Surgical quality control in an international randomized clinical trial.

One of the current international prospective clinical trials of the EORTC Melanoma Cooperative Group explores the usage of regional isolated perfusion as adjuvant in melanomas located on the extremities. In the design of the study it is necessary to define not only the extent of the surgery (perfusion+local excision versus local excision only), but also to ensure uniformity of surgery performed between surgeons and institutions. With on-site visits and general meetings with the participants, surgical protocol violations and misinterpretations of the protocol could be avoided. The conclusion is that accurate surgical quality control is time consuming, but not difficult.     

Registration for a large-scale randomized controlled trial of postsurgical adjuvant chemotherapy for lung cancer in Japan

Background. The reliability of results obtained from clinical trials depends on the study design and its implementation, but there are few reports on implementation. We aimed to describe one component of implementation, registration problems, as observed in a large-scale randomized trial of postsurgical adjuvant chemotherapy for lung cancer whose subjects were enrolled during the period from 1994 to 1997. Methods. The trial adopted central registration through telephone or facsimile entry at a randomization center. Unexpected entry processes were counted prospectively, with the reason noted. The time from the start of speaking on the telephone to entry completion was measured automatically by a computer system. Results. The office registered 999 of 1054 patient reports after checking eligibility criteria. Reasons for failure to meet the criteria were: age (22 patients), late entry – more than 6 weeks after surgery (10 patients), histology (8 patients), entry from hospitals for which the contract for trial participation had not been completed (5 patients), and other (10 patients). Among the 999 registered cases (807 telephone entries and 192 facsimile entries), 50 cases (5.0%) showed a lack of information on eligibility criteria on the first call: 17 made by telephone (2.1%) and 33 by facsimile (17.2%). The average time for registration by telephone was 2 min 51 s among the 766 registrations completed without problems on the first call. The busiest hours for the entry calls were 9:00 to 10:00 and 15:30 to 17:00. There was no difference in the number of entry calls among the days from Monday to Friday. Conclusion. Actual registration of a large-scale cancer trial in Japan was documented, which provided useful information for both the trial centers and the doctors engaging in clinical trials. Received: January 5, 1997 / Accepted: January 11, 1999     

Liquid-based cytology versus conventional Papanicolaou smear in an organized screening program : a prospective randomized study

BACKGROUND: The objective of this study was to evaluate whether liquid-based cytology (LBC) can improve high-standard cervical cancer screening cytology further. The primary endpoint was histopathologic high-grade lesions in current and subsequent screening rounds. The secondary endpoints were cytologic diagnosis and inadequate samples. METHODS: Women were randomized to smear taking by conventional Papanicolaou (Pap) smear or LBC according to the time of appointment. Eight thousand eight hundred ten conventional Pap smears and 4674 LBC samples were included. Evaluations of atypical cytology and referral to colposcopy and treatment were performed as routine procedures. Histopathologic diagnoses were retrieved from a regional database 8 months after the study was closed. The mean follow-up was 2 years and 9 months. RESULTS: Inadequate samples were observed in 0.3% of LBC samples versus 0.7% of Pap smears (P = .002). The total fraction of nonbenign diagnoses in cytology was 4.5% versus 3.5%, respectively (P < .001). Histopathologic evaluation was made on 570 patients constituting 4.6% of the LBC samples and 4% of the Pap smears. Forty percent more high-grade lesions were identified as a result of LBC sampling (1.20% vs 0.85%; P = .05). The influence of the sampling method was significant for all variables (odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.12-2.28) for high-grade lesions that were identified by histology when adjusting for age and screening unit in a logistic regression model. At the second follow-up 2 years and 1 month later, the OR was decreased only slightly (1.51; 95% CI, 1.13-2.01). CONCLUSIONS: In the ongoing cervical screening program of western Sweden, liquid cytology produced a significantly higher yield of histologic high-grade lesions compared with conventional Pap smears.     

TPF plus cetuximab induction chemotherapy followed by biochemoradiation with weekly cetuximab plus weekly cisplatin or carboplatin: a randomized phase II EORTC trial

BackgroundOur aim was to test the safety of cetuximab added to chemoradiation with either cisplatin or carboplatin after prior induction chemotherapy.MethodsPatients with stage III/IV unresectable, squamous cell carcinoma of the head and neck received up to four cycles of TPF-E (cisplatin and docetaxel 75 mg/m² on day 1 followed by 5-FU 750 mg/m²/day as a continuous infusion on days 1–5 plus cetuximab at a loading dose of 400 mg/m² followed by a weekly dose of 250 mg/m²), with prophylactic antibiotics but no growth factors. Patients not progressing after four cycles of TPF-E were randomly assigned to radiotherapy (70 Gy over 7 weeks in 2 Gy fractions) and weekly cetuximab with either weekly cisplatin 40 mg/m² or carboplatin, AUC of 1.5 mg/ml/min. Primary endpoint was feasibility.ResultsForty-seven patients were recruited. One patient did not start TPF (hypersensitivity reaction during the cetuximab loading dose). Induction TPF-E was discontinued in 12 patients due to toxicity (6 patients), medical decision (2), death (1), patient refusal (1), protocol violation (1), co-morbidity (1). Three further patients were not randomized [progressive disease (1), protocol violation (1), toxicity and co-morbidity (1)]. Of particular interest are three patients who suffered from bowel perforation, one patient who died as results of pneumonia and septic shock, and a second patient who was found dead at home 12 days after starting TPF-E (cause of death unknown). Weekly cisplatin and carboplatin was stopped early in seven and four patients, respectively. Radiotherapy was stopped in two patients with cisplatin and interrupted in one patient with cisplatin and four patients with carboplatin.ConclusionsThe addition of cetuximab to full dose TPF induction chemotherapy led to unacceptable complications and premature closing of the study. Only 34 out of 46 patients completed four cycles of TPF-E and only 30 started biochemoradiation.     

Analysis of cause-specific failure endpoints using simple proportions: an example from a randomized controlled clinical trial in early breast cancer

Purpose: To describe a statistically valid method for analyzing cause-specific failure data based on simple proportions, that is easy to understand and apply, and outline under what conditions its implementation is well-suited.

Methods and Materials: In the comparison of treatment groups, time to first failure (in any site) was analyzed first, followed by an analysis of the pattern of first failure, preferably at the latest complete follow-up time common to each group.

Results: A retrospective analysis of time to contralateral breast cancer in 777 early breast cancer patients was undertaken. Patients previously treated by mastectomy plus radiation therapy to the chest wall and regional nodal areas were randomized to receive further radiation and prednisone (R+P), radiation alone (R), or no further treatment (NT). Those randomized to R+P had a statistically significantly delayed time to first failure compared to the group randomized to NT (p = 0.0008). Patients randomized to R also experienced a delayed time to first failure compared to NT, but the difference was not statistically significant (p = 0.14). At 14 years from the date of surgery (the latest common complete follow-up time) the distribution of first failures was statistically significantly different between R+P and NT (p = 0.005), but not between R and NT (p = 0.09). The contralateral breast cancer first failure rate at 14 years from surgery was 7.2% for NT, 4.6% for R, and 3.7% for R+P. The corresponding Kaplan–Meier estimates were 13.2%, 8.2%, and 5.4%, respectively.

Conclusion: Analyzing cause-specific failure data using methods developed for survival endpoints is problematic. We encourage the use of the two-step analysis strategy described when, as in the example presented, competing causes of failure are not likely to be statistically independent, and when a treatment comparison at a single time-point is clinically relevant and feasible; that is, all patients have complete follow-up to this point.     

Superiority of second over first generation chemotherapy in a randomized trial for stage III-IV intermediate and high-grade non-Hodgkin's lymphoma (NHL): the 1980-1985 EORTC trial. The EORTC Lymphoma Group.

A first-generation CHOP-like cyclic combination chemotherapy (CT) regimen using cyclophosphamide 600 mg/m2 IV d1, hydroxorubicin (doxorubicin) 50 mg/m2 IV d1, VM26 60 mg/m2 IV d1, and prednisone 40 mg/m2 PO d1-5 (CHVmP) was compared to a second-generation combination wherein vincristine 1.4 mg/m2 IV and bleomycin 6 mg/m2 IM/IV were added at mid-interval (d15) to the former drugs (CHVmP + VB) in the treatment of intermediate- and high-grade malignant NHL. From April 1980 to January 1986, 141 eligible patients with stage III-IV unfavorable histologies (except T lymphoblastic NHL) entered this EORTC randomized trial. In both arms adjuvant radiotherapy (30 Gy) was given in instances of bulky or residual disease. In all patient subsets the outcome favored the second-generation regimen. The difference was even greater in patients with Diffuse Large Cell Lymphoma (DLCL). At 5 years, overall survival was 53% with CHVmP + VB versus 29% (p = 0.002). The advantage was due to a higher complete remission (CR) rate (80% versus 50%, p = 0.01). Indeed, once CR was achieved the relapse-free survival (RFS) was not significantly influenced (59% versus 49%). No significant additional toxicity could be attributed to vincristine and bleomycin. This study demonstrates a clear benefit for intermediate- and high-risk malignant NHL and particularly DLCL from intercalating non-myelotoxic drugs at mid-cycle intervals, without adverse effects.     

Promising results with exemestane in the first-line treatment of metastatic breast cancer: a randomized phase II EORTC trial with a tamoxifen control

Because tamoxifen (TAM), a nonsteroidal antiestrogen, is routinely used in the adjuvant setting, other hormone therapies are needed as alternatives for first-line treatment of metastatic breast cancer (MBC). Currently, exemestane (EXE) and other antiaromatase agents are indicated for use in patients who experience failure of TAM. In this multicenter, randomized, open-label, TAM-controlled (20 mg/day), phase II trial, we examined the activity and tolerability of EXE 25 mg/day for the first-line treatment of MBC in postmenopausal women. Exemestane was well tolerated and demonstrated substantial first-line antitumor activity based on intent-to-treat analysis of peer-reviewed responses. In the EXE arm, values for complete, partial, and objective response, clinical benefit, and time to tumor progression (TTP) exceeded those reported for TAM although no statistical comparison was made. Based on these encouraging results, a phase III trial will compare EXE and TAM.     

Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial

BackgroundIn uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM.Patients and methodsPatients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m² on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points.ResultsAccrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25–6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79–1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45–0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths.ConclusionHIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental.EudraCT number and ClinicalTrials.gov identifier2004-002245-12 and NCT00110123.     

Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy.

EORTC protocol 22791 compared once daily fractionation (CF) of 70 Gy in 35-40 fractions in 7-8 weeks, to pure hyperfractionation (HF) of 80.5 Gy in 70 fractions in 7 weeks using 2 fractions of 1.15 Gy per day, in T2-T3 oropharyngeal carcinoma (excluding base of tongue), N0,N1 of less than 3 cm. From 1980 to 1987, 356 patients were entered. In the final analysis (June 1990), the local control was significantly higher (p = 0.02 log-rank) after HF compared with CF. At 5 years, 59% of patients are local disease-free in the HF arm compared to 40% in the CF arm. The superiority of HF was demonstrated in patients staged T3N0,T3N1 but not in T2. The Cox model confirmed that the treatment regimen was an independent significant prognostic factor for locoregional control (p = 0.007 log-rank). This improvement of locoregional control was responsible for a trend to an improved survival (p = 0.08 log-rank). There was no difference in late normal tissue damage between the two treatment modalities.     

Variations in diagnostic and therapeutic procedures in a multicentre, randomized clinical trial (EORTC 10853) investigating breast-conserving treatment for DCIS.

AIMS: To evaluate the diagnostic and therapeutic procedures which were followed in a European Organization for Research and Treatment of Cancer (EORTC) randomized clinical trial investigating the role of radiotherapy in breast-conserving treatment (BCT) for ductal carcinoma in situ (DCIS) of the breast. METHODS: The medical files of 824 of the 1010 randomized patients (82%) were reviewed during site visits to 30 participating institutes. RESULTS: Large variations occurred, particularly in the surgical procedures and histopathological work-up which were performed. Important risk factors like tumour size and margin status were poorly quantified in the medical files. CONCLUSIONS: These findings emphasize the need for establishing uniform guidelines for diagnostic and therapeutic procedures for DCIS, and for clearly defined risk factors for recurrence after BCT for DCIS. Because of its randomized nature, the main question of the trial, i.e. the effect of radiotherapy on the risk of local recurrence, will not be influenced by variation. The risk of local recurrence in itself, and hence the success of BCT for DCIS, may however be influenced by the quality of the initial procedures that were conducted. Copyright Harcourt Publishers Limited.     

Promoting culturally appropriate colorectal cancer screening through a health educator: a randomized controlled trial

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer mortality in the US. Surveys reveal low CRC screening levels among Asians in the US, including Chinese Americans. METHODS: A randomized controlled trial was conducted with Chinese patients to evaluate a clinic-based, culturally and linguistically appropriate intervention promoting fecal occult blood test (FOBT) screening. The multifaceted intervention included a trilingual and bicultural health educator, bilingual materials (a video, a motivational pamphlet, an informational pamphlet, and FOBT instructions), and three FOBT cards. Patients in the control arm received usual care. Our primary outcome measure was FOBT screening within 6 months after randomization. The proportion of FOBT completion in the intervention and control arms was compared by using a chi-square test, and logistic regression analysis was performed to adjust for the effects of sociodemographic variables and prior screening history. Potential effect modifications were also tested by using logistic regression models. RESULTS: Our intervention had a strong effect on FOBT completion (intervention group, 69.5%; control group, 27.6%), and the adjusted odds of FOBT slightly increased to over 6-fold greater in the intervention arm compared with the control arm. No effect modification by age, gender, language, insurance, or prior FOBT was found. CONCLUSIONS: The authors' multifaceted, culturally appropriate intervention significantly increased FOBT screening in a group of low-income and less-acculturated minority patients. Given the large effect size, future research should determine the effective core component(s) that can increase CRC screening in both the general and minority populations.     

Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial

Background

Histopathological diagnosis of diffuse gliomas is subject to interobserver variation and correlates modestly with major prognostic and predictive molecular abnormalities. We investigated a series of patients with locally diagnosed anaplastic oligodendroglial tumors included in the EORTC phase III trial 26951 on procarbazine/lomustine/vincristine (PCV) chemotherapy to explore the diagnostic, prognostic, and predictive value of targeted next-generation sequencing (NGS) in diffuse glioma and to assess the prognostic impact of FUBP1 and CIC mutations.

Methods

Mostly formalin-fixed paraffin-embedded samples were tested with targeted NGS for mutations in ATRX, TP53, IDH1, IDH2, CIC, FUBP1, PI3KC, TERT, EGFR, H3F3A, BRAF, PTEN, and NOTCH and for copy number alterations of chromosomes 1p, 19q, 10q, and 7. TERT mutations were also assessed, with PCR.

Results

Material was available from 139 cases, in 6 of which results were uninformative. One hundred twenty-six tumors could be classified: 20 as type II (IDH mutation [mut], “astrocytoma”), 49 as type I (1p/19q codeletion, “oligodendroglioma”), 55 as type III (7+/10q– or TERTmut and 1p/19q intact, “glioblastoma”), and 2 as childhood glioblastoma (H3F3Amut), leaving 7 unclassified (total 91% classified). Molecular classification was of clear prognostic significance and correlated better with outcome than did classical histopathology. In 1p/19q codeleted tumors, outcome was not affected by CIC and FUBP1 mutations. MGMT promoter methylation remained the most predictive factor for survival benefit of PCV chemotherapy.

Conclusion

Targeted NGS allows a clinically relevant classification of diffuse glioma into groups with very different outcomes. The diagnosis of diffuse glioma should be primarily based on a molecular classification, with the histopathological grade added to it. Future discussion should primarily aim at establishing the minimum requirements for molecular classification of diffuse glioma.     

Hypnotherapy in radiotherapy patients: a randomized trial

PURPOSE: To determine whether hypnotherapy reduces anxiety and improves the quality of life in cancer patients undergoing curative radiotherapy (RT). METHODS AND MATERIALS: After providing written informed consent, 69 patients were randomized between standard curative RT alone (36 controls) and RT plus hypnotherapy (33 patients). Patients in the hypnotherapy group received hypnotherapy at the intake, before RT simulation, before the first RT session, and halfway between the RT course. Anxiety was evaluated by the State-Trait Anxiety Inventory DY-1 form at six points. Quality of life was measured by the Rand Medical Outcomes Study 36-item Health Survey (SF-36) at five points. Additionally, patients answered a questionnaire to evaluate their experience and the possible benefits of this research project. RESULTS: No statistically significant difference was found in anxiety or quality of life between the hypnotherapy and control groups. However, significantly more patients in the hypnotherapy group indicated an improvement in mental (p <0.05) and overall (p <0.05) well-being. CONCLUSION: Hypnotherapy did not reduce anxiety or improve the quality of life in cancer patients undergoing curative RT. The absence of statistically significant differences between the two groups contrasts with the hypnotherapy patients' own sense of mental and overall well-being, which was significantly greater after hypnotherapy. It cannot be excluded that the extra attention by the hypnotherapist was responsible for this beneficial effect in the hypnotherapy group. An attention-only control group would be necessary to control for this effect.     

EORTC workshop on clinical trial methodology in older individuals with a diagnosis of solid tumors

BackgroundDue to the aging of the population, the number of older patients diagnosed with a malignant disease is increasing. A multidisciplinary approach to the senior adult cancer patient is mandatory, to assure optimal diagnosis and therapeutic management.DesignEuropean Organisation for Research and Treatment of Cancer (EORTC) has currently defined senior adult oncology as one of its priorities and has established an active Elderly Task Force (ETF). Under the auspices of the EORTC, the ETF organized a workshop on clinical trial methodology in older cancer patients and in this article, we present the conclusions of this workshop.ResultsBesides the ‘classical’ efficacy end points, quality of life, functional status and independence of the patient should be assessed in clinical trials in older patients. The participants of the workshop agreed on the use of a minimum dataset for the assessment of global health and functional status in older cancer patients. The panel also recommended that optimization of collaboration with pharmaceutical industry requires reporting of age-related data (subgroup analyses of clinical trials, age-related pooled analyses and obligatory post-marketing studies in vulnerable and frail older patients).ConclusionThe identification of proper clinical outcomes and the validation of geriatric screening tools are needed for conducting sound and comparable clinical trials.     

Adjuvant radiotherapy and chemotherapy in resectable gastric cancer. A randomized trial of the gastro-intestinal tract cancer cooperative group of the EORTC

One hundred and fifteen patients with curative and palliative surgery for gastric cancer were randomized to receive radiotherapy alone (1) or in combination with short-term (ST) 5-FU (2), long-term (LT) 5-FU (3), ST and LT 5-FU (4). The ST 5-FU was given at a daily dose of 575 mg/m2, every 4-6 h during the first 4 days of treatment before starting irradiation. The LT 5-FU was given at a dosage of 750 mg/m2 every 2 weeks for 18 months or until progression. The median survival times for treatment 1 to 4 was respectively 12, 10, 15 and 18 months. There was a statistically significant overall difference between the four treatments (P = 0.041). However, when the comparisons were adjusted for the most significant prognostic factors, the difference in survival disappeared. Moreover, no difference was found between treatments in terms of time progression. Nevertheless, among 22 patients with residual tumour, the three who were still alive without disease progression (with survivals of 19+, 49+ and 90+ months at the time of this analysis) had been treated with radiotherapy combined with ST and LT 5-FU.