Henrik Schultz

Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial

BACKGROUND Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma. METHODS Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m(2) on days 1-5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34·0 Gy administered in 3·4 Gy fractions over 2 weeks), or standard radiotherapy (60·0 Gy administered in 2·0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623. FINDINGS 342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8·3 months [95% CI 7·1-9·5; n=93] vs 6·0 months [95% CI 5·1-6·8; n=100], hazard ratio [HR] 0·70; 95% CI 0·52-0·93, p=0·01), but not with hypofractionated radiotherapy (7·5 months [6·5-8·6; n=98], HR 0·85 [0·64-1·12], p=0·24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8·4 months [7·3-9·4; n=119] vs 7·4 months [6·4-8·4; n=123]; HR 0·82, 95% CI 0·63-1·06; p=0·12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0·35 [0·21-0·56], p<0·0001; HR for hypofractionated vs standard radiotherapy 0·59 [95% CI 0·37-0·93], p=0·02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9·7 months [95% CI 8·0-11·4] vs 6·8 months [5·9-7·7]; HR 0·56 [95% CI 0·34-0·93], p=0·02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0·97 [95% CI 0·69-1·38]; p=0·81). As expected, the most common grade 3-4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3-5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed. INTERPRETATION Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide. FUNDING Merck, Lions Cancer Research Foundation, University of Umeå, and the Swedish Cancer Society.

Surveillance following orchidectomy for stage I seminoma of the testis

From 1985 to 1988, 261 unselected patients entered a nationwide Danish study of surveillance only for testicular seminoma stage I. The median follow-up time after orchidectomy was 48 months, range 6-67 months. 49 patients relapsed (19%). Sites of relapse were paraaortic lymph nodes in 41 patients, pelvic lymph nodes in 5, inguinal lymph nodes in 2 and lung metastases in 1 patient. The median time to relapse was 14 months, range 2-37 months. The 4-year relapse-free survival was 80%. 37 of the relapsing patients (76%) had radiotherapy as relapse treatment. Of these patients, 4 (11%) had a second relapse and received chemotherapy. 1 died of disseminated seminoma. Of the relapsing patients, 12 (24%) had chemotherapy as relapse treatment because of bulky (11 patients) or disseminated disease (1 patient). None of these patients have had a second relapse. However, 2 patients died of infection due to chemotherapy-induced neutropenia. Thus, there have been three seminoma-related deaths (1.1%). The testicular tumour size had an independent prognostic significance. The 4-year relapse-free survivals were 94, 82 and 64% for tumours < 3, 3 to < 6 and > or = 6 cm, respectively. Patients with tumours > or = 6 cm will now be given prophylactic radiation treatment, whereas we will continue to use surveillance only after orchidectomy for patients with tumours < 6 cm.

Malignant fibrous histiocytoma: a retrospective study of 109 cases.

The purpose of this report is to assess the prognostic factors that could influence management and clinical outcome of malignant fibrous histiocytoma (MFH) of soft tissues. Between 1975 and 1998, 109 patients diagnosed with MFH of the soft tissues, seen at King Faisal Specialist Hospital and Research Center, have been reviewed. Of the 109 patients, 75 were men and 34 were women. The median age at presentation was 48 years (range: 3–94). Seven patients (6%) had regional nodal disease and 10 other patients (9%) with distant metastases were excluded from survival analysis. The remaining 92 patients had localized disease and had surgery as the primary treatment modality with or without radiotherapy and/or chemotherapy. Extremities were the most common location (58%). Tumors less than 5 cm represented 32%, whereas 68% had tumors 5 cm or more. Low-grade tumors constituted 46%, and the remaining 54% were high grade. Thirty-seven percent of patients had positive surgical margins histologically after complete gross resection. The 5- and 10-year relapse-free survival (RFS) rates were 39% and 36%, respectively. Isolated local recurrence occurred in 20 patients (22%), isolated metastatic disease without local recurrence in 9 patients (10%), and combined local and metastatic disease occurred in 20 patients (22%). The overall 5- and 10-year overall survival (OS) rates were 50% and 43%, respectively. On multivariate analysis, tumor size and radiation dose were significant factors for RFS (p = 0.04 and 0.0005, respectively). In terms of OS, size, histologic grade, and surgical margins were significant factors on multivariate analysis (p = 0.001. 0.006, and 0.0001, respectively). Complete surgical resection at the time of primary tumor presentation is likely to afford the best chance for RFS and OS. Radiation therapy plays an important role, in combination with surgery for better local control, particularly in high-grade lesions, and in cases with positive surgical margins after wide complete gross excision. The role of adjuvant chemotherapy remains investigational.

OPTIC GLIOMAS: A RETROSPECTIVE ANALYSIS OF 50 CASES

PURPOSE Gliomas of the optic pathways are rare childhood central nervous system tumors. The treatment approach is controversial because of its rarity and the slow and unpredictable growth rates of these lesions. METHODS AND MATERIALS We reviewed 50 patients with the diagnosis of optic pathway low-grade gliomas treated between January 1980 and December 1995 at King Faisal Specialist Hospital and Research Center, Saudi Arabia. Thirty-five patients presented with chiasmatic/hypothalamic (posterior tumors), and 15 with optic nerve gliomas with or without chiasmal involvement (anterior tumors). Evidence of neurofibromatosis was present in 18 patients. Twenty-nine patients underwent surgery (total or partial resection), and 12 of these received postoperative radiotherapy (RT). Sixteen patients were treated with primary RT. The radiation dose varied between 42 and 54 Gy (median dose 50). RESULTS The overall actuarial survival rate was 87.5% at 5 years and 75% at 10 years, and the corresponding progression-free survival (PFS) rates were 69% and 62%. Patients with anterior tumors fared better than those with posterior tumors, with a 10-year PFS rate of 72% and 58%, respectively; the difference, however, was not statistically significant (p = 0.58). A PFS advantage was found in favor of patients with posterior tumors treated with RT (primary or postoperative) compared with no RT, with 5-year PFS rates of 68% vs. 42% (p = 0.03). This, however, did not translate into a survival advantage because of the success of salvage treatment. CONCLUSION In multivariate analysis, age (<3 vs. >3 years) emerged as the only significant determinant for PFS with patients <3 years old faring worse (p = 0.03). Neurologic and endocrine dysfunction are significant problems that need to be addressed.

Primary thyroid lymphoma: a retrospective analysis of prognostic factors and treatment outcome for localized intermediate and high grade lymphoma.

&NA; Non‐Hodgkins lymphoma presenting in the thyroid gland is uncommon. A review of the King Faisal Specialist Hospital and Research Centre (KFSH & RC) experience was performed to assess treatment outcome and prognostic factors in this rare extranodal presentation of localized lymphoma. Sixty patients treated at KFSH & RC between 1975 and 1995 were identified, and their records were reviewed retrospectively. Eight patients who had stage III or IV disease, low grade, or did not complete their prescribed treatment were excluded from the study. There were 38 female and 14 male patients with a median age of 59.5 years at the time of diagnosis (range: 10—87 years). Thirty‐five of the 52 patients underwent diagnostic partial or total thyroidectomy at other institutions based on a preoperative assumption of thyroid carcinoma. All 52 patients had non‐Hodgkins lymphoma of intermediate (94%) or high (6%) grade. Detailed staging was carried out in all patients; 16 patients (31%) had disease confined to the thyroid gland (stage IE), whereas 36 (69%) had associated disease in cervical lymph nodes and/or the mediastinum (stage IIE) disease. All patients were treated with curative intent. A total of 18 patients (35%) were treated with a single‐modality treatment—radiotherapy alone in 2, chemotherapy alone in 13, and surgery alone in the remaining 3 patients. The majority of patients (34/52; 65%) were treated with a combined‐modality approach. The overall relapse‐free survival (RFS) and overall survival (OS) at 5 years were 72% and 88%, respectively. There were no significant differences in outcome between those treated with single‐modality and those with combined‐modality therapy. A univariate analysis showed that the presence of mediastinal lymph node involvement was the most important prognostic factor affecting both RFS and OS. Patients with Hashimoto thyroiditis and without “B” symptoms were found to have a significantly higher RFS without influence on the OS. However, patients who had a good performance status (PS) of 0, 1, and 2 were found to have a significantly higher overall survival in comparison to those with poor performance status. Age, sex, stage, histology, lactic acid dehydrogenase level, tumor bulk, and the treatment modality were not found to correlate with RFS or OS. Mediastinal involvement and PS were found to be the most important independent prognostic factors influencing RFS and OS.

Surveillance alone versus radiotherapy after orchiectomy for clinical stage I nonseminomatous testicular cancer. Danish Testicular Cancer Study Group.

From December 1980 to January 1984, all patients with stage I nonseminomatous testicular cancer in Denmark entered a randomized trial comparing surveillance only with radiotherapy after orchiectomy. One hundred fifty patients were assessable for the final analysis. Relapse occurred in 23 patients in the surveillance group and in 11 patients in the radiotherapy group. Radiotherapy completely prevented retroperitoneal relapse; 14 retroperitoneal relapses occurred in the surveillance-only group. All relapsing patients in the surveillance-only group are without evidence of disease with a median observation time after chemotherapy of 67 months. Two of the patients with relapse in the radiotherapy group died with disease; the others are alive without evidence of disease, with a median observation time after relapse treatment of 72 months. In the surveillance group, four relapses occurred later than 2 years after orchiectomy; only one such late relapse occurred in the radiotherapy group. Four of the retroperitoneal relapses occurred without concomitant increase in the serum marker levels (alpha-fetoprotein [AFP] and human chorionic gonadotropin [HCG]). It is concluded that surveillance only should replace radiotherapy after orchiectomy as standard treatment for clinical stage I nonseminomatous testicular cancer. Improved methods for control of retroperitoneal relapses, especially of embryonal carcinomas, are needed.

Testicular Seminoma in Denmark 1976–1980 Results of Treatment

Over a five-year period the DATECA Study included 554 consecutive patients with seminoma, representing practically all cases in the country. The stage distribution was: stage I 424 patients, stage II 110 patients, and stage III 17 patients. Typical seminoma was registered in 515 patients, anaplastic seminoma in 26 patients, and spermatocytic seminoma in 13 patients. The treatment was post-operative irradiation except in a few very advanced cases who received chemotherapy. Three-year corrected survival was: stage I 99 per cent, stage II 89 per cent, and stage III 65 per cent. Anaplastic seminoma showed a significantly higher rate of metastatic spread than typical seminoma and the prognosis was worse. Treatment-related complications were few, but adjuvant bleomycin combined with irradiation of advanced seminoma resulted in 2 deaths from pneumonitis.

A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy

Abstract The combination of irinotecan and bevacizumab has shown efficacy in the treatment of recurrent glioblastoma multiforme (GBM). A prospective, phase II study of 85 patients with various recurrent brain tumors was carried out. Primary endpoints were progression free survival (PFS) and response rate. Material and methods. Patients with recurrent primary brain tumors with performance status 0–2 were eligible. Intravenous bevacizumab 10 mg/kg and irinotecan 125/340 mg/m2 were administered every 14 days. Evaluation was carried out every eight weeks using MRI and Macdonald response criteria. Treatment was continued until progression. Results. In total 85 patients were included with the following histologies: GBM (n = 32), glioma WHO gr. III (n = 33), glioma WHO gr. II (n = 12) and others (n = 8). Patients received a median of four cycles. ORR (overall response rate) for glioblastoma was 25% and 59% achieved stable disease (SD). Median PFS was 5.2 months. For grade III gliomas ORR was 21% and 45% had SD. Median PFS was 3.7 months. No objective responses occurred in grade II gliomas. In the non-glioma population, one PR as well as several long PFS times were observed. Discussion and conclusion. The combination of bevacizumab and irinotecan is well tolerated and moderately efficacious in glioblastoma and glioma WHO gr. III. A majority of patients achieve at least disease stabilization. Prolonged progression-free survival in non-glioma patients warrants further research.

Stevens-Johnson syndrome in patients on phenytoin and cranial radiotherapy.

The use of phenytoin as a prophylactic anticonvulsant after brain surgery, particularly for brain tumors, is a common practice, regardless of whether the patient has a previous history of convulsions. This treatment policy assumes that the benefits exceed the risks. Four cases are described of adverse reactions to phenytoin during the concomitant use of cranial radiotherapy. In one patient this proved fatal. There is increasing anecdotal support in the literature for a synergistic effect between phenytoin therapy and cranial radiotherapy that can result in the life-threatening Stevens-Johnson syndrome. While the association is uncommon, four cases within 24 months in one department suggest that the routine use of postoperative phenytoin as a prophylactic anticonvulsant in the absence of a history of seizures may not be warranted, particularly if the patient is to receive cranial radiotherapy.

Tumour Markers in Testicular Germ Cell Tumours Five-Year Experience from the DATECA Study 1976–1980

Since Jan. 1, 1976, nearly all new cases of testicular germ cell tumours have been included in the Danish Testicular Carcinoma Study (DATECA), and have been monitored by the tumour markers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG). During the first five years, 1058 patients participated in the investigation, but only 603 of these patients were followed by preoperative as well as postoperative marker determinations in serum. The overall prevalence of marker positivity, i.e. elevated preoperative values for AFP and/or HCG, was 8 per cent for seminoma patients and 60 per cent for non-seminoma patients. Elevated levels of serum AFP and HCG were correlated to the presence of endodermal sinus tumour and choriocarcinoma elements, respectively, in the primary tumour. The presence of increased marker concentration in serum was correlated stage (higher percentage in higher stages) and to prognosis (marker negative patients had a better prognosis than marker positive patients). Marker production by seminoma patients seems to indicate a poor prognosis, especially for HCG producing seminomas.