Preliminary experience with gemcitabine and cisplatin adjuvant chemotherapy after liver transplantation for hepatocellular carcinoma

Aim

Liver transplantation (LT) criteria for treatment of hepatocellular carcinoma (HCC) were refined to improved survival and disease-free rates. Adjuvant chemotherapy might eliminate disseminated tumor cells after removal of the primary liver cancer and thereby benefit LT recipients. Our purpose was to evaluate the effect of an adjuvant chemotherapy (gemcitabine and cisplatin) on outcome of patients treated with LT for HCC.

Methods

Of the 99 patients who underwent liver transplantation from October 2001 through February 2006, there were 58 with HCC. Nine patients with extra-hepatic metastasis and four who died for noncancer-related reasons were excluded. Three groups (total n = 45) were compared: Group A (n = 15) met the Milan criteria and did not receive study chemotherapy, Group B (n = 13) did not fit the Milan criteria and did not receive chemotherapy, and Group C (n = 17) did not fit the Milan criteria and received gemcitabine and cisplatin.

Results

The chemotherapy regimen was well tolerated. Leukopenia, the need for granulocyte colony-stimulating factor treatment, or both occurred in four patients. The disease-specific survival rates were better for groups A and C than for group B (p = 0.02) and the disease-free survival rates were also better for groups A and C than for group B (p = 0.01).

Conclusions

Systemic gemcitabine and cisplatin may improve disease-specific and disease-free survival in HCC patients who do not meet the Milan criteria after LT.     

Treatment adherence in concurrent chemoradiation in patients with locally advanced non-small cell lung carcinoma: Results of daily intravenous prehydration

Purpose

To test the hypothesis that daily intravenous pre-hydration decreases renal toxicity and improves chemotherapy adherence in patients receiving daily cisplatin to concurrent radiotherapy for locally advanced non-small cell lung cancer (NSCLC).

Patients and methods

Patients with locally advanced NSCLC were treated between 2008 and August 2012 with daily 6 mg/m² cisplatin as a bolus injection in 10 ml; of saline and 66 Gy/24 fr radiotherapy in 32 days. Since January 2011, the administration of cisplatin was routinely preceded by intravenous pre-hydration with 1 L of natriumchloride 0.9%. Patients were divided in a pre-hydrated (PH) and non-pre-hydrated (NPH) cohort. Serum-creatinine and glomerular filtration rate (GFR) were assessed twice weekly during treatment. Retrospectively, baseline data, toxicity, treatment adherence and efficacy data were compared.

Results

Of the 356 patients 232 NPH patients and 100 PH patients were eligible. Patient-and treatment characteristics compared equally. The median of the maximum decrease in GFR was 24% and 8% for NPH and PH (p < 0.01), respectively. Sixty-nine percent of the patients in the NPH group completed the 24 administrations of cisplatin, as compared to 83% of the PH group (p < 0.01). Nineteen percent vs. 2% of the patients in the NPH and PH group discontinued cisplatin treatment because of renal toxicity. Surprisingly, the incidence of acute esophageal toxicity grade ?2 decreased following prehydration: 62% vs. 34% (p < 0.001) for the NPH and PH groups, respectively. The one-year survival was comparable between groups (75% for NPH and 71% for PH).

Conclusion

Daily pre-hydration was associated with a reduced rate of both renal and acute esophageal toxicity and an increased chemotherapy adherence in patients receiving daily dose of cisplatin and concurrent radiotherapy for locally advanced NSCLC.     

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer

Objectives

Four randomized phase II/III trials investigated the addition of cetuximab to platinum-based, first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis was performed to examine the benefit/risk ratio for the addition of cetuximab to chemotherapy.

Materials and methods

The meta-analysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients comprising respectively the combined intention-to-treat and safety populations of the four trials. The effect of adding cetuximab to chemotherapy was measured by hazard ratios (HRs) obtained using a Cox proportional hazards model and odds ratios calculated by logistic regression. Survival rates at 1 year were calculated. All applied models were stratified by trial. Tests on heterogeneity of treatment effects across the trials and sensitivity analyses were performed for all endpoints.

Results

The meta-analysis demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival (HR 0.88, p = 0.009, median 10.3 vs 9.4 months), progression-free survival (HR 0.90, p = 0.045, median 4.7 vs 4.5 months) and response (odds ratio 1.46, p < 0.001, overall response rate 32.2% vs 24.4%) compared with chemotherapy alone. The safety profile of chemotherapy plus cetuximab in the meta-analysis population was confirmed as manageable. Neither trials nor patient subgroups defined by key baseline characteristics showed significant heterogeneity for any endpoint.

Conclusion

The addition of cetuximab to platinum-based, first-line chemotherapy for advanced NSCLC significantly improved outcome for all efficacy endpoints with an acceptable safety profile, indicating a favorable benefit/risk ratio.     

Clinical significance of the neutrophil–lymphocyte ratio in venous thromboembolism patients with lung cancer

Background

The neutrophil–lymphocyte ratio (NLR) has been identified as a potentially useful marker for predicting clinical outcome in patients with cardiovascular disease, diabetes, and various malignancies. The aim of this study was to determine whether NLR at the time of venous thromboembolism (VTE) diagnosis is a prognostic factor for the response to anticoagulation and survival in lung cancer patients treated with anticoagulation for VTE.

Patients and methods

We retrospectively analyzed the clinical characteristics, laboratory parameters, and NLR in 114 lung cancer patients newly diagnosed with VTE, among 991 patients pathologically confirmed for lung cancer between July 2008 and August 2013.

Results

High NLR was significantly associated with high hematocrit (p = 0.028), high C-reactive protein (p = 0.002), and low albumin (p = 0.001). Compared with the low NLR group, stage IV non-small cell lung cancer (NSCLC) at the time of VTE diagnosis (55.6 vs. 74.6%, p = 0.055), central nervous system metastasis (5.8 vs. 25.8%, p = 0.004), and cancer progression (14.3 vs. 38.8%, p = 0.008) at the time of VTE diagnosis were also significant in the high NLR group. Moreover, the poor response to anticoagulation was statistically correlated with patients with NSCLC (p = 0.037), high NLR (p = 0.004), and low albumin (p = 0.029).

Conclusions

The results demonstrate that the NLR at the time of VTE diagnosis could be a useful biomarker for predicting the response and prognosis following anticoagulation in patients with lung cancer and VTE.     

Heat shock protein 70 as a predictive marker for platinum-based adjuvant chemotherapy in patients with resected non-small cell lung cancer

Objectives

Although adjuvant platinum-based chemotherapy improves survival in completely resected non-small cell lung cancer (NSCLC), its effect is limited. We evaluated whether the expression of heat shock protein 70 (Hsp70) is associated with clinical outcomes in patients with completely resected NSCLC who were treated with or without adjuvant platinum-based chemotherapy.

Patients and methods

Patients who underwent curative resection for NSCLC and diagnosed as stage IIA through IIIA were included. Immunohistochemical staining for Hsp70 was performed on surgical specimens and survival rates were compared by Hsp70 expression and adjuvant platinum-based chemotherapy.

Results

Of 327 enrolled patients, Hsp70 expression was positive in 220 (67.3%). For patients who did not receive adjuvant chemotherapy, Hsp70 expression did not significantly affect survival. However, for patients who received adjuvant chemotherapy, those with Hsp70-positive tumors had a longer disease-free survival outcome than cases with Hsp70-negative tumors (not reached vs. 27.3 months; P = 0.002), although there was no significant difference in overall survival (97.0 vs. 58.9 months, P = 0.080). In the adjuvant chemotherapy group, multivariate modeling showed that patients with Hsp70-postitive tumors had a lower risk of recurrence and death after adjusting for age, sex, performance status, pathologic stage, and histological type (disease-free survival: adjusted hazard ratio, 0.537; 95% CI, 0.362–0.796; P = 0.002; overall survival: adjusted hazard ratio, 0.663; 95% CI, 0.419–1.051; P = 0.080).

Conclusion

Hsp70 is a positive predictive factor in completely resected NSCLC with received platinum-based adjuvant chemotherapy.     

Temporal changes in the efficacy of chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck: A systematic review and meta-analysis

Background

Cytotoxic chemotherapy remains a standard treatment option for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN), but its effectiveness is debatable. We hypothesized palliative chemotherapy efficacy has decreased due to intensification of primary treatment, and investigated this by examining time trends of objective response rates (ORRs) in published reports of randomized trials (RCTs).

Methods

RCTs with at least one arm studying chemotherapy alone in RMSCCHN patients and reporting ORR were identified and data extracted. Eligible regimens had at least 6 trial arms reporting ORR over 20 years. Weighted linear regressions of ORR by year of publication for eligible regimens were done, and predictors of ORR and survival were examined.

Results

Three regimens were eligible for analysis: low dose methotrexate, single agent cisplatin, and cisplatin plus infusional 5-fluorouracil (PF). Linear regression showed decreasing ORRs over time for all three regimens studied: 23.5 to 9.8% (1980–2010) for methotrexate (p = 0.06), 19.6 to 8.8% (1980–2010) for cisplatin (p = 0.0013), and 37.6 to 27.9% (1990–2010) for PF (p = 0.11). Trial sample size, oropharynx cancer primary site, use of PF, and prior treatment increased over time. Use of PF and year of publication were the strongest predictors of ORR.

Conclusions

These data confirm the limited effectiveness of currently available palliative chemotherapy regimens for RMSCCHN patients. Novel therapeutics offering improvements in quality and quantity of life are urgently needed for these patients. Based on these results, the study of such agents as first-line therapy in RMSCCHN patients is entirely justifiable.     

Aprepitant in patients with advanced non-small-cell lung cancer receiving carboplatin-based chemotherapy

Objectives

Chemotherapy-induced nausea and vomiting (CINV) is an unanswered problem in cancer therapy. We evaluated the efficacy and safety of triple antiemetic therapy with aprepitant, a 5-hydroxytryptamine-3 (5-HT₃) receptor antagonist, and dexamethasone in patients with advanced non-small-cell lung cancer (NSCLC) who received carboplatin-based first-line chemotherapy.

Methods

Chemotherapy-naïve patients with NSCLC were enrolled in this randomized phase-II study. Patients were randomized to standard antiemetic therapy with a 5-HT₃ receptor antagonist and dexamethasone, and aprepitant add-on triple antiemetic therapy. The primary endpoint was the complete response rate (no vomiting and no rescue therapy) during the 120 h post-chemotherapy.

Results

A total of 134 patients were assigned randomly to the aprepitant group or the control group. The aprepitant group and the control group showed an overall complete response rate of 80.3% (95% confidence interval (CI), 69.2–88.1%) and 67.2% (95% CI, 55.3–77.2%; odds ratio (OR), 0.50; 95% CI, 0.22–1.10; p = 0.085), respectively. Among patients taking carboplatin and pemetrexed, adding aprepitant significantly improved the complete response rate in the overall phase (83.8% in the aprepitant group and 56.8% in the control group; OR, 0.26; 95% CI, 0.08–0.70; p < 0.01) and the delayed phase (86.5% in the aprepitant group and 59.1% in the control group; OR, 0.23; 95% CI, 0.07–0.65; p < 0.01).

Conclusion

Carboplatin-based chemotherapy has considerable emetic potential. Triple antiemetic therapy with aprepitant, a 5-HT₃ receptor antagonist, and dexamethasone improved the control of CINV prevention in patients receiving carboplatin and pemetrexed chemotherapy.     

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.     

Peritoneal carcinomatosis and liver metastases from colorectal cancer treated with cytoreductive surgery perioperative intraperitoneal chemotherapy and liver resection

Background

An aggressive therapy comprising of cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) and liver resection/ablation is generally not offered to patients with both colorectal peritoneal carcinomatosis (CRPC) and liver metastases (LM) as it no longer represents a loco-regional disease. We review the outcomes of patients who underwent an aggressive treatment with a curative intent for both CRPC and LM as a prelude towards determining the suitability of this treatment.

Methods

Patients with CRPC were treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy in our institution. Patients with LM underwent additional treatment of liver resection/ablation. The characteristics and survival of patients with isolated CRPC and those with both CRPC and LM were compared.

Results

Fifty-five patients underwent complete cytoreductive surgery for treatment of CRPC, amongst which 16 patients had LM. The overall median survival was 36 months. Fourteen of the 16 patients treated for CRPC and LM underwent synchronous treatment. When patients with CRPC alone or CRPC with LM were compared, patients with CRPC and LM had a lower PCI (p = 0.03), received less HIPEC infusion (p < 0.001), received less of both HIPEC and EPIC infusion (p = 0.007), had a shorter procedural duration (p = 0.001) and required less blood transfusion (p = 0.02). There was no difference in survival between patients who had CRPC alone or CRPC with LM who underwent aggressive treatment (p = 0.77).

Conclusions

A curative procedure may be offered to selected patients with CRPC and LM, especially in those with a low peritoneal cancer index.     

Platinum rechallenge in patients with advanced NSCLC: A pooled analysis

Introduction

The sole agents pemetrexed (PEM), docetaxel and anti-EGFR agents are approved second-line therapies for non-small cell lung cancer (NSCLC) after failure with cisplatin-based doublets. The potential usefulness of platinum-based doublets as rechallenge for second-line chemotherapy has not yet been established.

Methods

Studies that enrolled NSCLC platinum pre-treated patients were identified using electronic databases (MEDLINE and EMBASE). Pemetrexed and taxanes (TAXs)-based platinum combinations were considered. A systematic review was conducted using Comprehensive Meta-Analysis (version 2.2.064) software to calculate the event rate of response and 95% confidence interval. Median weighted progression-free survival (PFS) and overall survival (OS) time for PEM and TAXs-based doublets were compared by two-sided Student's t test. We tested for significant heterogeneity by Cochran's chi-square test and I² index.

Results

Eleven studies published between 1999 and 2012 were included in this analysis with a total of 607 patients enrolled; 468 were treated with PEM-doublets and 139 with TAXs-doublets. The overall response rate was 27.5% with a higher response rate of 37.8% (range, 29.7–46.7%) for TAXs-based treatment vs. 22% (range, 13.4–34.1%) for PEM-based combinations; (p < 0.0001). Median PFS and OS were 3.9 and 8.7 months with weighted PFS of 3.9 vs. 5.3 months (p < 0.0001) and similar OS for PEM vs. TAXs-based doublets.

Conclusions

With the limitations of small and not randomised trials included, this pooled analysis shows that NSCLC patients who relapsed after a first-line platinum-based chemotherapy obtain a tumour response of 27% from a platinum rechallenge containing PEM or TAXs. Response rate and median PFS appear better with TAXs-than with PEM-doublets.     

A phase II study of erlotinib in combination with bevacizumab versus chemotherapy plus bevacizumab in the first-line treatment of advanced non-squamous non-small cell lung cancer

Background

Molecularly targeted agents for non-small cell lung cancer (NSCLC) can provide similar efficacy to chemotherapy without chemotherapy-associated toxicities. Combining two agents with different modes of action could further increase the efficacy of these therapies. The TASK study evaluated the efficacy and safety of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with the anti-angiogenic agent bevacizumab as first-line therapy in unselected, advanced non-squamous NSCLC patients.

Methods

Patients were recruited from December 2007 to September 2008. Planned sample size was 200 patients, a total of 124 patients were randomized. Patients were randomized using a minimization algorithm 1:1 to receive bevacizumab (iv 15 mg/kg day 1 of each 21-day cycle) plus chemotherapy (gemcitabine/cisplatin or carboplatin/paclitaxel standard doses, 4–6 cycles) (BC arm) or bevacizumab plus erlotinib (p.o. 150 mg/day; BE arm) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). If the hazard ratio (HR) of PFS for BE relative to BC was above 1.25 at the pre-planned interim analysis in favor of BC, the study would be re-evaluated. Secondary endpoints included overall survival, response rate and safety.

Results

All randomized patients (n = 63 BE; n = 61 BC) were evaluated for the efficacy analyses. At the updated interim analysis, median PFS was 18.4 weeks (95% confidence interval [CI] 17.0–25.1) versus 25.0 weeks (95% CI 20.6–[not reached]) for BE versus BC, respectively (HR for death or disease progression, BE relative to BC, 2.05, p = 0.0183). The incidence of death was 19% for BE treatment compared with 11.5% for BC treatment. The HR for PFS at the updated interim analysis was above 1.25, therefore patients on the BE arm were permitted to change arms or switch to another drug and the study was terminated. Adverse events reported were as expected.

Conclusions

The TASK study did not show a benefit in terms of PFS for the combination of erlotinib with bevacizumab in unselected first-line advanced non-squamous NSCLC compared with chemotherapy plus bevacizumab.     

Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer

Background

Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens.

Methods

We identified paraffin-embedded NSCLC tissue blocks of known tissue platinum concentrations from 30 patients who underwent neoadjuvant platinum-based chemotherapy at MD Anderson Cancer Center. Expression of CTR1 in tumors and normal adjacent lung specimens was determined by immunohistochemistry with adequate controls.

Results

Tissue platinum concentration significantly correlated with tumor response in 30 patients who received neoadjuvant platinum-based chemotherapy (P < 0.001). CTR1 was differentially expressed in NSCLC tumors. A subset of patients with undetectable CTR1 expression in their tumors had reduced platinum concentrations (P = 0.058) and tumor response (P = 0.016) compared to those with any level of CTR1 expression. We also observed that African Americans had significantly reduced CTR1 expression scores (P = 0.001), tissue platinum concentrations (P = 0.009) and tumor shrinkage (P = 0.016) compared to Caucasians.

Conclusions

To our best knowledge this is the first study investigating the function of CTR1 in clinical specimens. CTR1 expression may be necessary for therapeutic efficacy of platinum drugs, consistent with previous preclinical studies. A prospective clinical trial is necessary to develop CTR1 into a potential biomarker for platinum drugs.     

The clinical significance of cytology versus histology-based diagnosis in small cell lung cancer: A retrospective study

Objectives

The aim of this study was to investigate the clinical significance of cytology versus histology-based diagnosis among patients diagnosed with small cell lung cancer (SCLC).

Materials and methods

Retrospective analysis of medical records of 443 patients with histologically or cytologically confirmed small cell lung carcinoma (SCLC) was performed. All patients received platinum-based chemotherapy regimens. Survival data (overall survival) were compared between patients with histology or cytology-based diagnosis in the overall study population as well as after stratification of patients according to disease stage (limited or extensive) at the time of diagnosis.

Results

Distribution of demographics and clinicopathological characteristics among the two groups (“histology” and “cytology”) was similar. No statistically significant differences in the survival curves between the “histology” and “cytology” groups were found in the overall study population (log rank test, p = 0.237), as well as in the subgroup of patients with limited disease (log rank test, p = 0.474). In contrast, patients with histology-based diagnosis had a statistically significant longer survival as compared to those with cytology-based diagnosis in the extensive disease subgroup (log rank test, p = 0.031), but this association was not retained after adjusting the analysis for demographics and clinical characteristics via a Cox regression model (HR = 1.18, 95% CI: 0.96–1.44, p = 0.110).

Conclusion

The results of our study suggest that the type of diagnostic modality employed (histology or cytology-based) for the establishment of a diagnosis of SCLC may not have a significant effect on the overall survival of patients. Further studies are warranted to further investigate this important, yet rather unexplored, issue.     

Association between polymorphisms of DNA repair genes and survival of advanced NSCLC patients treated with platinum-based chemotherapy

Background

Single nucleotide polymorphism (SNP) in DNA repair genes can be used to explain the differences in survival of platinum-treated non-small cell lung cancer (NSCLC) patients regardless of their performance status. To define the role of DNA repair gene SNPs in NSCLC patients, we investigated the association between survival and 12 different SNPs of 9 DNA repair genes.

Methods

340 patients were treated with platinum-based chemotherapy. Polymorphisms were detected by real time PCR with TaqMan probe, using genomic DNA extracted from peripheral blood samples. Multivariate logistic or Cox regression analyses were used to adjust for possible confounding variables.

Results

The median overall survival time was 15 months and it was significantly longer in patients harboring ERCC1 118 C/T or T/T allele: 18 months as compared to 13.8 months for the C/C allele (P = 0.014). Subgroup analysis revealed that ERCC1 118 C/T or T/T was associated with increased survival in elderly patients (P = 0.018), male (P = 0.022), squamous carcinoma (P = 0.003), smoker (P = 0.076) and those treated with non-gemcitabine/cisplatin or carboplatin (non-GP/GC) regimen (P = 0.023). XRCC3C/C was associated with better survival in non-gemcitabine/cisplatin treated patients (P = 0.014). Both of CCNH-V270A C/C or C/T and XPD 751 A/A showed a significant longer survival in the squamous cell carcinoma subgroup (P = 0.047 and P = 0.034 respectively).

Conclusion

Present data indicates that ERCC1 118 C/T or T/T might provide a better prognostic predictive marker of NSCLC patients treated with platinum-based chemotherapy, mainly in elderly subgroup, male, squamous carcinoma, smoker and those treated with non-GP/GC regimen.     

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.     

Effect of preoperative chemotherapy on liver resection for colorectal liver metastases

Aim

To compare the effects of preoperative chemotherapy on liver parenchyma morphology, as well as morbidity and mortality after liver resection for colorectal liver metastases.

Methods

Prospectively collected data on 173 patients undergoing liver resection for CLM between 1/2003 and 9/2005 was analysed in three groups: A: preoperative oxaliplatin (Ox, n = 70); B: other chemotherapeutic agents (OC, n = 60); and C: surgery alone without chemotherapy (SA, n = 43). Blood transfusion, hospital stay, operative procedure, peak postoperative bilirubin levels, complications and histopathology of the resected liver were compared.

Results

Intra-operative blood transfusion requirement (34%) and biliary complications (16%) was higher in patients receiving oxaliplatin-based chemotherapy (p = 0.01 and p = 0.06, respectively). Oxaliplatin-based chemotherapy was also associated with sinusoidal dilatation of mild grade in 52.8% vs. 26.6% and 23.3% patients (p = 0.007 and p = 0.004) in other groups, respectively. Steatosis was similarly distributed across the study group. Postoperative mortality was 2, 1 and 4 patients, respectively (p = ns).

Conclusion

Oxaliplatin-based preoperative chemotherapy is associated with vascular alterations in the liver parenchyma without significantly increasing the risk of steatosis, or postoperative morbidity and mortality.     

Metachronous hepatic metastases from gastric carcinoma: A multicentric survey

Background

The treatment of hepatic metastases from gastric cancer is controversial, due to biologic aggressiveness of the disease.

Objective

To survey the clinical approach to the subset of patients presenting with metachronous hepatic metastases as sole site of recurrence after curative resection of gastric cancer, focusing on the results achieved by different therapies and to investigate the prognostic factors of major clinical relevance.

Methods

Retrospective multi-center chart review evaluating 73 patients, previously submitted to D ≥ 2 gastrectomy for gastric cancer, who developed exclusive hepatic recurrence. Prognostic factors related to the patient, to the gastric malignancy and its treatment, and to the metastatic disease and its therapy were evaluated.

Results

Forty-five patients received supportive care, 17 were submitted to chemotherapy, and 11 to hepatic resection. Survival was independently influenced by the variables T (p = 0.019), N (p = 0.05) and G (p = 0.018) of the gastric primary and by the therapeutic approach to the metastases (p < 0.005). In particular, T4 gastric cancer, presence of lymph-node metastases and G3 tumor displayed a negative prognostic value. Therapeutic approach to the metastases was the principal prognostic variable: 1, 2, and 3 years survival rates were 22.2%, 4.4% and 2.2%, respectively, for patients without specific treatment; 44.9%, 12.8% and 6.4% after chemotherapy (p = 0.08) and 80.8%, 30.3% and 20.2% after surgical resection (p < 0.001).

Conclusions

Our data suggest some clinical criteria that may facilitate selection of therapy for patients with hepatic recurrence after primary gastric cancer resection. The best survival rates are associated with surgical treatment, which should be chosen whenever possible.     

Reduced chemotherapy sensitivity in EGFR-mutant lung cancer patient with frontline EGFR tyrosine kinase inhibitor

Objectives

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard first-line treatment for EGFR-mutant patients with non-small cell lung cancer (NSCLC). However, it remains unclear whether frontline EGFR TKIs affect subsequent chemo-sensitivity in EGFR-mutant patients. This study compared chemo-sensitivity in patients treated with post-TKI chemotherapy and first-line chemotherapy controls.

Materials and methods

This study included 203 EGFR-mutant patients. The study group contained 68 patients treated with chemotherapy after first-line EGFR-TKI and the control group contained 135 patients who received first-line chemotherapy. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were assessed.

Results

In study group, the RR of chemotherapy was 13.2% compared with 34.1% in the control group (P = 0.002). The median PFS of chemotherapy in the control group was significantly longer than in the study group (6.9 vs. 3.9 months, P < 0.001), while the RR (76.5% vs. 68.9%, P = 0.259) and PFS (11.0 vs. 10.2 months) of EGFR-TKI were similar between first- and second-line treatment. Cox regression analyses indicated that prior EGFR-TKI treatment had a higher risk for disease progression during chemotherapy treatment [hazard ratio (HR) = 3.06; 95% CI = 2.12–4.42, P < 0.001]. Median overall survival was 31.7 months in the control group and 23.5 months in the study group (P < 0.001). The adjusted HR for death in the study group was 1.91 (95% CI = 1.33–2.76; P < 0.001).

Conclusion

In EGFR-mutant patients, frontline EGFR-TKI significantly reduced the sensitivity of subsequent chemotherapy compared with that of TKI-naïve frontline chemotherapy. These findings need to be validated in further randomized trials.     

The impact of young age on breast cancer outcome

Aims

We conducted a retrospective analysis in order to evaluate the impact of age on women aged less than 35 years affected by breast cancer.

Materials and methods

Between January 1972 and December 2006, 346 patients aged less than 35 years underwent adjuvant treatment at Florence University. The mean age of the patient population was 32 years (range 22–35): 76 patients were under 30 years old, the remaining were above 30 years old.

Results

In our series, 215 patients received adjuvant radiotherapy to whole breast after conservative surgery, 131 patients underwent mastectomy without subsequent radiation therapy and 323 patients had lymphadenectomy; 191 patients received adjuvant chemotherapy, 73 with anthracycline-containing regimen. With a median time of 2.5 years (range 6 months to 27.6 years) local relapses were observed in 67 cases (19.4%). At the multivariate analysis of local disease-free survival, ductal and ductal plus lobular histotypes, having more than 3 positive nodes, and age emerged as independent significant relapse predictors (p = 0.018, p = 0.0005, p = 0.003 and p = 0.024, respectively). For the DSS analysis, the median follow-up was 6.8 years (range 0.6–36.7 years). At the multivariate analysis, age (p = 0.0038), positive nodes (p = 0.0035) and distant metastases (p < 0.0001) resulted to be independent death predictors. Patients younger than 30 had a worse prognosis. At the univariate analysis also local relapse resulted to be statistically significant (p = 0.0004).

Conclusions

Anthracycline-based chemotherapy seems to improve the outcome of these patients. However, there is an urgent need for tailored treatment investigations within the framework of randomized, controlled clinical trials.