Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response. METHODS: Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays. RESULTS: We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH-mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although follow-up time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitor-type immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified. CONCLUSION: IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples.

Pattern of relapse and outcome of non-metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience.

Over the last two decades, chemotherapy has been introduced in protocols for patients with intracranial germinoma with the objective of reducing the volume and the dose of irradiation without compromising survival rates. The aim of this work is to critically analyze the pattern of relapse in a cohort of patients with nonmetastatic germinoma prospectively treated with chemotherapy followed by focal field radiation. Data of all germinoma patients registered in the French protocol for intracranial germ cell tumors between 1990 and 1999 were reviewed. The pattern of relapse, management, and outcome were analyzed in 10 of 60 patients who developed a recurrence after initial treatment. In 9 patients, the site of recurrence was local or loco-regional, notably in the periventricular area for 8. One patient only had isolated distant leptomeningeal relapse. The review of the sites of relapse suggests that most recurrences could have been avoided with a larger ventricular field of radiation. Treatment at first relapse included chemotherapy (10 patients), high-dose chemotherapy and stem cell transplant (8 patients), and/or radiation therapy (4 patients). Five patients experienced a second relapse. At a median follow-up of 72 months since the first relapse, 8 patients are alive in second or third remission. This review identified an excess of periventricular relapses when the focal field of radiation is used in the combined management of germinoma. These relapses are predominantly marginal or outside radiation fields. Ventricular field radiation appears a logical alternative to decrease the incidence of such relapses. Future trials should aim at better identifying patients who may benefit from local and ventricular radiation, respectively.

[Merkel cell carcinoma: outcome and role of radiotherapy]. / Carcinome à cellules de Merkel : prise en charge et place de la radiothérapie.

Merkel cell carcinoma (MCC) are rare neuroendocrine malignant tumor of the skin, occurring in elderly patients. It affects primarily the sun-exposed areas of the skin, with approximately 50% of all tumors occurring in the face and neck and 40% in the extremities. Immunohistochemical markers (CK20+, CK7- and TTF1-) are used to distinguish between MCC and other tumors. MCC have a tendency to rapid local progression, frequent spread to regional lymph nodes and distant metastases. Due to the rarity of the disease, the optimal treatment has not been fully defined. Localized stages (stages I and II) are treated by surgical excision of the primary tumor (with 2 to 3 cm margin) and lymphadenectomy in case of node-positive disease, followed by external beam radiotherapy (EBRT) to a total dose of 50 to 60Gy in the tumor bed. Adjuvant EBRT has been shown to decrease markedly locoregional recurrences and to increase survival in recent studies. Treatment of lymph nodes area is more controversial. Chemotherapy is recommended only for metastatic disease.

Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial.

BACKGROUND: Postoperative policies of "wait-and-see" and radiotherapy for low-grade glioma are poorly defined. A trial in the mid 1980s established the radiation dose. In 1986 the EORTC Radiotherapy and Brain Tumor Groups initiated a prospective trial to compare early radiotherapy with delayed radiotherapy. An interim analysis has been reported. We now present the long-term results. METHODS: After surgery, patients from 24 centres across Europe were randomly assigned to either early radiotherapy of 54 Gy in fractions of 1.8 Gy or deferred radiotherapy until the time of progression (control group). Patients with low-grade astrocytoma, oligodendroglioma, mixed oligoastrocytoma, and incompletely resected pilocytic astrocytoma, with a WHO performance status 0-2 were eligible. Analysis was by intention to treat, and primary endpoints were overall and progression-free survival. FINDINGS: 157 patients were assigned early radiotherapy, and 157 control. Median progression-free survival was 5.3 years in the early radiotherapy group and 3.4 years in the control group (hazard ratio 0.59, 95% CI 0.45-0.77; p<0.0001). However, overall survival was similar between groups: median survival in the radiotherapy group was 7.4 years compared with 7.2 years in the control group (hazard ratio 0.97, 95% CI 0.71-1.34; p=0.872). In the control group, 65% of patients received radiotherapy at progression. At 1 year, seizures were better controlled in the early radiotherapy group. INTERPRETATION: Early radiotherapy after surgery lengthens the period without progression but does not affect overall survival. Because quality of life was not studied, it is not known whether time to progression reflects clinical deterioration. Radiotherapy could be deferred for patients with low-grade glioma who are in a good condition, provided they are carefully monitored.

Parenchymal pineal tumors: a clinicopathological study of 76 cases.

PURPOSE: The aim of this study was to identify factors that could lead to optimization of the management of pineal parenchymal tumors (PPT) which remains equivocal and controversial. METHODS AND MATERIALS: In order to determine factors that influence PPT prognosis, a series of 76 consecutive patients from 12 European centers with histologically proven tumors was retrospectively reviewed. The clinical records and material for histologic review were available in all cases. Follow-up was achieved in 90% of cases. RESULTS: According to WHO classification, there were 19 pineocytomas, 28 intermediate and mixed PPT, and 29 pineoblastomas. According to a four-grade institutional classification, there were 11 Grade 1, 27 Grade 2, 20 Grade 3, and 18 Grade 4. Surgical resection was attempted in 44 patients, whereas 30 had biopsy only. In one case, diagnosis was made at autopsy and in another on spinal deposits. Forty-four patients were irradiated following surgery, 15 patients received chemotherapy. Forty-one patients were alive (median follow-up: 85 months); 9 patients died perioperatively; 26 patients relapsed. Univariate analysis showed a good outcome correlated with age above 20 years, tumor diameter less than 25 mm, and low-grade histology. Multivariate analysis confirmed histology and tumor volume to be significant independent prognostic factors. The extent of surgery and radiotherapy had no clear influence on survival. CONCLUSIONS: This review highlights the prognostic features of PPT and may help to determine treatment strategies based on radiologic and pathologic characteristics.

Bone metastasis revealing hepatocellular carcinoma: a report of three cases with a long clinical course.

We report herein three cases of hepatocellular carcinoma revealed by bone metastases. The metastases were located in the skull, the iliac bone, and the femur. The metastases were treated by radiotherapy, and/or surgery. With regard to the liver malignancy itself, two patients were treated by tamoxifen and one by chemoembolizations. Two patients are alive 27 and 31 months after the first sign, and one died 31 months after the diagnosis. In conclusion, in patients with hepatocellular carcinoma revealed by bone metastases, long survival was obtainable in a few cases, and aggressive treatment could be of interest.

Sequential chemotherapy and radiotherapy for patients with squamous cell carcinoma of the esophagus.

BACKGROUND: Despite surgical improvements the prognosis of patients with squamous cell carcinoma (SCC) of the esophagus remains poor, with a 5-year survival rate of less than 20%. Most patients do not undergo surgery with curative intent. The aim of this study was to assess the toxicity and efficacy of sequential chemoradiotherapy. METHODS: Between May 1986 and June 1991, 50 patients with nonmetastatic SCC of the esophagus were included in this study. Three patients had recurrence after surgery, 8 patients were classified Stage I disease, 24 Stage II, 5 Stage III, and 10 Stage VI. Treatment consisted of cisplatin (100 mg/m2 on Days 1 and 29), 5-fluorouracil (5-FU) (600 mg/m2 on Days 2-9 and Days 30-33) and 30 Gy of radiotherapy (2 Gy x 15 on Days 8-26 and 30 Gy on Days 36-54). RESULTS: Thirty-seven patients (74%) received the whole treatment course; treatment was modified for 8 patients because of Grades III and IV hematologic, digestive, or renal toxicity. Five patients did not complete treatment because of disease progression or death. Median survival was 13 months; 1- and 2- year survival rates were 63% (49-75) and 36% (25-50), respectively. No late treatment complications were observed (in the 11 survivors after 2 years. CONCLUSIONS: Sequential chemoradiotherapy of SCC of the esophagus was well tolerated with acceptable acute morbidity and resulted in local control and survival results at least equivalent to those in trials of neoadjuvant chemoradiotherapy plus surgery.

A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus.

BACKGROUND: Despite well-established surgical approaches, the prognosis for patients with squamous cell carcinoma of the esophagus remains dismal. To assess the benefit of adjuvant chemotherapy and radiation therapy (CRT), a randomized trial with and without sequential preoperative CRT was undertaken; CRT combined 20 Gy and two courses of 5-FU and cisplatin. METHODS: Patients were included on the basis of the following criteria: squamous cell carcinoma of the esophagus, younger than 70 years of age, World Health Organization status below 2, estimated survival time greater than 3 months, and no previous treatment for the cancer. Patients were not included if they had experienced a loss in body weight greater than 15% or had tracheoesophageal fistula, metastases, or uncontrollable infection. RESULTS: Eighty-six patients thus fulfilled the criteria for inclusion (41 CRT, 45 non-CRT). The groups were well-matched for age, sex, tumor location, size, and grade. Operative mortality was 8.5% and 7%, respectively, for each group with a 27-day hospital stay for both groups. Long-term survival was not significantly different, with 47% of both groups alive at 1 year. CONCLUSIONS: The authors concluded that this neoadjuvant treatment did not change operative mortality or survival time for patients with squamous cell carcinoma of the esophagus.

Unusual combination of Cis platinum and radiotherapy followed by a three fractions per day irradiation in splitcourse: a phase I-II study in brain glioma patients.

An unusual protocol based on a preliminary clinical study on cylindromas metastasized to the lung was proposed to brain glioma patients: Day 2 100 mg/m2 i.v. Cis platinum (Cis PII) followed at days 3 and 5 by 6 Gy irradiation (RT) in two fractions and three days. Five cycles were scheduled at 21 days interval. On disease progression a three fractions per day radiotherapy regimen (3 FRT) in split-course (two series of 22.50 Gy in 15 fractions and five days separated by a two weeks period of rest) was then delivered to the patients. All patients had a measurable mass on the CT scan. 19 were entered into the study: 13 as first line therapy (group A) and six for salvage treatment (group B). Tolerance was globally good. Eight patients were considered responders at the end of five cycles of Cis PII-RT. They were all group A patients. Median symptom-free interval was six months for the whole population. Survival was twelve months. The 3 FRT was well tolerated but does not seem to have improved the therapeutic gain of the chemoradiotherapy combination. The present study concerns patients whose prognosis was poor on inclusion: surgery inadvisable or unsatisfactory and diagnosis mainly based on biopsy only. The number and the duration of responses justify further study into Cis PII as first line therapy as either an effective cytotoxic drug or a potential radio enhancer.

[Immunoscintigraphy, an aid to the oncologist--the Rennes experience in using anti-CEA, anti-CA 19.9 monoclonal antibodies and radiolabelled OC-125]. / L'immunoscintigraphie, une aide pour le cancérologue--expérience rennaise de l'utilisation des anticorps monoclonaux anti-ACE, anti-CA 19.9 et OC-125 radiomarqués.

Immunoscintigraphy is steadily asserting itself as a valuable method in the localization of malignant tumours, alongside other imaging techniques. A monoclonal antibody specific to one or several tumour cell lines is used. The antibody is labelled with a gamma emitter radioisotope and so that it can be detected in vivo. We have evaluated three monoclonal antibodies (F(ab')2 fragments): a mixture of anti-CEA and anti-19.9 antibodies in the investigation of colorectal carcinoma and the antibody OC-125 in ovarian cancer. In our experience, it appears that pelvic recurrence is the best indication for immunoscintigraphy. Antibodies can apparently be safely used in man. We noted no side-effect following the injection of anti-CEA, anti 19.9 and OC-125.

Squamous cell carcinoma of the esophagus. Treatment by combined vincristine-methotrexate plus folinic acid rescue and cisplatin before radiotherapy.

From January to November, 1981, 28 patients with unresectable squamous cell carcinoma of the esophagus were treated with two cycles of chemotherapy combining vincristine (V), methotrexate (M), folinic acid rescue, and cisplatin (P) on days 1 and 21. Split-course radiation therapy was delivered thereafter from day 42 on. Hematologic, renal, and neurologic tolerance was acceptable, but most of the patients experienced nausea and vomiting. Results evolution at day 40 showed a 61% partial response (PR) rate and a 7% complete response (CR) rate. One month after the end of radiation therapy, 43% PR and 32% CR were obtained. Median response duration was 8 months. Median survival was 11.6 months for patients overall, yielding 12.9 months for responders and 5.9 months for nonresponders. Based on the response rate obtained with combined chemotherapy, a randomized trial of VMP initial chemotherapy is currently being undertaken by our cooperative group to study whether such an initial treatment could improve resectability and radiation-mediated local control along with survival rate.