Class II versus Class III radical hysterectomy in early cervical cancer: An observational study in a tertiary center

Aims

The purpose of this observational study was to evaluate disease free survival (DFS), overall survival (OS), and local recurrence rate (LRR) in patients submitted to Class II RH compared with Class III RH in early FIGO stage cervical cancer (ECC).

Materials and methods

We investigated 127 patients with CC admitted to the National Cancer Institute of Milan from June 2001 to October 2011 treated with Class II RH, and compared them with 202 patients operated with Class III RH between March 1980 and March 2001. A total of 329 patients were collected.

Results

Median follow-up time was 91 months (IQ range:58–196). Five-year OS and DFS estimates were 89.5% (95%CI: 86.0–93.2%) and 85.6% (95%CI: 81.6–89.7%), respectively. Estimates of effect of surgical treatment (Class III RH versus Class II RH) on OS showed a HR of death = 3.38 (95%CI: 1.18–9.63, P = 0.0228), at univariable Cox analysis, and a HR = 3.08 (95%CI: 0.96–9.93; P = 0.0595) at multivariable analysis. For DFS, a HR of relapse = 2.51 (95%CI 1.10–5.72; P = 0.0290) comparing Class III vs Class II was found at multivariable analysis. Overall recurrence rate was 12.8%, whilst it was 16.3% for Class III and 7.1% for Class II respectively.

Conclusions

The present data suggest that the outcomes of Class II RH are comparable in terms of LRR and OS to those of Class III RH, according to literature data. The opportunity of extending the indication to all women with ECC needs further investigations. Clearer data are warranted by prospective controlled studies.     

Cross-validation analysis of the prognostic significance of mucin expression in patients with resected non-small cell lung cancer treated with adjuvant chemotherapy: Results from IALT,JBR.10 and ANITA

Introduction

CALGB 9633 was a randomized trial of observation versus adjuvant chemotherapy for patients with stage IB non-small cell lung cancer (NSCLC). In CALGB 9633, the presence of mucin in the primary tumor was associated with shorter disease-free survival (DFS; hazard ratio (HR) = 1.9, p = 0.002) and overall survival (OS; HR = 1.9, p = 0.004).

Methods

To validate these results, mucin staining was performed on primary tumor specimens from 780 patients treated on IALT, 351 on JBR.10 and 150 on ANITA. The histochemical technique using mucicarmine was performed. The prognostic value of mucin for DFS and OS was tested in a Cox model stratified by trial and adjusted for clinical and pathological factors. A pooled analysis of all 4 trials was performed for the predictive value of mucin for benefit from adjuvant chemotherapy.

Results

The cross-validation group had 48% squamous, 37% adenocarcinoma and 15% other NSCLC compared with 29%, 56%, and 15%, respectively in CALGB. Among 1262 patients with assessable results, mucin was positive in IALT 24%, JBR.10 30%, ANITA 22% compared with 45% in CALGB. Histology was the only significant covariate (p < 0.0001) in multivariate analysis with mucin seen more commonly in adenocarcinoma (56%) compared with squamous (5%) and other NSCLC (15%). Mucin was a borderline negative prognostic factor for DFS (HR = 1.2 [1.0–1.5], p = 0.06) but not significantly so for OS (HR = 1.1 [0.9–1.4], p = 0.25). Prognostic value did not vary according to histology: HR = 1.3 [1.0–1.6] in adenocarcinoma vs. 1.6 [1.2–2.2] for DFS in other histology (interaction p = 0.69). Mucin status was not predictive for benefit from adjuvant chemotherapy (test of interaction: DFS p = 0.27; OS p = 0.49).

Conclusions

Mucin was less frequent in the cross-validation group due to its higher percentage of squamous cell carcinomas. The negative impact of mucin was confirmed for DFS but not for OS. Mucin expression was not predictive of overall survival benefit from adjuvant chemotherapy.     

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.     

Evaluation of complete cytoreductive surgery and two intraperitoneal chemotherapy techniques in pseudomyxoma peritonei

Background

Pseudomyxoma peritonei (PMP) is a low-grade malignancy characterized by mucinous tumor on the peritoneal surface. Treatment involves cytoreductive surgery (CRS) to remove all macroscopic tumor and perioperative intraperitoneal chemotherapy (PIC) to eliminate remaining microscopic disease.

Patients and methods

Between 1994 and 2009, 93 patients were treated at the Norwegian Radium Hospital with complete CRS and PIC. PIC was administered as early postoperative intraperitoneal chemotherapy (EPIC) using mitomycin C (MMC) and 5-fluoruracil (n = 48) and as hyperthermic intraperitoneal chemotherapy (HIPEC) using MMC (n = 45). Patients were classified into three histopathological subgroups: Disseminated peritoneal adenomucinosis (n = 57), peritoneal mucinous carcinomatosis (n = 21) and an intermediate group (n = 15). Tumor distribution by peritoneal cancer index (PCI) was PCI ≤10 (n = 31), PCI 11–20 (n = 29), PCI ≥21 (n = 33).

Results

Recurrence was diagnosed in 38 patients and 25 patients died during follow-up. Estimated 10-year overall survival (OS) was 69% and 10-year disease-free survival (DFS) was 47%. Mean OS was 154 months (95% CI 131–171) and median OS was not reached (follow-up median 85 months (3–207)). Low-grade malignant histology (p = 0.001) and female gender (p = 0.045) were associated with improved OS. Almost equal OS and DFS were observed between patients treated with EPIC and HIPEC.

Conclusions

Patients treated for PMP with complete CRS and PIC achieved satisfactory long-term outcome. The most important prognostic factor was histopathological differentiation, but acceptable survival was observed even in patients with aggressive histology and extensive intraperitoneal tumor growth. Administration of EPIC and HIPEC was equally efficacious with respect to long-term outcome.     

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.     

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.     

Temporal trends from 1986 to 2008 in overall survival of small cell lung cancer patients

Objectives

An assessment of temporal trends in patient survival is important to determine the progress toward patient outcomes and to reveal where advancements must be made. This study assessed temporal changes spanning 22 years in demographics, clinical characteristics, and overall survival of small cell lung cancer (SCLC) patients.

Materials and methods

This analysis included 1032 SCLC patients spanning two time-periods from the H. Lee Moffitt Cancer Center and Research Institute: 1986–1999 (N = 410) and 2000–2008 (N = 622). Kaplan–Meier survival curves and log-rank statistics were used to assess survival rates across the two time-periods and multivariable Cox proportional hazards models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

The overall 5-year survival rate significantly increased from 8.3% for the 1986–1999 time-period to 11.0% (P < 0.001) for the 2000–2008 time-period, and the median survival time increased from 11.3 months (95% CI 10.5–12.7) to 15.2 months (95% CI 13.6–16.6). We also observed significant increases in stage-specific median survival times and survival rates across the two time-periods. A multivariable Cox proportional hazards model for the entire cohort revealed significant increased risk of death for patients diagnosed in 1986–1999 (HR = 1.29; 95% CI 1.11–1.49), patients diagnosed between 60 and 69 years of age (HR = 1.33; 95% CI 1.04–1.49) and over 70 years of age (HR = 1.63; 95% CI 1.26–2.11), men (HR = 1.33; 95% CI 1.16–1.53), patients with no first course treatment (HR = 2.17; 95% CI 1.57–3.00) and extensive stage SCLC (HR = 2.79; 95% CI 2.35–3.30).

Conclusion

This analysis demonstrated significant improvements in overall and stage-specific median survival times and survival rates of SCLC patients treated at the Moffitt Cancer Center from 1986 to 2008.     

Long-term outcomes following resection of retroperitoneal recurrence of colorectal cancer

Background

The role of curative-intent surgery for retroperitoneal recurrence (RPR) of colorectal cancer (CRC) remains controversial. We previously showed 0% mortality and acceptable morbidity in patients who underwent resection of RPR.¹ Here we examine long-term overall and disease-free survival (OS, DFS).

Methods

We identified patients who underwent resection for RPR of CRC between 01/1999 and 02/2010 from two prospective CRC databases.

Results

The study cohort was composed of 48 patients (26 women) whose median age was 60 (36–80) years. Eleven patients had previously undergone resection of a different focus of disease recurrence, and 8 patients had additional site(s) of distant metastatic disease at the time of RPR resection. Following surgery for RPR, 5 patients were left with gross residual disease, and 6 had microscopically positive margins. Median follow-up was 32 (3–127) months. At last follow-up, 13 patients had died of cancer and 1 of other causes. For the entire cohort of 48 patients, 5-year OS was 70% (median 80mo). In univariate analysis, OS was reduced in younger patients (p = 0.003) and in those with gross residual disease (p = 0.033). In patients who had grossly complete resection, 5-year DFS was 49% (median 38mo). Predictors of reduced DFS on multivariable analysis were young age and R1 resection.

Conclusion

OS and DFS after resection of RPR in well-selected patients were favorable. Patients with RPR of CRC should be considered for curative-intent surgery with careful discussion at multidisciplinary cancer conference.     

Impact of sentinel node tumor burden on outcome of invasive breast cancer patients

Background

The tumor status of the axillary lymph nodes is one of the most important prognostic factors in women with early breast cancer (BC). Sentinel lymph node (SLN) biopsy has become the standard staging procedure for patients with invasive BC, largely replacing axillary lymph nodes dissection (ALND). The exact impact on prognosis of SLN tumor burden is still object of controversy. The aim of this study was to correlate the tumor burden in the SLN with the outcome in a large cohort of women.

Patients and methods

1040 consecutive patients with clinical stage I–III invasive BC were prospectively collected on our Institutional BC database from January 2001 to January 2007. Patients were stratified into the following four groups based on the tumor burden of the SLN: macrometastases, tumor deposit ≥2 mm; micrometastases, tumor deposit ≥0.2 mm and <2 mm; isolated tumor cells (ITC), isolated tumor cells or tumor deposit <0.2 mm; negative, in case of patients with no evidence of tumor.

Results

At a median follow-up of 8.5 years, the tumor burden of SLN metastases resulted significant predictor of DFS (P < 0.0001) and OS (P = 0.042). Multivariate analysis showed that the tumor burden of SLN metastases and Ki 67 proliferative index maintained the statistical significance.

Conclusion

Patients with SLN micrometastases or ITC, do not seem to have a worse DFS or OS compared with SLN negative cases. There is a significant decrease in DFS and OS in patients with macrometastatic disease in the SLN.     

Adjuvant therapy options following curative treatment of hepatocellular carcinoma: A systematic review of randomized trials

Aims

Numerous postoperative therapies for preventing recurrence of hepatocellular carcinoma (HCC) have been reported, but their efficacy remains controversial and knowledge about adverse effects is limited. A systematic review of randomized controlled trials (RCTs) was performed to gain a comprehensive picture of the efficacy and risks of these therapies.

Methods

MEDLINE, EMBASE and the Cochrane Library were systematically searched through July 2011. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated.

Results

A total of 2989 patients from 28 RCTs involving 10 postoperative therapies were included. For interferon therapy, the estimated RR for the 2-year recurrence rate was 0.84 (95% CI 0.73–0.97, P = 0.02) and the overall survival (OS) was 1.15 (95% CI 1.07–1.22, P < 0.001). Postoperative therapy with the vitamin K2 analog did not lead to a significant reduction in the 1-year recurrence rate, with a pooled RR of 0.60 (95% CI 0.28–1.27, P = 0.18). However, it did slightly improve the 1-year OS, with a pooled RR of 1.03 (95% CI 1.00–1.05, P = 0.03). Transarterial chemotherapy with or without embolization, adoptive immunotherapy and heparanase inhibitor PI-88 therapy may delay tumor recurrence. The effects of acyclic retinoid, lipiodol-iodine-131 and tumor vaccine treatment were promising but require further study. All postoperative therapies except interferon administered intramuscularly were well tolerated by the majority of patients.

Conclusions

Use of adjuvant interferon is definitely associated with an increase in OS. Postoperative therapies involving acyclic retinoid, lipidol-iodine-131, or tumor vaccine may improve the OS of patients with HCC after curative treatment.     

Comparison of concomitant boost radiotherapy against concurrent chemoradiation in locally advanced oropharyngeal cancers: A phase III randomised trial

Purpose

To test the toxicity and efficacy of concomitant boost radiotherapy alone against concurrent chemoradiation (conventional fractionation) in locally advanced oropharyngeal cancer in our patient population.

Methods and materials

In this open-label, randomised trial, 216 patients with histologically proven Stage III–IVA oropharyngeal cancer were randomly assigned between June 2006 and December 2010 to receive either chemoradiation (CRT) to a dose of 66 Gy in 33 fractions over 6.5 weeks with concurrent cisplatin (100 mg/m² on days 1, 22 and 43) or accelerated radiotherapy with concomitant boost (CBRT) to a dose of 67.5 Gy in 40 fractions over 5 weeks. The compliance, toxicity and quality of life were investigated. Disease-free survival (DFS) and overall survival (OS) curves were estimated with the Kaplan–Meier method and compared using log rank test.

Results

The compliance to radiotherapy was superior in concomitant boost with lesser treatment interruptions (p = 0.004). Expected acute toxicities were significantly higher in CRT, except for grade 3/4 mucositis which was seen more in CBRT arm (39% and 55% in CRT and CBRT, respectively; p = 0.02). Late toxicities like Grade 3 xerostomia were significantly high in CRT arm than CBRT arm (33% versus 18%; p < 0.0001). The quality of life was significantly poor in CRT arm at all follow up visits (p < 0.0001). The rates of 2 year disease-free survival were similar with 56% in the chemoradiotherapy group and 61% in CBRT group (p = 0.2; HR-0.81, 95%CI-0.53–1.2). Subgroup analysis revealed that patients with nodal size >2 cm had significantly better DFS with CRT (p = 0.05; HR-1.59, 95%CI-0.93–2.7).

Conclusion

In selected patients of locally advanced oropharyngeal cancer, concomitant boost offers a better compliance, toxicity profile and quality of life with similar disease control, than chemoradiation.     

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.     

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.     

Diffusion-weighted magnetic resonance for prediction of response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: Preliminary results of a monoinstitutional prospective study

Purpose

To evaluate diffusion-weighted imaging (DWI) for assessment of treatment response in locally advanced rectal cancer (LARC) 8 weeks after neoadjuvant chemoradiotherapy (CRT).

Methods and materials

A total of 28 patients with LARC underwent magnetic resonance imaging (MRI) prior to and 8 weeks after CRT. Tumor volume (TV) was calculated on T2-weighted MRI scans as well as the apparent diffusion coefficient (ADC) was calculated using Echo-planar DWI-sequences. All data were correlated to surgical results and histopathologic tumor regression grade (TRG), according to Mandard's classification. Post-treatment difference ADC (%ΔADC) and TV (%ΔTV) changes at 8 weeks were compared complete response (CR; TRG1) and non-complete response tumors (non-CR; TRG2–5).

Results

The mean % ADC increase of CR group was significantly higher compared to non-CR group (77.2 ± 54.63% vs. 36.0 ± 29.44%; p = 0.05). Conversely, the mean % TV reduction did not significantly differ in CR group from non-CR group (73.7% vs. 63.77%; p = 0.21). Accordingly, the diagnostic accuracy of the mean % ADC increase to discriminate CR from non-CR group was significantly higher than that of the mean % TV reduction (0.913 vs. 0.658; p = 0.022). No correlation was found between mean % TV reduction and TRG (rho = 0.22; p = 0.3037), whereas a negative correlation between mean % ADC increase and TRG was recorded (r = −0.69; p = 0.006).

Conclusion

The mean % ADC increase appears to be a reliable tool to differentiate CR from non-CR after CRT in patients with LARC.     

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.     

Sentinel node status predicts survival in thick melanomas: The Oxford perspective

Aims

To determine the prognostic value of SLNB in patients with thick melanoma in terms of overall survival (OS) and recurrence-free survival (RFS).

Methods

136 patients with primary tumours (Breslow thickness ≥4.0 mm) underwent SLNB. OS and RFS were calculated and a multivariate Cox regression model used to determine the important prognostic factors for predicting OS and RFS.

Results

Median Breslow thickness was 5.5 mm and 60% were ulcerated. Median follow up was 4 years (95% CI = 4–5) with 54 patients having died at the time of analysis. 5-year OS for SLNB positive patients was 32%, compared to 78% for negative patients. The significant predictors of poorer OS were increasing age (p = 0.03), increasing Breslow thickness (p = 0.03) and SLNB positivity (p < 0.0001). 5 year RFS was significantly worse in the SLNB positive population compared to the negative patients (p < 0.0001); 27% versus 66% respectively.

Conclusions

Patients with a thick melanoma and a positive SLNB have a significantly worse RFS and OS compared to those with a negative SLNB. Over three-quarters of patients with a negative SLNB survived five years. These findings have implications for the subpopulations included in adjuvant therapy trials and we advocate SLNB be recommended in patients with thick melanomas.     

High preoparative levels of serum periostin are associated with poor prognosis in patients with hepatocellular carcinoma after hepatectomy

Aims

Periostin (POSTN) is implicated in cancer development and progression. The aim of this study was to evaluate the diagnostic and prognostic significance of serum POSTN in patients with hepatocellular carcinoma (HCC) receiving curative surgery.

Methods

Enzyme-linked immunosorbent assay was performed to determine serum POSTN levels in 69 healthy volunteers, 30 patients with hepatolithiasis, 27 patients with cirrhosis, and 56 HCC patients. The relationships between serum POSTN and clinicopathologic features were analyzed. Receiver operating characteristics analysis was used to calculate diagnostic accuracy of serum POSTN, serum alpha-fetoprotein (AFP), and their combination. The prognostic impact of serum POSTN on overall survival (OS) and relapse-free survival (RFS) was also investigated.

Results

The median serum POSTN level was significantly (P < 0.05) increased in HCC patients, compared to healthy controls, patients with hepatolithiasis, and patients with liver cirrhosis. Elevated serum POSTN was only significantly associated with Edmondson grade (P = 0.007). The combination of serum POSTN and AFP had a markedly higher area under the curve (0.805 (95% confidence interval [CI]: 0.677–0.932)) than POSTN (0.582 (95% CI: 0.427–0.736)) or AFP (0.655 (95% CI: 0.504–0.806)) alone. Kaplan–Meier analysis indicated that elevated serum POSTN was associated with OS (P = 0.031) and RFS (P = 0.027). Moreover, multivariate analysis revealed elevated serum POSTN as an independent poor prognostic marker for OS and RFS.

Conclusions

Preoperative serum POSTN has limited diagnostic value in distinguishing HCC from non-malignant liver diseases, but serves as independent prognostic biomarker in HCC patients.     

Impact of hepatectomy margin on survival following resection of colorectal metastasis: The role of adjuvant therapy and its effects

Introduction

The optimal width of microscopic margin and the use of adjuvant therapy after a positive margin for hepatic resection for colorectal liver metastasis (CRCLM) has not been conclusively determined. The aim of the current study is to evaluate the influence of width of surgical margin and adjunctive therapy upon disease free and overall survival.

Methods

All patients undergoing hepatectomy for CRCLM from 1997 to 2012 were identified from a prospectively maintained, IRB approved database. Patients were divided into four subgroups based on the parenchymal margin: positive, <0.1 cm, 0.1 cm–1 cm, and >1 cm.

Results

A total of 373 patients were included for analysis with a median follow up of 26 months (range 9–103 months) and a median overall survival of 53 months. The resection margin was positive (26 patients median OS 24 months), <0.1 cm (48 patients median OS 36 mon), 0.1 cm–1 cm (82 patients median OS 44 months), and >1 cm (217 patients median OS 64 months). The most common adjunctive therapy was chemotherapy, hepatic arterial therapy, or local. Patients with positive margins also had the shortest disease free survival (DFS), 16 months. The DFS was similar amongst the other margin groups (<0.1 cm: 21 months, 0.1–1 cm: 22 months, >1 cm 25 months). Hepatectomy margin independently influenced survival (p = 0.017) and disease free survival (p = 0.034). Patients with negative margins has similar overall recurrence rates (p = 0.36) and survival rates (p = 0.89).

Conclusions

A positive surgical margin indicates a worse overall biology of disease for patients undergoing hepatectomy for CRCLM, and appropriate multi-disciplinary therapy should be considered in this high risk patient population. Marginal width if a complete resection has been achieved does not adversely effect overall surgical in patients with CRCLM.     

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.