Individual Case Review Research Articles

Differences in Endpoints between the Swedish W-E (Two County) Trial of Mammographic Screening and the Swedish Overview: Methodological Consequences

To characterize and quantify the differences in the number of cases and breast cancer deaths in the Swedish W-E Trial compared with the Swedish Overview Committee (OVC) summaries and to study methodological issues related to trials in secondary prevention. The study population of the W-E Trial of mammography screening was included in the first (W and E county) and the second (E-county) OVC summary of all Swedish randomized mammography screening trials. The OVC and the W-E Trial used different criteria for case definition and causes of death determination. A Review Committee compared the original data files from W and E county and the first and second OVC. The reason for a discrepancy was determined individually for all non-concordant cases or breast cancer deaths. Of the 2615 cases included by the W-E Trial or the OVC, there were 478 (18%) disagreements. Of the disagreements 82% were due to inclusion/exclusion criteria, and 18% to disagreement with respect to cause of death or vital status at ascertainment. For E-County, the OVC inclusion rules and register based determination of cause of death (second OVC) rather than individual case review (W-E Trial and 1st OVC) resulted in a reduction of the estimate of the effect of screening, but for W-County the difference between the original trial and the OVC was modest. The conclusion that invitation to mammography screening reduces breast cancer mortality remains robust. Disagreements were mainly due to study design issues, while disagreements about cause of death were a minority. When secondary research does not adhere to the protocols of the primary research projects, the consequences of such design differences should be investigated and reported. Register linkage of trials can add follow-up information. The precision of trials with modest size is enhanced by individual monitoring of case status and outcome status such as determination of cause of death.

Identifying mild cognitive impairment at baseline in the Ginkgo Evaluation of Memory (GEM) study

Objectives: To identify, characterize and compare the frequency of mild cognitive impairment (MCI) subtypes at baseline in a large, late-life cohort (n = 3063) recruited into a dementia prevention trial. Method: A retrospective, data-algorithmic approach was used to classify participants as cognitively normal or MCI with corresponding subtype (e.g. amnestic vs. non-amnestic, single domain vs. multiple domain) based on a comprehensive battery of neuropsychological test scores, with and without Clinical Dementia Rating (CDR) global score included in the algorithm. Results: Overall, 15.7% of cases (n = 480) were classified as MCI. Amnestic MCI was characterized as unilateral memory impairment (i.e. only verbal or only visual memory impaired) or bilateral memory impairment (i.e. both verbal and visual memory impaired). All forms of amnestic MCI were almost twice as frequent as non-amnestic MCI (10.0% vs. 5.7%). Removing the CDR = 0.5 (‘questionable dementia’) criterion resulted in a near doubling of the overall MCI frequency to 28.1%. Conclusion: Combining CDR and cognitive test data to classify participants as MCI resulted in overall MCI and amnestic MCI frequencies consistent with other large community-based studies, most of which relied on the ‘gold standard’ of individual case review and diagnostic consensus. The present data-driven approach may prove to be an effective alternative for use in future large-scale dementia prevention trials.

Quality assurance in the 22991 EORTC ROG trial in localized prostate cancer: Dummy run and individual case review

Introduction EORTC trial 22991 was designed to evaluate the addition of concomitant and adjuvant short-term hormonal treatments to curative radiotherapy in terms of disease-free survival for patients with intermediate risk localized prostate cancer. In order to assess the compliance to the 3D conformal radiotherapy protocol guidelines, all participating centres were requested to participate in a dummy run procedure. An individual case review was performed for the largest recruiting centres as well. Materials and methods CT-data of an eligible prostate cancer patient were sent to 30 centres including a description of the clinical case. The investigator was requested to delineate the volumes of interest and to perform treatment planning according to the protocol. Thereafter, the investigators of the 12 most actively recruiting centres were requested to provide data on five randomly selected patients for an individual case review. Results Volume delineation varied significantly between investigators. Dose constraints for organs at risk (rectum, bladder, hips) were difficult to meet. In the individual case review, no major protocol deviations were observed, but a number of dose reporting problems were documented for centres using IMRT. Conclusions Overall, results of this quality assurance program were satisfactory. The efficacy of the combination of a dummy run procedure with an individual case review is confirmed in this study, as none of the evaluated patient files harboured a major protocol deviation. Quality assurance remains a very important tool in radiotherapy to increase the reliability of the trial results. Special attention should be given when designing quality assurance programs for more complex irradiation techniques.

Anastomotic Leaks after Bowel Resection: What Does Peer Review Teach Us about the Relationship to Postoperative Mortality?

Anastomotic leak is a dreaded complication of intestinal surgery and has been associated with a high mortality rate. But it is uncertain exactly which patient populations are at risk of death from the leak. We sought to assess the impact of surgeon volume on leak rate and to better understand the relationship of a leak to postoperative mortality. All adult patients having a small or large bowel resection with anastomosis at a university hospital from July 2003 to June 2006 were entered into a prospectively maintained quality database; data were entered by a specially trained nurse practitioner who rounded daily with housestaff. Patients with a postoperative leak based on standardized criteria were identified. Patient characteristics, surgical procedure, and operating surgeon were noted. Overall complication and leak rates by surgeon were compared using Fisher's exact test. Individual case review by a group of peers was performed for all patients with a leak who died, to determine the relationship to mortality. Five hundred fifty-six patients underwent resection with anastomosis during the study period. There were 27 patients with leaks (4.9%), 6 of whom died. Leak rate for the highest-volume surgeons ranged from 1.6% to 9.9% (p <0.01), and overall complication rate varied from 30.5% to 44% (p=0.04). In four of six deaths, leaks occurred in very ill patients undergoing emergency procedures and appeared to be premorbid events. In only one patient did the leak appear to be the primary cause of death. The variability in leak rate by surgeons doing similar operations suggests that many leaks may be preventable. But death after a leak is most often a surrogate for a critically ill patient and was infrequently the actual cause of death.

Quality Assurance of Radiotherapy in Cancer Treatment: Toward Improvement of Patient Safety and Quality of Care

The process of radiotherapy (RT) is complex and involves understanding of the principles of medical physics, radiobiology, radiation safety, dosimetry, radiation treatment planning, simulation and interaction of radiation with other treatment modalities. Each step in the integrated process of RT needs quality control and quality assurance (QA) to prevent errors and to give high confidence that patients will receive the prescribed treatment correctly. Recent advances in RT, including intensity-modulated and image-guided RT, focus on the need for a systematic RTQA program that balances patient safety and quality with available resources. It is necessary to develop more formal error mitigation and process analysis methods, such as failure mode and effect analysis, to focus available QA resources optimally on process components. External audit programs are also effective. The International Atomic Energy Agency has operated both an on-site and off-site postal dosimetry audit to improve practice and to assure the dose from RT equipment. Several countries have adopted a similar approach for national clinical auditing. In addition, clinical trial QA has a significant role in enhancing the quality of care. The Advanced Technology Consortium has pioneered the development of an infrastructure and QA method for advanced technology clinical trials, including credentialing and individual case review. These activities have an impact not only on the treatment received by patients enrolled in clinical trials, but also on the quality of treatment administered to all patients treated in each institution, and have been adopted globally; by the USA, Europe and Japan also.

General practitioners' experiences of the psychological aspects in the care of a dying patient

General practitioners (GPs) play an integral role in addressing the psychological needs of palliative care patients and their families. This qualitative study investigated psychosocial issues faced by GPs in the management of patients receiving palliative care and investigated the themes relevant to the psychosocial care of dying patients. Fifteen general practitioners whose patient had been recently referred to the Mt. Olivet Palliative Home Care Services in Brisbane participated in an individual case review discussions guided by key questions within a semistructured format. These interviews focused on the psychosocial aspects of care and management of the referred patient, including aspects of the doctor/patient relationship, experience of delivering diagnosis and prognosis, addressing the psychological concerns of the patients' family, and the doctors' personal experiences, reactions, and responses. Qualitative analysis was conducted on the transcripts of these interviews. The significant themes that emerged related to perceived barriers to exploration of emotional concerns, including spiritual issues, and the discussion of prognosis and dying, the perception of patients' responses/coping styles, and the GP's personal experience of the care (usually expressed in terms of identification with patient). The findings indicate the significant challenges facing clinicians in discussions with patients and families about death, to exploring the patient's emotional responses to terminal illness and spiritual concerns for the patient and family. These qualitative date indicate important tasks in the training and clinical support for doctors providing palliative care.

Quality Assurance in the EORTC Randomized Trial 22922/10925 Investigating the Role of Irradiation of the Internal Mammary and Medial Supraclavicular Lymph Node Chain Works

A quality assurance (QA) program in conjunction with the EORTC trial investigating the role of adjuvant internal mammary and medial supraclavicular irradiation in stage I-III breast cancer is presented. The results of a dummy run procedure and of an individual case review are compared to each other. The effects of recommendations based on QA procedures on the protocol compliance are evaluated. Prior to protocol activation all participating institutes were asked to produce treatment plans according to the guidelines of the protocol based on manual outlines of an average patient. Thereafter, they were asked to provide data on each of their first six randomized patients. The dummy run provided a lot of information on specific treatment techniques. In the individual case review, additional patient- and tumor-related data were collected, showing the use of anatomic information for treatment planning. A comparison between both procedures revealed that the individual case reports concurred more accurately with protocol guidelines than the dummy run. It was observed that the number of systematic protocol deviations was substantially decreased in trial patients compared to the dummy run case. Therefore, it is concluded that this extensive QA program had a positive effect on the consistency of all institutes participating in the trial.

3–40 Quality Assurance in the EORTC Phase III Randomised ‘Boost Vs No Boost’ Trial for Breast Conserving Therapy: Comparison of the Results of Two Individual Case Reviews Performed Early and Late During the Accrual Period

3–40 Quality Assurance in the EORTC Phase III Randomised ‘Boost Vs No Boost’ Trial for Breast Conserving Therapy: Comparison of the Results of Two Individual Case Reviews Performed Early and Late During the Accrual Period

Quality assurance of radiotherapy in the Japan Clinical Oncology Group trial 0211 concerning concurrent chemoradiotherapy for localized nasal NK/T-cell lymphoma: The individual case review

17561 Background: It is challenging to conduct a high quality multi-institutional clinical trial for localized nasal NK/T-cell lymphoma due to the anatomical complexity and its rarity. The purpose of this study was to evaluate the compliance with protocol guidelines in concurrent chemoradiotherapy for this disease among radiotherapy institutions participating in a multi-center phase I/II JCOG trial 0211. Methods: The treatment consisted of radiotherapy 50 Gy and 3 cycles of DeVIC chemotherapy [carboplatin, etoposide, ifosfamide, dexamethasone] (Yamaguchi M, et al.: Proc ASH, 2005). CT-based three-dimensional treatment planning was required to cover adequately target volumes and to minimize doses to organs at risk such as the eyes, the brain stem and the spinal cord. Patient data were sent to the review center after the treatments have been finalized. The following parameters were evaluated by the quality assurance review board: treatment records and charts; simulation films; portal images; prescribed dose; dose fractionation and overall treatment time; dose distributions; and dose to risk organs. Results: At the time of phase I analysis, 10 patients were enrolled in this study. In 2 of 10 cases, process of treatment planning was not available. There was no protocol violation. Major deviations were identified as follows: Delineation of clinical target volume (&lt; 2 cm from the edge of the gross tumor volume at any direction), 2/10; dose distribution (not covered by 90%-115% isodose line), 1/10; and dose to optic chiasm (&gt;40 Gy), 1/10. All cases were compliant in prescribed dose, dose fractionation, and overall treatment time. In the last 4 of 10 cases, attending radiation oncologists at the participating institutions were contacted by the radiation oncology study chair and they discussed the treatment planning just after patient enrollment. These 4 cases were all protocol compliant compared to 6 cases with 4 major deviations. Conclusions: Individual case review is essential in a multi-center clinical trial to keep enrolled cases protocol compliant and minimize inter-institutional variations. We expect that our quality assurance program will maintain the quality of the JCOG trial 0211. No significant financial relationships to disclose.

In‐utero intervention for hypoplastic left heart syndrome — a perinatologist's perspective

.Today,whenHLHSisdiagnosedinthenewborn,or suspected by prenatal ultrasound studies, surgicalinterventions typically take one of two directions – eitherthe multistaged reconstruction pioneered by Norwood toenable single ventricle survival or cardiac transplantation.Compassionate care, although increasingly controversial,remains an option in some centers. Although increasingsurvival rates following both multi-staged surgery ortransplant are being reported, the nature of theseinterventions is such that these children remain at lifelongrisk for cardiac and neurologic morbidity.Consideration of HLHS as a candidate for

The effect of terminations of pregnancy for fetal abnormalities on trends in mortality to one year of age in Western Australia

Summary highlighted the contribution of birth defects. Over this time there has also been an increasing number of terminations of pregnancy for fetal abnormality. However, the effect of these terminations on mortality rates in Australia has not yet been estimated. The Western Australian Birth Defects Registry (BDR) records all birth defects that are diagnosed in stillbirths, livebirths and in pregnancies terminated because of a fetal abnormality. All cases on the BDR over the period 1980-98 were categorised into one of eight main birth defect groups and analysed in four time periods to show trends. Linkage provided information on deaths to one year of age, defined as perinatal plus postneonatal deaths. The proportion of terminations for fetal abnormality that would have resulted in a death before one year of age was estimated in two ways. The first method used the proportion of births with a birth defect in each diagnostic category that resulted in a death. The second method involved determination of likelihood of survival to one year of all terminations for fetal abnormality through independent review by two experts. Whilst mortality to one year of age for all birth defects has declined from 4.36/1000 births in 1980-84 to 2.75/1000 births in 1995-98, terminations of pregnancies for fetal abnormalities increased from 1.19/1000 births to 4.70/1000 births. After including the estimated mortality associated with terminations for fetal abnormality, the decline in mortality to one year of age associated with birth defects from 1980 to 1998 changed from a 37% reduction to a 15% reduction based on observed mortality 1980-84, and an 11% increase in mortality based on individual case review, highlighting the importance of considering terminations in mortality analyses.

Quality assurance in the EORTC phase III randomised ‘boost vs. no boost’ trial for breast conserving therapy: Comparison of the results of two individual case reviews performed early and late during the accrual period

Background and purposeTo evaluate the impact of quality assurance on treatment compliance, we compared the outcome of the two individual case reviews (ICR) conducted early and late during the accrual period of a large prospective multi-centre trial. Patients and methodsAt the onset of the trial, medical files of five patients from each participating centre were evaluated for the compliance to the protocol for eligibility, surgery, pathology and radiotherapy and for the quality of reporting of the data on the case report forms. In nine major centres, this procedure was repeated near the end of the trial. ResultsBoth in the early and the late ICR, we found a very limited number of deviations from the guidelines for eligibility, staging, surgery, and pathology. Compliance to radiotherapy requirements was good with the exception of a too low minimal dose in 30% and the lack of target volume delineation in the majority of the evaluated patients. The comparison of the late with the early ICR demonstrated an improvement of the quality of data reporting by 6% and of target volume delineation from 33 to 53%. ConclusionsThe initial ICR has lead to the identification of a number of parameters, which needed a clarification in the protocol. These items have been corrected and the individual institutions have been made aware of the necessary adaptations. The evaluation at the end of the trial period showed that there was an improvement but also showed that continuous monitoring is necessary, especially for institutions which have the most deviations in the first ICR.

999 poster Quality assurance in the EORTC trial 22991: the individual case review

999 poster Quality assurance in the EORTC trial 22991: the individual case review

579 Quality assurance in the EORTC phase III randomised ‘boost versus no boost’ trial in breast conserving therapy: evaluation and comparison of the two individual case reviews done at the beginning and at the end of the accrual period

579 Quality assurance in the EORTC phase III randomised ‘boost versus no boost’ trial in breast conserving therapy: evaluation and comparison of the two individual case reviews done at the beginning and at the end of the accrual period

Radiotherapy (RT) and concomitant and adjuvant temozolomide (TMZ) versus radiotherapy alone for newly diagnosed glioblastoma (GBM): Overall results and recursive partitioning analysis (RPA) of a phase III randomized trial of the EORTC brain tumor and radiotherapy groups and the NCIC clinical trial group

The standard initial treatment for patients with GBM after biopsy or surgical resection is post-operative radiotherapy. Chemotherapy was shown to have only a minimal impact on outcome. In a previous phase II trial, we have suggested that adding TMZ to RT might improve survival (Stupp et al. JCO 20:1375–1382, 2002). In EORTC 26981/22981 NCIC CE3 we compared the efficacy of concomitant and adjuvant TMZ and RT to RT alone. Patients with newly diagnosed and histologically proven GBM (WHO grade IV), PS (WHO) 0–2, age 18–70 were eligible. The randomization was between standard RT (60 Gy in 30 daily fractions of 2 Gy, with a GTV-CTV margin of 2–3 cm), versus the same RT with concomitant TMZ (75 mg/m2 daily 7d/week for 35–42 d), followed by up to 6 cycles of adjuvant TMZ (150–200 mg/m2, daily × 5 d, q 28 d). Patients were stratified for institution, age, PS and extent of surgery. Primary endpoint was overall survival (OS) and secondary endpoints were progression free survival (PFS), quality of life and full toxicity profile. Pathology was centrally reviewed and quality control for RT was assessed by individual case reviews. Between July 2000 and March 2002, a total of 573 patients were randomized by 85 institutions. Sixteen percent of patients had a biopsy only, and 84 % had either partial (44 %) or complete (40 %) surgical tumor removal. Median age was 56 years (19–70.5), 63 % were male. PS was 0, 1 and 2 in 39 %, 48 % and 13 % of patients respectively. There was no difference in the prognostic factors between the two treatment arms. RT was delivered as prescribed in 93 % of patients, concomitant TMZ was administered without interruption in 76 % and temporarily interrupted in 11 %. Adjuvant TMZ was given to 76 % of patients and 36 % completed all 6 cycles. With a median follow-up of 2 years, 436 patients have died, 241 (84 %) in the control (RT only) arm and 195 (68 %) in the experimental (RT/TMZ) arm. Median survival was 12 months (95% c.i. 11.2–13.2) in the RT arm and 15 months (95% c.i. 13.6–16.8) in the RT/TMZ arm (p < .0001), and 2 year survivals were 8 % (95% c.i. 4–12 %) and 26 % (95% c.i. 20–32 %), respectively (p < .0001). The difference between the two treatment arms remained statistically significant in RPA classes III-V. Additional results and detailed analysis of prognostic classes will be presented. Concomitant and adjuvant TMZ/RT significantly improves overall survival compared to RT alone in newly diagnosed glioblastoma, regardless of the prognostic class

Quality assurance of the EORTC 26981/22981; NCIC CE3 intergroup trial on radiotherapy with or without temozolomide for newly-diagnosed glioblastoma multiforme: the individual case review

The phase III randomised European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trail Group (NCIC) Intergroup trial (EORTC 26981/22981; CE3) compares irradiation alone with irradiation plus temozolomide for patients with glioblastoma multiforme (GBM). We evaluated the compliance to radiotherapy (RT) guidelines. All 85 recruiting centres were invited to participate in the individual case review. Fifty-four centres (64%) entering 71% of the patients provided data on one randomly selected patient. All participating centres used individual head immobilisation and computerised tomography (CT)-based treatment planning. Most (74%) performed three-dimensional conformal radiotherapy (3-D-CRT) including dose–volume histograms. Ninety-four percent performed portal imaging at least once. Planning target volume (PTV) and structures at risk were delineated in most of the centres (94%). Although the PTV received <95% of the prescription dose (60 Gy in 2 Gy/fraction/day) in 39% of the centres; all except 2 centres delivered 50–60 Gy to the PTV. The maximum dose to the critical structures exceeded the protocol dose constraints in 39% of the reviewed patients, but in only 9% was this over the acceptable tolerance dose reported in the literature. We found a high rate of compliance with the protocol and general RT guidelines in the centres participating in this individual case review. In multicentre trials with a large of number of investigators from international and national groups, it is essential to confirm the interinstitutional consistency, qualitatively and quantitatively.

476 Quality assurance report of EORTC 26981/22981 trial on radiotherapy vs radiotherapy and temozolomide for newly diagnosed glioblastoma multiforme: individual case review

476 Quality assurance report of EORTC 26981/22981 trial on radiotherapy vs radiotherapy and temozolomide for newly diagnosed glioblastoma multiforme: individual case review

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.

476 Poster Quality assurance of the EORTC trial 22921 concerning pre-operative radiotherapy with or without chemotherapy for resectable rectal cancer: evaluation of the individual case review procedure

476 Poster Quality assurance of the EORTC trial 22921 concerning pre-operative radiotherapy with or without chemotherapy for resectable rectal cancer: evaluation of the individual case review procedure

Quality assurance in the EORTC 22921 trial on preoperative radiotherapy with or without chemotherapy for resectable rectal cancer: evaluation of the individual case review procedure

The aim of this study was to assess any inconsistency with the protocol guidelines for preoperative radiotherapy for rectal cancer among radiotherapy institutions participating in the framework of a multicentre phase-III European Organization for Research and Treatment of Cancer (EORTC) clinical trial. Twelve radiotherapy departments with more than 10% of the evaluable patients recruited in the trial, were invited to participate in this individual case review. Participating institutions were asked to send five full patient records with the chemotherapy charts, surgical and pathology reports, radiation treatment charts, treatment planning calculations, computed tomography (CT) scans, portal images and follow-up charts. The sample of the 5 patients per institution was randomly selected at the EORTC Data Center. All 12 departments participated. In 21 (35%) of the cases, a three-field technique with two lateral opposed wedge fields and a posterior field was used, while in 39 (65%) of the cases a four-field pelvic box technique was used. All participants used linear accelerators with a minimum of 6 MeV photon-beam energy. In general, the patients were eligible, documentation of clinical data was fair to good and there were no systematic major protocol deviations. The actual total dose was 44.7±a standard deviation (S.D.) of 4.6 Gy. Some variation was found in the fraction size. All institutions complied with the protocol in specifying the reference dose at the ICRU point. The clinical target volume (CTV) drawn on the CT scan was narrow in 7 (12%) cases, but eventually the actually treated volumes in terms of planned treatment volume (PTV) were correct. In two institutions, although the CTV was drawn correctly, the fields appeared to be narrow especially in cranio-caudal direction. Variations in treated volumes and total radiation dose were encountered in the individual case review. By providing recommendations early during the course of the trial, we expect to improve the inter-institutional consistency and to promote a high quality treatment in all of the participating institutions.