatment (P = 0.004) were significant predictive factors for time to subsequent LR. The type of original treatment (MRM or BCT) did not have any prognostic impact. It is concluded that the survival and time to subsequent LR after treatment for an early loco-regional recurrence after MRM or BCT was similar in these two European randomised trials. This suggests that both after MRM and BCT an early LR is an indicator of a biologically aggressive tumour; early loco-regional relapse carries a poor prognosis and salvage treatment only cures a limited number of patients, whether treated by MRM or BCT originally.

Accuracy in tangential breast treatment set-up: a portal imaging study

To test the accuracy and reproducibility of the tangential breast treatment set-up used in The Netherlands Cancer Institute, a portal imaging study was performed in 12 patients treated for early stage breast cancer. With an on-line electronic portal imaging device (EPID) images were obtained of each patient in several fractions and compared with simulator films and with each other. In five patients, multiple images (on the average 7) per fraction were obtained to evaluate set-up variations due to respiratory movement. The central lung distance (CLD) and other set-up parameters varied within one fraction about 1 mm (1 SD). The average variation of these parameters between various fractions was about 2 mm (1 SD). The differences between simulator and treatment set-up over all patients and all fractions was on the average 2-3 mm for the central beam edge to skin distance and the central lung distance. It can be concluded that the tangential breast treatment set-up is very stable and reproducible and that respiration does not have a significant influence on treatment volume. The EPID appears to be an adequate tool for studies of treatment set-up accuracy like this.

Quality assurance in conservative treatment of early breast cancer. Report on a consensus meeting of the EORTC Radiotherapy and Breast Cancer Cooperative Groups and the EUSOMA (European Society of Mastology).

A consensus on a quality assurance programme of the treatment of early breast cancer was reached in a multidisciplinary meeting of surgeons, pathologists, radiotherapists, physicists and radiographers. Guidelines for treatment preparation and execution have been set up, including careful location and excision with marking of the primary tumour. The target volumes for irradiation of the whole breast and boost area have been defined. Radiation dose prescription rules, specification and checking procedures are given, together with measures to achieve a homogeneous dose within the target volume. The rules for a quality assurance programme in each clinic are designed for checking equipment and treatment method.

Biopsy diagnosis of intraductal carcinoma is prognostic in intermediate and high risk prostate cancer patients treated by radiotherapy

AIM We investigated the prognostic significance of intraductal carcinoma of the prostate (IDC-P) in biopsies and transurethral resections prior to external beam radiotherapy with or without androgen deprivation. METHODS Cohort 1 consisted of 118 intermediate risk prostate cancer patients treated by radiotherapy, with biochemical relapse as primary end-point (median follow-up 6.5 years). Cohort 2 consisted of 132 high risk patients, enrolled in a phase III randomised trial (EORTC 22863) comparing radiotherapy alone to radiotherapy with long-term androgen deprivation (LTAD) with clinical progression free survival as primary end-point (median follow-up 9.1 years). Presence of IDC-P was identified after central review. Multivariable regression modelling and Kaplan-Meier analysis were performed with IDC-P as dichotomous variable. RESULTS IDC-P was a strong prognosticator for early (<36 months) biochemical relapse (HR 7.3; p = 0.007) in cohort 1 and for clinical disease-free survival in both arms of cohort 2 (radiotherapy arm: HR 3.5; p < 0.0001; radiotherapy plus LTAD arm: HR 2.8, p = 0.018). IDC-P retained significance after stratification for reviewed Gleason score in the radiotherapy arm (HR 2.3; p = 0.03). IDC-P was a strong prognosticator for metastatic failure rate (radiotherapy arm: HR 5.3; p < 0.0001; radiotherapy plus LTAD arm: HR 3.6; p = 0.05). CONCLUSIONS IDC-P in diagnostic samples of patients with intermediate or high risk prostate cancer is an independent prognosticator of early biochemical relapse and metastatic failure rate after radiotherapy. We suggest that the presence of IDC-P in prostate biopsies should routinely be reported.

Multidisciplinary management of hilar cholangiocarcinoma (Klatskin tumor): extended resection is associated with improved survival

BACKGROUND Effective diagnosis and treatment of patients with hilar cholangiocarcinoma (HCCA) is based on the synergy of endoscopists, interventional radiologists, radiotherapists and surgeons. This report summarizes the multidisciplinary experience in management of HCCA over a period of two decades at the Academic Medical Center in Amsterdam, with emphasis on surgical outcome. METHODS From 1988 until 2003, 117 consecutive patients underwent resection on the suspicion of HCCA. Preoperative work-up included staging laparoscopy, preoperative biliary drainage, assessment of volume/function of future remnant liver and radiation therapy to prevent seeding metastases. More aggressive surgical approach combining hilar resection with extended liver resection was applied as of 1998. Outcomes of resection including actuarial 5-year survival were assessed. RESULTS Eighteen patients (15.3%) appeared to have a benign lesion on microscopical examination of the specimen, leaving 99 patients with histologically proven HCCA. These 99 patients were analysed according to three 5-year time periods of resection, i.e. period 1 (1988-1993, n=45), 2 (1993-1998, n=25) and 3 (1998-2003, n=29). The rate of R0 resections increased and actuarial five-year survival significantly improved from 20±5% for the periods 1 and 2, to 33±9% in period 3 (p<0.05). Postoperative morbidity and mortality in the last period were 68% and 10%, respectively. CONCLUSION Extended surgical resection resulted in increased rate of R0 resections and significantly improved survival. Candidates for resection should be considered by a specialized, multidisciplinary team.

Quality assurance of the EORTC trial 22881/10882: “assessment of the role of the booster dose in breast conserving therapy”: the Dummy Run

The EORTC trial 22881/10882 is a randomised trial with the aim to assess the role of the boost dose in breast conserving therapy in stage I and II breast cancer. In order to detect potential protocol deviations concerning irradiation technique and in the dose specification procedure of participating institutions before actual patient accrual, a Dummy Run was performed. Three transverse sections of a patient were sent to 16 participating institutions with a request to make a three-plane treatment plan according to the protocol prescriptions. A treatment chart and beam data were also requested for recalculation of the dose. Additional information was asked in a questionnaire. On evaluation, the techniques differed considerably with respect to photon beam energy, varying between 60Co gamma-rays and 8 MV X-rays, and the use of wedge filters. Two institutions did not apply wedges, whereas wedge angles in the other institutions varied between 6 degrees and 45 degrees. Twelve institutions used collimator rotation and/or a table wedge to diminish the amount of irradiated lung volume. The dose was specified in a point according to the protocol prescription in 11 institutions and to the 90, 95 or 100% isodose curve in four. Twelve institutions applied lung density corrections during treatment planning, while nine reported problems with their planning system in off-axis dose distribution calculation and/or the simulation of collimator rotation. Recalculation of the dose at the isocentre showed agreement within 2% compared with the stated dose. The dose reported in the tumour excision area varied between 93 and 100%.(ABSTRACT TRUNCATED AT 250 WORDS)

EORTC guidelines for writing protocols for clinical trials of radiotherapy.

The concept of a Master Protocol for phase III studies was raised at the Steering Committee of the EORTC Radiotherapy Group, in order to make the work of the study coordinators easier, when writing protocols and to give them more homogeneity. The Master Protocol defines and clarifies in a logical order the different steps which must be taken when designing a randomized trial--from the rationale to the references. It pays particular attention to eligibility criteria, volumes of interest defined in agreement with ICRU Report 50 (gross tumor volume, clinical target volume, planning target volume and organs at risk), simulation procedure, treatment technique, normal tissue sparing, dose computation, equipment, dose specification (also in agreement with ICRU Report 50). Last but not least, the different procedures of quality assurance for protocols and patients are also defined (site visits, dummy run procedure, in vivo dosimetry, individual case review) to allow working plans to be made in advance. We are aware that this work is not exhaustive, but hope that the contents will be of help to those who are writing a protocol.

New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.

Quality assurance of EORTC trial 22922/10925 investigating the role of internal mammary—medial supraclavicular irradiation in stage I-III breast cancer: the individual case review

To assess consistency among participants in an European Organisation for Research and Treatment of Cancer (EORTC) phase III trial randomising between irradiation and no irradiation of the internal mammary and medial supraclavicular (IM-MS) lymph nodes, all participating institutes were invited to send data from 3 patients in each arm as soon as they started accrual. The evaluation focused on eligibility, compliance with the radiotherapy guidelines, treatment techniques and dose prescription to the IM-MS region. Nineteen radiotherapy departments provided a total of 111 cases, all being eligible. Minor discrepancies were found in the surgery and pathology data in almost half the patients. Major radiotherapy protocol deviations were very limited: 2 cases of unwarranted irradiation of the supraclavicular region and a significant dose deviation to the internal mammary region in 5 patients. The most frequently observed minor protocol deviation was the absence of delineation of the target volumes in 80% of the patients. By detecting systematic protocol deviations in an early phase of the trial, recommendations made to all the participating institutes should improve the interinstitutional consistency and promote a high-quality treatment.