Equivalent survival in patients with advanced stage IB–II and III–IVA cervical cancer treated by adjuvant surgery following chemoradiotherapy

Objectives

To evaluate survival in patients with advanced cervical cancer who underwent surgery after concurrent chemoradiotherapy.

Methods

One hundred and forty-four patients with biopsy-proven stage IB–IVA cervical cancer underwent adjuvant surgery after concurrent chemoradiotherapy. Surgical resection was classified as curative (no evidence of remaining disease after surgery) or palliative (remaining disease after surgery). Endpoints were pelvic control, overall survival (OS) and disease-free survival (DFS) at 5 and 10 years. Analysis included tumour FIGO stage, type of surgery (curative versus palliative), pelvic control, response to chemoradiotherapy and lymphatic status.

Results

Tumour FIGO stages were IB–II in 91 cases and III–IVA in 53 cases. Surgery was curative in 127 cases. Pelvic control was achieved in 114 patients and was equivalent in stage IB–II and III–IVA patients. So far, 60 patients have died. The 5-year OS and DFS rates were, respectively, 57.6% [95% CI: 49.1–67.5] and 65% [95% CI: 56.2–75]. OS was significantly affected by the type of surgery (p < 2.10⁻¹⁶), the presence of tumoural residue (p = 0.002) and the pelvic lymphatic status (p < 0.001). DFS was affected by the pelvic (p = 0.02) and para-aortic lymphatic status (p = 0.009). No significant difference was observed between OS and DFS in stage IB–II and III–IVA patients, whereas a macroscopic tumoural residue was observed in, respectively, 30.9 and 52.2% of cases (p = 0.022).

Conclusion

Survival rates were equivalent between patients with IB–II and III–IVA cervical cancer, suggesting that adjuvant surgery following chemoradiotherapy may improve local control.     

Lymph node ratio is an independent prognostic factor in patients with rectal cancer treated with preoperative chemoradiotherapy and curative resection

Purpose

To evaluate the prognostic effect of lymph node ratio (LNR) in patients with locally advanced rectal cancer who were treated with curative resection after preoperative chemoradiotherapy (CRT).

Methods

Between October 2001 and December 2007, 519 patients who had undergone curative resection of primary rectal cancer after preoperative CRT were enrolled. Of these, 154 patients were positive for lymph node (LN) metastasis and were divided into three groups according to the LNR (≤0.15 [n = 80], 0.16–0.3 [n = 44], >0.3 [n = 30]) to evaluate the prognostic effect on overall survival (OS) and disease-free survival (DFS).

Results

LNR (≤0.15, 0.16–0.3, and >0.3) was significantly associated with 5-year OS (90.3%, 75.1%, and 45.1%; p < 0.001) and DFS (66.7%, 55.8%, and 21.9%; p < 0.001) rates. In a multivariate analysis, LNR (≤0.15, 0.16–0.3, and >0.3) was a significant independent prognostic factor for OS (hazard ratios [HRs], 1, 3.609, and 8.197; p < 0.001) and DFS (HRs, 1, 1.699, and 3.960; p < 0.001). LNR had a prognostic impact on OS and DFS in patients with <12 harvested LNs, as well as in those with ≥12 harvested LNs (p < 0.05).

Conclusion

LNR was a significant independent prognostic predictor for OS and DFS in patients with locally advanced rectal cancer who were treated with curative resection after preoperative CRT.     

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

Objectives

Two phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed–cisplatin (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed–cisplatin without disease progression.

Methods

Overall survival (OS) and progression-free survival (PFS), analyzed by Kaplan–Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population.

Results

Outcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p = 0.117, HR = 1.16; median OS: 14.0 versus 14.2 months, p = 0.979, HR = 1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p < 0.00001, HR = 0.66; median OS: 16.9 versus 14.2 months, p = 0.003, HR = 0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1–44) following 4 cycles of pemetrexed–cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed–cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT.

Conclusions

The across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed–cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed–cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.     

Prognostic factors and assessment of staging systems for head and neck soft tissue sarcomas in adults

Objectives

The primary objectives of this study were to analyse the outcome of patients diagnosed with head and neck soft tissue sarcomas (HNSTS) and to identify relevant prognostic factors. As well as this, we compared the prognostic value of two staging systems proposed by the American Joint Committee on Cancer (AJCC) and the Memorial Sloan-Kettering Cancer Center (MSKCC).

Methods

From 07/1988 to 01/2008, the charts of 42 adult patients were retrospectively reviewed. Potential prognostic factors were analysed according to overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS).

Results

At 5 years, OS was 57%, DFS 47% and DSS 72%. On univariate analysis, statistically significant prognostic factors were for OS, distant or lymph node metastasis at diagnosis (p = 0.032), for DFS, margins after surgery (p = 0.007), for DSS, regional or distant metastasis at diagnosis (p = 0.002), initial AJCC and MSKCC stage (p = 0.018 and p = 0.048) and margins after surgery (p = 0.042). On multivariate analysis, margins remained statistically significant for DFS (p = 0.039) when there was a trend with the initial AJCC stage (p = 0.054) for OS. The AJCC staging system was of more prognostic value than the MSKCC staging system.

Conclusions

Achieving clear margins after surgery is vital for improved local control and the best chance of survival. Adjuvant chemotherapy and radiotherapy were not shown to provide additional benefit. To better identify prognostic factors, it seems essential to set up national and international databases allowing multicenter registration for those patients.     

Blood vessel invasion is a major feature and a factor of poor prognosis in sarcomatoid carcinoma of the lung

Objectives

Pulmonary sarcomatoid carcinomas (SC) are highly disseminated types of non-small-cell lung carcinoma. Their prognosis is poor. New therapeutic targets are needed to improve disease management.

Materials and methods

From 1995 to 2013, clinical and survival data from all consecutive patients with surgically treated SC were collected. Pathological and biomarker analyses were performed: TTF1, P63, c-MET and ALK expression (immunohistochemistry), PAS staining, ALK rearrangement (FISH), and EGFR, KRAS, HER2, BRAF, PIK3CA, and MET genes mutations (PCR).

Results

Seventy-seven patients were included. Median age was 61 years (53–69). Histological subtypes were pleomorphic carcinoma (78%), carcinosarcoma (12%), and giant-cell and/or spindle-cell carcinoma (10%). Blood vessel invasion (BVI) was present in 90% of cases. Morphology and immunohistochemistry were indicative of an adenocarcinoma, squamous, and adenosquamous origin in 41.5%, 17% and 11.5%, respectively, 30% remained not-otherwise-specified. KRAS, PIK3CA, EGFR, and MET mutations were found in 31%, 8%, 3%, and 3%, respectively. No tumors had HER2 or BRAF mutations, or ALK rearrangement, whereas 34% had a c-MET positive score. Five-year overall survival (OS) was 29% for the whole population. At multivariate analysis, tumor size <50 mm (HR = 1.96 [1.04–3.73], p = 0.011), no lymph-node metastasis (HR = 3.25 [1.68–6.31], p < 0.0001), no parietal pleural invasion (HR = 1.16 [1.06–1.28], p = 0.002), no BVI (HR = 1.22 [1.06–1.40], p = 0.005), and no squamous component (HR = 3.17 [1.48–6.79], p = 0.01) were associated with longer OS. Biomarkers did not influence OS.

Conclusion

Dedifferentiation in NSCLC could lead to SC and an epithelial subtype component could influence outcome. BVI was present in almost all SCs and was an independent factor of poor prognosis.     

Adjuvant extension of chemotherapy after neoadjuvant therapy may not improve outcome in early-stage breast cancer

Introduction

Neoadjuvant chemotherapy (NAC) is equivalent to adjuvant therapy (AdC) in terms of survival and disease-free interval. Many institutions add AdC after NAC and surgery. However, such extended chemotherapy (ExC) is not evidence based. Study aim was to investigate if ExC improved disease-free (DFS) and overall survival (OS).

Patients and Methods

From 1998 to 2006 356 consecutive patients received NAC (45 pts), AdC (221 pts) or ExC (90 pts). We analysed these 3 groups to determine effects of ExC and to identify patients who might benefit. NAC consisted in 93% of 3–6 cycles of epirubicin + docetaxel, AdC comprised EC ± taxanes in 72%. Median age in the NAC, AdC, and ExC-groups was 54, 56 and 52 years with follow-up of 30, 57, and 55 months.

Results

After NAC, 35% achieved downstaging and 10% pathologic complete remission. Surprisingly ExC seemed to result in reduction of 5-year DFS: compared to 85% and 82% after NAC and AdC, DFS was 61% after ExC (p = 0.001). OS was not significantly affected (79, 91, and 78% after NAC, AdC and ExC, p = 0.13). In multivariate analysis after correction for age, menopausal status, stage, grading, hormone receptors, her2-status, radiotherapy and surgery, ExC seemed to adversely affect DFS (HR 2.15, p = 0.008), loco-regional and distant recurrence-rates (HR 3.0, p = 0.03 and HR 2.0, p = 0.02).

Discussion

In this single-center analysis ExC could not show advantages in terms of DFS and OS. Because multivariate analyses of retrospective data cannot account for all potential biases, these data require confirmation in randomized clinical trials. Until then, extended chemotherapy should be considered carefully. As in previous studies, no differences were found between NAC and AdC groups.     

Evaluation and impact of residual disease in locally advanced cervical cancer after concurrent chemoradiation therapy: Results of a multicenter study

Background

The aim of this study was to evaluate the diagnosis and impact of residual disease (RD) after concurrent chemoradiation therapy (CRT) in locally advanced cervical cancer (FIGO IB2-IVA).

Methods

This retrospective multicenter study included 159 patients who were treated with completion surgery after CRT between 2006 and 2012. Magnetic resonance imaging (MRI) was performed 4–6 weeks after CRT and compared to pathological evidence of residual disease. Kaplan–Meier survival curves were plotted and univariate/multivariate analyses were performed to assess the association between RD and the outcome.

Results

Residual disease was present in 45.3% of the patients and detected by MRI in 57.1%. The MRI had a 29.2% false positive rate and an 11.1% false negative rate. The overall survival (OS) rates at 3 and 5 years were 78.6% (CI 95% [71%–86.9%]) and 76.5% (CI 95% [68.2%–85.7%]), respectively. The disease free survival (DFS) rates at 3 and 5 years were 73.4% (CI 95% [65.6%–82%]) and 71.1% (CI 95% [62.7%–80.1%]), respectively. RD greater than 10 mm decreased DFS (HR = 4.84, p = 0.03), whereas RD between 1 and 10 mm (HR = 0.31, p = 0.58) and less than 1 mm (HR = 0.37, p = 0.54) had no impact on DFS. The OS was not changed by RD.

Discussion

The MRI accuracy value is not sufficient to select patients who might benefit from completion surgery. Residual disease over 10 mm decreased DFS but did not impact OS.     

Influence of internal mammary node irradiation on long-term outcome and contralateral breast cancer incidence in node-negative breast cancer patients

Background and purpose

There is no general consensus concerning irradiation (RT) of internal mammary nodes (IMN) in axillary node-negative breast cancer. Based on a large series of patients treated in a single institute and followed up for a long period of time, we looked at the influence of IMN RT on late outcome of these patients as well as the development of contralateral breast cancer (CBC).

Patients and methods

The study was based on 1630 node-negative breast cancer patients treated in our institution between 1975 and 2008 with primary conservative surgery and axillary dissection or sentinel node examination. All patients received post-operative breast RT. IMN RT was more frequent in inner or central tumours. Kaplan–Meier (K–M) overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) according to IMN RT were calculated for all patients and for patients with inner/central tumours. The K–M rate of contralateral breast cancer (CBC) was also analysed and correlated with IMN RT.

Results

Prognostic variables such as tumour size, histological grade, and hormone receptors were not significantly different in the groups having received IMN RT or not. Considering all patients, OS was strictly comparable in the 2 groups: 10-year values were 85% (IMN RT) and 86% (no IMN RT), respective values at 20 years were 66.6% and 61.0% (p = 0.95). However, in patients presenting with inner/central tumours, OS was significantly improved in the IMN RT group with respective values of 92.5% and 87.2% at 10 years, and 80.2% and 63.3% at 20 years: Hazard ratio (HR) = 0.56 (0.37–0.85); p = 0.0052. Again, CSS was improved in patients with inner/central tumours having received IMN RT, with 20-year rates of 89.5% versus 79.1% in patients not receiving IMN RT (p = 0.047). No difference in DFS was noticed. The actuarial rate of CBC development was comparable between patients having received IMN RT and other patients. However, considering only patients alive 10 years after primary breast surgery, the K–M rate of CBC at 20 years was 5.3% in patients without IMN RT and 7.2% in patients with such RT; HR = 2.47 (1.23–4.95); p = 0.008.

Conclusions

IMN RT in node-negative tumours was associated with increase in OS and CSS in patients with inner or centrally located lesions. An increase in CBC development was also noticed in long-survivors of IMN RT patients; however, these findings have to be interpreted with caution because of the difference in follow-up between the 2 groups. Further studies are warranted to investigate the potential role of IMN irradiation in the development of CBC.     

The prognostic significance of extracapsular lymph node involvement in node positive patients with colonic cancer

Aims

In colonic cancer the prognostic significance of extracapsular lymph node involvement (LNI) is not established and is therefore the objective of this study.

Methods

Between January 1994 and May 2005, all patients who underwent resection for primary colonic cancer with lymph node metastasis were reviewed. All resected lymph nodes were re-examined to assess extracapsular LNI. In uni- and multivariate analysis disease-free survival (DFS) was correlated with various clinicopathologic factors.

Results

One hundred and eleven patients were included. In 58 patients extracapsular LNI was identified. Univariate analysis revealed that pN-stage (5-year DFS pN1 vs. pN2: 65% vs. 14%, p < 0.001), extracapsular LNI (5-year DFS intracapsular LNI vs. extracapsular LNI: 69% vs. 41%, p = 0.003), and lymph node ratio (5-year DFS <0.176 vs. ≥0.176: 67% vs. 42%, p = 0.023) were significant prognostic indicators. Among these variables pN-stage (hazard ratio 3.5, 95% confidence interval [CI]: 1.72–7.42) and extracapsular LNI (hazard ratio 1.98, 95% CI: 1.00–3.91) were independent prognostic factors. Among patients without extracapsular LNI, those receiving adjuvant chemotherapy had a significantly better survival (p = 0.010). In contrast, chemotherapy did not improve DFS in patients with extracapsular LNI.

Conclusion

Together with pN2 stage, extracapsular LNI reflects a particularly aggressive behaviour and has significant prognostic potential.     

EGFR mutations and clinical outcomes of chemotherapy for advanced non-small cell lung cancer: A meta-analysis

Background

This meta-analysis was performed to assess whether epidermal growth factor receptor (EGFR) mutation status was associated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy.

Method

We systematically identified eligible articles investigating the effects of chemotherapy in patients with NSCLC stratified by EGFR mutation status. The summary risk ratio (RR) for ORR and hazard ratios (HRs) for both PFS and OS were calculated using the inverse variance formula of meta-analysis.

Results

Identification for the current meta-analysis: 5 prospective studies (n = 875) and 18 retrospective studies (n = 1934) for ORR; 2 prospective studies (n = 434) and 10 retrospective studies (n = 947) for PFS; 2 prospective studies (n = 438) and 7 retrospective studies (n = 711) for OS. The ORR was significantly higher in patients with EGFR mutations in prospective studies (RR = 1.42; 95% confidence interval [CI], 1.16–1.74; P = 0.001), but not in retrospective studies (RR = 1.12; 95% CI, 0.96–1.32; P = 0.146). There was no obvious association between EGFR mutations and PFS both in prospective (HR = 0.84; 95% CI: 0.65–1.09; P = 0.197) and retrospective (HR = 1.02; 95% CI: 0.87–1.18; P = 0.838) studies. Association between EGFR mutations and OS was also not seen in prospective studies (HR = 0.74; 95% CI: 0.27–2.05; P = 0.566), but was seen in retrospective studies (HR = 0.48; 95% CI: 0.33–0.72; P < 0.001; I² = 75.9%; P < 0.001) with significant heterogeneity.

Conclusion

EGFR mutations in advanced NSCLC may be associated with higher ORRs to chemotherapy, but may have nothing to do with PFS and OS. Further prospective studies are required to identify the influence of EGFR mutations on chemotherapy effects in advanced NSCLC.     

Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer

Objectives

Retrospective subgroup analysis in JMDB study indicates that the between-arm differences in overall survival (OS) in the East Asian subgroup were consistent with those observed in the entire JMDB study population. This bridging study (JMIL) further evaluated the efficacy and safety of first-line pemetrexed/cisplatin (PC) versus gemcitabine/cisplatin (GC) in Chinese patients with nonsquamous non-small cell lung cancer (NSCLC). The primary endpoint of this local registration trial was designed to compare OS in the combined dataset, consisting of Chinese patients in JMIL and 1252 nonsquamous patients in JMDB.

Materials and methods

Chinese patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned (1:1) to 6 cycles maximum (21 days/cycle) of pemetrexed 500 mg/m² + cisplatin 75 mg/m² (day 1), or gemcitabine 1250 mg/m² (days 1 and 8) + cisplatin 75 mg/m² (day 1).

Results

In JMIL, 256 Chinese patients were randomized (PC, n = 126; GC, n = 130). Patient baseline characteristics were balanced between treatment arms. In the combined dataset, PC was superior to GC in prolonging OS, with adjusted hazard ratio (HR) of 0.87 (95% CI: 0.77–0.98, p = 0.023) and median OS of 11.76 versus 10.94 months. In the JMIL-only population, no significant OS difference observed between treatment arms (adjusted HR = 1.03 [95% CI: 0.77–1.39, p = 0.822]; unadjusted HR = 0.996 [95% CI: 0.74–1.33, p = 0.980]), nor for other secondary efficacy endpoints. Significantly fewer patients in the PC arm experienced drug-related grade 3/4 toxicities, 54 (43.2%) versus 71 (55.9%) for GC (p = 0.045), with significantly lower rates of leukocytopenia, thrombocytopenia, and fatigue.

Conclusion

This study showed that in the combined population, OS of PC was superior to GC, while in the Chinese-only population, no significant difference was observed; a better safety and risk/benefit profile was found in the PC arm. A PC regimen should be considered as a standard of care in Chinese nonsquamous NSCLC patients in a first-line setting.     

Prognostic value of sentinel node biopsy in 327 prospective melanoma patients from a single institution

Aim

To confirm the accuracy of sentinel node biopsy (SNB) procedure and its morbidity, and to investigate predictive factors for SN status and prognostic factors for disease-free survival (DFS) and disease-specific survival (DSS).

Materials and methods

Between October 1997 and December 2004, 327 consecutive patients in one centre with clinically node-negative primary skin melanoma underwent an SNB by the triple technique, i.e. lymphoscintigraphy, blue-dye and gamma-probe. Multivariate logistic regression analyses as well as the Kaplan–Meier were performed.

Results

Twenty-three percent of the patients had at least one metastatic SN, which was significantly associated with Breslow thickness (p < 0.001). The success rate of SNB was 99.1% and its morbidity was 7.6%. With a median follow-up of 33 months, the 5-year DFS/DSS were 43%/49% for patients with positive SN and 83.5%/87.4% for patients with negative SN, respectively. The false-negative rate of SNB was 8.6% and sensitivity 91.4%. On multivariate analysis, DFS was significantly worsened by Breslow thickness (RR = 5.6, p < 0.001), positive SN (RR = 5.0, p < 0.001) and male sex (RR = 2.9, p = 0.001). The presence of a metastatic SN (RR = 8.4, p < 0.001), male sex (RR = 6.1, p < 0.001), Breslow thickness (RR = 3.2, p = 0.013) and ulceration (RR = 2.6, p = 0.015) were significantly associated with a poorer DSS.

Conclusion

SNB is a reliable procedure with high sensitivity (91.4%) and low morbidity. Breslow thickness was the only statistically significant parameter predictive of SN status. DFS was worsened in decreasing order by Breslow thickness, metastatic SN and male gender. Similarly DSS was significantly worsened by a metastatic SN, male gender, Breslow thickness and ulceration. These data reinforce the SN status as a powerful staging procedure.     

Outcomes for a large series of radical cystectomies for bladder cancer

Aims

We present the characteristics and outcomes of a large Chinese series of patients treated with radical cystectomy and pelvic lymphadenectomy for invasive cancer of the bladder. Our aim is to determine the significant independent prognostic factors that determine this outcome.

Methods

The records of 356 patients with invasive bladder cancer, operated at three Chinese medical institutes between 1995 and 2004, were reviewed. Of the 356 patients, 324 (91.0%) were TCC, 24 (6.7%) were adenocarcinoma, eight (2.3%) were squamous carcinoma. The incidence of pelvic lymph node involvement was 22.8%. The mean (SD, range) follow-up of the 356 patients was 54.89 (31.66, 3–137) months. Multivariate analysis was used to assess the clinical and pathological variables affecting disease-free survival (DFS).

Results

The 1-, 2- and 5-year DFS rates were 87%, 75% and 48%, respectively. In multivariate analysis, tumor configuration (RR = 1.62, p = 0.012), multiplicity (RR = 1.41, p = 0.036), histological subtype (RR = 2.17, p < 0.001), tumor stage (RR = 2.50, p < 0.001), tumor grade (RR = 2.40, p < 0.001), node status (RR = 2.51, p < 0.001), neoadjuvant chemotherapy (RR = 0.46, p = 0.016) had independent significance for survival on multivariate analysis.

Conclusions

The results of this series show that radical cystectomy and pelvic lymphadenectomy provide durable local control and DFS in patients with invasive bladder cancer. Multivariates affect the prognosis after radical cystectomy for invasive bladder cancer. The treatment of invasive bladder cancer in China is still in need of improvement and normalization.     

The presence of extrathoracic metastasis is more prognostic of survival than Masaoka stage (IVa/IVb) in metastatic thymic epithelial tumor: A retrospective cohort study

Purpose

Our aim in this study was to identify independent prognostic factors for overall survival (OS) in order to explain the heterogeneity of OS in patients with metastatic thymic epithelial tumor (TET).

Methods

Sixty-one consecutive patients with histologic diagnosis of Masaoka stage IV TET between January 1980 and March 2009 were analyzed at a single institution. Masaoka stage IVa was defined as pleural or pericardial dissemination, and IVb as lymphogenous or hematogenous metastasis. Metastasis outside the thoracic cage was defined as extrathoracic metastasis. To identify prognostic factors, relationships between clinicopathologic factors and outcomes were analyzed.

Results

Of the 61 patients, 30 (49.2%) had thymoma, 28 (45.9%) had thymic carcinoma, and the remaining 3 (4.9%) had an unclear histologic subtype. The Masaoka stage was IVa in 27 patients (44.3%) and IVb in 34 patients (55.7%). Significant independent adverse prognostic factors for OS were histologic subtype and extrathoracic metastasis (hazard ratio [HR] = 3.09 and 6.03, 95% CI: 1.41–6.74 and 1.89–19.30, p = 0.005 and 0.002, respectively). The presence of extrathoracic metastasis was also an independent prognostic factor for decreased progression-free survival time (PFS) (HR = 6.62, 95% CI: 1.19–24.17, p = 0.004). The only significant criterion for prognostic discrimination was the presence of extrathoracic metastasis in metastatic TET.

Conclusions

Significant independent prognostic factors for lower OS were the histologic subtype of thymic carcinoma and the presence of extrathoracic metastasis. A new concept of extrathoracic metastasis might provide additional information for the understanding of metastatic TET.     

Prognostic role of hyponatremia in 564 small cell lung cancer patients treated with topotecan

Objectives

Hyponatremia is reported in about 15% of small cell lung cancer (SCLC). Variable results of the prognostic significance of low plasmatic sodium (Na_pl) have been reported. Our study was performed to investigate the prognostic role of hyponatremia in SCLC patients treated in second-line with topotecan chemotherapy.

Materials and methods

Data were retrospectively collected from a database including clinical data from 631 patients enrolled in 6 prospective topotecan iv studies. Final data were obtained from 564 patients in which data on baseline Na_pl were available. Univariate and multivariate analysis were carried out to study the possible correlation between Na_pl and second-line clinical outcomes.

Results

Hyponatremia (Na_pl < 135 mequiv./l) was present in 101 cases (17.9%). Na_pl was <125 mequiv./l in 16 patients (2.8%), 126–130 mequiv./l in 11 (2%), 130–134 mequiv./l in 74 (13.1%), while 463 patients (82.1%) showed normal values. The median survival was 28.7 weeks in patients with normal Na_pl, and 21.1 weeks in patients with hyponatremia (p < 0.0001, HR = 1.67, 95%CI = 1.32–2.10). By Cox multivariate analysis, hyponatremia was associated with poorer prognosis (p = 0.0024, HR = 1.44, 95%CI = 1.13–1.82). A not statistically significant trend of correlation between hyponatremia and progression-free survival (p = 0.085, HR = 1.23, 95%CI 0.97–1.55) and response rate (p = 0.5037, OR = 0.81, 95%CI 0.44–1.49) was observed.

Conclusion

Hyponatremia is an independent prognostic factor for patients with SCLC treated with topotecan in second-line setting. Further studies are needed to prospectically confirm these results and to develop an optimal therapy for hyponatremic patients.     

Elevated preoperative neutrophil to lymphocyte ratio predicts survival following hepatic resection for colorectal liver metastases

Background

The neutrophil–lymphocyte ratio (NLR) provides an indicator of inflammatory status. An elevated NLR has been shown to be a prognostic indicator in primary colorectal malignancy. The aim of this study was to establish whether NLR predicts outcome in patients undergoing resection for colorectal liver metastasis.

Design

Retrospective analysis of the white cell and differential counts for 440 patients undergoing liver resections for colorectal liver metastasis between January 1996 and January 2006. An NLR ≥ 5 was considered to be elevated.

Results

Two hundred and eighty-nine males and 151 females were included. Seventy-eight patients (18%) had an elevated NLR, 55 of whom died, giving elevated NLR a positive predictive value (PPV) for death of 71%. Sixty of the 78 patients had recurrent disease giving raised NLR an PPV for recurrence of 78%. The 5-year survival for patients undergoing resection with high NLR was significantly worse than that for patients with normal NLR (22% vs. 43%, p < 0.0001). Univariate analysis of factors affecting survival revealed raised NLR, number of metastases >8, tumour size >5 cm and age >70 significantly affected outcome. All factors except tumour size remained significant predictors of term survival on multivariate analysis (NLR:HR = 2.261, CI = 1.654–3.129, p < 0.0001, metastases >8:HR = 1.611, CI = 1.006–2.579, p = 0.047, age >70:HR = 1.418, CI = 1.049–1.930, p = 0.027). Elevated NLR was found to be the sole positive predictor of recurrence on univariate analysis (HR = 4.521, CI = 2.475–8.257, p < 0.0001).

Conclusion

Elevated NLR increases both risk of death and the risk of recurrence in patients who undergo surgery for CRLM. Preoperative NLR measurement may therefore provide a simple method of identifying patients with a poorer prognosis.     

Effect of NSAIDS and COX-2 inhibitors on the incidence and severity of asbestos-induced malignant mesothelioma: Evidence from an animal model and a human cohort

Objectives

Non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors have been associated with lower incidence rates of some cancers. Because asbestos can cause chronic inflammation at the pleural and peritoneal surfaces we hypothesised that NSAID and COX-2 inhibitors would inhibit the development of asbestos-induced mesothelioma.

Materials and methods

A murine model of asbestos-induced mesothelioma was used to test this hypothesis by providing the NSAID, aspirin, daily in the feed at 50 mg/kg or 250 mg/kg. In a parallel study, the relationship between the use of NSAID and COX-2 inhibitors and mesothelioma was investigated in a human cohort of 1738 asbestos exposed people living or working in Wittenoom, Western Australia (a crocidolite mine site).

Results

Aspirin did not alter the rate of disease development or increase the length of time that mice survived. Aspirin had a small but significant effect on disease latency (the time between asbestos exposure and first evidence of disease; p < 0.05) but disease progression was not affected by the continued presence of the drug. In the Wittenoom cohort, individuals who reported use of NSAIDs, COX-2 inhibitors or both did not have a lower incidence of mesothelioma (HR = 0.85; 95% CI = 0.53–1.37, p = 0.50), (HR = 0.69; 95% CI = 0.21–2.30, p = 0.55) and (HR = 0.43; 95% CI = 0.16–1.13, p = 0.087) respectively.

Conclusion

We conclude that NSAIDs and COX-2 inhibitors do not moderate mesothelioma development or progression in a human cohort exposed to asbestos and this result is confirmed in an autochthonous mouse model.     

Efficacy of epidermal growth factor receptor inhibitors versus chemotherapy as second-line treatment in advanced non-small-cell lung cancer with wild-type EGFR: A meta-analysis of randomized controlled clinical trials

Background

EGFR mutation status is closely related to the efficacy of EGFR-TKIs in advanced non-small cell lung cancer (NSCLC). EGFR-TKIs have become the standard first-line treatment for advanced EGFR-mutation NSCLC, while for EGFR wild-type tumors, the preferred first-line treatment is chemotherapy. However, the efficacy of EGFR-TKIs as second-line treatment in EGFR wild-type NSCLC remains controversial. We sought to evaluate the effectiveness of EGFR-TKI as second-line treatment in EGFR wild-type NSCLC.

Methods

Randomized controlled trials that compared EGFR-TKIs with chemotherapy in previously treated advanced NSCLC with wild-type EGFR were included. We performed a meta-analysis to evaluate the effectiveness of EGFR-TKIs compared with standard chemotherapy. The endpoints were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

Results

Six randomized controlled trials with a total of 990 patients with wild-type EGFR were included: 499 in the EGFR-TKIs group and 491 in the chemotherapy group. The results indicated that in the second-line treatment of EGFR wild-type advanced NSCLC, PFS was significantly inferior in the EGFR-TKIs group versus the chemotherapy group (HR = 1.37, 95% CI = 1.20–1.56, P < 0.00001). However, this significant difference did not translate into OS (HR = 1.02, 95% CI = 0.87–1.20, P = 0.81). ORR tended to favor chemotherapy but there was no significant difference compared with EGFR-TKI (RR = 1.77, 95% CI = 0.90–3.50, P = 0.10).

Conclusions

Chemotherapy improves PFS significantly but not OS, compared with EGFR-TKIs as a second-line treatment in advanced NSCLC with wild-type EGFR. Whether EGFR-TKIs should be used in EGFR wild-type patients should be considered carefully.     

Predictors of pulmonary toxicity in limited stage small cell lung cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70 Gy daily radiotherapy: CALGB 30904

Introduction

Standard therapy for limited stage small cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy followed by prophylactic cranial radiotherapy. Predictors of post chemoradiotherapy pulmonary toxicity in limited stage (LS) small cell lung cancer (SCLC) patients are not well defined. Current guidelines are derived from non-small cell lung cancer regimens, and do not account for the unique biology of this disease. Therefore, we analyzed patients on three consecutive CALGB LS-SCLC trials treated with concurrent chemotherapy and daily high dose radiotherapy (70 Gy) to determine patient and treatment related factors predicting for post-treatment pulmonary toxicity.

Methods

Patients treated on CALGB protocols 39808, 30002, 30206 investigating two cycles of chemotherapy followed by concurrent chemotherapy and 70 Gy daily thoracic radiation therapy were pooled. Patient, tumor, and treatment related factors were evaluated to determine predictors of grade 3–5 pulmonary toxicities after concurrent chemoradiotherapy.

Results

100 patients were included. No patient experienced grade 4–5 post-treatment pulmonary toxicity. Patients who experienced post-treatment pulmonary toxicity were more likely to be older (median age 69 vs 60, p = 0.09) and have smaller total lung volumes (2565 cc vs 3530 cc, p = 0.05).). Furthermore, exposure of larger volumes of lung to lower (median V5 = 70%, p = 0.09, median V10 = 63%, p = 0.07), intermediate (median V20 = 50, p = 0.04) and high (median V60 = 25%, p = 0.01) doses of radiation were all associated with post-treatment grade 3 pulmonary toxicity, as was a larger mean lung radiation dose (median 31 Gy) p = 0.019.

Conclusion

Post-treatment pulmonary toxicity following the completion of 2 cycles of chemotherapy followed by concurrent chemotherapy and high dose daily radiation therapy was uncommon. Care should be taken to minimize mean lung radiation exposure, as well as volumes of low, intermediate and high doses of radiation.     

Combined management of retroperitoneal sarcoma with dose intensification radiotherapy and resection: Long-term results of a prospective trial

Background

Late failure is a challenging problem following resection of retroperitoneal sarcoma (RPS). We investigated the effects of preoperative XRT plus dose escalation with early postoperative brachytherapy (BT) on long-term survival and recurrence in RPS.

Methods

From June 1996 to October 2000, eligible patients with resectable RPS were entered onto a phase II trial of preoperative XRT (45–50 Gray) plus postoperative BT (20–25 Gray). Kaplan Meier survival curves were constructed and compared by log rank analysis (SPSS 21.0).

Results

All 40 patients had preoperative XRT and total gross resection as part of the prospective trial, nineteen received BT (48%). Median follow-up was 106 months. For the entire cohort, OS at 5 and 10 years was 70% and 64%, respectively; RFS at 5 and 10 years was 69% and 63%. RFS was significantly reduced in high versus low grade RPS at 5 years (53% vs. 88%, p = 0.016), but not at 10 years (53% vs. 75%, p = 0.079). RFS and OS at 10 years were reduced in patients who presented with recurrent compared to primary disease (RFS 30% vs. 74%, p = 0.015; OS 36% vs. 76%, p = 0.036). At 10 years, neither RFS nor OS was improved in patients who received BT compared to those who did not (RFS 56% vs. 69%, p = 0.54; OS 52% vs.76%, p = 0.23).

Conclusions

In this prospective trial with mature follow-up, long-term OS and RFS in patients who underwent combined preoperative XRT plus resection of RPS compare favourably with those reported in retrospective institutional and population-based series. Postoperative BT was associated with unacceptable toxicity and did not contribute to disease control.

Condensed abstract

In a prospective trial with mature follow-up, preoperative radiation combined with complete resection of retroperitoneal sarcoma resulted in favourable long-term RFS and OS compared to historical controls. Dose escalation with postoperative brachytherapy was not associated with better disease control.