Svend Aage Engelholm

Exploratory Phase III Study of Paclitaxel and Cisplatin Versus Paclitaxel and Carboplatin in Advanced Ovarian Cancer

PURPOSE To determine the side effects and feasibility of cisplatin and carboplatin each in combination with paclitaxel as front-line therapy in advanced epithelial ovarian cancer. PATIENTS AND METHODS Patients were randomly allocated to receive paclitaxel 175 mg/m(2) intravenously as a 3-hour infusion followed by either cisplatin 75 mg/m(2) or carboplatin (area under the plasma concentration-time curve of 5), both on day 1. The schedule was repeated every 3 weeks for at least six cycles. Women allocated to paclitaxel-cisplatin were admitted to the hospital, whereas the carboplatin regimen was administered to outpatients. RESULTS A total of 208 eligible patients were randomized. Both regimens could be delivered in an optimal dose and without significant delay. Paclitaxel-carboplatin produced significantly less nausea and vomiting (P: <.01) and less peripheral neurotoxicity (P: =.04) but more granulocytopenia and thrombocytopenia (P: <.01). The overall response rate in 132 patients with measurable disease was 64% (84 of 132 patients), and in patients with elevated CA 125 levels at start, it was 74% (132 of 178 patients). With a median follow-up time of 37 months, the median progression-free survival time of all patients was 16 months and the median overall survival time was 31 months. The small number of patients entered onto the study caused wide confidence intervals (CIs) around the hazards ratio for progression-free survival of paclitaxel-carboplatin compared with paclitaxel-cisplatin (hazards ratio, 1.07; 95% CI, 0.78 to 1.48) and did not allow conclusions about efficacy. CONCLUSION Paclitaxel-carboplatin is a feasible regimen for outpatients with ovarian cancer and has a better toxicity profile than paclitaxel-cisplatin.

Phase II study on stereotactic body radiotherapy of colorectal metastases

Surgical resection provides long term survival in approximately 30% of patients with colorectal carcinoma (CRC) liver metastases. However, only a limited number of patients with CRC-metastases are amendable for surgery. We have tested the effect of stereotactic body radiotherapy (SBRT) in the treatment of inoperable patients with CRC-metastases. Sixty-four patients with a total number of 141 CRC-metastases in the liver (n = 44), lung (n = 12), lymph nodes (n = 3), suprarenal gland (n = 1) or two organs (n = 4) were treated with SBRT with a central dose of 15 Gy×3 within 5–8 days. Median follow-up was 4.3 years. After 2 years, actuarial local control was 86% and 63% in tumor and patient based analysis, respectively. Nineteen percent were without local or distant progression after 2 years and overall survival was 67, 38, 22, 13, and 13% after 1, 2, 3, 4 and 5 years, respectively. One patient died due to hepatic failure, one patient was operated for a colonic perforation and two patients were conservatively treated for duodenal ulcerations. Beside these, only moderate toxicities such as nausea, diarrhoea and skin reactions were observed. SBRT in patients with inoperable CRC-metastases resulted in high probability of local control and promising survival rate. One toxic death and few severe reactions were observed. For the majority of patients, the treatment related toxicity was moderate.

Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass

OBJECTIVE Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes. METHODS Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI. RESULTS 809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI=200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI). CONCLUSION HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women.

Strontium89 Chloride versus Palliative Local Field Radiotherapy in Patients with Hormonal Escaped Prostate Cancer: A Phase III Study of the European Organisation for Research and Treatment of Cancer Genitourinary Group

Abstract Objectives: To compare toxicity, subjective response rate, time to subjective progression and overall survival in patients with painful bone metastases of hormone-resistant prostate cancer (HRPC) treated with a single intravenous injection of 150MBq (4mCi) Strontium 89 Chloride (S) or palliative local field radiotherapy (R) with the usual radiotherapy regimen used at each centre. The costs of both treatments were also assessed. Patients and Methods: 101 patients were randomized to S and 102 to R. Time to event endpoints were compared with the Logrank test and Kaplan-Meier curves, in the intent-to-treat population (2-sided α =0.05). Results: Baseline characteristics of both groups were comparable. There was a borderline statistically significant difference in overall survival in favour of the local field radiotherapy (R: 11 months; S: 7.2 months; p =0.0457). There was no difference in progression-free survival or time to progression. Subjective response was seen in 34.7% in the S-arm and in 33.3% in the R-arm. A biochemical response was observed in 10% and 13% of the R- and S-groups, respectively. There was no difference in treatment toxicity between the two groups. Conclusion: In symptomatic HRPC, pain treatment with local field radiotherapy is associated with a better overall survival compared to Strontium 89 . The lower costs of local field radiotherapy also favour the use of this treatment in patients with HRPC. The reason for the apparent survival benefit of localised radiation treatment is not clear.

Docetaxel and cisplatin in metastatic urothelial cancer: a phase II study.

PURPOSE Docetaxel and cisplatin has documented single-agent activity and different toxicity profiles in patients with metastatic urothelial cancer. We performed a phase II study in which docetaxel was combined with cisplatin to evaluate response rate, toxicity, and survival. PATIENTS AND METHODS Eligibility criteria included performance status (World Health Organization [WHO]) less than 3; normal bone marrow, liver, and renal function; and no concurrent malignancy or symptomatic peripheral neuropathy. Docetaxel (Taxotere; Rhône-Poulenc Rorer, Paris, France) 75 mg/m2 was combined with cisplatin 75 mg/m2 every third week. Patients received premedication with prednisolone and clemastine. RESULTS A total of 25 patients were assessable for response and toxicity. Median age was 64 years; five patients had locoregional disease only and 20 had metastatic disease. Response was achieved in 15 patients (60%; 95% confidence interval [CI], 39% to 79%), including seven patients (26%) who achieved a complete response. Overall median survival time was 13.6 months (range, 1.5 to 26.4+). The most frequent toxicity was nausea and vomiting (80% of patients). Neutropenia grade 3 or 4 was observed in 56% of patients, but only one had febrile neutropenia. Mucositis and diarrhea were encountered in 13% of cycles, mostly grade 1 or 2. Peripheral neuropathy and skin changes grade 1 and 2 were observed in 76% and 36%, respectively. Fluid retention and hypersensitivity reactions were infrequent and mild. CONCLUSION The combination of docetaxel and cisplatin is effective and feasible in patients with metastatic urothelial cancer with a manageable safety profile.

Plasma YKL-40, as a prognostic tumor marker in recurrent ovarian cancer

Background. YKL‐40, a member of family 18 glycosyl hydrolases, is secreted by cancer cells. The function of YKL‐40 in cancer diseases is unknown, but it is a growth factor of connective tissue cells and probably has a role in inflammation and remodeling of the extracellular matrix, a process also involved in metastatic malignant diseases. High serum YKL‐40 has been associated with poor prognosis for patients with colorectal and recurrent breast cancer.

Should CA-125 Response Criteria Be Preferred to Response Evaluation Criteria in Solid Tumors (RECIST) for Prognostication During Second-Line Chemotherapy of Ovarian Carcinoma?

PURPOSE The aim of the study was to compare the prognostic value of a response by the Gynecologic Cancer Intergroup (GCIG) Cancer Antigen (CA) -125 response criteria and the Response Evaluation Criteria in Solid Tumors (RECIST) on survival in patients with ovarian carcinoma receiving second-line chemotherapy. PATIENTS AND METHODS From a single-institution registry of 527 consecutive patients with primary ovarian carcinoma, 131 records satisfied the inclusion criteria: ovarian carcinoma of International Federation of Gynecology and Obstetrics stage IC to IV, first-line chemotherapy with paclitaxel and a platinum compound, refractory or recurrent disease, and second-line chemotherapy consisting of topotecan or paclitaxel plus carboplatin. Univariate and multivariate analyses of survival were performed using the landmark method. RESULTS In patients with measurable disease by RECIST and with assessable disease by the CA-125 criteria (n = 68), the CA-125 criteria were 2.6 times better than the RECIST at disclosing survival. In a multivariate Cox analysis with inclusion of nine potential prognostic parameters, CA-125 response (responders v nonresponders; hazard ratio, 0.21; P < .001) and number of relapse sites (solitary v multiple; hazard ratio, 0.47; P = .020) were identified as contributory prognostic factors for survival, whereas the parameters of RECIST (responders v nonresponders), as well as the remaining variables, had nonsignificant prognostic impact. CONCLUSION The GCIG CA-125 response criteria are a better prognostic tool than RECIST in second-line treatment with topotecan or paclitaxel plus carboplatin in patients with ovarian carcinoma.

Randomized, open-label, phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer.

PURPOSE This study compared the efficacy and safety of patupilone with those of pegylated liposomal doxorubicin (PLD) in patients with platinum-refractory or -resistant epithelial ovarian, primary fallopian tube, or primary peritoneal cancer. PATIENTS AND METHODS Patients with three or fewer prior regimens were eligible if they had received first-line taxane/platinum-based combination chemotherapy and were platinum refractory or resistant. Patients were randomly assigned to receive patupilone (10 mg/m(2) intravenously every 3 weeks) or PLD (50 mg/m(2) intravenously every 4 weeks). RESULTS A total of 829 patients were randomly assigned (patupilone, n = 412; PLD, n = 417). There was no statistically significant difference in overall survival (OS), the primary end point, between the patupilone and PLD arms (P = .195; hazard ratio, 0.93; 95% CI, 0.79 to 1.09), with median OS rates of 13.2 and 12.7 months, respectively. Median progression-free survival was 3.7 months for both arms. The overall response rate (all partial responses) was higher in the patupilone arm than in the PLD arm (15.5% v 7.9%; odds ratio, 2.11; 95% CI, 1.36 to 3.29), although disease control rates were similar (59.5% v 56.3%, respectively). Frequently observed adverse events (AEs) of any grade included diarrhea (85.3%) and peripheral neuropathy (39.3%) in the patupilone arm and mucositis/stomatitis (43%) and hand-foot syndrome (41.8%) in the PLD arm. CONCLUSION Patupilone did not demonstrate significant improvement in OS compared with the active control, PLD. No new or unexpected serious AEs were identified.

Neoadjuvant Chemotherapy with Cisplatin and Methotrexate in Patients with Muscle-Invasive Bladder Tumours

This prospective, randomized study based on two associated trials was designed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b, NX-3, MO transitional cell carcinoma of the bladder. In the first trial, local treatment consisted of cystectomy (DAVECA 8901) and in the other trial the treatment was radiotherapy (DAVECA 8902); 153 eligible patients were randomized. The majority of the patients (89%) completed the protocol. The overall time to progression for all 153 patients was 12.9 months. Median time to progression was 14.2 months with chemotherapy and 11.4 months without chemotherapy. The actuarial 5-year overall survival rate for all 153 patients was 29%, and 29% for both treatment groups. Multivariate analyses showed that T-stage, tumour size and serum creatinine were independent prognostic factors for survival. The cystectomy trial included 33 patients. Median survival was 78.9 months, 82.5 months with chemotherapy and 45.8 months without chemotherapy (p=0.76). The radiotherapy trial included 120 patients. The median survival was 17.6 months. Median survival was 19.2 months in the group receiving chemotherapy and 16.3 in the group not receiving chemotherapy. The 5-year survival rate was 19% in the group receiving chemotherapy and 24% in the groups not receiving chemotherapy (p=0.98). Late toxicity grade 3 or 4 of the bladder was recorded in 25% of the patients (actuarial rate). Neoadjuvant chemotherapy with cisplatin and methotrexate did not significantly improve disease-free or overall survival in 153 randomized patients with invasive bladder cancer.

Differential regulation of VEGF, HIF1α and angiopoietin‐1, ‐2 and ‐4 by hypoxia and ionizing radiation in human glioblastoma

We examined how ionizing radiation (IR) delivered under either severe hypoxia (< 0.1% O2) or normoxia affects the expression of hypoxia inducible factor 1α (HIF‐1α) and the angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietins 1, 2 and 4 in U87 human glioblastoma cells. IR was delivered as single doses of 0, 2, 5, 10 and 20 Gy after 6‐hr hypoxic incubation and in normoxic controls. Irradiation at any dose did not affect the cellular protein levels of any of the angiopoietins, whereas hypoxia led to increasing levels of both angiopoietin‐4 and angiopoietin‐2. Levels of angiopoietin‐1 protein were unaltered throughout the observation period. A dose‐dependent increase in levels of secreted VEGF in the medium occurred after IR at doses from 5–20 Gy. In hypoxic cells, 20 Gy IR induced an additional significant increase in VEGF relative to nonirradiated hypoxic control cells with elevated baseline VEGF levels induced by hypoxia. HIF‐1α and glucose transporter‐1 (Glut‐1) were not correspondingly upregulated by IR. Blocking HIF‐1α by antisense treatment induced a reduced baseline VEGF at normoxia, while the relative upregulation of VEGF by IR was unaffected. These data provide evidence that VEGF is upregulated by IR by mechanisms independent of HIF‐1 transactivation.