Prognostic models predicting survival of patients with brain metastases: integration of lactate dehydrogenase, albumin and extracranial organ involvement.

AIMS: To explore the role of expanded assessment of metastatic extracranial organ involvement, as well as albumin and lactate dehydrogenase (LDH), i.e. surrogates of disease extent, in survival prediction models for patients with brain metastases. MATERIALS AND METHODS: A retrospective analysis of 189 patients treated with whole brain radiotherapy was carried out. Uni- and multivariate analyses included recursive partitioning analysis classes, basic score for brain metastases and diagnosis-specific graded prognostic assessment (DS-GPA). RESULTS: Elevated LDH correlated significantly with extracranial organ involvement, low albumin with primary tumour type and primary tumour control. Elevated LDH, low albumin and a combination of both correlated significantly with overall survival. LDH, albumin and the number of extracranial organs involved (none, one, two or more harbouring metastases) were independent prognostic factors in multivariate analyses (if added to the three established scores mentioned above and also if added to individual parameters such as age, performance status, etc.). A combination of these three new prognostic factors predicted very short survival (median 0.7 months if all three were present). CONCLUSION: We have previously defined patient groups in whom foregoing radiotherapy was unlikely to compromise survival. These were patients with a DS-GPA score of 0-1.5 points and age ≥75 years or Karnofsky performance status ≤50 or uncontrolled primary tumour with extracranial metastases to at least two organs. Patients with a combination of three new adverse features (elevated LDH plus low albumin plus extracranial metastases to at least two organs) might also be considered for best supportive care. Furthermore, it appears warranted to study whether scores such as DS-GPA can be optimised by integrating information on these three parameters.

Prediction of short survival in patients with brain metastases based on three different scores: a role for 'triple-negative' status?

AIMS: To evaluate models predicting short survival in patients with brain metastases treated with whole-brain radiotherapy (WBRT). MATERIALS AND METHODS: This was a retrospective analysis of 312 patients. Each patient was assigned to three different four-tiered prognostic scores: the Basic Score for Brain Metastases (BSBM), the Graded Prognostic Assessment (GPA) and the score developed by Rades et al. In addition, a 'triple-negative' cohort was evaluated (all three scores predicted unfavourable prognosis, n=30). RESULTS: No statistically significant survival differences were found between the most unfavourable BSBM, GPA, Rades et al. and 'triple-negative' groups. The BSBM best predicted short survival: patients classified in the unfavourable group (Karnofsky performance status <80, uncontrolled primary tumour and presence of extracranial metastases) had a 12.5% survival at 4 months and a 0% 1-year survival. Patients in this group who survived for 4 months or more had simultaneously detected cancer and brain metastases, were treatment naive, and received systemic therapy in addition to WBRT. Excluding this type of patient from the analysis resulted in survival figures that were indistinguishable from those obtained with best supportive care without WBRT in other studies. CONCLUSIONS: Although continuous research is necessary to identify patients who can be managed safely and palliated without WBRT, we feel that a model of the BSBM unfavourable group (Karnofsky performance status <80, uncontrolled primary tumour and presence of extracranial metastases) and no intent to treat systemically might form a basis for validation in other large databases. The triple-negativity criterion was not superior for predicting poor prognosis.

A phase II study of high-dose epirubicin in ovarian cancer patients previously treated with cisplatin. EORTC Gynecological Cancer Cooperative Group.

BACKGROUND: In vitro data demonstrated a dose-response relationship for doxorubicin in ovarian cancer cell lines. However, this dose-response question for anthracyclines has never been adequately addressed in ovarian cancer patients. A phase I study with epirubicin gave support to these in vitro findings and recommended a dose of 150 mg/m2 for phase II testing. PATIENTS AND METHODS: The present report concerns the final analysis of an EORTC-Gynecological Cancer Cooperative Group (GCCG) phase II study of high-dose epirubicin (HDE) in cisplatin-pretreated patients with epithelial ovarian cancer. A total of 100 eligible patients were included; 34 had progressed during first-line therapy (group 1), 17 had persistent disease after first-line therapy (group 2) and 49 had relapsed following an initial response to first-line therapy (group 3). All patients had measurable or evaluable disease, were aged < 75 years, had a WHO performance status 0-2, had adequate vital organ function and gave consent. Epirubicin was administered by rapid i.v. infusion at a dose of 150 mg/m2 and given at three-week intervals. Escalation to 180 mg/m2 was to be carried out if white blood cell nadir count was > 2.0 x 10(9)/l and platelet nadir count was > 75 x 10(9)/l. RESULTS: A total of 361 HDE treatment cycles were administered, the median number per patient being 4. Of the 85 patients who received at least two cycles of protocol treatment, 26 (31%) did not have any dose modification, 23 (26%) had dose reduction, while 36 (43%) had the dose increased to 180 mg/m2, at least for one cycle. The response rate in all eligible patients was 20% (95% confidence interval 13%-30%), 15% in group 1, 12% in group 2 and 27% in group 3. Patients with a cisplatin-free interval of > 12 months responded in 41%. The median duration of response was nine months (range 19 weeks to 3 years). Main toxicities were myelosuppression (leucopenia, neutropenia), nausea, vomiting, alopecia and mucositis. There were three cases of excessive toxicity leading to early discontinuation of HDE treatment and in one patient this contributed to death. No serious cardiotoxicity was recorded. CONCLUSIONS: It is concluded that HDE is active in platinum-pretreated patients with epithelial ovarian cancer and should be further studied in first-line in combination with paclitaxel and a platinum compound.

Phase II trial of vinorelbine in patients with advanced and/or recurrent cervical carcinoma: an EORTC Gynaecological Cancer Cooperative Group Study.

The objective of this phase II study was to assess the efficacy and toxicity of vinorelbine administered as a single agent in the treatment of chemonaïve cervical cancer patients. 46 patients (41 eligible) with cervical cancer (epidermoid or adenocarcinoma) and measurable metastatic and/or recurrent disease localised outside irradiated areas were treated with weekly intravenous (i.v.) vinorelbine 30 mg/m2 infused over 20 min. No prior chemotherapy was allowed. Median age was 53 years (range: 33-73), and performance status 1 (0-2). 31 patients (76%) had prior radiation therapy. There were 7 partial responders (17, 95% confidence interval (CI) 7-32) and 8 stable diseases (20%). Median duration of response was 5 months (4-11). Granulocytopenia was the major toxicity, with 47% of patients exhibiting grade 3 or 4 toxicity. Dose reduction and/or treatment delay was necessary in 28 patients (78%). Peripheral neuropathy reported in 10 patients was mild (grade 1 in 9 patients and grade 2 in 1 patient). In conclusion, single agent vinorelbine has moderate activity in recurrent or metastatic cervical cancer, but its reduced neurotoxicity warrants further study in combination with cisplatin.

Vascular endothelial growth factor measured in platelet poor plasma allows optimal separation between cancer patients and volunteers: a key to study an angiogenic marker in vivo?

BACKGROUND: Serum VEGF levels are elevated in cancer patients and are used as a tumor marker in different malignancies. We have measured VEGF levels in different blood compartments in cancer patients and healthy volunteers in order to assess the most suitable way of processing blood for measuring VEGF as a marker of tumor-angiogenesis. PATIENTS AND METHODS: VEGF concentrations were analyzed by an enzyme-linked immunosorbent assay in serum (VEGFS), EDTA plasma (VEGFEDTA), citrated plasma (VEGFC), CTAD-plasma (VEGFCTAD), platelet poor plasma (VEGFPPP), platelet rich plasma after induction of platelet activation (VEGFPRP). Platelet activation was assessed by measuring PF4 concentrations in different plasma samples. RESULTS: We observed higher VEGFS (P = 0.0027), VEGFEDTA (P = 0.003) and VEGFPPP (P = 0.0007) levels in cancer patients than in volunteers; VEGFPRP concentrations showed no significant difference (P = 0.208). Analysis of the correlation between VEGFplt and VEGFS in cancer patients showed a similar correlation in a comparable VEGFS concentration range as in the volunteers. When comparing VEGFC to VEGFCTAD, we find significantly higher VEGF and PF4 levels in citrated plasma (VEGF: P = 0.00019; PF4: P = 0.00023). CONCLUSIONS: It is likely that VEGFS in cancer patients encompass platelet-delivered VEGF and VEGF from other sources, notably from (neo)-angiogenesis in tumoral tissue. The best discrimination between volunteers and cancer patients was observed in PPP. As generating plasma can induce platelet activation, with consequent VEGF release from platelets, we suggest that to assess free circulating VEGF, CTAD plasma should be used.

Cyclophosphamide or ifosfamide in patients with advanced and/or recurrent endometrial carcinoma: a randomized phase II study of the EORTC Gynecological Cancer Cooperative Group.

UNLABELLED: Currently, available chemotherapy regimens for patients with advanced or recurrent endometrial cancer are generally not curative. Thus, there is a need to identify more active single agents in this disease. In this study patients pre-treated and not pre-treated with first line combination chemotherapy were entered into a randomized phase II study of either cyclophosphamide (CYCLO) or Ifosfamide (IFOS). PATIENTS AND METHOD: Sixty one eligible patients with recurrent or metastatic histologically proven, adenocarcinoma of the uterine corpus entered the study. The median age at entry was 62 (range 40-74) years. Twenty patients (33%) had prior hormonal treatment and 31 (51%) prior chemotherapy. CYCLO was given at a dose of 1200 mg/m2 and IFOS at a dose of 5 g/m2. Both drugs were administered i.v. over 24 hours on day one every three weeks. Adequate pre- and post hydration as well as use of Mesna in the Ifosfamide arm were mandatory. RESULTS: A median of two treatment cycles (range 1-12) per patient were given. In the chemotherapy-naive patients, in the CYCLO arm two PRs (RR 14%, C.I. 2-43%) were seen and in the IFOS arm two CRs, two PRs, (RR 25%, C.I. 7-52%) were observed. No responses were seen in pre-treated patients. The duration of responses were: 15+, 7+ months for the CRs, 15+ and 5 months for PRs in IFOS arm and 67+, 4 months in CYCLO arm. The hematological toxicity was dose-limiting and similar in both treatment arms. No serious non hematological toxicities were reported, but a transient increase of the creatinine blood level was seen in two IFOS patients (6%). CONCLUSION: Ifosfamide is an active drug in the treatment of chemotherapy-naive patients with advanced endometrial cancer and its application in currently used (combination) regimens should be considered.

PVB chemotherapy in patients with recurrent or advanced dysgerminoma: a Phase II study of the EORTC Gynaecological Cancer Cooperative Group.

Dysgerminoma accounts for 1% of all ovarian cancers and for 50% of all ovarian germ cell malignancies. Low stage patients (50%) can be cured with local treatment. The aim of this trial was to study the objective tumour response rate and toxicity of PVB (cisplatin, vinblastine, bleomycin) chemotherapy in patients with pure advanced or recurrent dysgerminoma. Eighteen eligible patients with advanced dysgerminoma were entered into this study. Three patients had local bulky recurrence only; all the others also had metastatic disease. The median age at entry was 27 years (range 1348). Seventeen patients had had prior surgery and one had undergone prior radiotherapy. The WHO performance status was 0 in 12 patients, 1 in three patients, and 2 in three patients. The treatment consisted of: intravenous or intramuscular bleomycin 30 mg on days 2, 9 and 16, intravenous vinblastine 0.15 mg/kg on days 1 and 2, and intravenous cisplatin 20 mg/m2 on days 1-5. This regimen was given at 3-week intervals for a total of four cycles. Twelve patients obtained a complete response (66%), five a partial response (28%), and one could not be evaluated because radiotherapy was administered immediately after chemotherapy. After a median follow-up of 76 months (range 4-132), 14 (78%) patients were alive and well. Two died of disease progression, one of neutropenic septicaemia and one of lung fibrosis. No unusual toxicity was reported. Alopecia, as well as nausea and vomiting, were common. Leucopenia (78%), thrombocytopenia (17%) and infection (11%) were the other severe (grade 3-4) side effects. The PVB chemotherapy regimen is highly effective in patients with advanced ovarian dysgerminoma. However, the BEP (bleomycin, etoposide, cisplatin) regimen, which is equally as potent and less toxic, is preferred.

Angiogenesis: possibilities for therapeutic interventions.

Vascular proliferation normally occurs only during embryonic development, the female reproductive cycle and wound healing. Various pathological conditions such as diabetic retinopathy are characterized by persistent, uncontrolled angiogenesis. At the other hand, impaired development of new blood vessels has been found to be related with myocardial infarction. A series of anti-angiogenic drugs are currently included in experimental cancer treatment, whereas the failure of ulcers to heal may be limited by increased angiogenesis upon administration of growth factors. In the present review control mechanisms of the vasculature are summarized and therapeutic approaches discussed.

An EORTC phase II study of the efficacy and safety of linomide in the treatment of advanced renal cell carcinoma.

The aim of this study was to determine the objective tumour response rate and duration of response and toxicity of linomide (Roquinimex) treatment in patients with disseminated renal cell carcinoma, pretreated or not pretreated with immunotherapy. From March 1991 to July 1992, 72 patients with metastatic and progressive renal cell cancer were entered of whom 9 (12%) were not evaluable for response. Linomide was given orally, twice weekly, 5 mg during the first week with dose escalation to 10 mg during the second week and 15 mg thereafter. Treatment was continued until disease progression or unacceptable toxicity. No haematological toxicity but slight anaemia was observed. A significant WBC (white blood cell count) increase (P < 0.0001, paired T-test) was found during treatment. The most often reported non-haematological side-effects were: flu-like syndrome (54%, grade III-IV 7%), nausea/vomiting (41% and 3%, respectively) and neurotoxicity (34% and 2%). Most side-effects were of mild or moderate intensity (WHO grade 1 or 2). The objective overall response rate was 4%: 1 CR and 2 PRs. Stable disease was reported for 28 patients (40%). The duration of response was 17, 22 and 30 (CR) months. Median time to progression was 5 months. Linomide at the given dose and schedule is well tolerated, but has limited antitumour activity in metastatic renal cell carcinoma.

Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients.

The concentration of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) was determined in the serum of 90 untreated and 42 treated metastatic cancer patients, including patients with colorectal, breast, ovarian and renal carcinomas, with an enzyme-linked immunosorbent assay (ELISA). Levels higher than the 95th percentile of the concentrations of a control group, i.e. 7.5 pg ml(-1) for bFGF and 500 pg ml(-1) for VEGF, were identified as 'elevated'. One measurement during follow-up was included into the analysis per patient. For 19 treated patients, consecutive serum samples were analysed. Fifty-seven per cent of all untreated patients had elevated serum levels of one or both angiogenic factors. The fraction of patients with elevated serum levels of bFGF and/or VEGF was similar in the different tumour types. Agreement of bFGF levels and VEGF levels, classified in relation to their respective cut-off values, was present in 67% of all patients. Fifty-eight per cent of the patients with progressive disease during treatment compared with 15% of the patients showing response to treatment (chi-squared test P < 0.05) had elevated bFGF and/or VEGF serum levels. When consecutive serum samples were analysed, two-thirds of the patients showing progressive disease had increasing serum levels of the angiogenic factors compared with less than one-tenth of the patients showing response (chi-squared test P < 0.05). The lack of association between the serum bFGF and VEGF levels and the tumour type may suggest an aspecific host reaction responsible for solid tumour-related angiogenesis. The main determinants of the serum bFGF and VEGF concentration are the progression kinetics of the metastatic carcinomas.

A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer. European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council Working Party on Superficial Bladder Cancer.

PURPOSE: The use of prophylactic agents after primary resection can decrease the incidence of tumor recurrence in patients with stage TaT1 bladder cancer. However, the long-term impact on progression to muscle invasive disease as well as on duration of survival is unknown. A combined analysis of individual patient data from previously performed European Organization for Research and Treatment of Cancer (EORTC) and Medical Research Council (MRC) randomized clinical trials was done in an attempt to answer these crucial questions. We compared immediate versus no adjuvant prophylactic treatment after transurethral resection with respect to disease-free interval, time to progression to muscle invasive disease, time to appearance of distant metastases, duration of survival and progression-free survival. MATERIALS AND METHODS: All EORTC and MRC prophylactic, randomized phase III trials with primary or recurrent, stage TaT1 transitional cell bladder cancer that compared transurethral resection alone or with adjuvant prophylactic treatment were included in the study. Four EORTC and 2 MRC trials using intravesical chemotherapy or oral agents and including a total of 2,535 patients were studied. RESULTS: A statistically significant effect of adjuvant treatment over no adjuvant treatment was found in terms of the duration of the disease-free interval (p < 0.01). No clear advantage of adjuvant treatment was shown with respect to progression to invasive disease, time to appearance of distant metastases or duration of survival and progression-free survival. Median survival followup was 7.8 years. CONCLUSIONS: Despite prologation of the disease-free-interval adjuvant treatment has no apparent long-term impact on the evolution of stage TaTi bladder cancer.

Oral ifosfamide/mesna versus intravenous ifosfamide/mesna in non-small-cell lung cancer: a randomized phase II trial of the EORTC lung cancer cooperative group.

BACKGROUND: Chronic oral administration of anticancer drugs may offer therapeutic advantages. PATIENTS AND METHODS: A total of 68 patients with advanced non-small-cell lung cancer, not previously treated by chemotherapy, were randomized to receive either ifosfamide given orally (OSI) at a dose of 1 g/day for 14 days every 4 weeks, or as a 1-hour intravenous infusion (IVI) at a dose of 1.6 g/m2/day for 5 days every 4 weeks. According to the route of ifosfamide administration, patients received either mesna i.v. or mesna film-coated tablets for uroprotection. RESULTS: Eight patients were found to be ineligible for the study and therefore excluded for all analyses. Thirty-three patients received IVI, and 27 patients OSI. One patient randomized to OSI died before treatment was initiated, leaving 59 patients fully evaluable for toxicity. Hematological toxicity was less severe for patients on OSI, but CNS toxicity was reported more frequently on OSI (39%; 12% grade III/IV), than on IVI (15%; 9% grade III/IV), which caused the premature close of the study. Other non-hematological adverse events were of modest clinical significance and comparable in both arms. Forty-nine patients were considered evaluable for response: in the IVI arm, 5 (17%) of the 29 evaluable patients obtained a partial remission, and 7 patients a no change (24%). In the OSI arm, 2 (10%) of the 20 evaluable patients obtained a partial remission, and 11 (52%) a stable disease. CONCLUSIONS: Both arms have some activity in non-small-cell lung cancer; while OSI was less myelosuppressive than IVI, it was associated with a higher incidence of CNS toxicity. Oral administration of ifosfamide, in the schedule and daily dose tested here cannot be recommended.

High dose epirubicin is effective in measurable metastatic prostate cancer: a phase II study of the EORTC Genitourinary Group.

39 hormone-resistant prostate cancer patients with bidimensionally measurable metastatic lesions were given epirubicin 100 mg/m2 intravenously every 3 weeks. One patient was ineligible and excluded from analyses. According to WHO criteria, 9 patients (24%) had a partial response, 16 patients (42%) had stable disease (including 3 patients (8%) with a partial response not confirmed 1 month later), 11 patients (29%) had progressive disease, and in 2 patients (5%) response was not evaluated. Toxicity was as expected. Fifty-five per cent of patients had WHO grade 3/4 toxicity for white blood cells, and 3% of patients grade 3 toxicity for platelets. Other toxicities included nausea and vomiting, mucositis and alopecia. 2 patients with pre-existing cardiac disease developed cardiotoxicity (1 grade 2, 1 grade 3). An attempt was made to correlate response with prostate specific antigen (PSA) measurements. A positive trend was seen, but 2 non-responding patients showed a > 50% decrease in value.

High-dose epirubicin in platinum-pretreated patients with ovarian carcinoma: the EORTC-GCCG experience.

BACKGROUND: A dose-response relationship for doxorubicin in ovarian cancer (OC) cell lines has been demonstrated in vitro. However, this has never been carefully addressed in the clinic. These data and the more favourable toxicity profile of the anthracycline analogue epirubicin were reasons to study high-dose epirubicin (HDE) in OC patients who relapsed on/after platinum-based chemotherapy. This was done both in a phase I/II feasibility study (n = 27; HDE dose 120-200 mg/m2 q3 weeks) and a still ongoing straightforward phase II study (n = 91; HDE dose 150-180 mg/m2 q 3 weeks). RESULTS: Responses were observed at all dose levels. Overall 24 of the 118 patients responded (20%), which is much higher than reported with lower doses (7% with doses of 60-110 mg/m2). The most important side effects were myelosuppression, alopecia, nausea and vomiting and mucositis. CONCLUSION: HDE is tolerable and has activity in second-line after platinum-based chemotherapy in OC patients.

A report comparing the use of tropisetron (Navoban), a 5-HT3 antagonist, with a standard antiemetic regimen of dexamethasone and metoclopramide in cisplatin-treated patients under conditions of severe emesis.

This report of a double-blind, randomized study performed to evaluate the comparative antiemetic efficacy of tropisetron (Navoban; Sandoz Pharma Ltd, Basel, Switzerland), a new 5-hydroxytryptamine receptor antagonist, focuses on treatment during stages of chemotherapy when nausea and vomiting are particularly severe. One hundred fifteen chemotherapy-naive patients with malignant disease were administered either tropisetron (n = 58) or a dexamethasone dose plus a metoclopramide dose (n = 57) during 5 days of two successive cycles of chemotherapy. Within the first 24 hours after receiving cisplatin-based chemotherapy, 76% of patients in the tropisetron group remained free of vomiting (with 59% of patients free of nausea) compared with 39% of patients free of vomiting in the conventionally treated group (30% of patients free of nausea). Improved control of emesis also was observed over 4 consecutive days of follow-up in the tropisetron group. The difference in incidence of nausea and vomiting between the patient groups was statistically significant (P < .05). The efficacy of tropisetron was well maintained during the second consecutive chemotherapy cycle; during the first 24 hours, 72% and 62% of patients remained free of vomiting and nausea, respectively. Tropisetron appears to be a highly effective, well tolerated, and simple to use antiemetic agent for patients receiving chemotherapy.

[Evaluation of the results of combined treatment of patients with testicular seminoma in the II stage of clinical advancement]. / Ocena wyników skojarzonego leczenia chorych na nasieniaki jadra w II stopniu zaawansowania klinicznego.

An attempt to introduce combined therapy for patients with testicular seminoma in the II degree of clinical advancement was undertaken at the Centre of Oncology. Combined therapy consisted of 3 courses of PVB in the following daily doses: DDP 100 mg/m2 i.v. on the first day; VLB 10 mg i.v. on the first and second day; bleomycin 30 mg i.v. on the second, ninth and sixteenth day every 21 days, and 60Co on lymphatic glands area in which metastases were diagnosed prior to chemotherapy. Twenty three patients were treated that way between January 1985 and June 1989. Mean follow-up period after the treatment was 14 months. One patient died for the tumor, metastases to the lungs were diagnosed in one patient 9 months after completion of the treatment which ameliorated after "second" chemotherapy, and 22 patients (96%) are still free from the symptoms of active disease.

Risk-related adjuvant chemotherapy for stage I non-seminoma of the testis.

Seventy-Two patients with stage I testicular non-seminoma presenting between January 1984 and December 1988 were managed either by adjuvant chemotherapy in the presence of histological adverse prognostic factors or by surveillance if none of these factors were present. The determining factors were vascular invasion, lymphatic invasion, involvement of the epididymis, involvement of the rete testis. Thirty patients were treated with three courses of platinum, vinblastine and bleomycin (PVB) and 42 were managed by surveillance. All 72 patients are alive and have been free of disease from 12-60+ months. One of 42 patients managed by surveillance relapsed 16 months after orchidectomy and he has been disease-free for 32+ months after chemotherapy. No relapses occurred in patients treated with adjuvant chemotherapy. The results confirm the suggestion by Peckham (Hoskin et al., 1986) that histopathological analysis of the primary tumour can provide the basis for subsequent management either by surveillance or chemotherapy.