Influence of volumetric modulated arc therapy and FET-PET scanning on treatment outcomes for glioblastoma patients.

BACKGROUND: We sought to assess the influence of the clinical introduction of new radiotherapy technologies on glioblastoma patients' outcomes. METHODS: Newly diagnosed glioblastoma patients treated with 60 Gy and temozolomide (2005-2014) were analyzed. The patients' GTV and CTV were defined based on MR (n = 521) or FET-PET/MR (n = 190), and were treated using conformal radiotherapy (CRT, n = 159) or image-guided volumetric modulated arc therapy with hippocampal sparing (IG-VMAT, n = 362). Progression-free survival (PFS) was assessed using the McDonald criteria. Associations between clinical data, dosimetry data, treatment technology, for PFS and overall survival (OS) were explored. RESULTS: The PFS (7 months) and OS (15 months) were unaffected by CRT, IG-VMAT and FET-PET technology. Mean brain dose was correlated with tumor volume, and was lower for IG-VMAT vs. CRT (p < 0.001). Larger mean brain dose was associated with inferior PFS (univariate/multivariate Cox models, p < 0.001) and OS (univariate, p < 0.001). Multivariate Cox models revealed association of larger mean brainstem dose (p < 0.001), BTV (p = 0.045), steroid use at baseline (p = 0.003), age (p = 0.019) and MGMT status (p = 0.022) with lower OS. CONCLUSIONS: Introduction of hippocampal-sparing IG-VMAT technology appeared to be safe, and may have reduced toxicity and cognitive impairment. Larger mean brain dose was strongly associated with inferior PFS and OS.

Hypoxia-inducible factors--regulation, role and comparative aspects in tumourigenesis.

Hypoxia-inducible factors (HIFs) play a key role in the cellular response experienced in hypoxic tumours, mediating adaptive responses that allow hypoxic cells to survive in the hostile environment. Identification and understanding of tumour hypoxia and the influence on cellular processes carries important prognostic information and may help identify potential hypoxia circumventing and targeting strategies. This review summarizes current knowledge on HIF regulation and function in tumour cells and discusses the aspects of using companion animals as comparative spontaneous cancer models. Spontaneous tumours in companion animals hold a great research potential for the evaluation and understanding of tumour hypoxia and in the development of hypoxia-targeting therapeutics.

Effects of isoflurane anesthesia and pilocarpine on rat parotid saliva flow.

The purpose of this study was to investigate the effects of isoflurane on unstimulated and pilocarpine-stimulated parotid saliva secretion. Ten male Sprague-Dawley rats weighing 350-400 g were randomized into two groups, and the saliva flow rate and lag phase were measured at two doses of isoflurane in a crossover study design. Increasing the isoflurane concentration from 1% to 2% was associated with a 19% decrease in saliva secretion rate, and the lag to saliva secretion was increased by 155%. To clarify whether the effect of isoflurane (1.5%) on the parotid flow varied with stimulus intensity, we measured the parotid flow induced by seven different doses of pilocarpine on sham-irradiated rats and rats irradiated with single doses of 15 Gy. A maximal pilocarpine response was obtained with 1.5 mg/kg in both irradiated and sham-irradiated rats; however, the parotid flow of the irradiated rats was 50% slower than that of the sham-irradiated rats. In conclusion, 1.5% isoflurane was found to be a good compromise between proper anesthesia and isoflurane-induced inhibition of saliva secretion. Pilocarpine induces saliva secretion in a dose-dependent matter, with supra-maximal stimulation achieved using 1.5 mg/kg.

A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours.

BACKGROUND: This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the anti-tumour activity of the combination in solid tumours. METHODS: Cohorts of three to six patients were treated with escalating doses of belinostat administered intravenously once daily, days 1-5 q21 days; on day 3, carboplatin (area under the curve (AUC) 5) and/or paclitaxel (175 mg m(-2)) were administered 2-3 h after the end of the belinostat infusion. RESULTS: In all 23 patients received 600-1000 mg m(-2) per day of belinostat with carboplatin and/or paclitaxel. No DLT was observed. The maximal administered dose of belinostat was 1000 mg m(-2) per day for days 1-5, with paclitaxel (175 mg m(-2)) and carboplatin AUC 5 administered on day 3. Grade III/IV adverse events were (n; %): leucopenia (5; 22%), neutropenia (7; 30%), thrombocytopenia (3; 13%) anaemia (1; 4%), peripheral sensory neuropathy (2; 9%), fatigue (1; 4%), vomiting (1; 4%) and myalgia (1; 4%). The pharmacokinetics of belinostat, paclitaxel and carboplatin were unaltered by the concurrent administration. There were two partial responses (one rectal cancer and one pancreatic cancer). A third patient (mixed mullerian tumour of ovarian origin) showed a complete CA-125 response. In addition, six patients showed a stable disease lasting > or =6 months. CONCLUSION: The combination was well tolerated, with no evidence of pharmacokinetic interaction. Further evaluation of anti-tumour activity is warranted.

Does the use of diagnostic PET/CT cause stage migration in patients with primary advanced ovarian cancer?

OBJECTIVE: To investigate if the use of diagnostic FDG-PET/CT leads to stage migration in patients with advanced ovarian cancer and to evaluate the prognostic significance of FDG-PET/CT. METHODS: From September 2004 to August 2007, 201 patients with a Risk of Malignancy Index (RMI) >150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within 2 weeks prior to standard surgery/debulking of a pelvic tumor. On 15 August, 2009 overall survival and prognostic variables were analysed in 66 ovarian cancer patients (64 stage III and 2 stage IV). RESULTS: Median follow-up was 30.2 months; median age was 62.5 years (range 35-85 years); 97% (64/66) had a performance status

Three-dimensional endoluminal ultrasound-guided interstitial brachytherapy in patients with anal cancer.

BACKGROUND: New techniques using image guidance other than computed tomography (CT) and traditional two-dimensional (2D) endosonography might improve interstitial brachytherapy in patients with anal cancer. PURPOSE: To investigate a new technique guided by three-dimensional (3D) endosonography used in our institution. MATERIAL AND METHODS: Seventeen patients with anal carcinoma were referred to interstitial brachytherapy under 3D endosonographic guidance after external radiotherapy. The procedure was initiated by anal endosonography performed with a 10-MHz rotating endoprobe. Cross-sectional images of the anal sphincters were stored on a 3D system during retraction of the endoprobe through the anal canal. Afterward, any projection could be reconstructed. From this scanning, the optimal positioning of the needles was determined. The needles were inserted through holes in an externally fixated anal template. A repeated endosonography assured that optimal tumor coverage could be obtained by adjusting the number, dwell positions, and/or position of the needles. RESULTS: In all patients, endosonography was able to visualize the extension of the tumors and the position of each needle in 3D. CONCLUSION: 3D endosonography guidance of interstitial brachytherapy in anal carcinoma seems to optimize the implant procedure and offer better information for dose planning.

Prediction of suboptimal primary cytoreduction in primary ovarian cancer with combined positron emission tomography/computed tomography--a prospective study.

OBJECTIVE: To prospectively identify combined PET/CT predictors of incomplete/suboptimal primary cytoreduction in advanced ovarian cancer. METHODS: From September 2004 to March 2007, 179 patients with a Risk of Malignancy Index (RMI) >150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within 2 weeks prior to standard surgery/debulking of a pelvic tumor. Ten PET/CT features were identified and evaluated as predictors of cytoreduction in 54 patients with advanced ovarian cancer. RESULTS: Complete cytoreduction (no macroscopic residual disease) was achieved in 35% and optimal cytoreduction (<1 cm residual disease) was achieved in 56%. Using univariate analysis, predictors of incomplete cytoreduction were large bowel mesentery implants (LBMI) (P<0.003), pleural effusion (P<0.009), ascites (P<0.009) and peritoneal carcinosis (P<0.01). LBMI (P<0.03) and ascites (P<0.05) were also predictors of suboptimal cytoreduction. Using multivariate analysis, LBMI was the only independent predictor of incomplete cytoreduction (P=0.004) and no predictor of suboptimal cytoreduction was found. CONCLUSION: PET/CT predictors of cytoreduction were found. But they should not be used to withhold patients form primary cytoreductive surgery. We suggest PET/CT as a supplementary image modality prior to surgery in primary OC patients whenever accurate and comprehensive preoperative evaluation of primary tumor and metastases is desired.

Pre-treatment prediction of chemoresistance in second-line chemotherapy of ovarian carcinoma: value of serological tumor marker determination (tetranectin, YKL-40, CASA, CA 125).

OBJECTIVE: To examine if the determination of the levels of serological tumor markers at time of relapse had any predictive value for chemoresistance in the second-line treatment of ovarian cancer patients. METHODS: From a registry of consecutive single-institution patients with epithelial ovarian carcinoma pretreated with paclitaxel plus platinum, we selected 82 patients with (a) solid tumor recurrence, and (b) second-line chemotherapy consisting of topotecan (platinum-resistant disease) or paclitaxel plus carboplatin (platinum-sensitive disease). Stored serum samples were analyzed for the biochemical tumor markers tetranectin, YKL-40, CASA (cancer-associated serum antigen), and CA 125. The serum tumor marker levels at time of relapse were correlated with response status at landmark time after 4 cycles of second-line chemotherapy. Univariate and multivariate logistic regression analyses (chemoresistant vs non-chemoresistant disease) were performed. RESULTS: At landmark time, 26% of patients had progression according to the GCIG (Gynecologic Cancer Intergroup) progression criteria. In univariate logistic regression analysis, the tumor markers tetranectin (OR 0.4; 95% CI: 0.2-0.8; p=0.008), YKL-40 (OR 1.8; 95% CI: 1.0-3.3; p=0.045), and CASA (OR 1.8; 95% CI: 1.2-2.7; p=0.007) had predictive value for second-line chemoresistance, whereas serum CA 125 had no predictive value. In a multivariate logistic regression analysis, serum tetranectin and CASA both had independent predictive value for chemoresistance. The combined determination of tetranectin and CASA had a specificity of 90% with 33% sensitivity for the prediction of chemoresistance (area under the receiver operating characteristic curve = 0.78; 95% CI: 0.66-0.91; p=0.001). CONCLUSION: Low serum levels of tetranectin, or high serum levels of CASA or YKL-40, are associated with increased risk of second-line chemoresistance in patients with ovarian cancer.

Cancer-associated serum antigen level: a novel prognostic indicator for survival in patients with recurrent ovarian carcinoma.

The aim was to examine the value of the pretherapeutic serum cancer-associated serum antigen (CASA) level as a prognostic factor for survival in patients with recurrent epithelial ovarian carcinoma. Serum levels of CASA and cancer antigen (CA)125 were prospectively determined in 70 consecutive patients with recurrent ovarian cancer before the start of second-line chemotherapy. Univariate and multivariate analyses of survival were performed. The median level of serum CASA was 6.5 U/mL (range: 0.2-1437 U/mL). Univariate analysis showed that patients with a CASA level >10.0 U/mL had significantly shorter survival than patients with CASA level < or =10.0 U/mL (P= 0.002). Using different CASA cutoff levels (6.0, 6.5, and 10.0 U/mL), multivariate Cox analyses identified CASA as an independent prognostic factor for survival at every cutoff level. The strongest prognostic function for CASA was found at a cutoff level of 10.0 U/mL (>10 vs < or =10 U/mL; hazard ratio, 2.7; 95% confidence interval, 1.6-4.7; P < 0.001). The pretreatment CA125 level was not found to be significantly associated with survival by any of the cutoffs (35, 65, 132, and 339 U/mL). A pretreatment elevated level of the tumor marker CASA is an adverse prognostic factor for survival in patients with ovarian cancer relapse.

Do CA125 response criteria overestimate tumour response in second-line treatment of epithelial ovarian carcinoma?

Recent studies indicate that cancer antigen 125 (CA125) response criteria tend to overestimate a tumour reduction measured by standard WHO response criteria in recurrent epithelial ovarian carcinoma. The aim of the study was to validate the recently introduced GCIG (The Gynaecological Cancer Intergroup) CA125 response criteria in predicting a tumour response measured by WHO (World Health Organization) criteria. Changes in CA125 levels (GCIG criteria) were retrospectively compared with alterations in the tumour load (WHO criteria) during second-line chemotherapy with topotecan or paclitaxel-platinum in 124 consecutive patients with recurrent or refractory disease. In patients assessable by both response criteria (n=72), the overall response rate using GCIG CA125 criteria was 57% (95% confidence interval (CI): 45-69%) and significantly higher than the response rate of 39% (95% CI: 28-51%) using WHO response criteria (P=0.045). The GCIG CA125 criteria had a sensitivity of 96% (95% CI: 82-100%), a specificity of 68% (95% CI: 52-81%) and an accuracy of 79% (95% CI: 68-88%) in predicting a response measured by WHO criteria. In conclusion, the GCIG CA125 response criteria seem to overestimate a tumour response by WHO criteria when monitoring the efficacy of second-line chemotherapy with topotecan or paclitaxel-platinum in patients with epithelial ovarian carcinoma.

Strontium(89) 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.

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 alpha=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.

Results of reinduction therapy with paclitaxel and carboplatin in recurrent epithelial ovarian cancer.

OBJECTIVE: The purpose of the study was to evaluate the treatment results and toxicity of a retreatment regimen of paclitaxel and carboplatin in patients with ovarian cancer relapse. METHODS: A retrospective analysis of 241 consecutive patients with primary epithelial ovarian cancer receiving paclitaxel and a platinum analogue as first-line treatment was performed. Relapse treatment of platinum-sensitive patients consisted of paclitaxel (175 mg/m(2)) over 3 h followed by carboplatin at an area under the concentration-time curve of 5, repeated every 3 weeks. RESULTS: Forty-three patients with relapse were treated with paclitaxel and carboplatin after a median progression-free interval from the end of first-line chemotherapy of 15.8 months (range 6.0-41.7 months). In patients with evaluable disease the overall response rate was 84% (95% CI: 68.0-93.8%). The progression-free survival and overall survival from start of relapse treatment were a median of 9.7 months (range 1.4-26.9 months) and 13.1 months (range 4.5-35.5 months), respectively. In a multivariate Cox analysis independent prognostic factors for progression-free survival after first relapse were response to relapse treatment (P = 0.002, hazard ratio = 13.9) and time to first recurrence (P = 0.016, hazard ratio = 0.167). The planned treatment was accomplished by 67% of patients. Grade 4 neutrocytopenia over 1 week was observed in 9.3% of patients. Grade 1-2 peripheral neuropathy was reported in 30% of patients. Only 1 patient had her paclitaxel dose attenuated because of grade 4 neuropathy. CONCLUSION: Retreatment with paclitaxel and carboplatin in patients with platinum-sensitive epithelial ovarian cancer relapse yielded a high response rate and encouraging progression-free survival and overall survival. Paclitaxel-carboplatin reinduction therapy is generally well tolerated and the toxicity is manageable.

The prognostic value of pretherapeutic tetranectin and CA-125 in patients with relapse of ovarian cancer.

OBJECTIVE: The aim of the study was to examine the prognostic values of, respectively, tetranectin (TN) and CA-125 measured in serum from patients presenting with relapse of ovarian cancer (OC). METHODS: TN and CA-125 were measured in serum samples from 75 patients with relapse of OC before the start of second-line chemotherapy. The endpoint used was death of OC. The variables were analyzed by univariate life table analysis and multivariate Cox analysis. RESULTS: A significantly shortened survival was found for patients with low serum TN values compared to patients with serum TN levels above one of the cutoff levels. The survivals are illustrated by life tables. No prognostic function was found for CA-125. TN and relapse

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.

Effect of topotecan on serum CA-125 in patients with advanced epithelial ovarian cancer.

The effect of topotecan on CA-125 serum levels was evaluated in 30 patients with advanced epithelial ovarian cancer. All patients had progressive disease and were relapsing during (11 patients) or after (19 patients) chemotherapy containing paclitaxel and platinum. Topotecan (1.0 mg/m(2)/day) was administered intravenously on Days 1-5 every 3 weeks. The patients had received a median of 2 (1-5) prior regimens. Four patients had increased CA-125 only, and 26 had both measurable disease and increased CA-125. Two patients (7%) achieved a clinical partial response with durations of 5 and 10+ months, respectively. Eighteen other patients (60%) exhibited no clinical change with a median duration of 5+ months (range: 2-11+ months). Among these patients 9 (30%) had a biochemical response. The rate of change in CA-125 (s, slope of the exponential regression curve) during treatment with topotecan was compared with s over a period before treatment. A decrease in s was observed in 20 patients (74%). Comparing the mean values of s before and during topotecan, a significant (P = 0.005) decrease was seen in the CA-125 serum levels. The mean doubling times before and during treatment were 59 and 1421 days, respectively. Toxicity was mainly hematologic. Neutropenia grades III and IV were seen in 16 and 10 patients, respectively. No patients died due to side effects. Generally the side effects were mild to moderate. In conclusion, at the given dose intensity topotecan shows activity in advanced paclitaxel- and platinum-resistant ovarian cancer based on CA-125 measurements.

Radiotherapy in the management of cervical cancer in elderly patients.

PURPOSE: To report treatment results and complications experienced by elderly patients treated with curatively intended radiotherapy for cancer of the uterine cervix. PATIENTS AND METHODS: One hundred and fourteen elderly patients (median 75.5 years, range 70.0-85.9) consecutively referred for curative radiotherapy in the period 1987-1996 were prospectively followed with regard to tumour control and complications. The importance of age, stage (FIGO), tumour size, histology, tumour fixation, haemoglobin, concurrent disease, performance status (WHO) and type of radiotherapy were assessed using univariate and multivariate analyses. RESULTS: Treatment was completed as planned in 68%, delayed in 29% and stopped prematurely in 3%. The frequency of grade 3 late complications was 11% and the actuarial probability at 5 years was 20%. Overall 5-year survival according to FIGO was 61% (I), 34% (II) and 25% (III). Cox multivariate analysis identified tumour size as independent prognostic factor for tumour control, disease-free survival and overall survival. FIGO stage was predictive for late grade 2 complications. We were unable to identify significant factors with respect to grade 3 complications. Age was not a significant parameter for any of the investigated endpoints. CONCLUSION: Elderly patients in good performance status with advanced cancer of the uterine may tolerate radical radiotherapy with acceptable morbidity and reasonable survival. Radiotherapy may also be a good alternative in early stage disease for surgically unfit elderly patients.

Comparative genomic hybridization reveals a recurrent pattern of chromosomal aberrations in severe dysplasia/carcinoma in situ of the cervix and in advanced-stage cervical carcinoma.

We analyzed 17 cases of dysplasia/carcinoma in situ (CIS) of the cervix and 29 advanced-stage cervical squamous cell carcinomas by comparative genomic hybridization (CGH). A comparable recurrent pattern of aberrations was detected in both preinvasive and invasive cases, although the total number of aberrations was much higher in the latter category. The most consistent chromosomal gain was mapped to chromosome arm 3q in 35% of preinvasive cases and in 72% of invasive cases. Chromosome aberrations were detected in 13/17 preinvasive cases with a total of 61 involved chromosome arms. In the invasive cases, frequent gains also occurred on 1q (45%), 8q (41%), 15q (41%), 5p (34%), and Xq (34%), and frequent losses were mapped to chromosome arms 3p (52%), 11q (48%), 13q (38%), 6q (38%), and 4p (34%). A recurrent pattern of aberrations has not previously been described in preinvasive lesions of the cervix. Our finding is surprising considering that only few preinvasive lesions are expected to progress to invasive cancer.