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.     

Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy

Background and purpose

Chest wall recurrences of breast cancer are a therapeutic challenge and durable local control is difficult to achieve. Our objective was to determine the local progression free survival (LPFS) and toxicity of thermochemoradiotherapy (ThChRT) for chest wall recurrence.

Methods

Twenty-seven patients received ThChRT for chest wall failure from 2/1995 to 6/2007 and make up this retrospective series. All received concurrent superficial hyperthermia twice weekly (median 8 sessions), chemotherapy (capecitabine in 21, vinorelbine in 2, and paclitaxel in 4), and radiation (median 45 Gy). Patients were followed up every 1.5-3 months and responses were graded with RECIST criteria and toxicities with the NCI CTC v4.0.

Results

Twenty-three (85%) patients were previously irradiated (median 60.4 Gy) and 22 (81%) patients received prior chemotherapy. Median follow-up was 11 months. Complete response (CR) was achieved in 16/20 (80%) of patients with follow-up data, and 1 year LPFS was 76%. Overall survival was 23 months for patients with CR, and 5.4 months in patients achieving a partial response (PR) (p = 0.01). Twenty-two patients experienced acute grade 1/2 treatment related toxicities, primarily moist desquamation. Two patients experienced 3rd degree burns; all resolved with conservative measures.

Conclusions

ThChRT offers durable palliation and prolonged LPFS with tolerable acute toxicity, especially if CR is achieved.     

The importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy - Results from the randomized DAHANCA 5 study

Background and purpose

Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of haemoglobin (Hb) often have a poor response to radiation which may be related to hypoxia induced radioresistance. The aim of the study was to evaluate the prognostic significance of low Hb level and its modification by transfusion in HNSCC patients treated with radiotherapy. The study was performed as a subrandomization in the DAHANCA 5 trial.

Material and methods

Patients were randomized to treatment with the hypoxic radiosensitizer nimorazole or placebo, and in addition, patients with “low” pre-irradiation Hb values (females < 13 g/dL; males < 14.5 g/dL) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a Hb level in the “high” value range.

Results

A total of 414 patients were included, 243 patients had high Hb levels and 171 patients had low Hb levels. Of the low Hb patients, 82 were randomized to receive transfusion and 89 not to receive transfusion. The treatment arms were well balanced. In the majority of patients, transfusion resulted in increased Hb levels although this tended to decline throughout treatment. Patients with high Hb levels had a significantly better probability of locoregional control, disease-specific survival and overall survival compared to ‘low Hb no transfusion’ patients. In the low Hb group, transfusion did not improve the outcome in locoregional control, disease-specific survival or overall survival. In multivariate analyses, T and N classifications were significant for all outcome measures, whereas there was no significant influence of transfusion or Hb level on endpoints.

Conclusion

The univariate prognostic significance of high Hb level was demonstrated in patients with HNSCC treated with radiotherapy; however, transfusion prior to and during treatment did not improve the outcome in patients with low Hb values.     

Preoperative concomitant boost intensity-modulated radiotherapy with oral capecitabine in locally advanced mid-low rectal cancer: A phase II trial

Purpose

We aimed to assess the safety and efficacy of preoperative intensity-modulated radiotherapy (IMRT) with oral capecitabine in patients with locally advanced mid-low rectal cancer using a concomitant boost technique.

Materials and methods

Patients with resectable locally advanced mid-low rectal cancer (node-negative ?T3 or any node-positive tumor) were eligible. The eligible patients received IMRT to 2 dose levels simultaneously (50.6 and 41.8 Gy in 22 fractions) with concurrent capecitabine 825 mg/m² twice daily 5 days/week. The primary end point included toxicity, postoperative complication, and pathological complete response rate (ypCR). The secondary endpoints included local recurrence rate, progression-free survival (PFS), and overall survival (OS).

Results

Sixty-three eligible patients were enrolled; five patients did not undergo surgery. Of the 58 patients evaluable for pathologic response, the ypCR rate was 31.0% (95% CI 19.1-42.9). Grade 3 toxicities included diarrhea (9.5%), radiation dermatitis (3.2%), and neutropenia (1.6%). There was no Grade 4 toxicity reported. Four (6.9%) patients developed postoperative complications. Two-year local recurrence rate, PFS, and OS were 5.7%, 90.5%, and 96.0%, respectively.

Conclusions

The design of preoperative concurrent boost IMRT with oral capecitabine could achieve high rate of ypCR with an acceptable toxicity profile.     

Multicentre phase I-II trial of capecitabine and oxaliplatin in combination with radiotherapy for unresectable pancreatic and biliary tract cancer: The CORGI-U study

Background and Purpose

In this multicentre phase I-II trial we evaluated the feasibility and efficacy of capecitabine and oxaliplatin followed by the combination of these two drugs with radiotherapy in patients with locally advanced pancreatic or biliary tract cancer.

Material and methods

Thirty-nine patients with inextirpable adenocarcinoma of the pancreas, gallbladder or extrahepatic bile ducts were included. Two cycles of XELOX (capecitabine 1000 mg/m² bid d1-14 + oxaliplatin 130 mg/m² d1, q3w) were followed by XELOX-RT (radiotherapy (50.4 Gy), combined with capecitabine 750-675 mg/m² bid every radiotherapy day and oxaliplatin 40-30 mg/m² once weekly). Primary end-points were tolerance (phase I) and objective response (phase II).

Results

The maximum tolerated doses of oxaliplatin and capecitabine to combine with irradiation were 30 mg/m² and 675 mg/m², respectively. Twenty-one percent (95% CI: 9-38%) of evaluable patients achieved partial response. Five patients went through surgery (three R0 resections). Two-year survival was 28%, and estimated local tumour control rate at 2 years was 72%. The most common grade 3-4 toxicity was nausea and vomiting.

Conclusions

XELOX-RT (30 mg/m² oxaliplatin/675 mg/m² capecitabine in combination with 50.4 Gy/28 fractions) was well tolerated and effective for locally advanced pancreatic and biliary tract cancer.     

Prognostic impact of peritonealisation in rectal cancer treated with preoperative chemoradiotherapy: Extraperitoneal versus intraperitoneal rectal cancer

Background and purpose

The oncologic outcomes of extraperitoneal (EP) rectal cancer are known to differ from those of intraperitoneal (IP) rectal cancer; however, these differences have not been studied in rectal patients treated by preoperative chemoradiotherapy (CRT). The aim of this study is to evaluate the prognostic impact of peritonealisation in rectal patients treated by preoperative CRT.

Materials and methods

This study analyzed the data of 362 patients who received preoperative CRT and underwent curative surgery for locally advanced rectal cancer at 3-9 cm above the anal verge. Patients were categorised into EP and IP groups based on whether peritonealisation was present, according to pathology reports. The oncologic outcomes between the two groups were compared.

Results

Peritonealisation was absent in 330 patients and present in 32 patients. In univariate analysis, disease-free survival was significantly worse in the EP group than in the IP group (73.0% versus 93.5%, p = 0.035). Multivariate analysis revealed the following independent risk factors for recurrence: the absence of peritonealisation (p = 0.023), ypT stage (p = 0.015) and ypN stage (p < .0001).

Conclusions

Peritonealisation of rectal cancer may be a prognostic factor of disease-free survival in patients with rectal cancer treated by preoperative CRT and surgery.     

A study of middle ear function in the treatment of nasopharyngeal carcinoma with IMRT technique

Purpose

This study evaluates the difference in damage to middle ear function with CRT and IMRT techniques in the treatment of nasopharyngeal carcinoma (NPC). We explore the isthmus of the Eustachian tube (ET) as the key anatomic site for the prevention of radiation-induced otitis media with effusion.

Methods and materials

Eighty-two patients with NPC were divided into two groups: 40 patients treated with CRT and 42 patients treated with IMRT. The difference between dosage over the middle ear cavity and the isthmus of the ET was evaluated in both CRT group and IMRT group. All patients underwent hearing tests including pure tone audiometry and impedance audiometry before and after RT.

Results

The dosage difference to the middle ear cavity and isthmus between these two groups was statistically significant (p < 0.05). The difference in hearing test results between these two groups was also statistically significant (p < 0.05). If we limited the dose to the middle ear cavity under 34 Gy and the dose to the isthmus under 53 Gy with IMRT, we may decrease radiation-induced OME even with the larger 2.25 Gy fraction size.

Conclusions

IMRT may have better protected the middle ear function compared with the CRT technique, even with larger fraction sizes than for the conventional CRT technique.     

Pre-operative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer: a phase II trial

Background

To evaluate the safety and efficacy of pre-operative chemoradiation, using capecitabine, oxaliplatin and bevacizumab with standard doses of radiation, in patients with high-risk rectal cancer.

Methods

Patients with locally advanced or low rectal cancer were treated with capecitabine 825 mg/m² twice daily on days 1-14 and 22-35, oxaliplatin 50 mg/m² on days 1, 8, 22 and 29, bevacizumab 5 mg/kg on days 14, 1, 15 and 29, and radiation 50.4 Gy in 28 fractions including boost. Total mesorectal excision was performed 7-9 weeks after chemoradiation. The primary end-point was complete tumour regression (ypT0NX) by central review.

Findings

Forty-two evaluable patients were enrolled, and 38 proceeded to definitive surgery. Eighteen patients (43%) had clinical T4 tumours and/or N2 tumours. Mean relative dose intensity was >90% for all systemic agents, and 97% for radiation. Grade 3/4 diarrhoea occurred in 10 patients (24%) and pain in 4 patients (10%) pre-operatively, while grade 3/4 pain, fatigue and infection were each reported among 5 patients (13%) post-operatively. Re-operation due to complications occurred in 4 patients (11%). Complete tumour regression (ypT0) was seen in 9 patients (23.7%) of which two had N1 disease and the pathological complete response (pCR) rate (ypT0N0) was 18.4%. Central review changed pathologic stage in six cases (16%).

Interpretation

In this study, pre-operative bevacizumab added to oxaliplatin, capecitabine and radiation was safe and resulted in a promising tumour regression rate. Surgical complications were closely monitored and occurred with the expected frequency. Central pathology review should be considered for trials with pathologic response as the primary end-point.

Funding

British Columbia Cancer Agency, Hoffmann-La Roche Canada and Sanofi-Aventis.     

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.     

Weekly docetaxel in metastatic breast cancer patients: no superior benefits compared to three-weekly docetaxel

Background

In anthracycline-pretreated metastatic breast cancer (MBC) patients, it is unknown whether weekly single-agent docetaxel is preferable to 3-weekly docetaxel regarding its toxicity and efficacy profile.

Patients and methods

In this multicenter, randomised, open-label phase III trial, 162 patients were randomised to weekly docetaxel (group A) or 3-weekly docetaxel (group B). The primary end-point was tolerability; secondary end-points were efficacy and quality of life (QoL).

Results

Group A (weekly docetaxel, n = 79) experienced less haematological toxicity, with just 1.3% versus 16.9% febrile neutropenia in group B (3-weekly docetaxel, n = 77) (p = 0.001). Not this difference, but fatigue and general malaise foremost led to more patient withdrawals in group A (24 versus 12 patients, p = 0.032), less patients completing treatment (29 versus 43 patients, p = 0.014) and reduced dose-intensity (15.6 versus 26 mg/m²/week, 58% versus 70% of projected dose, p = 0.017). As a result, 3-weekly docetaxel was related to better overall survival in multivariate analysis (hazard ratio 0.70, p = 0.036), although in univariate analysis efficacy was similar in both groups. Reported QoL was similar in both groups, but less effective treatment with more general toxicity led to less completed QoL forms in group A (65.4% versus 50%, p=0.049).

Conclusion

Weekly docetaxel is less well tolerated than a 3-weekly schedule, due to more non-haematological toxicity, despite less febrile neutropenia. Also, no efficacy benefits can be demonstrated for weekly docetaxel, which may even be inferior based on multivariate analysis. Therefore, a 3-weekly schedule should be preferred in the setting of MBC.     

Impact of PARP-1 and DNA-PK expression on survival in patients with glioblastoma multiforme

Purpose

To analyze, whether higher tumor levels of DNA repair enzymes contribute to worse treatment results of glioblastoma multiforme (GBM) patients after postoperative radiotherapy.

Materials and methods

Thirty four patients with GBM received postoperative radiotherapy. Tumor sections were examined for poly-ADP ribose polymerase-1 (PARP-1) and DNA protein kinase (DNA-PK) expression. Immunohistochemical staining intensities of PARP-1 and DNA-PK were determined (score 0-3) and expression levels were correlated with patients overall survival.

Results

Median survival time of the whole study group was 10.0 months (95% CI 8.1-11.9). Median survival of patients with high and low (?median and <median) tumor PARP-1 levels were 10.0 months (95% CI 7.9-12.1) and 12.0 months (95% CI 8.3-15.7), respectively (p = 0.93). In contrast, median survival of patients with high and low tumor DNA-PK levels were 9.0 months (95% CI 7.2-10.8) and 13.0 months (95% CI 10.7-15.3), respectively (p = 0.02). In multivariate analysis, DNA-PK expression emerged as a significant independent predictor for overall survival (HR 3.9, 95% CI 1.5-10.7, p = 0.01).

Conclusion

This hypothesis generating study showed that high tumor levels of DNA-PK correlate with poor survival of GBM patients. Further studies are needed to confirm these results and to clarify whether DNA-PK inhibitors might have a potential to radiosensitize GBM and improve the treatment outcome of this devastating disease.     

Loss of lamin A/C expression in stage II and III colon cancer is associated with disease recurrence

Aim of the study

Loss of the nuclear lamina protein lamin A/C (LMNA) has been observed in several human malignancies. The present study aimed to investigate associations between LMNA expression and clinical outcome in colon cancer patients.

Patients and methods

Clinicopathological data and formalin-fixed paraffin embedded tissues were collected from 370 stage II and III colon cancer patients. Tissue microarrays were constructed, stained for lamin A/C and evaluated microscopically. Microsatellite instability status was determined for 318 tumours.

Results

Low levels of LMNA expression were observed in 17.8% of colon tumours, with disease recurrence occurring in 45.5% of stage II and III colon cancer patients with LMNA-low expressing tumours compared to 29.6% of patients with LMNA-high expressing tumours (p = 0.01). For stage II patients, disease recurrence was observed for 35.7% of LMNA-low compared to 20.3% of LMNA-high expressing tumours (p = 0.03). Microsatellite stable (MSS) tumours exhibited more frequently low LMNA expression than microsatellite instable (MSI) tumours (21% versus 9.8%; p = 0.05). Interestingly, disease recurrence among LMNA-low and LMNA-high expressing MSS tumours varied significantly for stage III patients who had not received adjuvant chemotherapy (100% versus 37.8%; p < 0.01) while no such difference was observed for patients who received adjuvant chemotherapy (46.7% versus 46.0%; p = 0.96).

Conclusion

These data indicate that low expression of LMNA is associated with an increased disease recurrence in stage II and III colon cancer patients, and suggest that these patients in particular may benefit from adjuvant chemotherapy.     

Robotic system-based fractionated stereotactic radiotherapy in locally recurrent nasopharyngeal carcinoma

Purpose

We reviewed survival, local control, and toxicity in patients with locally recurrent nasopharyngeal carcinoma (NPC) who had been treated with fractionated stereotactic radiotherapy (FSRT).

Materials and methods

Between June 2002 and March 2008, we retrospectively reviewed 35 patients with locally recurrent NPC treated using FSRT with CyberKnife. Gross tumor volumes ranged from 2.6 to 64.0 ml (median, 7.9 ml). Radiation doses were prescribed at the isodose line (75-84% of the maximum dose; median, 80%). The prescribed dose of FSRT ranged from 24 to 45 Gy (median, 33 Gy) in three or five fractions.

Results

The overall survival (OS) rate, local failure-free survival (LFFS) rate, and disease progression-free survival (DPFS) rate at 5 years were 60%, 79%, and 74%, respectively. Twenty-three patients achieved complete response after FSRT. Only T stage at recurrence was an independent prognostic factor for OS and DPFS. Five patients exhibited severe late toxicity (Grade 4 or 5).

Conclusions

With regard to OS and LFFS, our study provided favorable outcomes. The incidence of severe late toxicities was acceptable in our study. FSRT would be considered as the alternative treatment of choice in re-irradiation for locally recurrent NPC.     

Feasibility of metronomic oral cyclophosphamide plus prednisolone in elderly patients with inoperable or metastatic soft tissue sarcoma

Background

The number of elderly people with soft tissue sarcoma (STS) is increasing. A sizeable population of elderly patients with STS is unfit for conventional doxorubicin- or ifosfamide-based chemotherapy. We assessed the feasibility of metronomic oral cyclophosphamide (CPM) in this population.

Patients and methods

Patients aged 65 years or older with unresectable STS received CPM 100 mg twice daily plus prednisolone 20 mg daily, the first week of a 2-week cycle in the outpatient setting. Main evaluation criterion was safety. Secondary evaluation criteria were objective response rate and progression-free survival.

Results

Twenty-six patients (median age: 72, range 66-88) received a total of 330 cycles (median per patient: 10, range 2-41) as first (n = 19) or second-line chemotherapy (n = 7). The most frequent histological subtypes were poorly differenciated sarcoma (n = 8), leiomyosarcoma and liposarcoma (n = 5 each) and angiosarcoma (n = 3). Grade ?3 lymphopenia was observed in 81% of pts but no opportunist infection occurred. Grade 3 anaemia and thrombocytopenia occurred in 2 pts (8%) each. No other grade 3-4 toxicity was seen. The response rate was 26.9% (95%CI: 9.9-44.0) and the disease control rate (responses and stable disease >12 weeks) was 69.2% (95%CI: 51.5-87.0). One complete (hepatic epithelioid haemangio-endothelioma) and 6 partial responses (including 5 pts with radiation-induced sarcomas) were seen. Progression-free survival ranged from 0 to 20.6 months (median: 6.8 months) and was significantly longer in patients with radiation-induced sarcomas (median: 7.8 versus 5.2 months, p = 0.02).

Conclusion

Metronomic CPM showed good safety results for this frail population, with promising activity in patients with radiation-induced sarcoma. Toxicity profile was favourable, allowing prolonged home staying and rare treatment discontinuations. A larger prospective study is warranted to confirm these encouraging results in elderly with STS.     

Tumour regression grading in patients with residual rectal cancer after preoperative chemoradiation

Background and purpose

To explore the utility of tumour regression grading (TRG, the amount of residual tumour cells in relation to extension of fibrosis) after chemoradiation of rectal cancer.

Materials and methods

Of 131 patients who received preoperative chemoradiation in the frame of the randomized trial, pathological complete response (pCR, TRG0), good regression (TRG1), moderate regression (TRG2), and poor regression (TRG3) were recorded in 17%, 31%, 31%, and 22% of patients, respectively.

Results

The rates of ypN-positive category for TRG0, TRG1, TRG2, and TRG3 groups were 5%, 23%, 45%, and 46%, respectively, p = 0.001. When ypT-category and TRG were evaluated by the logistic regression analysis, only ypT-category remained significant for independent prediction of the risk for mesorectal nodal metastases, p = 0.006. The 4-year (median follow-up) disease-free survival (DFS) for TRG0, TRG1, TRG2, and TRG3 groups were 91%, 67%, 54%, and 47%. When patients with persistent disease (TRG1 vs. TRG2 vs. TRG3) were analyzed separately, TRG had no prognostic value for DFS, p = 0.402.

Conclusions

TRG in patients with residual cancer had no prognostic value for the incidence of nodal disease and for DFS. Our findings and literature data question the need for the inclusion of TRG assessment into a routine pathological report.     

A phase I trial combining oral cisplatin (CP Ethypharm) with radiotherapy in patients with locally advanced head and neck squamous cell carcinoma

Purpose

To determine the maximum tolerated dose (MTD) of oral cisplatin (CP Ethypharm®) in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC) and the recommended dose for phase II trials.

Patients and methods

Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. CP Ethypharm® was administered on five consecutive days every other week for 7 weeks (4 treatment cycles) in combination with radiotherapy. Eighteen patients with locally advanced HNSCC were allocated to four cisplatin dose levels: 10 mg/m²/day: 4 patients; 15 mg/m²/day: 4, 20 mg/m²/day: 5 and 25 mg/m²/day: 5. The inclusion of patients was dictated by occurrence of dose limiting toxicities (DLTs) at each dosing level.

Results

The most frequently experienced AEs were gastrointestinal (GI) disorders. Five DLTs were observed, including three at 25 mg/m² level (two grade 2 renal toxicities, one grade 3 GI and renal toxicities), one at 20 mg/m² level (grade 3 GI disorders), one at 10 mg/m² level (grade 4 mucositis). PK analysis showed no significant difference of C_max values between day 1 and day 5 of treatment at each dose level (total & ultrafilterable platinum).

Conclusion

Due to 3 DLTs experienced at 25 mg/m²/day, MTD was reached and the recommended dose for phase II studies was determined as 20 mg/m²/day.     

The economic burden of metastatic breast cancer: a systematic review of literature from developed countries

Objective

Breast cancer, the most common malignant cancer among women in Western countries, has poor prognosis following metastasis. New therapies potentially extend survival, but their value is questioned when benefits are incremental and expensive. The objective of our study was to understand the economic impact of metastatic breast cancer (MBC) and its treatment, and to evaluate the designs of these studies.

Methods

We systematically reviewed the MEDLINE-indexed, English-language literature, identifying 31 articles on the economic evaluation of MBC in 10 developed countries, including studies of per-patient costs, gross national costs, and cost-effectiveness models. We also included health technology assessments (HTAs) from government and regulatory agencies.

Results

Total per-patient costs of MBC are only available for Sweden ($17,301-$48,169 annually, depending on patient age (2005 USD)). Most economic analyses of per-patient direct costs originate from the US; across all countries, data indicate that this burden is substantial. Gross national costs of MBC are available only for the UK (cost of incident MBC cases is estimated to be $22 million annually (2002 GBP)). Many cost-effectiveness analyses suggest that a number of new and established treatments are cost-effective compared to standard care in various countries, but many offer small increments in survival. The cost-effectiveness of trastuzumab, capecitabine, and nab-paclitaxel has been evaluated in many recent studies.

Conclusion

Most economic evaluations of MBC have utilized secondary rather than primary data, and have used scenarios and assumptions which may be inaccurate or outdated. The quality of evidence disseminated to decision-makers could be improved by adherence to best practices in cost-effectiveness analyses.     

Low ERCC1 mRNA and protein expression are associated with worse survival in cervical cancer patients treated with radiation alone

Purpose

To evaluate the association of excision repair cross-complementation group 1 (ERCC1) expression, using both mRNA and protein expression analysis, with clinical outcome in cervical cancer patients treated with radical radiation therapy (RT).

Experimental design

Patients (n = 186) with locally advanced cervical cancer, treated with radical RT alone from a single institution were evaluated. Pre-treatment FFPE biopsy specimens were retrieved from 112 patients. ERCC1 mRNA level was determined by real-time PCR, and ERCC1 protein expression (FL297, 8F1) was measured using quantitative immunohistochemistry (AQUA®). The association of ERCC1 status with local response, 10-year disease-free (DFS) and overall survival (OS) was analyzed.

Results

ERCC1 protein expression levels using both FL297 and 8F1 antibodies were determined for 112 patients; mRNA analysis was additionally performed in 32 patients. Clinical and outcome factors were comparable between the training and validation sets. Low ERCC1 mRNA expression status was associated with worse OS (17.9% vs 50.1%, p = 0.046). ERCC1 protein expression using the FL297 antibody, but not the 8F1 antibody, was significantly associated with both OS (p = 0.002) and DFS (p = 0.010). After adjusting for pre-treatment hemoglobin in a multivariate analysis, ERCC1 FL297 expression status remained statistically significant for OS [HR 1.9 (1.1-3.3), p = 0.031].

Conclusions

Pre-treatment tumoral ERCC1 mRNA and protein expression, using the FL297 antibody, are predictive factors for survival in cervical cancer patients treated with RT, with ERCC1 FL297 expression independently associated with survival. These results identify a subset of patients who may derive the greatest benefit from the addition of cisplatin chemotherapy.     

Duration of prior gefitinib treatment predicts survival potential in patients with lung adenocarcinoma receiving subsequent erlotinib

Purpose

We investigated survival potential in patients receiving erlotinib after failure of gefitinib, focusing on response and time to progression (TTP) with gefitinib.

Methods

We retrospectively reviewed lung adenocarcinoma patients who received erlotinib after experiencing progression with gefitinib. Our primary objective was to evaluate the prognostic significance of erlotinib therapy.

Results

A total 42 lung adenocarcinoma patients were included in this study. Overall disease control rate was 59.5% (partial response [PR], 2.4%; stable disease [SD], 57.1%). Median overall survival was 7.1 months, and median progression-free survival was 3.4 months. The number of patients who achieved PR and non-PR (SD+ progressive disease [PD]) with gefitinib were 22 (52%) and 20 (48%), respectively. Patients with PR for gefitinib showed significantly longer survival times than those with non-PR (9.2 vs. 4.7 months; p = 0.014). In particular, among PR patients, those with TTP <12 months on gefitinib showed significantly longer survival times than those with TTP ≥12 months (10.3 vs. 6.4 months; p = 0.04).

Conclusions

Erlotinib may exert survival benefit for lung adenocarcinoma patients with less than 12 months of TTP of prior gefitinib who achieved PR for gefitinib.     

Stereotactic body radiotherapy for local boost irradiation in unfavourable locally recurrent gynaecological cancer

Purpose

To evaluate outcome of radiotherapy for locally recurrent cervical and endometrial cancer.

Materials and methods

Nineteen patients were treated for a locally recurrent cervical (n = 12) or endometrial (n = 7) cancer median 26 months after initial surgery (n = 18) or radiotherapy (n = 1). The whole pelvis was irradiated with 50 Gy conventionally fractionated radiotherapy (n = 16). Because of large size of the recurrent cancer (median 4.5 cm) and peripheral location (n = 12), stereotactic body radiotherapy (SBRT; median 3 fractions of 5 Gy to 65%) was used for local dose escalation instead of (n = 16) or combined with (n = 3) vaginal brachytherapy.

Results

After median follow-up of 22 months, 3-year overall survival was 34% with systemic progression the leading cause of death (7/10). Median time to systemic progression was 16 months. Three local recurrences resulted in a local control rate of 81% at 3 years. No correlation between survival, systemic or local control and any patient or treatment characteristic was observed. The rate of late toxicity > grade II was 25% at 3 years: two patients developed a grade IV intestino-vaginal fistula and one patient suffered from a grade IV small bowel ileus.

Conclusion

Image-guided SBRT for local dose escalation resulted in high rates of local control but was associated with significant late toxicity.