Cisplatin And 5-fluorouracil Research Articles

RM-017 Systemic chemotherapy in advanced gastric carcinoma: a comparison of docetaxel, cisplatin and fluorouracil (DCF) versus cisplatin and fluorouracil (CF); versus epirubicin, cisplatin and fluorouracil (ECF) regimens in clinical setting, a retrospective study

RM-017 Systemic chemotherapy in advanced gastric carcinoma: a comparison of docetaxel, cisplatin and fluorouracil (DCF) versus cisplatin and fluorouracil (CF); versus epirubicin, cisplatin and fluorouracil (ECF) regimens in clinical setting, a retrospective study

WS7-1 - Difference of Neoadjuvant Treatment for Esophageal Cancer Between Japan and Western Countries

Surgery is a major modality in the treatment of esophageal cancer in Japan.In 1980s, radical esophageal cancer surgery, transthoracic esophagectomy with extensive lymphadenectomy, had been established as a standard procedure. In order to improve the survival, a number of studies have been carried out on adjuvant therapy.In 1990s, JCOG9204 was initiated to determine whether postoperative chemotherapy using cisplatin and 5-fluorouracil (CF) had an additive effect on survival and in patients undergoing radical surgery for locally advanced esophageal squamous cell carcinoma (LAESCC). On the basis of these data, postoperative adjuvant CF came to be the standard treatment for LAESCC in the early 2000s.In 2000s, JCOG9907 was initiated to determine the optimal perioperative timing of chemotherapy for LAESCC, that is, pre or post surgery. PFS, the primary endpoint, did not reach the stopping boundary, but OS in the pre group was superior to that in the post group. Therefore, early publication was recommended. Based on these results, preoperative CF came to be regarded as the standard treatment for patients with LAESCC.On the other hand, in Western countries, preoperative chemoradiotherapy followed by surgery is regarded as a standard care for advanced esophageal cancer from the results of CALGB9781 trial, CROSS trial, meta-analyses, and so on. However, at the present time, it is difficult to adapt the treatment of Western country to clinical practice in Japan, because there are a lot of differences in the aspects of tumor biology or surgical procedure between the Western countries and Japan.From December 2012, JCOG1109, a phase III trial comparing three preoperative treatment (CF, CF plus docetaxel (DCF), and CF plus radiotherapy) for LAESCC, have been initiated. Many oncologists in Western country, not only in Japan, pay a lot of attention for this trial, because it is possible to compare the standard preoperative treatment between Japan and Western countries.

WS7-3 - Recent Advance and Development in the Treatment for Metastatic Esophageal Cancer

Systemic chemotherapy with cisplatin and 5-fluorouracil (CF) has long been the standard care for metastatic or recurrent esophageal cancer (EC) for over a period of decades with response rate (RR) of 13-36 % and median overall survival (mOS) of 6-9 months. In 2013, the results of JCOG 0807, phase I/II study of biweekly docetaxel plus CF (bDCF), were disclosed: RR was 62%; median progression-free survival was 5.8 months; and mOS was 11.1 months. It is notable that there was only 26% of grade 3/4 neutropenia, and no patient suffered from febrile neutropenia without prophylactic G-CSF. bDCF achieved reduction of toxicities with promising efficacy. A phase III study comparing bDCF with CF is now planning.As for molecular targeting therapy, inhibitors of epidermal growth factor receptor (EGFR), namely cetuximab, panitumumab, and gefitinib, have most been investigated, none of which demonstrated clinical efficacy in phase III studies. A gene mutation analysis indicated that alteration patterns of mutated EGFR in EC are not similar to that observed in other cancers.BKM120, an inhibitor of the pan-class I phosphatidylinositol 3-kinase (PI3K) family of lipid kinase, is under study. It is implicated that activation of PI3K signaling pathway promotes metastasis, and PIK3CA encoding PI3K catalytic alpha polypeptide is one of the frequently mutated genes in EC. Inhibition of the pathway by BKM120 may leads to suppression of tumor cell growth and survival.A trial of ONO-4538 (Nivolumab), a monoclonal antibody directed against programed cell death-1 (PD-1), is also ongoing. Nivolumab binds to PD-1 and blocks the binding of its ligands PD-L1/L2, then activates T-cells and cell-mediated immune responses against tumor cells.Next step of development in EC treatment should be focused on identification of driver somatic mutations or other predictive biomarkers. Accompanied with developing therapeutic agents, exploration of these biomarkers is underway.

Comparison of preoperative chemotherapy using docetaxel, cisplatin and fluorouracil with cisplatin and fluorouracil in patients with advanced carcinoma of the thoracic esophagus

We retrospectively compared preoperative docetaxel, cisplatin, and fluorouracil (DCF) with cisplatin and fluorouracil (CF) in patients with esophageal cancer. The study included patients with advanced thoracic esophageal carcinoma (excluding T4 tumors) receiving preoperative chemotherapy. In the DCF group, five patients received two courses of treatment every 4 weeks, and 33 patients received three courses every 3 weeks. In the CF group, 38 patients received two courses of treatment every 4 weeks. Patients underwent curative surgery 4-5 weeks after completing chemotherapy. Patient demographic characteristics did not differ between the two study groups. The incidence of a grade 3 or 4 hematologic toxicity was significantly higher in the DCF group (33 patients) than in the CF group (five patients; P < 0.001). Curative resection was accomplished in 79% of patients in the DCF group and 66% in the CF group (P = 0.305). There were no in-hospital deaths. The incidence of perioperative complications did not differ between the groups. A grade 2 or 3 histological response was attained in a significantly higher proportion of patients in the DCF group (63%) than in the CF group (5%; P < 0.001). Progression-free survival and overall survival were significantly higher in the DCF group (P = 0.013, hazard ratio 0.473; P = 0.001, hazard ratio 0.344). In conclusion, a grade 3 or 4 hematologic toxicity was common in the DCF group but was managed by supportive therapy. Histological response rate, progression-free survival, and overall survival were significantly higher in the DCF group compared with the CF group.

A Gene Expression Signature of Acquired Chemoresistance to Cisplatin and Fluorouracil Combination Chemotherapy in Gastric Cancer Patients

BackgroundWe initiated a prospective trial to identify transcriptional alterations associated with acquired chemotherapy resistance from pre- and post-biopsy samples from the same patient and uncover potential molecular pathways involved in treatment failure to help guide therapeutic alternatives.Methodology/Principal FindingsA prospective, high-throughput transcriptional profiling study was performed using endoscopic biopsy samples from 123 metastatic gastric cancer patients prior to cisplatin and fluorouracil (CF) combination chemotherapy. 22 patients who initially responded to CF were re-biopsied after they developed resistance to CF. An acquired chemotherapy resistance signature was identified by analyzing the gene expression profiles from the matched pre- and post-CF treated samples.The acquired resistance signature was able to segregate a separate cohort of 101 newly-diagnosed gastric cancer patients according to the time to progression after CF. Hierarchical clustering using a 633-gene acquired resistance signature (feature selection at P<0.01) separated the 101 pretreatment patient samples into two groups with significantly different times to progression (2.5 vs. 4.7 months). This 633-gene signature included the upregulation of AKT1, EIF4B, and RPS6 (mTOR pathway), DNA repair and drug metabolism genes, and was enriched for genes overexpressed in embryonic stem cell signatures. A 72-gene acquired resistance signature (a subset of the 633 gene signature also identified in ES cell-related gene sets) was an independent predictor for time to progression (adjusted P = 0.011) and survival (adjusted P = 0.034) of these 101 patients.Conclusion/SignificanceThis signature may offer new insights into identifying new targets and therapies required to overcome the acquired resistance of gastric cancer to CF.

Feasibility study of neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil (DCF) for clinical stage II/III esophageal squamous cell carcinoma.

95 Background: In JCOG 9907, neoadjuvant chemotherapy with cisplatin and 5-fluorouracil (CF) improved overall survival without additional serious adverse events in treating stage II/III esophageal squamous cell carcinoma (ESCC). However, ESCC patient survival remains unsatisfactory. We conducted a feasibility study of neoadjuvant chemotherapy with docetaxel plus CF (DCF) for clinical stage II/III ESCC. Methods: Eligibility criteria included clinical stage II/III (non-T4) ESCC, PS 0–1, and age 20–70 years. Chemotherapy consisted of a 1-h infusion of docetaxel at 70 mg/m2 and 2-h infusion of cisplatin at 70 mg/m2 (day 1), and continuous infusion of 5-FU 750 mg/m2 (days 1 to 5). Antibiotic prophylaxis on days 5 to 15 was mandatory. This regimen was repeated every 3 weeks (maximum 3 cycles) until unacceptable toxicity, patient refusal, or disease progression was observed. After chemotherapy completion, transthoracic esophagectomy with extended (&gt; D2) lymphadenectomy was performed. The primary endpoint was the completion rate of protocol treatment. Results: From July 2009 to Feb 2010, 34 patients were enrolled, including 2 ineligibles. The 32 eligibles had a median age of 61 (range 36–70; male/female: 30/2), with PS0/1 of 20/12 and cStage IIA/IIB/III of 6/8/18. During chemotherapy, the most common grade-3 or -4 toxicities were neutropenia (88%), febrile neutropenia (3%), anorexia (9%), and stomatitis (6%). Thirty-one (97%) patients underwent surgery. The protocol completion rate was 87.5% (28/32). No treatment-related death was observed, and the operative morbidity incidence was comparable to those in previous studies. According to RECIST, the overall response rate was 61.5% after DCF completion. Primary-lesion pathological complete response was achieved in 26% of patients (8/31) who underwent esophagectomy. Conclusions: Neoadjuvant DCF was well tolerated. Although these data are preliminary, the protocol is highly promising and warrants further investigation. No significant financial relationships to disclose.

Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy

To identify transcriptional profiles predictive of the clinical benefit of cisplatin and fluorouracil (CF) chemotherapy to gastric cancer patients, endoscopic biopsy samples from 96 CF-treated metastatic gastric cancer patients were prospectively collected before therapy and analyzed using high-throughput transcriptional profiling and array comparative genomic hybridization. Transcriptional profiling identified 917 genes that are correlated with poor patient survival after CF at P<0.05 (poor prognosis signature), in which protein synthesis and DNA replication/recombination/repair functional categories are enriched. A survival risk predictor was then constructed using genes, which are included in the poor prognosis signature and are contained within identified genomic amplicons. The combined expression of three genes—MYC, EGFR and FGFR2—was an independent predictor for overall survival of 27 CF-treated patients in the validation set (adjusted P=0.017), and also for survival of 40 chemotherapy-treated gastric cancer patients in a published data set (adjusted P=0.026). Thus, combined expression of MYC, EGFR and FGFR2 is predictive of poor survival in CF-treated metastatic gastric cancer patients.

Gene set comparison analyses of gene expression signatures for the acquired chemotherapy resistance.

10609 Background: A prospective, high-throughput transcriptional profiling study was performed using endoscopic biopsy samples from 22 metastatic gastric cancer patients who had partial response to cisplatin and fluorouracil (CF) combination chemotherapy. An acquired resistance signature was identified by comparing samples collected at progressive disease and pretreatment samples of these responders. Given that the activity of complex regulatory network in stem cells can be best detected by expression analysis of many genes, we performed several gene set comparison analyses comparing our acquired resistance signature with published embryonic stem (ES) cell signatures. Methods: The similarity of the acquired resistance signature to published ES cell signatures was tested using gene set comparison algorithms, which analyzed our acquired resistance signature for differential expression between ES cells and differentiated tissues. For each source dataset, a P value was computed for each gene for the differential expression between pre-defined classes. A summary statistic was computed that summarized these P values over the user-defined gene set; the summary statistic is average log(P) for the LS summary of how the P values differ from a uniform distribution for LS. Results: The acquired resistance gene signature was enriched for genes overexpressed in published ES cell signatures. Our acquired resistance signature was found to be highly enriched for genes over-expressed in at least 5/20 human ES cells profiling studies (LS P value=3.0 × 10-3). Even after the ES cell signature was modified to exclude genes listed in the “proliferation” category of Gene Ontology and the proliferation cluster of breast cancer, the overlap was still statistically significant. Notably, genes overlapping between ES cell signatures and the acquired resistance signature could segregate newly-diagnosed metastatic gastric cancer patients according to progression-free survival (adjusted P value, 0.011). Conclusions: This gene set comparison analysis demonstrates the signficant overlap between the ES cell signature and our drug resistance signatures. No significant financial relationships to disclose.

Feasibility Study of Moderately Accelerated Intensity-Modulated Radiotherapy Plus Concurrent Weekly Cisplatin After Induction Chemotherapy in Locally Advanced Head-and Neck Cancer

To evaluate the feasibility and efficacy of moderately accelerated intensity-modulated radiation therapy (IMRT) along with weekly cisplatin, after induction chemotherapy, in patients with locally advanced unresectable head and neck cancer (HNC). Patients with Stage III or IV locally advanced HNC, without progressive disease after three courses of induction chemotherapy, received concurrent chemo-IMRT (weekly cisplatin 30 mg/m(2) plus simultaneous integrated boost IMRT). A total of 67.5 Gy in 30 fractions were delivered to primary tumor and involved nodes, 60 Gy in 30 fractions to high-risk nodal areas, and 55.5 Gy in 30 fractions to low-risk nodal areas. In all, 36 patients (median age, 56 years) with International Union Against Cancer (UICC) Stage III (n = 5) and IV (n = 31) were included. Of the 36 patients, 17 had received CF (cisplatin and 5-fluorouracil (CF) and 19 had received docetaxel cisplatin and 5-fluorouracil (DCF). During concurrent chemoradiation, 11 of 36 patients (30.5%) experienced Grade III mucositis (CF, 47%; DCF, 15%; p < 0.04). Grade III pharyngeal-esophageal toxicity was observed in 5 of 19 patients (26.3%; CF, 0.0%; DCF, 26.3%; p = 0.02). Two patients died of complications (5.5%). After chemoradiation, the complete response rate was 63.8%. Two-year local control was 88.7%. Two-year progression free survival and overall survival were 74.5% and 60.9%, respectively. In our experience, a moderately accelerated chemo-IMRT was feasible after induction chemotherapy. However, a noteworthy early death rate of 5.5% was observed. Intensive supportive care strategies should be defined to better manage radiation-induced toxic effects. Longer follow-up is required to determine the incidence of late radiation toxicities and tumor control rates.

Abstract 4284: Embryonic stem cell signature is enriched in the acquired resistance signature of gastric cancer patients to cisplatin/fluorouracil, and segregates newly diagnosed patients according to treatment outcome

Abstract Although cytotoxic chemotherapy remains the primary treatment option for metastatic cancer patients, even clinical responders ultimately develop the acquired resistance to chemotherapy. We hypothesized that identifying transcriptional alterations associated with acquired chemotherapy resistance from pre- and post-biopsy samples from the same patient would uncover potential molecular pathways involved in treatment failure. The serial collection of solid tumor samples from the same patients has been extremely difficult, but gastric cancer provides a unique opportunity since repeated endoscopies may be performed. We performed a prospective, high-throughput transcriptional profiling study using endoscopic biopsy samples from metastatic gastric cancer patients treated with cisplatin and fluorouracil (CF) combination chemotherapy at National Cancer Center in Korea. Twenty-two patients who initially responded to CF (with partial response according to WHO criteria) were biopsied a second time after they developed resistance to CF (at progressive disease according to WHO criteria). An acquired chemotherapy resistance signature was identified by analyzing the DNA microarray (U133A) expression profiles from the matched pre- and post-CF treated samples. The similarity of the acquired resistance signature to published embryonic stem (ES) cell signatures was tested using gene set comparison algorithms of BRB-ArrayTools. The acquired resistance gene signature was enriched for genes over-expressed in the published ES cell signature (defined by genes over-expressed in at least 5/20 human ES cells profiling studies) (LS P value&amp;lt;0.005). When this ES cell signature was modified to exclude genes listed in the Proliferation category of Gene Ontology and the proliferation cluster of breast cancer, the overlap between this amended ES expression set and our acquired resistance signature was still statistically significant. Importantly, genes overlapping between the ES cell signatures and the acquired resistance signature could segregate 101 newly-diagnosed metastatic gastric cancer patients according to progression-free survival and overall survival after CF chemotherapy (adjusted P values, 0.011 and 0.034, respectively). Thus, ES cell signature is enriched in our acquired resistance signature to CF, and may represent the core gene expression signature for clinical chemoresistance. To our knowledge, this work is the first study demonstrating the enrichement of ES cell signature in clinical specimens collected at the time of acquired resistance to cytotoxic chemotherapy. Genes contained in our acquired resistance signature may serve as clinically relevant molecular target candidates (supported in part by NIH Intramural Program, CCR, NCI; and by Korean NCC Grant 0910570). Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4284.

Gene expression signatures to predict the response of gastric cancer to cisplatin and fluorouracil

4628 Background: A prospective high-throughput gene expression study was conducted to identify transcriptional profiles predictive of a clinical response to cisplatin and fluorouracil (CF) combination chemotherapy and to identify dysregulated genes associated with acquired resistance to CF. Methods: Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer (MGC) patients (pts) prior to CF (n = 123) and following the development of resistance (n = 22) at the National Cancer Center of Korea from 2001 to 2006, and analyzed using CGH and expression microarrays. We developed 2 survival risk predictors. The first predictor was constructed using genes in DNA amplicons and identified in the expression signature that correlates with survival (intrinsic resistance signature). The second predictor was based on the acquired resistance signature, which was identified by comparing matched expression array data from initially responsive patients prior to treatment with profiles obtained at progressive disease. Results: Array CGH revealed the gene amplification of MYC, EGFR, and FGFR2 whose Affymetrix U133A signals significantly correlated with a poor prognosis (P values, 0.0154, 0.0096, and 0.0057) of training set pts (n = 96). Three-gene-predicted high-risk group of the validation cohort (n = 10) demonstrated a shorter median survival than low-risk (n = 17) group (7.4 vs 16.8 months; p = 0.047). The 3-gene signature, as a continuous variable, was the independent predictor for overall survival (OS) and time to progression (TTP) (adjusted P, 0.021, and 0.012). Importantly, the acquired resistance signature strongly overlapped the intrinsic resistance signature (LS P&lt;10-5), and was highly enriched for MYC target genes (LS p = 2x10-5). A predictor based on MYC target genes within the acquired resistance signature was the independent predictor for OS and TTP of 101 separate pts (adjusted p, 0.015, and 0.011). Conclusions: Combined overexpression of MYC, EGFR, and FGFR2 predicts a poor response of MGC pts to CF. There is significant overlap between intrinsic and acquired resistance signatures of MGC, where the MYC gene network plays a central role. This is the first demonstration that the acquired resistance signature predicts the initial response to chemotherapy. No significant financial relationships to disclose.

Induction Cisplatin and Fluorouracil-Based Chemotherapy Followed by Concurrent Chemoradiation for Muscle-Invasive Bladder Cancer

To evaluate a multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer. Patients with stages T2-4aN0M0 bladder cancer suitable for cystectomy underwent radical transurethral resection and induction chemotherapy, followed by concurrent chemoradiotherapy (CCRT). Patients with a Karnofsky performance status (KPS) <80 or age > or =70 years underwent Protocol A: induction chemotherapy with three cycles of the cisplatin and 5-fluorouracil (CF) regimen, and CCRT with six doses of weekly cisplatin and 64.8 Gy radiotherapy given with the shrinking-field technique. Patients with KPS > or =80 and age <70 years underwent Protocol B: induction chemotherapy with three cycles of weekly paclitaxel plus the CF regimen, and CCRT with six doses of weekly paclitaxel and cisplatin plus 64.8 Gy radiotherapy. Interval cystoscopy was employed after induction chemotherapy and when radiotherapy reached 43.2 Gy. Patients without a complete response (CR) were referred for salvage cystectomy. Among 30 patients (median, 66 years) enrolled, 17 and 13 patients underwent Protocol A and B, respectively. After induction chemotherapy, 23 patients achieved CR. Five (17%) of 7 patients without CR underwent salvage cystectomy. Overall, 28 patients (93%) completed the protocol treatment. Of 22 patients who completed CCRT, 1 had recurrence with carcinoma in situ and 3 had distant metastases. After a median follow-up of 47 months, overall and progression-free survival rate for all patients were 77% and 54% at 3 years, respectively. Of 19 surviving patients, 15 (79%) retained functioning bladders. Our protocols may be alternatives to cystectomy for selected patients who wish to preserve the bladder.

Optimizing docetaxel chemotherapy in patients with cancer of the gastric and gastroesophageal junction

Advanced gastroesophageal cancer patients are often treated with systemic combination chemotherapy. The V-325 study demonstrated that adding docetaxel (D) to a frequently used regimen of cisplatin and 5-fluorouracil (CF) provided benefits with regard to overall survival, response rate, time-to-disease progression, clinical benefit, and health-related quality of life. Although the DCF regimen provides these advantages, it is accompanied by an increase in toxicity compared with the doublet regimen. The toxicity profile of DCF is acceptable only with appropriately selected patients and comprehensive toxicity management strategies. The objective of the current review was to identify trials that investigated modifications to the original DCF regimen to improve its toxicity profile and summarize response rate and toxicities. An attempt was also made to summarize ongoing modifications of the DCF regimen. MEDLINE, major meeting proceedings, and the government clinical trials website were searched until 2007. The modified DCF regimens appear to improve the toxicity profile when compared with the original DCF regimen. The docetaxel-based triplet combinations appear to have a higher response rate than the doublet combinations. Many institutions and cooperative groups continue to study docetaxel-based modifications of the DCF regimen to treat patients with gastroesophageal carcinoma. However, although modified DCF reduces the frequency of severe toxicities previously reported with DCF, considerably more advances are needed to improve the safety, survival, and convenience of patients with advanced gastroesophageal cancer.

Clinical Benefit With Docetaxel Plus Fluorouracil and Cisplatin Compared With Cisplatin and Fluorouracil in a Phase III Trial of Advanced Gastric or Gastroesophageal Adenocarcinoma: The V-325 Study Group

For patients with advanced gastric or gastroesophageal cancer (AGGEC) providing clinical benefit with improved palliation is highly desirable. However, a prospective evaluation of clinical benefit in AGGEC patients has never before been reported in a phase III setting. In a multinational trial (V325), 445 patients were randomly assigned and treated with either docetaxel plus cisplatin and fluorouracil (DCF) or cisplatin and fluorouracil (CF). Clinical benefit was prospectively evaluated in this trial as a secondary end point. The primary measure for clinical benefit analysis was time to definitive worsening by one or more categories of Karnofsky performance status (KPS). Secondary clinical benefit end points included time to 5% definitive weight loss, time to definitive worsening of appetite by one grade, pain-free survival (defined as time to first appearance of pain), and time to first cancer pain-related opioid intake. Clinical benefit assessments were recorded at each clinic visit. Clinical benefit assessments were performed in more than 75% of patients throughout V325. DCF significantly prolonged time to definitive worsening of KPS compared with CF (median, 6.1 v 4.8 months; hazard ratio, 1.38; 95% CI, 1.08 to 1.76; log-rank P = .009). Although time to definitive weight loss and time to definitive worsening of appetite favored DCF, the results were not statistically significant. Pain-free survival and time to first cancer pain-related opioid intake were comparable. To our knowledge, V325 is the first phase III trial to report clinical benefit in AGGEC patients. Clinical benefit was assessed beyond protocol-specific chemotherapy. The addition of D to CF not only significantly improved clinical benefit but also improved quality of life, time to progression, and overall survival compared with CF.

Zytostatische Chemoptherapie beim Ösophagus Karzinom

BACKGROUND: More than two-thirds of patients diagnosed with esophageal cancer will have unresectable disease. Despite advances in diagnostic and surgical techniques and improved pre- and postoperative care, the prognosis of most patients is poor. This review will focus on the use of chemotherapy for patients with metastatic disease. METHODS: A computerized (MEDLINE) search was performed to identify papers published on this topic between 1966 and 2006. RESULTS: A total of 55 trials were subsequently identified. Two randomized trials compared palliative chemotherapy with best supportive care in 180 patients with advanced esophageal cancer. CONCLUSION: Combination chemotherapy as compared to monochemotherapy is associated with significantly higher response rates but nevertheless results in similar survival. CF (Cisplatin and 5-fluorouracil) currently represents one of the most effective regimens for metastatic esophageal cancer, while among the newer combinations, irinotecan or taxane-based regimens have also given promising results. However, confirmatory and adequately powered and designed phase III studies are urgently needed to improve patients' outcomes and for better palliation of symptoms.

Induction chemotherapy with paclitaxel, cisplatin and5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial

BackgroundThe aim of this study was to evaluate the efficacy and toxicity of a combination of paclitaxel, cisplatin and 5-fluorouracil (PPF) as induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). MethodsSeventy patients with previously untreated stage III–IV SCCHN were included in this phase II trial. Induction treatment consisted of a maximum of three outpatient courses of paclitaxel 175 mg/m2 as a 3-h infusion on day 1, cisplatin 100 mg/m2 on day 2, and 5-fluorouracil (5-FU) 500–750 mg/m2/day as a 24-h continuous infusion on days 2–6, repeated every 3 weeks. The 5-FU dose was reduced from 750 mg/m2/day to 500 mg/m2/day due to the excessive toxicity observed in the first 14 patients enrolled. Local treatment consisted of radiotherapy and/or surgery. ResultsTwo-hundred-and-one cycles were administered to 70 patients. The main toxicities of PPF were neutropenia (grade 4, 14%; febrile neutropenia, 4%), peripheral neuropathy (grade 2–3, 14%) and catheter-associated venous thrombosis (7%). There were three early deaths (two from neutropenic sepsis and one from pulmonary embolism), and 13 patients required hospitalization due to toxicity. Other side effects included mucositis, anorexia, diarrhea, myalgias and alopecia. The overall response rate to PPF was 88%, including 59% complete responses (CR) and 29% partial responses. The CR rates at the primary tumor and neck lymph nodes were 74% and 62%, respectively. With a median follow-up of 51 months (range 40–63 months), the estimated 5-year time-to-disease progression and overall survival rates were 56% and 44%, respectively. ConclusionsThe PPF regimen has major antitumor activity and is associated with manageable toxicity as induction treatment in SCCHN patients. The high complete response rate and favorable long-term outcome justify further evaluation of this chemotherapy combination.

Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck: A phase III study of the EORTC Head and Neck Cancer Cooperative Group

The EORTC Head and Neck Cancer Cooperative Group conducted a randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in chemotherapy naive patients with recurrent or metastatic squamous cell carcinoma of the head and neck. The primary objectives of this study were to investigate whether the CF regimen was in anyway superior to the CABO regimen and to detect any superiority of these two combinations over cisplatin alone. Three hundred eighty-two patients were randomized to one of three treatments: (1) methotrexate (40 mg/m2) days 1 and 15, bleomycin (10 mg) and vincristine (2 mg) days 1, 8 and 15, cisplatin (50 mg/m2) day 4, repeated every 21 days, (2) cisplatin (100 mg/m2) and 5-FU (1 g/m2 x 4), repeated every 21 days, and (3) cisplatin (50 mg/m2) days 1 and 8, repeated every 28 days. After 3 cycles, all responding and stable disease patients in the three arms of the study continued with cisplatin alone. The overall response rates to CABO (34%) and CF (31%) were superior to C (15%) (p < 0.001, p = 0.003, respectively). In addition, complete response rate to CABO (9.5%) was superior to that of C (2.5%) (p = 0.02), and also superior to that of CF (1.7%) (p = 0.01). Response was associated with performance status and prior treatment, but by multivariate analysis treatment type was the important determinant of response (p = 0.0006). Although CABO and CF were superior to C with respect to time to progression within the first 6 to 8 months after randomization, there was no overall difference in progression-free survival or survival between the three arms of the study. Both hematologic and non-hematologic toxicity were worse in the combination chemotherapy arms. We conclude that the CF regimen has no advantage over the CABO regimen, which in fact showed a higher complete response rate. Both combinations showed improved response rates but also more toxicity and no improvement in overall survival in comparison with cisplatin alone.