Taxane-sensitivity of ovarian carcinomas previously treated with paclitaxel and carboplatin

Purpose

The aim of the present study was to investigate, in ovarian carcinoma cases, the predictive association between the treatment-free interval (TFI) after an initial paclitaxel plus carboplatin (TC) therapy and the subsequent effectiveness of a second-line taxane-containing chemotherapy.

Methods

Patients with a TFI < 6 months from the first-line TC therapy were treated with a combination chemotherapy using docetaxel and irinotecan; patients with a TFI ≥ 6 months were retreated with the same regimen as the initial TC therapy. The clinical data of these patients were retrospectively analyzed for this study.

Results

The response rate of those with a TFI equal to 6–12 months was greater than that of those with a TFI < 6 months (p = 0.014) and less than that of those with a TFI > 12 months (p = 0.012). The progression-free survival of the cases with TFI equal to 6–12 months was longer than that of those with TFI < 6 months (p = 0.012) and shorter than that of those with TFI > 12 months (p = 0.0011). Overall survival of cases with a TFI equal to 6–12 months was longer than that of those with TFI < 6 months (p = 0.012) and shorter than that of those with TFI > 12 months (p = 0.0005).

Conclusions

The effectiveness of using a second-line taxane-containing chemotherapy was shown to be predictable by the TFI after the first-line taxane-containing chemotherapy, implying that the theory of ‘taxane-sensitivity’ may be applied for second-line chemotherapy in the same way as that of ‘platinum-sensitivity’.     

Prognostic factors in patients with advanced biliary tract cancer receiving chemotherapy

Purpose

Prognostic factors for patients with advanced biliary tract cancer receiving chemotherapy are presently not well established. Gallbladder cancer and intra-hepatic cholangiocarcinoma are previously reported prognostic factors of poor prognosis; however, tumor volume has not been analyzed in these previous reports.

Methods

We analyzed 56 consecutive patients with advanced biliary tract cancer who had received gemcitabine and S-1 combination chemotherapy as first-line palliative chemotherapy. Prognostic factors, including the baseline sum longest diameter (BSLD) representing tumor volume in Response Evaluation Criteria in Solid Tumor, were evaluated.

Results

By multivariate analysis, age ??70 (HR 3.01, 95% CI 1.25?C7.31, P?=?0.014) and larger BSLD (HR 1.09, 95% CI 1.01?C1.18, P?=?0.021) were statistically significant independent predictors of poor prognosis. Primary biliary site was not identified as a prognostic factor (P?=?0.728). Median survival times of patients with BSLDs????9.0?cm and BSLDs?>?9.0?cm were 18.7 and 8.8?months, respectively (P?=?0.024).

Conclusions

Age and BSLD were identified as strong prognostic factors for patients with advanced biliary tract cancer receiving chemotherapy. Tumor volume might be more important than primary biliary site for the prognosis of advanced biliary tract cancer.     

Gemcitabine in the management of metastatic breast cancer: a systematic review

Background

A systematic review of the evidence for gemcitabine chemotherapy, alone or in combination, in women with metastatic/advanced breast cancer was undertaken in order to determine gemcitabine’s role in the first-line and/or second-line or greater setting.

Methods

MEDLINE, EMBASE, the American Society of Clinical Oncologists, San Antonio Breast Cancer Symposium proceedings, and the Cochrane Library were searched through September 2006 for randomized controlled trials and non-randomized phase two trials.

Results

Eighty-three trials were identified, including four randomized phase III trials. All of the phase III trials included first-line patients. Two of the phase III trails demonstrated clinical benefit with gemcitabine-based chemotherapy in terms of superior efficacy or less toxicity while two phase III trials found no clinical benefit based on less efficacy or increased toxicity. Although 78 phase II trials of gemcitabine alone or in combination with other chemotherapy agents were identified, few combinations showed results compelling enough to warrant randomized trials.

Conclusion

Available data do not support the acceptance of gemcitabine as a standard therapeutic option in women with metastatic breast cancer in the third-line or greater setting, nor should it be considered as first-line therapy in anthracycline naïve women. Gemcitabine appears to be most effective when administered with a taxane (docetaxel/paclitaxel) in the first- or second-line setting, with gemcitabine/taxane combinations representing a viable alternative to currently accepted taxane combinations such as capecitabine/docetaxel. There is no evidence at this time to support the use of gemcitabine triplets, given the equal efficacy to anthracycline triplets and the added toxicity.

     

The effect of post-progression survival on overall survival among patients with sensitive relapse of small cell lung cancer

Recent studies have suggested that, among patients with advanced lung cancer, subsequent treatment after failure of first-line or second-line chemotherapy has a greater effect on overall survival (OS) than tumor shrinkage or progression-free survival (PFS). However, no studies have examined this issue among patients with sensitive relapse of small cell lung cancer (SCLC). We retrospectively evaluate 77 patients with sensitive relapse of SCLC who received second-line chemotherapy after first-line platinum doublet chemotherapy between January 1999 and November 2013. The analyses included patient characteristics, treatment parameters, tumor shrinkage, PFS, post-progression survival (PPS), and OS. Spearman rank correlation analysis and linear regression analysis revealed that PPS was strongly correlated with OS (r?=?0.91, p?<?0.01, R²?=?0.96), PFS was moderately correlated with OS (r?=?0.58, p?<?0.01, R²?=?0.28), and tumor shrinkage was weakly correlated with OS (r?=?0.34, p?<?0.01, R²?=?0.12). A multivariate Cox proportional hazards model with a stepwise regression procedure revealed that PPS was significantly associated with age at the start of second-line chemotherapy, best response to second-line and third-line chemotherapy, and the number of regimens after progression beyond second-line chemotherapy (p?<?0.05). These findings suggest that PPS has a stronger effect than PFS on OS among patients with sensitive relapse of SCLC. Thus, response to second-line chemotherapy and subsequent treatment for disease progression after second-line chemotherapy may be important factors that influence OS.     

Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy

Background

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined.

Methods

Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated.

Results

Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 %, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 % of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 %) and phlebitis (6 %).

Conclusion

Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment.     

Therapie des fortgeschrittenen Magenkarzinoms

Context

In the metastatic setting treatment goals are palliative. Chemotherapy can prolong survival, improve symptoms and can help to maintain a better quality of life.

Objective

The aim of this study was to discuss the new treatment options and the existing results in advanced gastric cancer.

Material and methods

Treatment recommendations are given in consideration of updated literature (Pubmed, MEDLINE and manual search).

Results

Combination chemotherapy including a platinum compound and a fluoropyrimidine are regarded as the gold standard of care. Oxaliplatin can substitute for cisplatin while capecitabine or S1 can substitute for infusional 5-FU. In elderly patients oxaliplatin has advantages compared with cisplatin. Triplet combinations containing a platinum salt, a fluoropyrimidine and a taxane or (with less evidence) an anthracycline are more efficacious but also expose patients to more side effects. Second line chemotherapy is indicated for patients who progress during or after first line chemotherapy. The monoclonal antibody trastuzumab has been shown to prolong survival when combined with cisplatin and 5-FU or capecitabine in gastric cancer patients with overexpression of the growth factor HER2.

Conclusion

The therapeutic options for advanced gastric cancer have significantly increased. Presently, there are several effective treatment regimens available.     

Hyaluronan-Irinotecan improves progression-free survival in 5-fluorouracil refractory patients with metastatic colorectal cancer: a randomized phase II trial

Purpose

The objective of this study was to conduct a randomised phase II study in second-line metastatic colorectal cancer with the purpose of confirming preliminary clinical data indicating that the formulation of irinotecan with the drug carrier, hyaluronan (HA) reduced toxicity of the drug.

Methods

Irinotecan-na?ve patients were randomized to receive either irinotecan (350?mg/m²) or HA-Irinotecan (HA 1,000?mg/m² and irinotecan at 350?mg/m²) every 3?weeks for a maximum of eight cycles.

Results

Seventy-six patients (41 HA-Irinotecan and 35 irinotecan-alone) were enrolled. There was no significant difference in any individual, or overall, grade 3 or 4 toxicity. There was a trend for increased diarrhea in the HA-Irinotecan-treated patients (20 versus 9%; P?=?21), potentially explained by a disproportionate number of baseline toxicity-associated risk factors in this treatment group. The median number of cycles completed was six for HA-Irinotecan patients and two for irinotecan-alone patients (P?=?0.005). When compared to the control arm, HA-Irinotecan patients had a significantly longer median progression-free survival of 5.2 versus 2.4?months (P?=?0.017) and time to treatment failure (4 vs. 1.8?months; P?=?0.007). Median overall survival was 10.1?months for HA-Irinotecan compared to 8.0?months for irinotecan patients (P?=?0.196).

Conclusion

Further studies are required to define the safety of the formulation of irinotecan with HA. While this study was not adequately powered to demonstrate survival differences, these phase II data indicated HA-Irinotecan to be a promising therapy demonstrating improved efficacy compared to irinotecan-alone.     

A retrospective study of docetaxel or paclitaxel in patients with advanced or recurrent esophageal squamous cell carcinoma who previously received fluoropyrimidine- and platinum-based chemotherapy

Introduction

Fluoropyrimidine plus platinum (FP)-based chemotherapy has been widely used as a first-line regimen for advanced or recurrent esophageal cancer, and taxanes have shown efficacy after FP-based chemotherapy, but there is no standard regimen for second-line chemotherapy (SLC). We retrospectively investigated the clinical features of taxane therapy in SLC for esophageal squamous cell carcinoma (ESCC).

Methods

The selection criteria were pathologically proven ESCC; advanced or recurrent disease previously treated with FP at our hospital; performance status (PS) 0–2; and adequate organ function. Docetaxel (DTX) was administered 3-weekly at 70 mg/m². Paclitaxel (PTX) was administered at 100 mg/m² weekly for 6 weeks, with 1 week’s rest.

Results

The analysis covered 163 patients from August 2006 to June 2012. Median age was 64 years (range 37–83: DTX group 132 patients and PTX group 31). Progression-free survival and median overall survival (OS) were 2.3 and 6.1 months, respectively, with PTX and 2.3 and 5.3 months with DTX. Response rates were 20.7 % for PTX and 5.9 % for DTX. The rate of grades 3–4 neutropenia was higher with DTX (32.6 %) than with PTX (16.1 %). Grade 3 febrile neutropenia was seen in 6.1 % of DTX recipients but in no PTX group. According to multivariate analyses of OS, PS 2, number of metastatic sites ≧2, and CRP ≧1 mg/dL were independent predictors of poor prognosis.

Conclusions

PTX and DTX were both effective in SLC for ESCC, but their toxicity profiles differed. In terms of febrile neutropenia, PTX seems more appropriate.     

Galectin-3 genetic variants are associated with platinum-based chemotherapy response and prognosis in patients with NSCLC

Aim

To explore the association between the galectin-3 genetic polymorphisms and Platinum-based chemotherapy response as well as the prognosis of non-small cell lung cancer (NSCLC).

Method

Three hundred twenty patients with Stage III (A+B) or IV NSCLC were enrolled. A Platinum-based chemotherapy was given to each subjects and therapeutic effect was evaluated. The two galectin-3 genetic polymorphisms, namely, galectin-3 +191 A>C and +292 A>C, were genotyped.

Results

The polymorphic genotypes and the allele frequency of galectin-3 +191 A>C were not significantly different between responders and non-responders to chemotherapy. For galectin-3 +292 A>C, the AA genotype and A allele distribution were significantly higher in responders than in non-responders. Logistic regression analysis showed CC genotype of galectin-3 +292 presented higher risk of being non-responders compared with the AA genotype (OR?=?2.96, 95?% CI: 1.55?C5.47; P?<?0.001). The overall survival in patients with AA genotype of galectin-3 +292 were significantly longer than in those with CC genotype (25.6 vs. 19.5?months, P?=?0.013). The hazard ratio for CC genotype of galectin-3 +292 was 2.43 (95?% CI: 2.03?C3.98, compared with AA carriers, P?=?0.003).

Conclusion

The galectin-3 genetic polymorphisms of galectin-3 +292, rather than galectin-3 +191, were associated with the chemotherapy response and prognosis of NSCLC.     

Concurrent use of proton pump inhibitors or H2 blockers did not adversely affect nilotinib efficacy in patients with chronic myeloid leukemia

Purpose

The impact of proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (H2 blockers) on the efficacy of nilotinib was evaluated.

Methods

Retrospective analyses were performed in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP; N?=?492) and in patients with imatinib-resistant or imatinib-intolerant Ph+ CML-CP (N?=?256) treated with nilotinib.

Results

In the newly diagnosed population, 87 (17.7?%) and 49 (10.0?%) patients received PPIs and H2 blockers, respectively. Major molecular response at 12?months was achieved by 59 (49.6?%) patients who received at least one PPI or H2 blocker (n?=?119) and 153 (41.0?%) patients who did not receive any comedication (n?=?373; P?=?0.13). PPIs and H2 blockers were used by 77 (30.1?%) and 17 (6.6?%) patients with imatinib-resistant or imatinib-intolerant CML-CP, respectively. Major cytogenetic response by 12?months was achieved by 55 (64.0?%) patients who received at least one PPI or H2 blocker (n?=?86) versus 98 (57.6?%) patients who did not receive any comedication (n?=?170; P?=?0.40); 39 (45.3?%) versus 65 (38.2?%), respectively, achieved complete cytogenetic response by 12?months (P?=?0.34). Similar findings were observed in patients who received comedication for >50?% of the time on nilotinib therapy. Nilotinib steady-state trough concentration was not affected by the presence of PPIs or H2 blockers.

Conclusions

Concurrent use of PPIs or H2 blockers did not affect the pharmacokinetics and efficacy of nilotinib in patients with Ph+ CML-CP.     

Phase II gemcitabine and capecitabine combination therapy in recurrent or metastatic breast cancer patients pretreated with anthracycline and taxane

Purpose

We conducted a phase II study evaluating safety and efficacy of combination gemcitabine and capecitabine therapy for metastatic breast cancer patients following anthracycline and taxane treatment in Korea.

Methods

This was a single-arm, non-randomized phase II study. Patients received 1,000 mg/m² gemcitabine intravenously over 30 min on days 1 and 8, and 1,250 mg/m² capecitabine orally twice daily on days 1–14 until disease progression or intolerable toxicity occurred. This regimen was repeated every 3 weeks. The primary outcome assessed was overall response rate [ORR, complete response (CR) + partial response (PR) as the best response], and secondary outcomes were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) [maintenance of CR + PR + stable disease (SD) for at least 3 months], drug toxicity, and predictive factors for response to this regimen.

Results

Of 41 patients, the ORR was 39.0 % (CR 0 %; PR 39.0 %), and DCR was 78.0 % using this chemotherapy. DCR for 6 and 12 months was 68.3 and 26.8 %, respectively. Median PFS was 10.0 months [95 % confidence interval (CI) 7.8–12.1], and median OS was 25.1 months (95 % CI 18.2–32.1). Prominent toxicities were neutropenia and hand–foot syndrome. Most adverse events were well known, relatively moderate, and reversible. Taxane sensitivity [odds ratio (OR) 0.169; 95 % CI 0.034–0.826; P = 0.028] and hepatic metastasis (OR 0.097; 95 % CI 0.017–0.559; P = 0.009) were significantly predictive of response to gemcitabine and capecitabine combination.

Conclusions

This study showed reproducible anticancer activity and tolerable toxicity of gemcitabine and capecitabine combination therapy in recurrent or metastatic Korean breast cancer patients previously treated with anthracycline and taxane.     

Predictive value of APE1, BRCA1, ERCC1 and TUBB3 expression in patients with advanced non-small cell lung cancer (NSCLC) receiving first-line platinum–paclitaxel chemotherapy

Purpose

Drug resistance is not only one of the major obstacles to treatment but also a poor prognosis in advanced non-small cell lung cancer (NSCLC) patients. The aim of this study was to evaluate the predictive value of APE1, BRCA1, ERCC1 and TUBB3 in advanced NSCLC patients who received platinum–paclitaxel treatment.

Methods

One hundred and thirty-six advanced NSCLC patients, who were treated with first-line platinum–paclitaxel chemotherapy, were enrolled in this study. The protein expression levels of APE1, BRCA1, ERCC1 and TUBB3 were assessed by immunohistochemistry and analyzed for the association with response to chemotherapy and progression-free survival (PFS) and overall survival (OS).

Results

Patients with negative expression of APE1, ERCC1 or TUBB3 benefited from platinum plus paclitaxel regimen chemotherapy. ERCC1-negative patients had better PFS (P = 0.016) and OS (P = 0.030) compared with positive patients. Similarly, the APE1-negative patients showed better PFS (P = 0.004) and longer OS though statistically insignificant. Multivariate analysis showed that APE1 and ERCC1 were independent predictor for PFS (HR 2.07; P = 0.004 and HR 1.66; P = 0.016) and OS (HR 1.99; P = 0.008 and HR 1.64; P = 0.040). Moreover, patients with both APE1- and ERCC1-negative or both APE1- and TUBB3-negative tumors had significantly higher response rate, longer median PFS and OS following treatment with platinum and paclitaxel (P < 0.05).

Conclusion

The data indicate that APE1, ERCC1 and TUBB3 could be a useful biomarker to predict clinical outcome in patients with advanced NSCLC receiving first-line platinum–paclitaxel chemotherapy.     

Prognostic significance of breast cancer subtype and p53 overexpression in patients with locally advanced or high-risk breast cancer treated using upfront modified radical mastectomy with or without post-mastectomy radiation therapy

Background

Although post-mastectomy radiation therapy (PMRT) has shown benefits, its effects in patient subpopulations remain uncertain. Therefore, we assessed whether breast cancer subtype and p53 overexpression were associated with outcome after modified radical mastectomy (MRM), with or without PMRT.

Methods

We retrospectively analyzed the records of patients who underwent MRM, with or without PMRT, between January 1991 and December 2008. Patients were considered eligible if they had T3 or T4 stage disease; any T stage with N2 or N3 stage; any T or N stage with positive, close (<1?mm) resection margins; or skin, nipple, or pectoral muscle invasion. We used immunohistochemistry and/or fluorescent in situ hybridization to determine breast cancer subtypes and p53 overexpression status.

Results

We found that 104 patients were eligible, including 59 (56.7%) who underwent PMRT and 45 (43.3%) who did not. Median follow-up duration was 61.3?months (range 16.1–232.7). Overall survival (OS) was significantly longer in patients who underwent PMRT (P?=?0.029). This trend was evident in the subgroup of luminal type A breast cancer (P?=?0.017) and non-p53 overexpression (P?=?0.026) patients. However, there was no significant survival benefit from PMRT in the subgroup of triple negative (TN) breast cancer (P?=?0.528) and p53 overexpression (P?=?0.189) patients.

Conclusions

The benefit of PMRT differed among subgroups with different breast cancer subtype and p53 overexpression. More efficacious systemic treatment strategies are needed, especially in patients at high risk for distant metastasis, to obtain optimal therapeutic gain.     

Prospective multicenter study to investigate the introduction rate of second-line S-1 in gemcitabine-refractory unresectable pancreatic cancer

Purpose

S-1 is one of the second-line candidate agents for gemcitabine-refractory unresectable pancreatic cancer. Two phase II studies have been reported for second-line chemotherapy with S-1, but these studies did not investigate introduction rate and suitable dose of second-line S-1. Therefore, we conducted a prospective multicenter study in which chemo-na?ve patients were enrolled and had two levels of S-1 dose.

Methods

Chemo-na?ve patients with unresectable pancreatic cancer were enrolled. This study started with 80?mg/m²/day dose of S-1 as second-line chemotherapy and tolerability was checked. When tolerability was not confirmed in initial patients, the dose of S-1 was shifted to 60?mg/m²/day. When tolerability was confirmed at 80 or 60?mg/m²/day, the study continued, and up to 20 patients were accumulated with the dose. In addition, the introduction rate of second-line S-1 was examined.

Results

Six of the initial 7 patients with 80?mg/m²/day dose of S-1 completed one course of second-line chemotherapy. Twenty patients were accumulated with an 80?mg/m²/day dose of S-1. With the exception of one patient continued gemcitabine chemotherapy, two of the remaining 19 patients withdrew from this study because of toxicity during the period of gemcitabine chemotherapy. Fifteen of the remaining 17 gemcitabine-refractory patients could complete one course of S-1 as second-line chemotherapy with acceptable toxicity.

Conclusions

This prospective multicenter study showed that 15 (78.9%) out of 19 chemo-na?ve unresectable pancreatic cancer patients could complete one course of 80?mg/m²/day dose of S-1 as second-line chemotherapy after first-line gemcitabine chemotherapy failure with tolerable toxicity.     

A randomized phase II study to compare oxaliplatin plus 5-fluorouracil and leucovorin (FOLFOX4) versus oxaliplatin plus raltitrexed (TOMOX) as first-line chemotherapy for advanced colorectal cancer

Introduction

The aim of this study was to compare TOMOX versus FOLFOX4 as first-line treatment of advanced colorectal cancer (CRC).

Materials and methods

191 chemotherapy-na?ve patients were randomized to receive TOMOX or FOLFOX4. Patients were evaluated every 3?months and chemotherapy was continued until disease progression or unacceptable toxicity. Overall response rate was the primary endpoint.

Results

183 patients were included in the intent-to-treat analysis (92 TOMOX and 91 FOLFOX4). Overall response rate was 45.6 and 36.3?% (p?=?0.003) for TOMOX and FOLFOX4, respectively. No statistically significant differences were observed in overall survival (15.6 and 17.2?months; p?=?0.475); progression-free survival (7.7 and 8.7?months; p?=?0.292), and response duration (6.4 and 7.6?months; p?=?0.372) for TOMOX and FOLFOX4, respectively. Grades 3 and 4 neutropenia (p?p?=?0.028) were more common with the FOLFOX4 regimen, while hepatic disorders and asthenia were higher in TOMOX group (p?=?ns). There were two treatment-related deaths in the FOLFOX4 arm and one in the TOMOX arm. Quality of life analysis based on the SF-36 revealed differences between the two regimens for physical and mental composite scores after 6?weeks, and for body pain and emotional role functioning after 6 and 12?weeks; all of these favored the FOLFOX4 arm (p????0.05).

Conclusions

TOMOX and FOLFOX4 seem to have similar efficacy and are well tolerated in the first-line treatment for advanced CRC with different profiles of toxicity. The convenient TOMOX regimen may offer an alternative to fluoropyrimidine-based regimens.     

Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group

Purpose

Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy.

Methods

In a multicenter clinical trial (E1201), 81 eligible treatment-na?ve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ??3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6?weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification.

Results

Grade ??3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5?? flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P?=?0.005). No SNP was associated with myelosuppression.

Conclusions

This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.     

Comparison of efficacy and toxicity of second-line combination chemotherapy regimens in patients with advanced urothelial carcinoma

Background

The aim of this study was to evaluate the efficacy and toxicities of second-line chemotherapy regimens with docetaxel and gemcitabine (GD), or paclitaxel and gemcitabine (GP) for advanced or metastatic urothelial carcinoma (UC) that did not respond to first-line platinum-based chemotherapy.

Methods

From 2002 to 2017, 78 patients with metastatic UCs that progressed after platinum-based chemotherapy were treated with either GD (n?=?41) or GP (n?=?37). We compared these two different regimens by analyzing their efficacy and toxicities in a retrospective manner.

Results

Of the 78 patients enrolled in this study, it was possible to determine treatment efficacy in 70; the proportion of patients with objective response and disease control were 8.6 (9/70) and 54.3% (38/70), respectively. The median progression-free survival and overall survival in the total population (GP and GD) were 3.5 (95% CI 0.6–53.3) and 9.6 months (95% CI 1.2–53.3), respectively. There was no significant difference between the two regimens (GD or GP) regarding survival outcomes. Treatment-related adverse events were mostly manageable, but one patient died as a result of febrile neutropenia. The presence of liver metastasis and anemia (Hb?<?10.0 g/dl) was prognostic factors for worse survival.

Conclusions

Combination chemotherapy with either GP or GD was a favorable and well-tolerated second-line treatment regimen for patients with advanced or metastatic UC following the failure of a platinum-based regimen. Further study using a large prospective cohort is needed to identify patients who will benefit from second-line combination therapy.

     

Clinical characteristics and treatment outcomes of gastric cancer patients with isolated para-aortic lymph node involvement

Background

Although gastric cancer with isolated para-aortic lymph node (PAN) involvement is considered an advanced disease, the clinical characteristics of it have not been comprehensively elucidated.

Patients and methods

We reviewed the medical records of 1,277 patients received palliative chemotherapy with advanced gastric cancer according to metastatic sites: PAN-only metastasis, single organ metastasis other than PAN, and multiple organ metastasis. Time to other organ metastasis (TTOM) was determined only in PAN-only metastasis group as the time interval between initial diagnosis of recurrence or de novo metastasis and confirming distant metastasis beyond PAN area.

Results

The median overall survival (OS) of patients with PAN-only metastasis was significantly longer than that of patients with single organ metastasis other than PAN or multiple organ metastasis (13.8?months vs. 11.4?months vs. 8.4?months; P?<?0.001). In the PAN-only metastasis group, patients with recurrent diseases showed longer TTOM beyond the PAN area (10.7 vs. 7.7?months; P?=?0.037) and OS (23.8 vs. 12.8?months; P?=?0.010) than those with de novo metastatic disease and it was validated by multivariate analysis.

Conclusion

Patients with isolated PAN metastasis showed an excellent prognosis compared with patients with metastasis at other sites and it was primarily evident in patients with recurrent PAN metastasis.     

Epidemiology and prevalence of oropharyngeal candidiasis in Spanish patients with head and neck tumors undergoing radiotherapy treatment alone or in combination with chemotherapy

Objective

To describe the oropharyngeal candidiasis (OPC) prevalence in Spanish patients with head and neck cancer undergoing radiotherapy, alone or combined with chemotherapy. Secondary objectives were to determine the prevalence of Candida species colonization, and to explore whether different Candida species colonizing the oral cavity and the treatment were associated with a higher prevalence of OPC.

Methods

This is an observational, cross-sectional, multicentre study, conducted in Spanish radiation oncology units. Patients were diagnosed with head and neck cancer and started a radiotherapy treatment alone or combined with chemotherapy at the moment of their inclusion (N?=?92).

Results

The OPC prevalence was 26?%. The identification of colonizing pathogens was performed in 49 patients, and Candida albicans was the dominant yeast (69?%), while non-albicans Candida was only found in 15 patients (31?%). Patients with C. albicans colonization had a significant higher prevalence of OPC compared to patients colonized by non-albicans Candida (p?=?0.0273), but no difference was found regarding the OPC prevalence in patients receiving only radiotherapy compared to patients with both radiotherapy and chemotherapy treatments.

Conclusions

Our data represent a step further in the knowledge of Candida species present in Spanish patients with head and neck tumors under radiation therapy. This is an essential step to manage the prophylaxis and treatment of OPC, since it might lead to severe clinical complications causing treatment interruption and, thus, representing a reduction in anti-tumor efficacy.     

Pharmacologic and phenotypic study of docetaxel in patients with ovarian or primary peritoneal cancer

Purpose

The objectives of this study were to determine whether the midazolam clearance predicted docetaxel pharmacokinetics, CA-125 change, and response and to assess the impact of cytochrome P450 (CYP) 3A5 and ATP-binding cassette, subfamily B, member 1 (ABCB1) genotypes on docetaxel pharmacokinetics and pharmacodynamics in ovarian or primary peritoneal cancer patients.

Methods

Thirty-four patients with advanced ovarian and primary peritoneal cancer were administered docetaxel at 75?mg/m² as a 1-h infusion in combination with carboplatin IV over 30?min at a target AUC of 5?mg/ml?min. Cycles were repeated every 21?days for 6 cycles. Midazolam was administered at 2?mg as a 30-min IV infusion the day prior to cycle one of docetaxel administration. Pharmacokinetic studies of docetaxel and CYP3A5 and ABCB1 genotype studies were performed.

Results

There was an inverse relationship between midazolam clearance (CL) and CA-125 level after cycle 6 where a higher midazolam CL was associated with a CA-125?<10?U/ml (P?=?0.007) and CA-125?<15?U/ml (P?=?0.048). The CA-125 categories were associated with response achieved (complete response/partial response) (CR/PR), stable disease (SD), and progressive disease (PD) at the end of therapy (P?=?0.0173). Docetaxel CL was not related to midazolam CL or genotype. Docetaxel exposure and genotypes were not related to toxicity or response (P?>?0.05).

Conclusions

The midazolam CL predicted CA-125 levels and response that was independent of other factors including docetaxel pharmacokinetics. Future studies need to evaluate the mechanism for the relationship between midazolam CL and response in patients with ovarian cancer.