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.     

Prognostic significance of CD24 protein expression in patients treated with adjuvant radiotherapy after radical hysterectomy for cervical squamous cell carcinoma

Background and purpose

The CD24 marker is expressed in various carcinomas and is associated with shorter survival rates. We evaluated the prognostic significance of CD24 protein overexpression in patients treated with post-operative radiotherapy (RT) after surgery, and its prognostic significance and specific role stratified by adjuvant treatment modalities.

Materials and methods

We determined the CD24 expression status of 140 patients with cervical squamous cell carcinoma treated with RT alone or with chemoradiotherapy (CRT) after radical hysterectomy procedures.

Results

CD24 expression was detected in 59 patients (42%) and was significantly associated with locoregional failure-free survival (LRFFS) (p = 0.0218), distant metastasis-free survival (DMFS) (p = 0.0001), and overall survival (OS) (p = 0.0053). In the multivariate analysis, CD24 positivity was also significantly associated with DMFS (p = 0.025) and OS (p = 0.045). CD24 expression stratified by post-operative treatments (CRT or RT alone) was associated with DMFS (p = 0.0001) but not with LRFFS (p = 0.4423) in the CRT group. However, CD24 expression was associated with LRFFS (p = 0.0198) but not with DMFS (p = 0.5269) in the RT alone group.

Conclusions

CD24 expression is an independent prognostic marker in patients with cervical squamous cell carcinoma, even adjuvant treatment after surgery. And this study reveals different prognostic role of CD24 expression in two subgroups treated differently after surgery. Therefore, new therapeutic strategies targeting CD24 expression stratified by subgroups might have important clinical implications.     

Residual DNA and chromosomal damage in ex vivo irradiated blood lymphocytes correlated with late normal tissue response to breast radiotherapy

Purpose

To test the association of DNA double-strand break (DSB) repair and chromosomal radiosensitivity in ex vivo irradiated blood lymphocytes with late-onset normal tissue responses following breast radiotherapy.

Methods

Breast cancer patients with minimal (controls) or marked late radiotherapy changes (cases) were retrospectively selected. DSB were quantified by γH2AX/53BP1 immunofluorescence microscopy 0.5 and 24 h after exposure of unstimulated blood lymphocytes to 0.5 and 4 Gy X-rays, respectively. Chromosomal aberrations were scored in blood lymphocyte metaphases after 6 Gy X-rays.

Results

Despite similar foci levels at 0.5 h in cases (n = 7) and controls (n = 7), foci levels 24 h after 4 Gy irradiation differed significantly between them (foci per cell were 12.8 in cases versus 10.2 in controls, p = 0.004). Increased chromosomal radiosensitivity was also observed in cases (aberrations per cell were 5.84 in cases versus 3.79 in controls, p = 0.001) with exchange and deletion type aberrations contributing equally to the difference between cases and controls. Residual foci correlated with formation of deletions (Spearman’s R = 0.589, p = 0.027) but not exchanges (R = 0.367, p = 0.197) in blood lymphocytes from the same patients.

Conclusions

Higher levels of exchange type aberrations observed among radiosensitive breast cancer patients suggest a role for DSB misrepair, in addition to residual damage, as determinants of late normal tissue damage. Correlation of residual foci levels with deletion type aberration yields in the same cohort confirms their mechanistic linkage.     

Constitutive expression of γ-H2AX has prognostic relevance in triple negative breast cancer

Background and purpose

Constitutive γ-H2AX expression might indicate disruption of the DNA damage repair pathway, genomic instability, or shortened telomeric ends. Here, we quantified expression of endogenous γ-H2AX and its downstream factor 53BP1 in a large number of breast cancer cell lines (n = 54) and a node-negative breast cancer cohort that had not received adjuvant systemic treatment (n = 122).

Materials and methods

Formalin fixed paraffin embedded breast cancer cell lines and tumors were immunohistochemically analyzed for γ-H2AX and 53BP1 expression, and related to cell line, patient and tumor characteristics and to disease progression.

Results

In breast cancer cell lines, γ-H2AX positivity was associated with the triple negative/basal like subgroup (p = 0.005), and with BRCA1 (p = 0.011) or p53 (p = 0.053) mutations. Specifically in triple negative breast cancer patients a high number of γ-H2AX foci indicated a significantly worse prognosis (p = 0.006 for triple negative vs. p = 0.417 for estrogen receptor (ER), progesterone receptor (PR) or HER2 positive patients). A similar association with disease progression was found for 53BP1. In a multivariate analysis with tumor size, grade, and triple negativity, only the interaction between triple negativity and γ-H2AX remained significant (p = 0.002, Hazard Ratio = 6.77, 95% CI = 2.07-22.2).

Conclusions

Constitutive γ-H2AX and 53BP1 staining reveals a subset of patients with triple negative breast tumors that have a significantly poorer prognosis.     

Prognostic effect of stromal lymphocyte infiltration in thymic carcinoma

Background

The purpose of this study was to clarify the relationship between the tumor infiltrating lymphocytes and clinical outcome in patients with thymic carcinoma.

Methods

Tissue specimens from 32 patients who underwent surgical resection for thymic carcinoma were immunohistochemically analyzed for CD4, CD8 and CD20 expression.

Results

Tumor-infiltrating lymphocytes were generally more abundant in the stroma. The patients with low CD4+ lymphocytes (p = 0.037) and low CD20+ lymphocytes (p = 0.045) within tumor stroma showed poor survival. Furthermore, concurrent low levels of CD4+ and CD20+ (p = 0.014), CD8+ and CD20+ (p = 0.025), and, CD4+, CD8+, and CD20+ (p = 0.025) in tumor stroma were significantly associated with poor prognosis when compared to the others group.

Conclusion

Our results indicate that infiltrating CD4+, CD8+, and CD20+ lymphocytes in cancer stroma may cooperate to suppress cancer progression and their presence together appear to be prognostic factor in thymic carcinoma.     

Double-scattered proton-based stereotactic body radiotherapy for stage I lung cancer: A dosimetric comparison with photon-based stereotactic body radiotherapy

Purpose

Stereotactic body radiotherapy (SBRT) has gained popularity in the treatment of early-stage non-small-cell lung cancer (NSCLC) because of its ability to deliver conformal radiation doses to small targets. However, photon-based SBRT (xSBRT) is associated with significant grade 3+ toxicities. In this study, we compare xSBRT treatment plans with proton-based SBRT (pSBRT) to determine whether dose to normal structures could be reduced if SBRT was delivered with protons.

Materials and methods

Eight patients with medically inoperable, peripherally located stage I NSCLC were treated with xSBRT to 48 Gy in 4 12-Gy fractions. These patients were retrospectively re-planned using the same treatment volumes with 3-dimensional conformal double-scatter proton therapy. A Wilcoxon paired test compared dosimetric parameters between the plans for each patient.

Results

Compared with xSBRT there was a dosimetric improvement with pSBRT for these volumes: lung V5 (median difference [MD] = 10.4%, p = 0.01); V10 (MD = 6.4%, p = 0.01); V20 (MD = 2.1%, p = 0.01); V40 (MD = 1.5%, p = 0.05); and mean lung dose (MD = 2.17 Gy, p = 0.01). There were also benefits (p = <0.05) in D0.1cm3 and D5cm3 with pSBRT to the heart, esophagus, and bronchus.

Conclusions

In a dosimetric comparison between photon and proton-based SBRT, protons resulted in lower doses to critical organs at risk and a smaller volume of non-targeted normal lung exposed to radiation (V5, V10, V20, and V40). The clinical significance and relevance of these dosimetric improvements remain unknown.     

High-dose radiotherapy or concurrent chemo-radiation in lung cancer patients only induces a temporary, reversible decline in QoL

Background and purpose

Aggressive radiotherapy or concurrent chemo-radiation therapy for lung cancer leads to a high incidence of severe, mostly esophageal, toxicity. The purpose of this study was to investigate the evolution of quality of life (QoL) in patients with lung cancer, selected for curative radiotherapy (RT) or chemo-RT.

Methods

Seventy-five lung cancer patients completed a longitudinal the EORTC QLQ-C30 and LC13. Linear mixed regression models were fitted to investigate the impact of different factors on overall QoL.

Results

Overall QoL decreased shortly after the end of RT (4 points, p = 0.19), but increased back to baseline within 3 months. Mean scores of role functioning (p = 0.018), cognitive functioning (p = 0.002), dyspnoea (EORTC QLQ-LC13; p = 0.043), dysphagia (p = 0.005) and hoarseness (p = 0.029), showed a significant worsening over time. Emotional functioning (p = 0.033) improved significantly over time.Severe esophagitis (?grade 2) was reported in only 12% of the patients. Next to maximal esophageal toxicity ?grade 2 (p = .0.010), also tumor stage IIIA (p < 0.001), tumor stage IIIB (p = 0.003), gender (p = 0.042) and fatigue (p < 0.001) appeared to be significant predictors of QoL.

Conclusion

High-dose radiotherapy or concurrent chemo-radiation in the treatment of lung cancer seems to be a well-tolerated treatment option with preservation of QoL.     

Define relative incomplete resection by highest mediastinal lymph node metastasis for non-small cell lung cancers: rationale based on prognosis analysis

Purpose

Present research aimed to explore the rationale of defining RIR operations by metastatic status of highest nodes.

Patients and methods

549 surgical patients, bearing pN2-NSCLCs, were enrolled in the current study. R1/R2 nodes on the right side and L4 nodes on the left were taken as the highest mediastinal lymph nodes. The operations were defined “Complete Resection (CR)” if the highest nodes were negative. Operations were otherwise “Relative Incomplete Resections (RIR)” if the nodes were positive. Exclusion criteria included: metastatic carcinomas or small cell lung cancer, prior history of induction therapy, exploratory thoracotomy, palliative resection, and massive pleural dissemination, as well as cases without “highest” mediastinal nodal pathology. The survival rate was calculated using the life-table and Kaplan-Meier method. Comparisons between groups were calculated using the Log-rank test.

Results

A total of 6865 lymph nodes (5705 mediastinal and 1160 regional, average 12.6 ± 6.4 nodes for each patient) were removed. Total cases included 246 RIR (100 left and 146 right side) and 303 CR (108 left and 195 right). The overall 5-year survival rate was 22% and the median survival time was 28.29 months. Five-year survival rates of the CR and RIR group were statistically significant (29% and 13%, respectively p < 0.0001). L4 and R1/R2 lymph nodes had similar position for defining RIR; no obvious survival difference was indicated between either side (p = 0.464 in CR groups, p = 0.647 in RIR groups). N2 subcategories and skip-metastasis were closely associated with highest nodal involvement (p < 0.0001). Multivariate analysis showed CR/RIR assignment, tumor size, N2 disease stratification, pathological T status, and number of positive mediastinal nodes were risk factors for 5-year survival in the present case series.

Conclusion

Involvement of the highest mediastinal lymph nodes is highly predictive of poor prognosis and indicates an advanced stage of the disease. Therefore, it may be appropriate to assign R1/R2 or L4 as criterion for defining RIR or CR cases in surgical NSCLC cases.     

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.     

8 Gy single-dose radiotherapy is effective in metastatic spinal cord compression: Results of a phase III randomized multicentre Italian trial

Background and purpose

In a previous randomized trial we showed that the short-course radiotherapy (RT) regimen of 8 Gy × 2 was feasible in patients with metastatic spinal cord compression (MSCC) and short life expectancy. This phase III trial was planned to determine whether in the same category of patients 8 Gy single-dose is as effective as 8 Gy × 2.

Materials and methods

Three hundred and twenty-seven patients with MSCC and short life expectancy were randomly assigned to a short-course of 8 Gy × 2 or to 8 Gy single-dose RT. Median follow-up was 31 months (range, 4-58).

Results

A total of 303 (93%) patients are assessable, 150 treated with the short-course and 153 with the single-dose RT. No difference in response was found between the two RT schedules adopted. Median duration of response was 5 and 4.5 months for short-course and single-dose RT (p = 0.4), respectively. The median overall survival was 4 months for all cases. Light acute toxicity was registered in a minority of cases. Late toxicity was never recorded.

Conclusions

Both RT schedules adopted were effective. As already shown in several trials evaluating RT regimens in uncomplicated painful bone metastases, also MSCC patients may achieve palliation with minimal toxicity and inconvenience with a single-dose of 8 Gy.     

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.     

Expression of estrogen receptor beta predicts a clinical response and longer progression-free survival after treatment with EGFR-TKI for adenocarcinoma of the lung

Purpose

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (EGFR-TKI) demonstrates a dramatic clinical response for the lung adenocarcinoma patients harboring a somatic mutation of EGFR. Such EGFR mutations are frequently found in adenocarcinoma with a strong expression of estrogen receptor (ER) beta, which has been shown to correlate with a favorable prognosis for the patients with EGFR mutations. The aim of this study is to elucidate the correlation between expression of ER beta and the therapeutic effect of EGFR-TKI in adenocarcinoma of the lung.

Patients and methods

Forty-three patients who were treated with EGFR-TKI for adenocarcinoma of the lung were evaluated. The expression of ER beta and the EGFR mutation were evaluated by immunohistochemistry and the polymerase chain reaction, respectively. Patients divided into two groups by the nuclear expression of ER beta. The clinical response and survival data were compared between the two groups.

Result

Strong (S) and weak (W) expression of ER beta was observed in 21 and 22 patients, respectively. EGFR mutations were detected in 30 (69.8%) cases. The S group had more frequent EGFR mutations than the W group (85.7%, 54.5%, p = 0.045). The S group had better response rate (p = 0.006) and longer progression-free survival (PFS; p = 0.001) than the W group. Even in a limited analysis in the patients with EGFR mutations, the S group had tended to have a better response rate (77.8%, 41.7%, p = 0.063), and significant longer PFS (p = 0.012) than the W group.

Conclusion

A strong expression of ER beta predicts a good clinical outcome for patients with adenocarcinoma of the lung after treatment with EGFR-TKI. This suggests that the expression status of ER beta can be a candidate surrogate marker for EGFR-TKI treatment of patients with adenocarcinoma of the lung. Further investigation will be necessary to identify biomarkers using a larger cohort of patients in a prospective study.     

Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: a verification study

Background

A recent study by Dhillon et al. [12], identified both angioinvasion and mTOR as prognostic biomarkers for poor survival in early stage NSCLC. The aim of this study was to verify the above study by examining the angioinvasion and mTOR expression profile in a cohort of early stage NSCLC patients and correlate the results to patient clinico-pathological data and survival.

Methods

Angioinvasion was routinely recorded by the pathologist at the initial assessment of the tumor following resection. mTOR was evaluated in 141 early stage (IA-IIB) NSCLC patients (67 - squamous; 60 - adenocarcinoma; 14 - others) using immunohistochemistry (IHC) analysis with an immunohistochemical score (IHS) calculated (% positive cells × staining intensity). Intensity was scored as follows: 0 (negative); 1+ (weak); 2+ (moderate); 3+ (strong). The range of scores was 0-300. Based on the previous study a cut-off score of 30 was used to define positive versus negative patients. The impact of angioinvasion and mTOR expression on prognosis was then evaluated.

Results

101 of the 141 tumors studied expressed mTOR. There was no difference in mTOR expression between squamous cell carcinoma and adenocarcinoma. Angioinvasion (p = 0.024) and mTOR staining (p = 0.048) were significant univariate predictors of poor survival. Both remained significant after multivariate analysis (p = 0.037 and p = 0.020, respectively).

Conclusions

Our findings verify angioinvasion and mTOR expression as new biomarkers for poor outcome in patients with early stage NSCLC. mTOR expressing patients may benefit from novel therapies targeting the mTOR survival pathway.     

Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: Comparison with a contemporaneous cohort with pathologically proven disease

Introduction

As a finding of benign disease is uncommon in Dutch patients undergoing surgery after a clinical diagnosis of stage I NSCLC, patients are also accepted for stereotactic ablative radiotherapy (SABR) without pathology. We studied outcomes in patients who underwent SABR after either a pathological (n = 209) or clinical diagnosis (N = 382).

Materials and methods

Five hundred and ninety-one patients with a single pulmonary lesion underwent SABR after either a pathological- or a clinical diagnosis of stage I NSCLC based on a ¹⁸FDG-PET positive lesion with CT features of malignancy. SABR was delivered to a total dose of 60 Gy in 3, 5 or 8 fractions, and outcomes were compared between groups with and without pathological diagnosis.

Results

Patients with pathology had significantly larger tumor diameters (p < .001) and higher predicted FEV1% values (p = .025). No significant differences were observed between both groups in overall survival (p = .99) or local control (p = .98). Regional and distant recurrence rates were also similar.

Conclusions

In a population with a low incidence of benign ¹⁸FDG-PET positive lung nodules, clinical SABR outcomes were similar in large groups of patients with or without pathology. The survival benefits reported after the introduction of SABR are unlikely to be biased by inclusion of benign lesions.     

Adjuvant chemoradiotherapy with or without intraoperative radiotherapy for the treatment of resectable locally advanced gastric adenocarcinoma

Purpose

To document the long-term efficacy of intraoperative electron radiotherapy (IOERT) followed by concurrent chemotherapy and external-beam radiotherapy (EBRT) in the management of locally advanced gastric cancer.

Materials and methods

A total of 97 consecutive patients with T3/4 or N+ gastric adenocarcinoma were enrolled. Fifty-one patients received adjuvant chemoradiotherapy (EBRT group) and 46 received IOERT (dose range, 12-15 Gy) followed by chemoradiotherapy (EBRT + IOERT group).

Results

The 5-year locoregional control rates were 50% and 35% in the two groups with or without IOERT, respectively (p = 0.04). Two patients had recurrence within the IOERT field in the EBRT + IOERT group and 14 patients recurred in the same area in the EBRT group (p = 0.02). Multivariate analyses revealed that adjuvant IOERT was an independent prognosticator for both local-regional control (p = 0.02) and disease-free survival (p = 0.05). G3/4 late toxicity was observed in 5 patients in the EBRT + IOERT group, but none in the EBRT group (p = 0.02).

Conclusions

Higher radiation dose may contribute to the improvement of local control, especially in the field encompassed by IOERT. The addition of IOERT to surgery and adjuvant chemoradiation deserves further investigation in a randomized trial.     

Tubulin, BRCA1, ERCC1, Abraxas, RAP80 mRNA expression, p53/p21 immunohistochemistry and clinical outcome in patients with advanced non small-cell lung cancer receiving first-line platinum-gemcitabine chemotherapy

Background

The aim of this study was to assess the predictive value of tumor expression of nine genes on clinical outcome in patients with advanced NSCLC receiving platinum-gemcitabine chemotherapy.

Methods

Quantitative PCR or immunohistochemistry were used to analyze the expression of β-tubuline IIA (TUBB2A), β-tubuline III (TUBB3), BRCA1, ERCC1, Abraxas (ABRX) and RAP80 in mRNA isolated from paraffin-embedded tumor biopsies of 45 NSCLC patients treated as part of a larger observational trial. All patients received first-line platinum-gemcitabine chemotherapy for stage IIIB or IV NSCLC.

Results

Median progression-free survival (PFS) was 7 months, overall survival (OS) 12 months. A partial treatment response was found in 14 patients (33%). Patients with low ERCC1 or ABRX expression had a significantly better response to chemotherapy (R = −0.45, p < 0.01 for ERCC1; R = −0.40, p = 0.016 for ABRX). A significant correlation was found between the individual time for PFS and the expression of both ERCC1 (R = −0.36, p = 0.015) and ABRX (R = −0.46, p = 0.001). Patients with low ERCC1 expression had a longer OS as compared to patients with high ERCC1 expression (HR = 0.26, log-rank p = 0.02).

Conclusions

The study confirms tumor expression of ERCC1 as a predictor for clinical outcome in patients with advanced NSCLC receiving platinum-based chemotherapy, and found ABRX expression to be similarly predictive of clinical outcome. Prospective validation is warranted and - if confirmed - non platinum-containing chemotherapy should be explored as the preferred treatment in patients with high ERCC1 or ABRX expression and no activating mutations of EGFR.     

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.     

Prognostic significance of IGF-1R expression in patients treated with breast-conserving surgery and radiation therapy

Background

Insulin-like growth factor (IGF) receptor is a key receptor in apoptotic protection, cell adhesion, longevity, and transformation into a cancerous cell and can induce malignant changes in the presence of the IGF ligand. Over-expression of IGF-1R has been associated with resistance to radiation. Inhibitors of IGF-1R have been shown to enhance tumor radiation sensitivity and amplify radiation therapy-induced apoptosis. The purpose of this study is to evaluate the prognostic significance of IGF-1R expression in patients with breast cancer treated with breast conserving therapy.

Materials and methods

Paraffin specimens from 345 women with early stage breast cancer treated with BCT were constructed into tissue microarrays and stained for IGF-1R, COX-2 and p53. The molecular profiles were correlated with clinical-pathologic factors, overall, local, and distant relapse-free survival. The association between IGF-1R, other co-variables, and outcome was assessed.

Results

IGF-1R over-expression was identified in 197 cases (57%). IGF-1R over-expression was found to be correlated with African-American race (p = 0.0233), p53 status (p = 0.0082) and COX-2 expression (p < 0.0001). While IGF-1R over-expression was associated with lower overall survival (p = 0.0224) in node-negative patients, there was no impact of IGF-1R expression on local control.

Conclusions

In node-negative patients, patients with high levels of IGF-1R were found to have a significant reduction in overall survival, but no apparent effect on local control. Given the limited published data on IGF-1R in early stage, conservatively treated patients, further studies investigating IGF-1R expression in this cohort are necessary.     

Adding external beam to intra-luminal brachytherapy improves palliation in obstructive squamous cell oesophageal cancer: A prospective multi-centre randomized trial of the International Atomic Energy Agency

Background

Whether the combination of high dose-rate brachytherapy (HDRBT) and External Beam Radiation Therapy (EBRT) is superior to HDRBT alone for the palliation of oesophageal cancer has only been explored in a previous IAEA pilot randomized trial.

Methods

Two hundred and nineteen patients were randomized to adding EBRT or not, after receiving two fractions of HDRBT within 1 week. Each HDRBT consisted of 8 Gy prescribed at 1 cm from source centre. Patients randomized to EBRT received 30 Gy in 10 fractions. The primary outcome was dysphagia-relief experience (DRE). Additional outcomes included various scores, performance status, weight and adverse events. A majority of charts, imaging and radiotherapy plans were externally audited.

Results

Median follow-up was 197 days, with a median OS of 188 days and an 18% survival rate at 1 year. DRE was significantly improved with combined therapy, for an absolute benefit of +18% at 200 days from randomization (p = 0.019). In longitudinal regression analyses, scores for dysphagia (p = 0.00005), odynophagia (p = 0.006), regurgitation (p = 0.00005), chest pain (p = 0.0038) and performance status (p = 0.0015) were all significantly improved. In contrast, weight, toxicities and overall survival were not different between study arms.

Conclusion

Symptom improvement occurs with the addition of EBRT to standard HDRBT. The combination is well tolerated and relatively safe.     

Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for anal carcinoma: Are there differences between HIV-positive and HIV-negative patients in the era of highly active antiretroviral therapy?

Purpose

To report treatment compliance, toxicity and clinical outcome of chemoradiotherapy (CRT) for anal carcinoma in HIV-negative vs. HIV-positive patients treated with highly active antiretroviral therapy.

Material and methods

Between 1997 and 2008, 25 HIV-positive and 45 HIV-negative patients received CRT (50.4 Gy at 1.8 Gy/fraction plus 5.4-10.8 Gy boost; 5-fluorouracil, 1000 mg/m², Days 1-4 and 29-32, mitomycin C, 10 mg/m², Days 1 and 29). Median follow-up was 51 (range, 3-235) months.

Results

HIV-positive patients were significantly younger (mean age, 47 vs. 57 years, p < 0.001) and predominantly male (92% vs. 29%, p < 0.001). CRT could be completed in all patients with a reduction of chemotherapy and/or RT-interruption in 28% and 8%, respectively, in HIV-positive patients, and in 9% and 11%, respectively, in HIV-negative patients. Acute Grade 3/4-toxicity occurred in 44% vs. 49% (p = 0.79). Initial complete response (84% vs. 93%, p = 0.41), 5-year rates of local control (65% vs. 78%, p = 0.44), cancer-specific (78% vs. 90%, p = 0.17) and overall survival (71% vs. 77%, p = 0.76) were not significantly different.

Conclusion

HIV-positive patients with anal cancer can be treated with standard CRT, with the same tolerability and toxicity as HIV-negative patients. Long-term local control and survival rates are not significantly different between these groups.