Sally Stenning

Long-Term Results of a Randomized Trial of Surgery With or Without Preoperative Chemotherapy in Esophageal Cancer

PURPOSE OEO2 is a randomized, controlled trial of preoperative chemotherapy in patients undergoing radical surgery for esophageal cancer. Random assignment was to surgery alone (S) or to two cycles of combination cisplatin and fluorouracil before surgery (CS). Initial results reported in 2002 demonstrated an advantage for both disease-free and overall survival in the CS group. The analysis has now been updated after a median follow-up of 6 years. PATIENTS AND METHODS OEO2 recruited 802 patients, 400 on CS and 402 on S. The nature of the first recurrence event and cause of death are detailed. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. Survival by extent of resection is presented. RESULTS There were 655 deaths, 335 for S and 320 for CS. The survival benefit has been maintained with a hazard ratio (HR) of 0.84 (95% CI, 0.72 to 0.98; P = .03) which in absolute terms is a 5-year survival of 23.0% for CS compared with 17.1% for S. The treatment effect is consistent in both adenocarcinoma and squamous cell carcinoma. The first disease-free survival event was macroscopic residual disease from incomplete resection (R2) or no resection in 26.4% of the S group versus 14.3% of the CS P < .001. Three-year survival by type of resection was R0 42.4%, R1 was 18.0%, and R2 was 8.6%. CONCLUSION Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care.

Medical Research Council prospective study of surveillance for stage I testicular teratoma. Medical Research Council Testicular Tumors Working Party.

PURPOSE A prospective study of surveillance after orchidectomy alone in patients with stage I nonseminomatous germ cell testicular tumor (NSGCT) was performed to determine the relapse-free rate and to identify the histologic criteria that predict for relapse. PATIENTS AND METHODS Three hundred ninety-six patients from 16 United Kingdom and one Norwegian centers were entered onto the study between January 1, 1984 and October 1, 1987 of whom 373 were eligible for analysis. In a previous retrospective study, we defined a prognostic index based on histologic criteria that identified a group of patients with a high risk of relapse. This index was based on the presence of venous and lymphatic invasion, undifferentiated cells, and the absence of yolk sac elements in the primary tumor. RESULTS The 2-year actuarial relapse-free rate after orchidectomy was 75% (95% confidence interval, 71% to 79%), and the rate at 5 years was 73%. Five patients died of tumor or treatment-related complications, which resulted in a 5-year survival of 98%. The relapse-free rate in patients with three or four risk factors was 54%. CONCLUSIONS This study confirms the safety of surveillance as a method of management and identifies a group of patients with a high risk of relapse. A prospective phase II study has been initiated to determine whether two courses of platinum-based adjuvant chemotherapy will prevent relapse in these high-risk patients.

Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council study BRO4: an interim analysis

PURPOSE There is no consensus on the treatment strategy for adult patients with cerebral low-grade glioma. The diagnosis and primary treatment are usually undertaken by surgery. Some investigators doubt the efficacy of postoperative radiotherapy (RT), whereas others advise routine postoperative RT. We report the primary results of a multicenter randomized trial on this controversy. METHODS AND MATERIALS From 24 European centers, 311 adult patients with low-grade glioma were randomized centrally after surgery from March 1986 through September 1997, between the two arms of the trial. The irradiated group received 54 Gy in 6 weeks. The other patients did not receive any treatment after surgery until the tumor showed progression, defined as clinical-neurologic deterioration and evidence of progressive tumor on imaging. RESULTS Of 290 eligible and assessable patients (93%), the irradiated group showed a significant (log-rank p = 0.02) improvement in time to progression but not in overall survival, with a median follow-up of 5 years. The 5-year estimate was, respectively, 63% vs. 66% (overall survival) and 44% vs. 37% (time to progression) for the treated and control arms. Different treatment modalities, including RT, were undertaken for the 85 controls when a progressive tumor was noted. CONCLUSION Early postoperative conventional RT such as that used for this protocol appears to improve the time to progression or progression-free survival, but not overall survival, for patients with low-grade glioma.

Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report.

PURPOSE This United Kingdom Medical Research Council (UK-MRC) study prospectively evaluated efficacy and long-term toxicity of adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis (NSGCTT). PATIENTS AND METHODS Eligible patients were those identified by the local histopathologist as having features confirmed in MRC surveillance studies to indicate an approximate 50% risk of relapse. Central histopathology review was undertaken. Chemotherapy consisted of two courses of cisplatin 100 mg/m2, bleomycin 30 mg weekly x 3, and etoposide 120 mg/m2 x 3, every 21 days (BEP). RESULTS One hundred fourteen eligible cases were enrolled. Median time of follow-up was 4 years, with 93 patients followed-up for at least 2 years. There have been two relapses, including one patient who did not have a germ cell tumor (GCT), according to the reference histopathologist. This patient is alive with active disease, the other has died. There was one death after a cerebrovascular accident during treatment. Assessment of fertility, lung function, and audiometry pretreatment and more than 9 months posttreatment indicated no clinically significant changes. A mean decrease in transfer factor coefficient (KCO) of 15% of the predicted value was noted, but no patient had symptomatic respiratory dysfunction. CONCLUSION There have been only two relapses among 114 cases of high-risk stage I NSGCTT treated with two courses of adjuvant BEP chemotherapy. The 95% confidence interval (CI) excludes a true relapse rate of more than 5%. Of 104 patients confirmed on histopathology review to have GCT, there has been only one relapse. Adjuvant chemotherapy is free from significant long-term toxicity, offering an effective alternative to surveillance or retroperitoneal lymph node dissection (RPLND) followed by surveillance, and may be preferred by some patients.

Randomized trial of Bleomycin, Etoposide, and Cisplatin compared with Bleomycin, Etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer : a multiinstitutional medical research council/European organization for research and treatment of cancer trial

PURPOSEThis prospective randomized multicenter trial was designed to evaluate the efficacy of carboplatin plus etoposide and bleomycin (CEB) versus cisplatin plus etoposide and bleomycin (BEP) in first-line chemotherapy of patients with good-risk nonseminomatous germ cell tumors.PATIENTS AND METHODSBetween September 1989 and May 1993, a total of 598 patients with good-risk nonseminomatous germ cell tumors were randomized to receive four cycles of either BEP or CEB. In each cycle, the etoposide dose was 120 mg/m2 on days 1, 2, and 3, and the bleomycin dose was 30 U on day 2. BEP patients received cisplatin at 20 mg/m2/d on days 1 to 5 or 50 mg/m2 on days 1 and 2. For CEB patients, the carboplatin dose was calculated from the glomerular filtration rate to achieve a serum concentration x time of 5 mg/mL x minutes. Chemotherapy was recycled at 21-day intervals to a total of four cycles.RESULTSOf patients assessable for response, 253 of 268 (94.4%) of those allocated to receive BEP achieved a complete response...

Randomized Trial of 30 Versus 20 Gy in the Adjuvant Treatment of Stage I Testicular Seminoma: A Report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328)

PURPOSE To assess the possibility of reducing radiotherapy doses without compromising efficacy in the management of patients with stage I seminoma. PATIENTS AND METHODS Patients were randomly assigned 20 Gy/10 fractions over 2 weeks or 30 Gy/15 fractions during 3 weeks after orchidectomy. They completed a symptom diary card during treatment and quality-of-life forms pre- and post-treatment. The trial was powered to exclude absolute differences in 2-year relapse rates of 3% to 4% (alpha = .05 [one sided]; 90% power). RESULTS From 1995 to 1998, 625 patients were randomly assigned to treatment. Four weeks after starting radiotherapy, significantly more patients receiving 30 Gy reported moderate or severe lethargy (20% v 5%) and an inability to carry out their normal work (46% v 28%). However, by 12 weeks, levels in both groups were similar. With a median follow-up of 61 months, 10 and 11 relapses, respectively, have been reported in the 30- and 20-Gy groups (hazard ratio, 1.11; 90% CI, 0.54 to 2.28). The absolute difference in 2-year relapse rates is 0.7%; the lower 90% confidence limit is 2.9%. Only one patient has died from seminoma (allocated to the 20-Gy treatment group). CONCLUSION Treatment with 20 Gy in 10 fractions is unlikely to produce relapse rates more than 3% higher than for standard 30 Gy radiation therapy, and data on an additional 469 patients randomly assigned in a subsequent trial support and strengthen these results. Reductions in morbidity enable patients to return to work more rapidly. Prolonged follow-up is required before any inference can be made about any impact of allocated treatment on new primary cancer diagnoses.

Viable Malignant Cells After Primary Chemotherapy for Disseminated Nonseminomatous Germ Cell Tumors: Prognostic Factors and Role of Postsurgery Chemotherapy—Results From an International Study Group

PURPOSE To assess the value of postsurgery chemotherapy in patients with disseminated nonseminomatous germ-cell tumors (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy. PATIENTS AND METHODS The outcome of 238 patients was reviewed. Tumor markers had normalized in all patients before resection. A multivariate analysis of survival was performed on 146 patients. RESULTS The 5-year progression-free survival (PFS) rate was 64% and the 5-year overall survival (OS) rate was 73%. Three factors were independently associated with both PFS and OS: complete resection (P <.001), < 10% of viable malignant cells (P =.001), and a good International Germ Cell Consensus Classification (IGCCC) group (P =.01). Patients were assigned to one of three risk groups: those with no risk factors (favorable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). The 5-year OS rate was 100%, 83%, and 51%, respectively (P <.001). The 5-year PFS rate was 69% (95% confidence interval [CI], 62% to 76%) and 52% (95% CI, 40% to 64%) in postoperative chemotherapy recipients and nonrecipients, respectively (P <.001). No significant difference was detected in 5-year OS rates. After adjustment on the three prognostic factors, postoperative chemotherapy was associated with a significantly better PFS (P <.001) but not with better OS. Patients in the favorable risk group had a 100% 5-year OS, with or without postoperative chemotherapy. Postoperative chemotherapy appeared beneficial in both PFS (P <.001) and OS (P =.02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group. CONCLUSION A complete resection may be more critical than recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable options depending on the completeness of resection, IGCCC group, and percent of viable cells. Validation is necessary.

Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214)

PURPOSE Initial results of a randomized trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage I seminoma found carboplatin had a noninferior relapse-free rate (RFR) and had reduced contralateral germ cell tumors (GCTs) in the short-term. Updated results with a median follow-up of 6.5 years are now reported. PATIENTS AND METHODS Random assignment was between RT and one infusion of carboplatin dosed at 7 × (glomerular filtration rate + 25) on the basis of EDTA (n = 357) and 90% of this dose if determined on the basis of creatinine clearance (n = 202). The trial was powered to exclude a doubling in RFRs assuming a 96-97% 2-year RFR after radiotherapy (hazard ratio [HR], approximately 2.0). RESULTS Overall, 1,447 patients were randomly assigned in a 3-to-5 ratio (carboplatin, n = 573; RT, n = 904). RFRs at 5 years were 94.7% for carboplatin and 96.0% for RT (RT-C 90% CI, 0.7% to 3.5%; HR, 1.25; 90% CI, 0.83 to 1.89). One death as a result of seminoma (in RT arm) occurred. Patients receiving at least 99% of the 7 × AUC dose had a 5-year RFR of 96.1% (95% CI, 93.4% to 97.7%) compared with 92.6% (95% CI, 88.0% to 95.5%) in those who received lower doses (HR, 0.51; 95% CI, 0.24 to 1.07; P = .08). There was a clear reduction in the rate of contralateral GCTs (carboplatin, n = 2; RT, n = 15; HR, 0.22; 95% CI, 0.05 to 0.95; P = .03), and elevated pretreatment follicle-stimulating hormone (FSH) levels (> 12 IU/L) was a strong predictor (HR, 8.57; 95% CI, 1.82 to 40.38). CONCLUSION These updated results confirm the noninferiority of single dose carboplatin (at 7 × AUC dose) versus RT in terms of RFR and establish a statistically significant reduction in the medium term of risk of second GCT produced by this treatment.

Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: a Randomized Medical Research Council/European Organization for Research and Treatment of Cancer study

PURPOSE The aim of this randomized trial was to assess the potential therapeutic advantage of an intensive induction-sequential chemotherapy schedule (bleomycin, vincristine, cisplatin [BOP])/etoposide, ifosfamide, cisplatin, and bleomycin [VIP-B]), compared with a regimen based on bleomycin, etoposide, and cisplatin (BEP) (BEP/etoposide and cisplatin [EP]) for the treatment of patients with poor-prognosis metastatic nonseminomatous germ cell tumors (NSGCTs). PATIENTS AND METHODS Patients had one or more of the following: a retroperitoneal mass > or = 10 cm in diameter; mediastinal or supraclavicular mass > or = 5 cm in diameter; at least 20 lung metastases (any size); liver, bone, or brain metastases; and serum beta human chorionic gonadotropin (betaHCG) > or = 10,000 IU/L or alfa fetoprotein (AFP) > or = 1,000 IU/L. A total of 380 patients were accrued between May 1990 and June 1994 into this joint Medical Research Council (MRC)/European Organization for Research and Treatment of Cancer (EORTC) trial; of these, nine patients were deemed ineligible. RESULTS There was no significant difference between the two arms in the proportion of patients who achieved a complete response (CR) with chemotherapy alone, ie, 79 of 185 assessable patients (57%) with BEP/EP and 72 of 186 (54%) with BOP/VIP-B (P = 0.687). With a median follow-up of 3.1 years (maximum, 5.8), a total of 107 patients (28%) had progressive disease. There was no significant difference in time to first disease progression, or failure-free or overall survival between the two arms (P = 0.21, 0.101, and 0.190, respectively). The 1-year failure-free survival rates for BEP/EP and BOP/VIP-B were 60% (95% confidence interval [CI], 53% to 67%) and 53% (95% CI, 47% to 61%). Grade 3 or 4 myelosuppression, febrile neutropenia, and weight loss were more pronounced with BOP/VIP-B than with BEP/EP, and there were more toxic deaths with BOP/VIP-B than BEP/EP (18 [9%] v nine [5%]). CONCLUSION The intensive BOP/VIP-B therapy was associated with more toxicity, but there was no evidence of an improvement in response rate or survival compared with treatment with BEP/EP.

Randomized Trial of Two or Five Computed Tomography Scans in the Surveillance of Patients With Stage I Nonseminomatous Germ Cell Tumors of the Testis: Medical Research Council Trial TE08, ISRCTN56475197—The National Cancer Research Institute Testis Cancer Clinical Studies Group

PURPOSE Surveillance is a standard management approach for stage I nonseminomatous germ cell tumors (NSGCT). A randomized trial of two versus five computed tomography (CT) scans was performed to determine whether the number of scans influenced the proportion of patients relapsing with intermediate- or poor-prognosis disease at relapse. METHODS Patients with clinical stage I NSGCT opting for surveillance were randomly assigned to chest and abdominal CT scans at either 3 and 12 or 3, 6, 9, 12, and 24 months, with all other investigations identical in the two arms. Three of five patients were allocated to the two-scan schedule. Four hundred patients were required. RESULTS Two hundred forty-seven patients were allocated to a two-scan and 167 to five-scan policy. With a median follow-up of 40 months, 37 relapses (15%) have occurred in the two-scan arm and 33 (20%) in the five-scan arm. No patients had poor prognosis at relapse, but two (0.8%) of those relapsing in the two-scan arm had intermediate prognosis compared with 1 (0.6%) in the five-scan arm, a difference of 0.2% (90% CI, -1.2% to 1.6%). No deaths have been reported. CONCLUSION This study can rule out with 95% probability an increase in the proportion of patients relapsing with intermediate- or poor-prognosis disease of more than 1.6% if they have two rather than five CT scans as part of their surveillance protocol. CT scans at 3 and 12 months after orchidectomy should be considered a reasonable option in low-risk patients.