A multicentre dose-escalating study of cabazitaxel (XRP6258) in combination with capecitabine in patients with metastatic breast cancer progressing after anthracycline and taxane treatment: a phase I/II study

Background

Most patients with metastatic breast cancer (MBC) progress after chemotherapy. Cabazitaxel (XRP6258) is a new taxoid that is active in chemotherapy-resistant tumour cell lines. The objectives of this phase I/II study were to assess the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and activity of cabazitaxel plus capecitabine in patients with MBC who had been previously treated with taxanes and anthracyclines.

Patients and methods

In part I, we used a 3 + 3 dose-escalation scheme to assess the MTD of intravenous cabazitaxel (day 1) with oral capecitabine twice daily (days 1-14) every 3 weeks. In part II, we evaluated the objective response rate (ORR) at the MTD.

Results

Thirty-three patients were enrolled and treated (15 in part I; 18 in part II). Cabazitaxel 20 mg/m² plus capecitabine 1000 mg/m² was the MTD. Pharmacokinetic analysis showed no apparent drug-drug interaction. In all patients, the main grade 3-4 toxicities were asthenia (n = 5), hand-foot syndrome (n = 5), neutropenia (n = 21), neutropenic infection (n = 1), and neutropenic colitis (n = 1). One patient had febrile neutropenia. Antitumour activity was observed at all dose-levels with two complete responses, five partial responses (PRs), and 20 disease stabilisations (seven unconfirmed PR). At the MTD, 21 patients were evaluable for efficacy. The ORR was 23.8% (95% CI: 8.2-47.2%). The median response duration was 3.1 months (95% CI: 2.1-8.4 months), with four of five lasting for more than 3 months. Median time to progression was 4.9 months.

Conclusions

Cabazitaxel combined with capecitabine is active, has a safety profile consistent with a taxane plus capecitabine combination and warrants further investigation in patients with MBC.     

Results of high dose-rate brachytherapy boost before 2D or 3D external beam irradiation for prostate cancer

Background and purpose

To evaluate biochemical control and treatment related toxicity of patients with localized adenocarcinoma of the prostate treated with high dose-rate brachytherapy (HDRB) combined with conventional 2D or 3D-conformal external beam irradiation (EBI).

Material and methods

Four-hundred and three patients treated between December 2000 and March 2004. HDRB was delivered with three fractions of 5.5-7 Gy with a single implant, followed by 45 Gy delivered with 2D or 3D conformal EBI.

Results

The median follow-up was 48.4 months. Biochemical failure (BF) occurred in 9.6% according to both ASTRO and Phoenix consensus criteria. Mean time to relapse was 13 and 26 months, respectively. The 5-year BF free survival using the ASTRO criteria was 94.3%, 86.9% and 86.6% for the low, intermediate and high risk groups, respectively; using Phoenix criteria, 92.4%, 88.0% and 85.3%, respectively. The only predictive factor of BF in the multivariate analysis by both ASTRO and Phoenix criteria was the presence of prostate nodules detected by digital palpation, and patients younger than 60 years presented a higher chance of failure using Phoenix criteria only.

Conclusions

Treatment scheme is feasible and safe with good efficacy.     

Risk of cardiac dysfunction with trastuzumab in breast cancer patients: a meta-analysis

Background

Trastuzumab is used widely for the treatment of early and advanced breast cancer. However, concerns have arisen regarding its cardiac toxicity. We did a systematic review and meta-analysis of published randomized controlled trials (RCTs) to assess the overall risk of cardiac dysfunction associated with trastuzumab treatment.

Methods

We searched PubMed and Web of Science (January 1966-July 2009) and American Society of Clinical Oncology conferences held (January 2000-July 2009) for relevant articles and abstracts. Summary incidence rates, relative risks (RRs), and 95% confident intervals (CIs) were calculated using a fixed-effects or random-effects model.

Results

11,882 patients from 10 RCTs were included for analysis. The incidences of LVEF decrease and congestive heart failure (CHF) were 7.5% (95% CI 4.2-13.1) and 1.9% (95% CI 1.0-3.8) among patients receiving trastuzumab. Trastuzumab significantly increased the risk of LVEF decrease (RR = 2.13, 95% CI, 1.31-3.49; p = 0.003). In addition, it significantly increased the risk of CHF (RR = 4.19, 95% CI 2.73-6.42; p < 0.00001). The increased risk of CHF was observed in patients with early stage (RR = 4.05, 95% CI 2.49-6.58; p < 0.00001) as well as metastatic disease (RR = 4.75, 95% CI 1.93-11.71; p = 0.0007). Furthermore, trastuzumab significantly increased the risk of CHF (RR = 4.27, 95% CI 2.75-6.61, p < 0.00001) in patients receiving anthracycline-based chemotherapy, but not in patients receiving non-anthracycline chemotherapy (RR = 2.42, 95% CI 0.36-16.19, p = 0.36).

Conclusion

The addition of trastuzumab to anthracycline-based chemotherapy significantly increase the risk of cardiac dysfunction in breast cancer patients. Further studies are recommended for non-anthracycline chemotherapy.     

Haematologic toxicities associated with the addition of bevacizumab in cancer patients

Background

Bevacizumab is currently approved for the treatment of several malignancies. Haematologic toxicities are not among the main concerns associated with bevacizumab, but they have been occasionally reported. We performed a meta-analysis to determine the incidence and risk of haematologic toxicities associated with bevacizumab.

Methods

Pubmed databases from 1966 to September 2010 were searched for studies reported, as well as American Society of Clinical Oncology meetings. Bevacizumab randomised clinical trials with adequate safety data profile were included. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR) and 95% confidence intervals (CI).

Results

15,263 patients were included. The incidence of bevacizumab-associated all-grade and high-grade haematologic toxicities were, respectively: anaemia: 18.7% and 3.9%; neutropenia: 25.0% and 18.5%; and thrombocytopenia: 13.9% and 3.4%. Febrile neutropenia incidence was 3.8%. Compared to placebo/control arms, bevacizumab was associated with a decreased risk of all-grade (RR = 0.81; 95%CI 0.68-0.96; p = .016) and high-grade (RR = 0.73; 95%CI 0.60-0.89; p = .002) anaemia, and increased risks of all-grade (RR = 1.15; 95%CI 1.01-1.30; p = .033) and high-grade (RR = 1.08; 95%CI 1.02-1.13; p = .005) neutropenia, all-grade thrombocytopenia (RR = 1.22; 95%CI 1.00-1.48; p = .047) and febrile neutropenia (RR = 1.31; 95%CI 1.08-1.58; p = .006).

Conclusions

Bevacizumab is associated with a lower risk of anaemia and increased risks of neutropenia, thrombocytopenia and febrile neutropenia.     

Dose-response relations for stricture in the proximal oesophagus from head and neck radiotherapy

Background and purpose

Determination of the dose-response relations for oesophageal stricture after radiotherapy of the head and neck.

Material and methods

In this study 33 patients who developed oesophageal stricture and 39 patients as controls are included. The patients received radiation therapy for head and neck cancer at Karolinska University Hospital, Stockholm, Sweden. For each patient the 3D dose distribution delivered to the upper 5 cm of the oesophagus was analysed. The analysis was conducted for two periods, 1992-2000 and 2001-2005, due to the different irradiation techniques used. The fitting has been done using the relative seriality model.

Results

For the treatment period 1992-2005, the mean doses were 49.8 and 33.4 Gy, respectively, for the cases and the controls. For the period 1992-2000, the mean doses for the cases and the controls were 49.9 and 45.9 Gy and for the period 2001-2005 were 49.8 and 21.4 Gy. For the period 2001-2005 the best estimates of the dose-response parameters are D₅₀ = 61.5 Gy (52.9-84.9 Gy), γ = 1.4 (0.8-2.6) and s = 0.1 (0.01-0.3).

Conclusions

Radiation-induced strictures were found to have a dose response relation and volume dependence (low relative seriality) for the treatment period 2001-2005. However, no dose response relation was found for the complete material.     

3D Dosimetric verification of volumetric-modulated arc therapy by portal dosimetry

Background and purpose

To demonstrate the feasibility of back-projection portal dosimetry for accurate 3D dosimetric verification of volumetric-modulated arc therapy (VMAT), pre-treatment as well as in vivo.

Materials and methods

Several modifications to our existing approach were implemented to make the method applicable to VMAT: (i) gantry angle-resolved data acquisition, (ii) calculation of the patient transmission, (iii) compensation for detector ‘flex’ and (iv) 3D dose reconstruction and evaluation.

Results

Planned and EPID-(Electronic Portal Image Detector)-reconstructed dose distributions show good agreement for pre-treatment verification of two prostate, a stereotactic lung and a head-and-neck VMAT plan and for in vivo verification of VMAT treatments of prostate and lung cancer. Averaged over pre-treatment verifications, planned and measured isocentre dose ratios were −1.2% (range [−4.7%,1.8%]). 3D gamma analysis (3% maximum dose, 3 mm) revealed mean γ 〈γ_mean〉 = 0.37 [0.34,0.39], maximum 1% γ 〈γ_1%〉 = 0.72 [0.66,0.81] and percentage of points with γ ? 1 〈P_γ ? 1〉 = 99% [97%,100%]. For in vivo verification, the average isocentre dose ratio was −1.2% [−0.8%,−1.7%], 〈γ_mean〉 = 0.52 [0.40,0.64], 〈γ_1%〉 = 0.92 [0.76,1.08] and 〈P_γ ? 1〉 = 96% [93%,100%].

Conclusions

Our portal dosimetry method was successfully adapted for verification of VMAT treatments, pre-treatment as well as in vivo.     

External beam radiotherapy plus single-fraction high dose rate brachytherapy in the treatment of locally advanced prostate cancer

Purpose

To evaluate the efficacy and toxicity of external beam radiation therapy (EBRT) plus high-dose-rate brachytherapy (HDRB) as a boost in patients (pts) with intermediate or high-risk prostate cancer.

Methods and materials

From 2002 to July 2012, 377 pts with a diagnosis of intermediate or high-risk prostate cancer were treated with EBRT plus HDRB. Median patient age was 66 years (range, 41–86). Most patients (347 pts; 92%) were classified as high-risk (stage T2c–T3, or PSA > 20 ng/mL, or GS ? 8), with 30 patients (8%) considered intermediate risk. All patients underwent EBRT at a prescribed dose of 60.0 Gy (range, 45–70 Gy) to the prostate and seminal vesicles. A total of 120 pts (31%) received a dose of 46 Gy (45–50 Gy) to the true pelvis. All pts received a single-fraction 9 Gy (9–15 Gy) HDR boost. Most patients (353; 94%) were prescribed complete androgen deprivation therapy (ADT). Overall survival (OS), cause-specific survival (CSS), and biochemical relapse-free survival (BRFS) rates were calculated. In the case of BRFS, patients with <26 months of follow-up (n = 106) were excluded to minimize the impact of ADT.

Results

The median follow-up for the entire sample was 50 months (range, 12–126), with 5-year actuarial OS and CSS, respectively, of 88% (95% confidence interval [CI]: 84–92) and 98% (95% CI: 97–99). The 5-year BRFS was 91% (95% CI: 87–95) in the 271 pts with ?26 months (median, 60 months) of follow-up. Late toxicity included grade 2 and 3 gastrointestinal toxicity in 17 (4.6%) and 6 pts (1.6%), respectively, as well as grades 2 and 3 genitourinary toxicity in 46 (12.2%) and 3 pts (0.8%), respectively.

Conclusion

These long-term outcomes confirm that EBRT plus a single-fraction HDRB boost provides good results in treatment-related toxicity and biochemical control. In addition to the excellent clinical results, this fractionation schedule reduces physician workload, treatment-related expenses, patient discomfort and risks associated with anaesthesia. We believe these findings support the use of single-fractionation boost techniques.     

Toxicity after reirradiation of pulmonary tumours with stereotactic body radiotherapy

Purpose

To assess toxicity and feasibility of reirradiation with stereotactic body radiotherapy (SBRT) after prior lung SBRT for primary lung cancer or lung metastases.

Patients and materials

Twenty-nine patients reirradiated with SBRT on 32 lung lesions (11 central, 21 peripheral) were retrospectively reviewed. Median follow-up time was 12 months (range 1-97). The primary endpoint was toxicity, secondary endpoints were local control and overall survival time. Toxicity was scored according to the NCI-CTCAE version 3.

Results

Grade 3-4 toxicity was scored 14 times in eight patients. Three patients died because of massive bleeding (grade 5). Larger clinical target volumes (CTV) and central tumour localization were associated with more severe toxicity. There was no correlation between mean lung dose (MLD) and lung toxicity. Local control at 5 months after reirradiation was 52%, as assessed by CT-scan (n = 12) or X-thorax (n = 3). A larger CTV was associated with poorer local control. Kaplan-Meier estimated 1- and 2-year survival rates were 59% and 43%, respectively.

Conclusions

Reirradiation with SBRT is feasible although increased risk of toxicity was reported in centrally located tumours. Further research is warranted for more accurate selection of patients suitable for reirradiation with SBRT.     

Association of urethral toxicity with dose exposure in combined high-dose-rate brachytherapy and intensity-modulated radiation therapy in intermediate- and high-risk prostate cancer

Introduction

To report acute and late toxicities in patients with intermediate- and high-risk prostate cancer treated with combined high-dose-rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT).

Materials and methods

From March 2003 to September 2005, 64 men were treated with a single implant HDR-B with 21 Gy given in three fractions, followed by 50 Gy IMRT along with organ tracking. Median age was 66.1 years, and risk of recurrence was intermediate in 47% of the patients or high in 53% of the patients. Androgen deprivation therapy was received by 69% of the patients. Toxicity was scored according to the CTCAE version 3.0. Median follow-up was 3.1 years.

Results

Acute grade 3 genitourinary (GU) toxicity was observed in 7.8% of the patients, and late grades 3 and 4 GU toxicity was observed in 10.9% and 1.6% of the patients. Acute grade 3 gastrointestinal (GI) toxicity was experienced by 1.6% of the patients, and late grade 3 GI toxicity was absent. The urethral V₁₂₀ (urethral volume receiving ?120% of the prescribed HDR-B dose) was associated with acute (P = .047) and late ? grade 2 GU toxicities (P = .049).

Conclusions

Late grades 3 and 4 GU toxicity occurred in 10.9% and 1.6% of the patients after HDR-B followed by IMRT in association with the irradiated urethral volume. The impact of V₁₂₀ on GU toxicity should be validated in further studies.     

MRI before and after external beam intensity-modulated radiotherapy of patients with prostate cancer: The feasibility of monitoring of radiation-induced tissue changes using a dynamic contrast-enhanced inversion-prepared dual-contrast gradient echo sequence

Purpose

To identify and quantify suitable pharmacokinetic MRI parameters for monitoring tissue changes after external beam intensity-modulated radiotherapy of prostate cancer.

Material and methods

Six patients with biopsy-proven prostate cancer (initial PSA, 6.0-81.4 ng/ml) underwent MRI at 1.5 T using a combined endorectal/body phased-array coil and a dynamic contrast-enhanced inversion-prepared dual-contrast gradient echo sequence (T1/T2^∗w; 1.65 s temporal resolution). MRI was performed before and immediately after radiotherapy, at 3 months and at 1 year. Perfusion, blood volume, mean transit time, delay, dispersion, interstitial volume, and extraction coefficient were calculated in prostate cancer and normal prostate for all four time points using a sequential 3-compartment model.

Results

Prostate cancer and normal prostate tissue showed a statistically significant decrease in perfusion (p = 0.006, p = 0.001) and increase in extraction coefficient (p = 0.004, p < 0.001). For prostate cancer, there was also a decrease in vascular volume (p = 0.034). The other parameters investigated showed no statistically significant changes. Statistically significant differences between prostate cancer and normal prostate tissue were only observed before radiotherapy, when prostate cancer showed significantly higher perfusion (1.84 vs. 0.12 ml/cm³ min, p = 0.028) and a smaller extraction coefficient (0.42 vs. 0.64, p = 0.028).

Conclusions

Two pharmacokinetic parameters, perfusion and extraction coefficient, appear to be suitable candidates for monitoring the response to percutaneous intensity-modulated radiotherapy of prostate cancer.     

Parity, early menopause and the incidence of bladder cancer in women: a case-control study and meta-analysis

Introduction

Incidence rates of bladder cancer are notably higher in men than in women. While there is evidence that reproductive and hormonal risk factors may influence risk of bladder cancer, data are inconclusive.

Materials and methods

We examined reproductive, menstrual and hormonal use history in our population-based case-control study of bladder cancer in New Hampshire (NH), USA (n = 207 women cases and n = 463 women controls). Additionally, we performed a meta-analysis of the published literature. We used unconditional logistic regression analysis to compute adjusted odds ratios associated with each risk factor in the NH study. We combined these estimates with those from the published literature using inverse variance effects models.

Results

In the NH study, a slightly decreased odds ratio was found among women who had ever had a birth compared to nulliparous women and an elevated odds ratio among women who underwent surgical menopause (bilateral oophorectomy), especially at an early age. No overall associations were found with oral contraceptive use or hormone replacement therapy. These findings were generally in agreement with the meta-analytic results for which the combined relative risk (RR) estimate was reduced among ever parous women (combined RR estimate for ever parous versus nulliparous = 0.66, 95% confidence intervals [95% CI] 0.55-0.79) and elevated among those undergoing an early menopause (combined RR estimate for early versus late menopause = 1.59, 95% CI 1.31-1.92). No consistent risk was observed for the other factors.

Discussion

Some reproductive and menstrual factors appear to be related to the incidence of bladder cancer among women; but whether effects are due to female hormones is uncertain.     

The potential role of G2- but not of G0-radiosensitivity for predisposition of prostate cancer

Purpose

Comparing the chromosomal radiosensitivity of prostate cancer patients with that of healthy donors.

Materials and methods

The study was performed on 81 prostate cancer patients characterised by a clinical stage of predominantly pT2c or pT3a and a median age of 67 years. As healthy donors 60 male monozygotic twin pairs were recruited with a median age of 28 years. Chromosomal radiosensitivity was measured using both G0- and G2-assay.

Results

No difference between healthy donors and prostate cancer patients was detected concerning G0-radiosensitivity, since medians were similar (Hodges-Lehmann estimate: −0.05, 95% CI: −0.18-0.08, p = 0.4167). However, a pronounced difference was determined for G2-radiosensitivity with prostate cancer patients showing a significantly higher sensitivity compared to healthy donors (Hodges-Lehmann estimate: −0.41, 95% CI: −0.53 to −0.30, p = 1.75⁻⁹). Using the 90% quantile of G2-radiosensitivity in healthy donors as a threshold for discrimination the fraction of prostate cancer patients with elevated radiosensitivity increased to 49%.

Conclusion

G2-, but not G0-radiosensitivity is a promising marker for predisposition of prostate cancer.     

GWAS-identified colorectal cancer susceptibility locus associates with disease prognosis

Purpose

Extensive evidence has suggested that risk factors of cancer development may also modulate cancer clinical outcome. Recent genome-wide association (GWA) studies identified several single nucleotide polymorphisms (SNPs) predisposing to colorectal cancer (CRC). Given the pivotal importance of these variants in CRC, we sought to evaluate their associations with clinical outcomes of the disease.

Experimental Design

In a well-characterised cohort including 380 Chinese CRC patients, we genotyped seven SNPs identified in previous multi-stage GWA studies and analysed their associations with patient recurrence and survival.

Results

One SNP on chromosome 15q13, rs4779584 was associated with reduced risk of death with a hazard ratio (HR) of 0.33 (95% confidence interval [CI] 0.15-0.72, P = 0.007). Another SNP in a gene-desert region on chromosome 10p14, rs10795668, was associated with a reduced risk of recurrence with an HR of 0.55 (95% CI 0.30-1.00, P = 0.05). In a stratified analysis, this association was only evident in patients receiving chemotherapy (HR = 0.32, 95% CI 0.14-0.78, P = 0.01, log rank P = 0.004), but not in those without chemotherapy (HR = 1.08, 95% CI 0.43-2.73, P = 0.87, log rank P = 0.66). Moreover, we found that the effects of chemotherapy on CRC recurrence was only evident in patients with the variant-containing genotypes (HR = 0.35, 95% CI 0.13-0.94, P = 0.04) but not in those with the wild-type genotype of rs10795668. Further analyses indicated a borderline significant interaction effect (P interaction = 0.05) between rs10795668 and chemotherapy on patient recurrence.

Conclusions

Our data suggested that rs10795668, a CRC susceptibility variant identified by GWA studies, might be used as a biomarker to identify CRC patients with high risk of recurrence after chemotherapy.     

Histopathological and immunohistochemical features associated with clinical response to neoadjuvant gefitinib therapy in early stage non-small cell lung cancer

Background

Matrix metalloproteinases (MMPs) are considered important players in angiogenesis and cancer progression. Several drugs developed for targeting MMPs have until now been without clinical efficacy. As both malignant cells and cells of the surrounding stroma contribute to tumor growth, we have explored the impact of MMP-2, -7 and -9 expression in both the tumor and stromal compartment of non-small-cell lung cancers (NSCLC).

Patients and methods

From 335 unselected stage I to IIIA NSCLC carcinomas, duplicate tumor and tumor-associated stromal cores were collected in tissue microarrays (TMAs). Immunohistochemistry was used to detect the expression of MMP-2, -7 and -9 in tumor and stromal cells.

Results

In univariate analyses, high tumor cell MMP-7 expression (P = 0.029) and high stromal MMP-9 expression (P = 0.001) were positive prognostic factors. In the multivariate analysis, high tumor cell MMP-7 expression (HR 1.58, CI 1.08-2.32, P = 0.020) and high stromal MMP-9 expression (HR 1.92, CI 1.25-2.96, P = 0.003) were independent positive prognostic factors for disease-specific survival.

Conclusion

High levels of MMP-7 in tumor cells and high levels of MMP-9 in tumor associated stroma were independent positive prognostic factors in NSCLC patients.     

Promoter methylation of BRMS1 correlates with smoking history and poor survival in non-small cell lung cancer patients

Purpose

To investigate whether methylation of BRMS1 is associated with clinical outcomes in patients with NSCLC.

Methods

Methylation status of BRMS1 was examined in 325 NSCLC patients who were treated with surgery. We analyzed associations between the methylation of BRMS1 genes separately and available epidemiologic and clinical information including smoking status, gender, age, and histological type, or the stage of the tumor.

Results

In the cohort of 325 NSCLC cases, 152 samples were identified as methylated (46.77%). Promoter methylation of BRMS1 was present only in 6 specimens (8.42%) in adjacent non-cancerous tissues (P = 2.257 × 10⁻¹⁴). Patient smoking history had a positive correlation with methylation rate of BRMS1 (OR = 2.508, 95%CI(1.516, 4.151)). Compared with unmethylated group, methylated group showed the lower level of BRMS1 mRNA (P = 0.013). And patients with a high level of BRMS1 mRNA expression had significantly better overall survival than those with low expression (P = 0.002). Multivariate Cox proportional hazard regression analysis also showed that promoter methylation of BRMS1 was significantly unfavorable prognostic factors (hazard ratio, 1.912; 95% CI, and 1.341-2.726).

Conclusions

These results provide clinical evidence to support the notion that BRMS1 is a NSCLC metastasis suppressor gene. Measuring methylation status of BRMS1 promotor is a useful marker for identifying NSCLC patients with worse disease-free survival.     

Early CT and FDG-metabolic tumour volume changes show a significant correlation with survival in stage I-III small cell lung cancer: A hypothesis generating study

Background

Many patients with stage I-III small cell lung cancer (SCLC) experience disease progression short after the completion of concurrent chemoradiotherapy (CRT). The purpose of the current study was to evaluate whether CT or FDG metabolic response early after the start of chemotherapy, but before the beginning of chest RT, is predictive for survival in SCLC.

Methods

Fifteen stage I-III SCLC patients treated with concurrent CRT with an FDG-PET and CT scan available before the start of chemotherapy and after or during the first cycle of chemotherapy, but before the start of radiotherapy, were selected. The metabolic volume (MV) was defined both within the primary tumour and in the involved nodal stations using the 40% (MV40) and 50% (MV50) threshold of the maximum SUV. Metabolic and CT response was assessed by the relative change in MV and CT volume, respectively, between both time points. The association between response and overall survival (OS) was analysed by univariate cox regression analysis. The minimum follow-up was 18 months.

Results

Reductions in MV40 and MV50 were −36 ± 38% (126.4 to 68.7 cm³) and −44 ± 38% (90.2 to 27.8 cm³), respectively. The median CT volume reduction was −40 ± 64% (190.6 to 113.8 cm³). MV40 and MV50 changes showed a significant association with survival (HR = 1.02, 95% CI: 1.00-1.04 (p = 0.042); HR = 1.02, 95% CI: 1.00-1.04 (p = 0.048), respectively), indicating a 2% increase in survival probability for 1% reduction in metabolic volume. The CT volume change was also significantly correlated with survival (HR = 1.01, 95% CI: 1.00-1.03, p = 0.007).

Conclusions

This hypothesis generating study shows that both the early CT and the MV changes show a significant correlation with survival in SCLC. A prospective study is planned in a larger patient cohort to allow multivariate analysis, with the final aim to select patients early during treatment that could benefit from dose intensification or alternative treatment.     

Carboplatin chemotherapy in patients with recurrent high-grade glioma

Aims

To investigate the efficacy of carboplatin chemotherapy in patients with recurrent high-grade glioma (HGG) who had received at least two previous lines of chemotherapy.

Materials and methods

Case notes of patients who had received chemotherapy with carboplatin for recurrent HGG between June 2005 and July 2008 were reviewed. Baseline characteristics and outcomes after treatment were recorded.

Results

Twenty-six patients received carboplatin as third- or fourth-line chemotherapy for recurrent HGG (grade III glioma n = 8; grade IV glioma n = 18). The median number of cycles completed was 2.5. The most common reasons for discontinuing treatment were progressive disease and death (n = 19; 73%). Three patients (12%) had a partial response, five (19%) had stable disease and 18 (69%) had progressive disease. Six month progression-free survival was 23% (25% in patients with grade III glioma and 22% in patients with grade IV glioma). The median time to disease progression from the first treatment with carboplatin was 9.0 weeks. The median survival was 19.4 weeks (27.9 weeks for patients with grade III glioma and 8.1 weeks for patients with grade IV glioma). Among patients with either stable disease or a partial response, the median survival was 42.4 weeks compared with 11.7 weeks in patients with progressive disease (hazard ratio for death with progressive disease on treatment: 5.02; 95% confidence interval 1.64-15.4; P = 0.005). Carboplatin was well tolerated overall.

Conclusions

Single-agent carboplatin has modest activity in patients with recurrent HGG who have received at least two lines of chemotherapy. The overall time to progression is short and over two-thirds of patients had to discontinue treatment due to progressive disease. Among the small proportion of patients achieving stable disease or a partial response to treatment, the median survival is improved. More effective but well tolerated regimens are required for this patient population.     

Outcomes from Gleason 7, intermediate risk, localized prostate cancer treated with Iodine-125 monotherapy over 10 years

Background and purpose

The effect of predominating Gleason grade (3 + 4 versus 4 + 3) in Gleason sum score (GS) 7 prostate cancer (PCa) on brachytherapy outcomes is unclear. The 10 year experience of permanent brachytherapy monotherapy at a single UK centre for GS 7, intermediate risk (Memorial Sloan-Kettering model), PSA ? 10 ng/ml, localised PCa is reported.

Materials and methods

Between 1995 and 2004, the outcomes of 187 patients with GS 7 PCa (PSA ? 10 ng/ml) were analysed from a cohort of 1298 men treated with permanent Iodine-125 prostate brachytherapy, including PSA relapse-free survival (PSA-RFS).

Results

Median follow-up was 5.0 years (range 2.0-10.1 years). One patient has died of PCa. At 10 years, PSA-RFS was 82.4%/78% (ASTRO consensus and nadir +2 definitions). For GS 3 + 4, 5 year PSA-RFS was 86.7%/87.9% and for GS 4 + 3: 85.2%/96.6% respectively, with no significant difference between groups. Five year PSA-RFS (ASTRO) of 92.6% was seen for D₉₀ ? 140 Gy (50% total), compared with 77.0% below 140 Gy (p = 0.08).

Conclusions

Iodine-125 brachytherapy monotherapy achieved good rates of medium term biochemical control in GS 7, intermediate risk localised PCa patients. There was a trend to improved outcomes in men with a D90 in excess of 140 Gy.     

Retrospective analysis of definitive radiotherapy for patients with superficial esophageal carcinoma: Consideration of the optimal treatment method with a focus on late morbidity

Purpose

To evaluate the clinical efficacy of definitive radiotherapy for patients with superficial esophageal cancer.

Material and methods

From 1990 through 2006, 97 patients with stage I disease were treated with radiotherapy with or without chemotherapy. All patients were diagnosed with panesophagoscopy and computed tomography. Chemotherapy was added in 61 patients, and intra-cavitary brachytherapy (ICBT) was used in 27 patients.

Results

The patients were 90 men and seven women with a median age of 65.7 years (range; 41-89). At last follow-up with a median follow-up duration of 35.7 months, 3 year-overall and progression-free survival (PFS) rates were 81.5% (95% C.I. = 73.3-89.7%) and 55.8% (95% C.I. = 45.2-66.4%), respectively. Shorter tumor length was a significantly favorable factor for the PFS rate (P = 0.02) and local failure-free (LFF) rate (P = 0.007) on both univariate and multivariate analyses. Although the addition of ICBT had no apparent benefit for survival or tumor control, the rate of severe adverse effects including lethal esophageal ulcers, showed a higher tendency in patients receiving ICBT.

Conclusions

Our results regarding efficacy from the viewpoint of organ preservation are promising. Special care would be taken for the use of ICBT for patients with superficial esophageal cancer, especially if they have received chemoradiotherapy.