Teniposide Sometimes Effective in Brain Metastases from Non-small Cell Lung Cancer

In a prospective study we have treated 13 patients with brain metastases from non-small cell lung cancer with intravenous teniposide, at a dose of 150mg/m2 on days 1, 3 and 5 given every 3 weeks on an out-patient basis. Six of the 13 patients had previously been treated for brain metastases by surgery and/or radiotherapy. Seven patients experienced neurological improvement. Objective response was obtained in 3 patients (23%) (2 PR, 1 CR), and stabilization in 5 patients. Duration of response in the 3 patients with objective response was 16 weeks, 40 weeks and 80 weeks, respectively. In 2 of these patients extracranial disease responded also to teniposide therapy. Although toxicity of teniposide therapy was relatively mild, there was one patient who died as a consequence of leukopenic sepsis. The results demonstrate that teniposide has some activity in de novo as well as recurrent brain metastases from non-small cell lung cancer.     

Long-term survival following concurrent chemoradiotherapy in patients with non-small-cell lung cancer with concomitant brain metastases only

We report two patients with non-small-cell lung cancer (NSCLC) with concomitant metastases to the brain only who received chemotherapy with concurrent radiotherapy for the thoracic disease and brain disease, resulting in long-term survival. One patient was a 56-year-old woman who was diagnosed as having adenocarcinoma and showed T2N1 thoracic disease; the other patient was a 57-year-old man diagnosed with squamous cell carcinoma who had T1N3 thoracic disease. Both patients demonstrated multiple metastases to the brain only. Chemotherapy, consisting of cisplatin (40mg/m²) and docetaxel (40mg/m²), was administered on days 1 and 8, with the drugs being given separately, and the chemotherapy was repeated every 4 weeks for up to three cycles. Whole-brain irradiation (2Gy/day; total, 36Gy) and thoracic irradiation (2Gy/day; total, 60Gy) were started on days 1 and 29, respectively. Toxicities encountered were manageable by conventional therapy. The concurrent chemoradiation therapy resulted in complete regression of the brain disease in both patients. Brain disease relapsed in the female patient, but it is being controlled by the administration of gefitinib. She has survived for 53 months since the start of treatment, without new metastatic lesions or relapse of the thoracic lesions. The male patient has survived for 37 months without new metastatic lesions or relapses. Concurrent chemoradiotherapy in which radiotherapy is applied to both the brain and thoracic lesions may be effective for patients with NSCLC with metastases to the brain only.     

Gemcitabine and Radiotherapy in the Treatment of Brain Metastases from Transitional Cell Carcinoma of the Bladder: A Case Report

Hematogenous metastases occur in over 50% of muscle-invasive transitional cell carcinomas (TCC) of the bladder. Despite treatment (mostly surgery and radiotherapy), patients with brain metastases have an especially poor prognosis (median survival 2–5 months), making palliative treatment an important consideration. We followed a 60-year-old man with multiple brain metastases who was ultimately treated with gemcitabine chemotherapy. He underwent a cystectomy in 1997 because of a T3a N0 M0 G3 TCC of the bladder. Two years later, he developed one brain metastasis and one lung metastasis. Both metastases were resected and adjuvant chemotherapy was planned. Before chemotherapy, the patient suffered from headaches and symptoms of hemiparesis. A magnetic resonance imaging (MRI) showed multiple brain metastases of up to 2cm, particularly in the brain stem. The patient underwent whole-brain radiotherapy with 30Gy, followed by four cycles of a 3-week gemcitabine (800mg/m² on days 1 and 8) schedule. Another MRI showed a nearly complete response after four cycles of chemotherapy, with only small residual tumors remaining in the brain stem. This impressive activity was accomplished without adverse side effects, suggesting that radiotherapy combined with gemcitabine monotherapy may be an excellent choice for palliative treatment of TCC of the bladder.     

Local Recurrence of Metastatic Brain Tumor after Stereotactic Radiosurgery or Surgery Plus Radiation

In this study, we compared the recurrence of metastatic brain tumors after radiosurgery versus after surgery plus radiation, and analyzed the factors associated with the recurrence of brain metastases. Twenty-eight and 35 patients with metastatic brain tumors underwent radiosurgery (52 lesions) and surgery plus radiation (46 lesions), respectively, between 1995 and 2001. The median tumor volume was 1.55ml (range: 0.02–10.4ml) in radiosurgery patients and 17.9ml (range: 0.26–195ml) in surgery plus radiation patients. The median radiosurgical tumor central and margin doses were 28.9 and 23.8Gy (range: 20–35 and 25–15Gy), respectively. The median total dose was 46.7Gy (range: 30–63Gy) in the surgery plus radiation group.The recurrence time from surgery plus radiation group (25 months) was significantly longer than that from the radiosurgery group (7.2 months) (p=0.0199). The factors affecting the recurrence of brain metastases after radiosurgery were size, central dose of radiation and histology (colon vs. others). No factors affected the recurrence of brain metastases after surgery plus radiation. To avoid early recurrences of metastatic brain tumors, surgery plus radiation is the preferable therapeutic modality. The size and histology of brain metastases, and the dose of radiation should be considered for the effective treatment of tumors by radiosurgery.     

Brain metastasis in pediatric extracranial solid tumors: survey and literature review

Objectives: Brain is a rare site of metastasis in most extracranial pediatric solid tumors. The aim of this study is to investigate the incidence, treatment, prognosis of brain metastasis in extracranial pediatric malignant tumors in a single institution and to review the literature.Methods: From September 1989 to December 2002, 1100 children 16years of age with extracranial solid tumors including lymphomas were diagnosed and treated in the Division of Pediatric Oncology, Oncology Institute, Istanbul University. Patients with parenchymal metastases in the brain were assessed.Results: Sixteen (10 female, 6 male) of 1100 patients (1.45%) with extracranial solid tumors developed brain metastases. The median age of the patients was 10.5 (1–16)years. The diagnosis was sarcomas in 12 patients: 5 osteosarcomas, 4 Ewings sarcoma family tumors, 1 rhabdomyosarcoma, 1 clear cell sarcoma of the soft tissue, 1 alveolar soft part sarcoma. Two patients had Wilms tumor and two had germ cell tumors. Four patients (25%) had brain metastasis at diagnosis. Twelve (75%) developed brain metastasis during therapy or relapse at a median duration of 16 (1–70)months from initial diagnosis. All patients had metastases to various sites, mostly lung, at the time the brain metastases were detected. Treatment included surgery, followed by postoperative radiotherapy (RT) and chemotherapy (CT) in 1, S and RT in 1, S in 1, RT and CT in 6, RT in 1, CT in 1 and no treatment in 5. Only one patient with alveolar soft part sarcoma is alive with disease 20months from diagnosis of brain metastasis. All other patients died at a median time of 2months (2days–6months) from the time of brain metastasis.Conclusions: Children with metastatic cancer who develop headaches or any other neurologic symptom should be investigated for possible brain metastasis. Although, the outcome for these patients is dismal in this series and in the literature; reports of long term survival in a few cases with Wilms tumor, osteosarcoma and alveolar soft part sarcoma who had isolated brain metastasis, suggest that a subset of patients may benefit from therapy.This study was partially presented as a poster in the International Society of Pediatric Oncology (SIOP) meeting in Porto, 2002 and in the 10th International Symposium on Pediatric Neuro-oncology, London in June 2002.     

Postoperative adjuvant chemotherapy with cisplatin,cyclophosphamide, and anthracycline (doxorubicin,epirubicin, pirarubicin) for endometrial cancer

Background Doxorubicin and cisplatin are the most commonly used chemotherapeutic agents in the treatment of endometrial cancer, but their clinical efficacy is still controversial. The aim of this study was to retrospectively assess the efficacy and toxicity of combination chemotherapy using cisplatin, cyclophosphamide, and anthracy-clines in patients with stage III/IV adenocarcinoma of the endometrium.Methods Forty patients with advanced endometrial cancer received postoperative adjuvant combination chemotherapy, using cisplatin (50 or 70mg/m²), cyclophosphamide (500mg/m²), and one of three anthracyclines (10 patients with doxorubicin [50mg/m²], 18 with epirubicin [50mg/m²], and 12 with pirarubicin [40mg/m²]), from 1987 to 1999. All patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, with pelvic lymph node dissection in 36 patients and paraaortic lymph node biopsy in 38 patients. Patients were considered eligible if they had adnexal metastasis, paraaortic lymph node metastasis, positive peritoneal cytology, or distant metastasis. The patients were divided into two groups: patients with no measurable lesion (group 1; n = 27), and those with residual measurable lesion (group 2; n = 13) after surgery. The response rate and progression-free survival rate were evaluated in group 2.Results In group 1, 7 patients (26%) had recurrence, and all of them died of the disease. No patients in stage IIIa (n = 10), however, had recurrence. In group 2, 6 of the 13 (46%) showed response to chemotherapy (complete response [CR], 31%; partial response [PR], 15%). Toxicity was moderate: 10 patients had grade 4 neutropenia; and dose reductions were mandated in 12 patients.Conclusion In group 1, the survival of patients receiving chemotherapy was considered favorable, but patients with recurrent lesions had poor prognosis. On the other hand, in group 2, the efficacy of the chemotherapy was almost equal to that reported in the literature; however, this regimen did not contribute to an improvement in the survival rate. In conclusion, a new effective regimen of postoperative adjuvant therapy is highly desirable in patients with measurable residual lesions.     

Noninvasive detection of alterations in chromosome numbers in urinary bladder cancer cells,using fluorescence in situ hybridization

Background Bladder cancers have a high potential for recurrence and sometimes become invasive even in superficial cases. In this process, gene mutations in tumor suppressor genes such as p53, on chromosome 17, or p16, on chromosome 9, are thought to be important. In order to investigate whether the detection of alterations in chromosome number might be used as an alternative to invasive techniques for the assessment of clinical bladder cancer, fluorescence in situ hybridization (FISH) was employed to analyze chromosome numbers in a series of patients.Methods A total of 40 patients with transitional cell carcinomas (stages Ta to T4, including carcinoma in situ [CIS]) were examined for abnormal numbers of chromosomes 9 and 17, by FISH, using 41 and 42 samples of voided urine, respectively. Tumor grades were as follows: G1:G2:G3 = 4:21:17. Urinary cytology and presence of bladder tumor antigen (BTA) were also checked in the same samples. One hundred cells were examined in each sample, and abnormality was concluded to be present when more than 20% of cells demonstrated polysomy (defined as three or more chromosomes).Results Seventeen of 41 samples (41.5%) were abnormal with regard to chromosome 9, and 17 of 42 (40.5%) were abnormal for chromosome 17. Both chromosomes were affected in 13 cases, of which 8 were positive for urinary cytology and BTA. Univariate analysis, performed with urinary cytology, BTA, tumor grade, tumor stage, involvement of vessels, pattern of invasion, number of tumors, and prognosis as parameters, demonstrated a significant influence of urinary cytology (P = 0.0368 and P = 0.0278 for chromosomes 9 and 17, respectively), BTA (P = 0.0094 for chromosome 17), involvement of vessels (P = 0.0262 for chromosome 17), pattern of invasion (P = 0.0028 and P = 0.0327 for chromosomes 9 and 17), grade (P = 0.0213 and P = 0.0174 for chromosomes 9 and 17), and stage (P = 0.0457 for chromosome 17). All the other parameters also tended to be linked with the changes in chromosomes, except for tumor number. Multivariate analysis demonstrated significant differences for tumor grade (P = 0.0166) and pattern of invasion (P = 0.0006) for chromosome 9.Conclusion Voided-urine FISH is an effective noninvasive method for the detection of altered chromosome numbers in bladder cancer cells, and may provide an indication of tumor progression when combined with urinary cytology and BTA.     

Biweekly administration regimen of docetaxel combined with CPT-11 in patients with inoperable or recurrent gastric cancer

Background. Both docetaxel (TXT) and irinotecan (CPT-11) are active chemotherapeutic agents for gastric cancer. We designed a biweekly administration regimen of TXT combined with CPT-11 for 4 weeks as one cycle in patients with inoperable or recurrent gastric cancer, and conducted a dose-escalation study. Methods. Patients with histologically confirmed gastric cancer were treated with the regimen. The dosage levels of TXT and CPT-11 were as follows: level 1, 30mg/m² and 50mg/m²; level 2, 35 and 50mg/m²; level 3, 40 and 50mg/m²; level 4, 40 and 60mg/m²; and level 5, 50 and 60mg/m². The dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle. Results. Grade 4 neutropenia was observed at level 3, but no other DLT was observed at less than level 4 during the first cycle. However, three patients at level 3 could not continue treatment without a decrease in the dosage after the second cycle. Based on these results, level 2 was considered to be the clinically recommended dosages. Conclusion. Biweekly TXT and CPT-11 was well tolerated. The recommended dosages of TXT and CPT-11 for a phase II trial are 35mg/m² and 50mg/m², respectively.     

Results of Three-dimensional Stereotactically-guided Radiotherapy in Recurrent Medulloblastoma

Purpose: To evaluate survival rates and side effects after stereotactically-guided radiotherapy (SRT) in patients with recurrent medulloblastoma of the brain. Methods and materials: Between 1992 and 2000, 20 patients with 29 radiological manifestations were treated with fractionated SRT (n=21) or radiosurgery (n=8). Median age was 16 years with 6 patients 14 years. All patients had prior cranio-spinal radiotherapy plus boost to the posterior fossa with a total dose of 54Gy. Time to recurrence was 33 months mean. Eighteen of the 29 lesions were located within the boost volume. Chemotherapy was given according to current international study protocols (HIT) in all patients. Mean total dose for re-irradiation was 24Gy for fractionated stereotactically-guided radiotherapy, and 15Gy for radiosurgery. Mean follow-up was 88.5 months. Results: Overall local control was 89.7%. Thirteen recurrences showed partial or complete response in CT/MR-imaging, 13 showed stable disease. Local tumor progression was seen 5 months mean after radiotherapy in three cases. A multifocal intracranial progression was seen in 9 patients, 5 patients developed additional spinal metastases. Thirteen patients died with disseminated cranio-spinal progression, after 72.6 months median. No late toxicity >CTC II especially no brain radionecrosis was seen after radiotherapy. Conclusion: SRT is effective and safe in the treatment of recurrent medulloblastoma to improve local control without evident side effects. The main problem remains the control of subclinical cranio-spinal dissemination.     

Intra-arterial Cisplatin Plus Oral Etoposide for the Treatment of Recurrent Malignant Glioma: A Phase II Study

Twenty-five adults with recurrent malignant glioma were enrolled into a phase II clinical study. All patients had undergone surgical resection and had failed radiotherapy and first-line treatment with nitrosourea-based chemotherapy; five had failed second-line chemotherapy. Our objective was to test the efficacy of combining intra-arterially (IA) infused cisplatin and oral etoposide. Using conventional angiographic technique to access anterior/posterior cerebral circulation, cisplatin 60mg/m² was administered by IA infusion on day 1 of treatment. Oral etoposide 50mg/m²/day was given days 1–21, with a 7day rest interval between courses. Response to treatment was evaluated in 20 patients. Two patients with anaplastic astrocytoma had partial responses (PR) and six patients experienced stable disease (SD) for an overall response rate (PR + SD) of 40%. The median time to disease progression (MTP) following treatment for the responder subgroup was 18weeks. The median survival time from treatment (MST) for the responders (n=8) and non-responders (n=12) was 56.5weeks and 11weeks, respectively. Combined IA cisplatin and oral etoposide was well-tolerated, but produced an objective response in only a minority of patients. Those considered responders (PR + SD) experienced significant survival advantage when compared to the non-responders. Nonetheless, IA delivery of chemotherapy is an expensive and technologically burdensome treatment for most patients to access, requiring proximity to a major center with neuro-oncological and neuroradiological clinical services. This is of special concern for patients suffering recurrent disease with progressive neurological symptoms at a time in their course when quality of life must be safeguarded and palliation of symptoms should be the therapeutic goal. Despite the efforts of previous investigators to use this combination of agents to treat recurrent malignant glioma, we cannot recommend the use of IA chemotherapy for salvage treatment of thisbreak disease.     

Inflammatory Breast Carcinoma: Pathological or Clinical Entity?

Inflammatory breast carcinoma (IBC) diagnosis is usually based in the presence of typical clinical symptoms (redness and edema in more than 2/3 of the breast), which are not always associated with pathologic characteristics (subdermal lymphatics involvement). Whether exclusively pathologic findings without clinical symptoms are sufficient for IBC diagnosis remains controversial. A retrospective analysis of 163 clinically diagnosed IBC (CIC) either with dermal lymphatics invasion or not, was compared with another group of 99 patients with dermal lymphatics invasion without clinical symptoms (occult inflammatory carcinoma) (OIC). The following clinical and pathological characteristics have been analyzed and compared: age, menopausal status, clinical axillar node involvement, symptoms duration before diagnosis, grade, estrogen receptors, presence of metastases at diagnosis, local recurrence, metastasic dissemination, disease-free (DFS) and overall survival (OS). Median age was younger in CIC (52.3 vs. 63.8 years; p<0.001). Symptom duration before diagnosis were significantly shorter in CIC (3.4 vs. 6.8 months; p<0.0001). Visceral (36.2% vs. 17.2%; p=0.001) and brain metastases (7.4% vs. 1%; p=0.02) was significantly more frequent in CIC. Negative estrogen receptors were more frequent in CIC (34.9% vs. 65.1%; p<0.004). Five-years DFS (25.6 vs. 51.6%; p<0.0001) and OS (28.6 vs. 40%; p<0.05) were shorter in CIC. CIC (regardless of subdermal lymphatics involvement) must be clearly differentiated from OIC. Prognosis of CIC patients is poorer, so this two entities should be clearly differentiated when therepeutic results are reported.     

Postoperative Radiation Therapy for Pituitary Adenoma

Background: We evaluated the efficacy of postoperative radiation therapy (RT), prognostic factors for local control probability, dose response relationship and treatment sequelae in 75 patients with pituitary adenoma. Materials and methods: A total dose of 48–60Gy (median: 50Gy) was delivered with a conventional fractionation schedule after surgery. Of 75 patients, 55 (73%) were followed for more than 5 years and 27 (36%) were followed for more than 10 years with a median of 95 months. Results: Five- and 10-year local control probabilities were 87.1% and 85.0%, respectively. Univariate analysis revealed that age (p=0.007), tumor volume smaller than 30cm³ (p=0.018) and the absence of prolactin secretion (p=0.003) were significantly favorable prognostic factors for local control probability. After multivariate analysis combining these 3 factors, tumor volume smaller than 30cm³ (p=0.017) and age (p=0.039) were statistically significant. Patients with prolactinoma greater than 30cm³ showed particularly poor local control rates. No significant improvement of the local control rate was detected with increasing total irradiation doses between 48 and 60Gy (p=0.29). The most common side effect was hypopituitarism, and there were no severe sequelae such as optic neuropathy or brain necrosis. Conclusion: Except with prolactinoma, the dose of postoperative RT for pituitary adenoma should not exceed 50Gy. Large prolactinoma, however, was very difficult to control with the irradiation doses between 50 and 60Gy, and would be good candidates for stereotactic radiosurgery or stereotactic radiation therapy.     

Brain Metastases from Fallopian Tube Carcinoma Responsive to Intra-arterial Carboplatin and Intravenous Etoposide: A Case Report

Fallopian tube carcinoma is the least common neoplasm of the female genital tract. Although rare, neurological complications such as brain metastases can develop. It remains unclear, however, what role chemotherapy has in the treatment of these patients and what route of administration is most effective. Intra-arterial (IA) regional administration of chemotherapy may increase intra-tumoral drug concentrations and improve efficacy. We report the case of a 47-year-old woman who developed bilateral fallopian tube cancer and multifocal brain metastases. After progression through radiation therapy and oral chemotherapy, she was placed on IA carboplatin (200mg/m²/d×2 days every 4 weeks) and intravenous etoposide (100mg/m²/d×2 days every 4 weeks). During treatment she had objective tumor shrinkage that has remained stable for more than 12 months. For patients with fallopian tube carcinoma that develop brain metastases and respond poorly to surgery and/or irradiation, multi-agent chemotherapy containing carboplatin should be considered. The effectiveness of carboplatin may be improved if administered by the IA route.     

Prognostic significance of acute presentation with emergency complications of gastric cancer

Background Although acute complications necessitating emergency hospital admission are well documented in patients with carcinoma of the colon, comparable data for patients with gastric carcinoma is thin. The aim of this study, therefore, was to examine the outcomes of patients presenting to hospital as acute admissions with emergency complications of previously undiagnosed gastric cancer.Methods Three hundred consecutive patients with gastric adenocarcinoma were studied prospectively, and subdivided into two groups according to whether the patients were referred as acute emergencies (n = 116) or as outpatients (n = 184).Resuslts The commonest emergency complications were: abdominal pain (57%), vomiting (41%), gastrointestinal bleeding (37%), dysphagia (26%), and a palpable mass (18%). Stages of disease were significantly more advanced in patients presenting acutely (I:II:III:IV = 7:11:27:71) compared with patients referred via outpatients (20:23:50:91, ² = 3.955; DF, 1; P = 0.047). R0 gastrectomy was significantly less likely after acute presentation (23 patients; 20%) compared with patients referred via outpatients (70 patients; 38%; ² = 11.037; DF, 1; P = 0.001). Cumulative 5-year survival for patients referred acutely was 9%, compared with 22% after outpatient referral (² = 9.11; DF, 1; P = 0.0025). Multivariate analysis revealed two factors to be significantly and independently associated with durations of survival: stage of disease (hazard ratio [HR], 1.742; 95% confidence interval [CI], 1.493–2.034; P = 0.0001) and presentation with acute complications (HR, 1.561; 95% CI, 1.151–2.117; P = 0.004).Conclusion Emergency complications of gastric cancer are a significant and independent prognostic marker of poor outcome.Presented at: British Society of Gastroenterology, Birmingham 2003, and 5th International Gastric Cancer Congress, Rome 2003.     

Malignant Germ Cell Tumors Metastatic to the Brain: A Model for a Curable Neoplasm? The Freiburg Experience and a Review of the Literature

The aim of this study on malignant germ cell tumors metastasizing to the brain is (a) to report our institutional experience, (b) to present three patients surviving for more than seven years, and (c) to review the literature with regard to long-term survival.From 1985 to 2000, 916 consecutive patients were treated with whole brain radiation therapy for brain metastases at our hospital. Eleven patients had cerebral lesions from histologically proven malignant germ cell tumors. Brain metastases were diagnosed at presentation (n = 2), following complete remission (n = 3), or along with extracerebral tumor progression (n = 6). Seven patients had a single brain metastasis. Three patients underwent resection. Eight patients reached the planned total dose of 50Gy. Eight patients had chemotherapy.Median survival was 6.6 months. The long-term survivors all had an isolated cerebral relapse after complete remission, presented with a single brain metastasis, and were treated with resection and whole brain radiation therapy to a total dose of 50Gy. The first patient died from a late relapse 89 months after the diagnosis of brain metastasis, the second patient is well and alive at 95 months. The third patient is currently being treated for a second malignancy originating from the lung. He is alive at 194 months, the longest survival for brain metastases from malignant germ cell tumors ever reported.Altogether, our study demonstrates that advanced extracerebral disease at initial diagnosis and isolated cerebral relapse after complete remission do not preclude long-term survival. Resection and whole brain radiation therapy might result in durable cerebral control with minimal morbidity.     

High-dose chemotherapy with autologous stem cell rescue for children with high risk and recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors

Current treatment for high risk and recurrent medulloblastoma (MB) and supratentorial primitive neuroectodermal tumors (stPNET) has a very poor prognosis in children. High dose chemotherapy (HDCT) and autologous stem cell rescue have improved survival rates. We present 19 patients (thirteen classified in the high risk group and six patients with recurrent disease) that received HDCT and autologous stem cell rescue.In the high risk group [Med Pediatr Oncol 38 (2002) 83], all patients underwent neurosurgical debulking. Standard chemotherapy was prescribed in 10 patients. Radiotherapy was given to 4 patients (all older than 4years old). In the recurrence disease group [Childs Nerv Syst 15 (1999) 498], five patients underwent surgery. Radiotherapy was given to those who were not previously irradiated. The HDCT in twelve patients consisted of busulfan 4mg/kg/day, orally over 4days in 6-hourly divided doses and melphalan at a dose of 140mg/m²/day by intravenous infusion over 5min on day –1. Three patients additionally received thiotepa 250mg/m²/day intravenously over 2days and four patients additionally received topotecan 2mg/m²/day over 5days by intravenous infusion over 30min. The other seven patients received busulfan and thiotepa at the same doses.Patients stem cells were mobilized with granulocyte colony-stimulating factor at a dose of 12g/kg twice daily subcutaneously for four consecutive days. Cryopreserved peripheral blood progenitor cells were re-infused 48h after completion of chemotherapy. With a median follow-up of 34months (range 5–93) eight complete responses and one partial response were observed. Three patients died of treatment-related toxicities (15%). The 2 year event-free survival was 37.67±14% in all patients and 57±15% for the high risk group.Therefore we conclude that HDCT may improve survival rates in patients with high risk/recurrent MB and stPNET despite treatment toxicity.     

Prolonged Infusional Topotecan and Accelerated Hyperfractionated 3d-conformal Radiation in Patients with Newly Diagnosed Glioblastoma – A Phase I Study

Purpose: Topotecan has demonstrated exceptional central nervous system penetration as well as radiosensitizing properties in glioblastoma xenografts [Chastagner et al., Int J Radiat Oncol Biol Phy 50: 777–782, 2001]. This phase I trial was performed to determine the maximum tolerated dose and the recommended dose of topotecan continuous infusion administered together with concomitant radiotherapy in patients with glioblastoma. Patients and methods: A total of 20 patients were treated in this trial. Twenty one day topotecan continuous infusion was escalated from 0.3mg/m²/d in increments of 0.1mg/m²/d and cohorts of 3–6 patients until maximum tolerated dose was reached; Three-dimensional (3d) conformal radiotherapy was applied concurrently twice daily with a fraction size of 1.75Gy up to 57.75Gy total dose. Three additional cycles of maintenance topotecan chemotherapy were scheduled. Results: Fifty-three courses were performed in 5 dose levels (0.3mg/m²/d: 12 cycles, 0.4mg/m²/d: 6 cycles, 0.5mg/m²/d: 10 cycles, 0.6mg/m²/d: 6 cycles, 0.7mg/m²/d: 19 cycles). Maximum tolerated dose was reached at dose level 5 (0.7mg/m²/d), because 3/7 patients suffered from dose limiting toxicity. These were febrile sinusitis, bacterial sepsis and grade 4 thrombocytopenia. Neutropenia of grade 4 was encountered in 2 cycles (0.5 and 0.7mg/m²/d). Response data were available in 17 patients, 3 of which (18%) achieved partial remission, 12 (71%) stable disease throughout the observation period and 2 (11%) progressive disease. Conclusion: The recommended dose for further trials will be 0.6mg/m²/d topotecan administered as 21 days continuous infusion in combination with accelerated 3d conformal radiation.     

Five-day infusion fluorouracil plus vinorelbine in women with breast cancer previously treated with anthracyclines and paclitaxel

The continuous infusion of fluorouracil presents a superior pharmacological profile than its bolus administration, while vinorelbine is a new drug associated with good clinical activity in pretreated metastatic breast cancer. We investigated the combination of this two antitumor drugs with the aim to determine a tolerant and active second-line therapy in metastatic pretreated patients. Patients and methods.Fifty six patients pretreated with chemotherapy received a median of six cycles [2–11] of fluorouracil, 700mg/m² for 5 day-continuous i.v. infusion and vinorelbine, 20mg/m² on days 1 and 6, every three weeks. The inclusion and evaluation criteria required measurable disease by conventional clinical and/or instrumental means. Findings.Iatrogenic toxicity in 340 administered cycles was mild: stomatitis==11% (Grade 3==5%), constipation and abdominal pain==12, G2 neutropenia==4, G1 thrombocytopenia==0.5. In nine cases moderate infections occurred and six women experienced catheter related complications. Complete and partial remissions were observed in 12% and 36% of evaluable patients, respectively. In particular major tumor regression was documented in 28% of anthracyclines or taxol unresponsive cases. Conclusions.This drug combination is active in metastatic pretreated breast cancer patients and devoid of serious iatrogenic toxicity. Although it deserves future optimization, for instance with the inclusion of oral fluoropirimidines, it represents a good choice for second-line or non cross-resistant regimens.     

A Critical Examination of the Results from the Harvard-MIT NCT Program Phase I Clinical Trial of Neutron Capture Therapy for Intracranial Disease

A phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase I trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24–78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The ¹⁰B carrier, L-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250mgkg^–1 over 1h (10 subjects), 300mgkg^–1 over 1.5h (two subjects), or 350mgkg^–1 over 1.5–2h (10 subjects). The pharmacokinetic profile of ¹⁰B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.     

Polyadenylic–Polyuridylic Acid Plus Locoregional Radiotherapy Versus Chemotherapy with CMF in Operable Breast Cancer: a 14 Year Follow-up Analysis of a Randomized Trial of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC)

With a median follow-up of 14 years, the combination of polyadenylic–polyuridylic acid plus locoregional radiotherapy (257 patients) has significantly improved disease-free survival (p=0.03) and significantly reduced the incidence of metastases (p=0.04) when compared to CMF alone (260 patients), in women with operable breast cancer. The trial does not, however, permit an appreciation of the respective role of radiotherapy and PolyAU in these results.