5-fluorouracil Induction Chemotherapy Research Articles

Abstract 1999: DCAF7 acts as a scaffold to recruit USP10 for G3BP1 deubiquitylation and facilitates chemoresistance and metastasis in nasopharyngeal carcinoma

Abstract Though docetaxel plus cisplatin and 5-fluorouracil (TPF) induction chemotherapy becomes the standard care for locoregionally advanced nasopharyngeal carcinoma (NPC), some patients could not benefit from this therapy. The underlying mechanisms remain unclear. We found that DCAF7 was highly expressed in TPF resistant NPC patients, and promoted the cisplatin resistance and metastasis of NPC cells. Mechanistically, DCAF7 facilitates the interaction between USP10 and G3BP1, resulting in the removal of K48-linked ubiquitylation of G3BP1 at Lys76 mediated by USP10, thus preventing the degradation of G3BP1 through ubiquitin-proteasome pathway, and facilitates the stress granule (SG)-like structures formation. Moreover, knockdown of G3BP1 successfully reversed the SG-like structures formation and oncogenic effects exerted by DCAF7. Importantly, NPC patients with elevated DCAF7 expression exhibited high risks of metastasis, and is associated with a poor prognosis. This study identifies DCAF7 as a pivotal cisplatin resistance gene, and sheds light on the underlying mechanism of TPF resistance in NPC patients. The DCAF7-USP10-G3BP1 axis provides potential therapeutic targets and biomarker for NPC treatment. Citation Format: Qing-Jie Li, Xue-Liang Fang, Ying-Qin Li, Jia-Yi Lin, Cheng-Long Huang, Shi-Wei He, Sheng-Yan Huang, Jun-Yan Li, Sha Gong, Kai-Lin Chen, Na Liu, Jun Ma, Yin Zhao, Ling-Long Tang. DCAF7 acts as a scaffold to recruit USP10 for G3BP1 deubiquitylation and facilitates chemoresistance and metastasis in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1999.

Induction Chemotherapy in Squamous Cell Carcinoma of Tongue—Still a Slippery Role?

Abstract Background Tongue cancers are more common in the Indian subcontinent and a leading cause of morbidity and mortality among oral cavity cancers. Induction chemotherapy has been considered an intriguing and smart option for many reasons, but even after years of studies and debates, its role has not been fully established in the management of tongue cancers. Materials and Methods In this study, we evaluated 17 patients with oral tongue carcinomas with locally advanced stage, enrolled into a protocol of three drug (docetaxel, cisplatin, 5-fluorouracil) induction chemotherapy for three cycles. After completion of the three cycles, patients were clinically and radiologically re-evaluated and surgery was done if locally operable. Results At the completion of three cycles, five patients were partial responders, four patients were complete responders, and five patients had progressive disease after three cycles. Those patients with response underwent surgery. There were no significant morbid intraoperative or postoperative complications observed in seven out of nine patients. At the end of treatment completion, five out of nine patients had tumor residue/high-risk features and were planned for adjuvant radiotherapy. Conclusion For locally advanced oral tongue carcinomas, the role of induction chemotherapy before surgery has been fruitful and its impact on function preservation with acceptable oncological clearance is an emerging alternative. Spacing chemotherapy and radiotherapy reduce the incidence of adverse effects of combined treatment.

Circulating Tumor Cell Detection during Neoadjuvant Chemotherapy to Predict Early Response in Locally Advanced Oropharyngeal Cancers: A Prospective Pilot Study.

Patients with locally advanced oropharyngeal carcinoma treated with neoadjuvant chemotherapy are reassessed both radiologically and clinically to adapt their treatment after the first cycle. However, some responders show early tumor progression after adjuvant radiotherapy. This cohort study evaluated circulating tumor cells (CTCs) from a population of locally advanced oropharyngeal carcinoma patients treated with docetaxel, cisplatin, and 5-fluorouracil (DCF) induction chemotherapy or DCF with a modified dose and fractioned administration. The counts and phenotypes of CTCs were assessed at baseline and at day 21 of treatment, after isolation using the RosetteSepTM technique based on negative enrichment. At baseline, 6 out of 21 patients had CTCs (28.6%). On day 21, 5 out of 11 patients had CTCs (41.6%). There was no significant difference in the overall and progression-free survival between patients with or without CTCs at baseline (p = 0.44 and 0.78) or day 21 (p = 0.88 and 0.5). Out of the 11 patients tested at day 21, 4 had a positive variation of CTCs (33%). Patients with a positive variation of CTCs display a lower overall survival. Our findings suggest that the variation in the number of CTCs would be a better guide to the management of treatment, with possible early changes in treatment strategy.

The baseline oral microbiota predicts the response of locally advanced oral squamous cell carcinoma patients to induction chemotherapy: A prospective longitudinal study

PurposeAmong oral squamous cell carcinoma (OSCC) patients who receive docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy, those with a favorable pathological response tend to obtain satisfactory clinical outcomes, while the total population exhibit no survival benefit. Thus, there is an urgent need to improve the therapeutic effect of TPF by applying personalized treatment according to distinct biomarkers. Methods and materialsIn the present study, we collected oral rinse samples from 44 OSCC patients enrolled in our prospective multicenter random phase II trial before TPF induction chemotherapy to conduct 16S rRNA gene sequencing and metagenomic analysis. Patients were administrated with two cycles of TPF induction chemotherapy (75 mg/m2 cisplatin and 75 mg/m2 docetaxel on day 1 and 750 mg/m2 fluorouracil from the first to the fifth day), and then divided into responsive and nonresponsive groups according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ResultsIn the 16S rRNA gene sequence analysis, Fusobacterium and Mycoplasma were more enriched in the nonresponsive group, while Slackia was more enriched in the responder group at the genus level. In the metagenomic shotgun sequencing analysis, Fusobacterium nucleatum was more enriched in the nonresponsive group. Functional analysis showed that the platinum drug resistance pathway and microRNAs in cancer and RNA degradation pathways were remarkably associated with patient sensitivity to induction chemotherapy. ConclusionsOur data suggest that the oral microbiome may play an important role in the OSCC patient sensitivity to TPF induction chemotherapy and offer novel potential biomarkers for predicting the response to TPF induction chemotherapy.

Intensified Total Neoadjuvant Therapy in Patients With Locally Advanced Rectal Cancer: A Phase II Trial

AimsWe assessed the efficacy and safety of total neoadjuvant therapy, including targeted agent plus FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) induction chemotherapy followed by intensified chemoradiotherapy (CRT) and surgical resection, in patients with locally advanced rectal cancer. Materials and methodsThis was a single-arm, single-centre phase II trial. Eligible patients had non-metastatic locally advanced rectal adenocarcinoma. Based on Ras-BRAF status, patients were treated with bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) plus FOLFOXIRI regimen followed by oxaliplatin–5-fluorouracil-based CRT and surgery. The primary end point was pathological complete response rate. Secondary end points were toxicity, compliance, tumour downstaging, complete resection, surgical complications, local and distant failures and overall survival. The sample size was planned to expect an absolute 20% improvement in pathological complete response rate over historical literature data with an α error of 0.05 and a power of 80%. ResultsBetween October 2015 and September 2019, 28 patients (median age 66 years) were enrolled. All patients had regional lymph node involvement at diagnosis. FOLFOXIRI plus bevacizumab was administered in 11 mutated Ras-BRAF patients, whereas the 17 wild-type Ras-BRAF patients received FOLFOXIRI plus panitumumab/cetuximab. Overall, total neoadjuvant therapy was well tolerated and 26 patients (92.9%) completed the programmed strategy. A complete response was achieved in nine cases (32.1%) and a nearly pathological complete response (ypT1 ypN0) in two patients (7.2%). There was no evidence of febrile neutropenia and no grade 4 adverse events were recorded. Radical resection was achieved in all cases. ConclusionFOLFOXIRI plus targeted agent-based induction chemotherapy and intensified CRT before surgery showed promising clinical activity and was well tolerated in locally advanced rectal cancer patients. This phase II trial provides a strong rationale for phase III studies.

A multicenter randomized phase II trial of hyperthermia combined with TPF induction chemotherapy compared with TPF induction chemotherapy in locally advanced resectable oral squamous cell carcinoma

Background Hyperthermia has been reported to cause cancer stage regression, thus providing surgical opportunities in patients with unresectable tumors and improving the quality of life of patients by preserving certain organs. Methods A prospective open-label phase II trial was conducted to evaluate the efficacy of hyperthermia combined with induction chemotherapy in patients with locally advanced resectable oral squamous cell carcinoma (OSCC). Patients received hyperthermia combined with two cycles of 5-fluorouracil, cisplatin, and docetaxel (TPF) induction chemotherapy regimens or TPF induction chemotherapy alone, followed by radical surgery with postoperative radiotherapy. The primary endpoint was the clinical response rate of the induction chemotherapy. The secondary endpoints were overall survival (OS), disease-free survival (DFS), and toxicity. Results A total of 120 patients were enrolled, and 115 patients were included in the clinical response analysis. The clinical response rate was significantly higher in the experimental arm than in the control arm (65.45% vs. 40.00%, p = 0.0088). There were no unexpected toxicities, and hyperthermia and induction chemotherapy did not increase the perioperative morbidity rate. Moreover, there was a significant improvement in DFS, but no significant difference in OS between the two arms. In the subgroup analysis, increased OS and DFS rates were associated with patients with favorable clinical response after induction chemotherapy in the total population, experimental arm, and control arm. Conclusions Our study demonstrates that hyperthermia combined with induction chemotherapy is associated with a high response rate and provides a new treatment option for patients with resectable stage III or IVA OSCC.

Long term complications and prognostic factors in locally advanced nasopharyngeal carcinoma treated with docetaxel, cisplatin, 5-fluorouracil induction chemotherapy followed by concurrent chemoradiotherapy: A retrospective cohort study.

This study was conducted to evaluate the long term complications and their risk factors including of survival outcomes in patients with locally advanced nasopharyngeal cancer (NPC) treated with docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy (CCRT).Among the patients who were diagnosed as NPC, we consecutively evaluated the late complications in 104 patients who completed 3 cycles of TPF induction chemotherapy followed by CCRT and received regular follow-up by otolaryngologist and oncologist. The prognostic factors for overall survival, relapse free survival and each complication were analyzed based on clinical characteristics.Over a median follow-up of 54 months (range, 7.9–152.9 months), 5-year overall survival rate was 87% for stage II, 89% for stage III, 87% for stage IV patients. The significant prognostic factor for survival is complete response rate after CCRT in multivariate analysis. The most frequent toxicity was ear complication (29.8%) including of hearing loss requiring hearing aid (6.7%) and bone necrosis (3.8%). Decreased renal function over grade 2 was occurred in only 4 patients (3.8%) regardless of the cumulative dose of cisplatin. The long term complications did not affect the survival outcome. Patients who received radiation therapy more than 5400 cGy had better survival outcome than those who did not. However, ear complication was significantly related to radiation dose (≥ 6,600 cGy) and type of radiation therapy (conventional). Age over 65 years was a significant risk factor for both ear and renal toxicity. In conclusion, close follow-up to monitor long-term complications should be performed in patients treated with TPF induction chemotherapy followed by CCRT treatment, especially in elderly patients. Reestablishing the optimal chemotherapeutic agent during CCRT and adjustment of radiation dose after induction chemotherapy could be helpful to reduce the toxicity associated with the subsequent treatment strategy for locally advance NPC patients.

Efficacy and feasibility of induction chemotherapy with paclitaxel, carboplatin and cetuximab for locally advanced unresectable head and neck cancer patients ineligible for combination treatment with docetaxel, cisplatin, and 5-fluorouracil.

Docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy (ICT) is a treatment option for locally advanced unresectable head and neck squamous cell carcinoma (LA-HNSCC). However, patients with advanced age, or renal, cardiac or neurogenic dysfunction are ineligible for ICT-TPF. We retrospectively assessed 24 unresectable LA-HNSCC patients who received paclitaxel, carboplatin and cetuximab (PCE) as ICT at the Shizuoka Cancer Center between April 2013 and October 2018. Patient characteristics were as follows: median age, 72years (range 60-81); 0, 1, and 2 performance status (PS), 1, 15, and 8 patients, respectively, and creatinine clearance ≥ 60mL/min or < 60mL/min, 8 and 16 patients, respectively. The main reasons for PCE selection were renal impairment, older age, cardiac dysfunction, poor PS, and cerebral infarction. Twenty-two patients (92%) completed two or three cycles of ICT-PCE. After ICT-PCE, one patient (4%) and 20 patients (83%) achieved a complete response and partial response, respectively. Twenty-one patients (87%) advanced to definitive locoregional treatment. Median observation period was 25.2months. The 12-month progression-free and overall survival rates were 75 and 92%, respectively. Median progression-free survival and overall survival were 29.4 and 34.8months, respectively. Grade 3 or 4 toxicities included neutropenia (58%), oral mucositis (8%), and febrile neutropenia (4%). ICT-PCE may be a tolerable and potential option for unresectable LA-HNSCC patients ineligible for TPF.

MiR-92b as a marker for TPF induced chemotherapy response prediction and prognosis evaluation in with advanced oral squamous cell carcinoma patients

This study aimed to explore the clinical value of miR-92b in advanced oral squamous cell carcinoma (OSCC) and to observe the relationship between miR-92b and TPF induced chemotherapy and prognosis. Totally 114 patients with advanced OSCC admitted to our hospital were selected as the study subjects, all of whom received docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy. In addition, another 80 healthy subjects who underwent physical examination in our hospital from the same period were enrolled. The serum expression of miR-92b was detected by qRT-PCR. Serum miR-92b was up-regulated in patients with advanced OSCC, and its expression was associated with higher TNM staging and lymph node metastasis. The receiver operating characteristic (ROC) curve revealed that the area under the curve (AUC) of serum miR-92b for the diagnosis of advanced OSCC was 0.931. After treatment, the miR-92b expression was significantly reduced, and the ROC curve showed an AUC value of 0.889 for predicting treatment sensitivity of serum miR-92b. What's more, Logistic indicated that TNM staging, lymph node metastasis and serum miR-92b expression were independent risk factors affecting the treatment efficacy. Survival analysis demonstrated that OSCC patients with high miR-92b expression had poorer OS and DFS compared to patients with low miR-92b expression. Multivariate Cox regression exhibited that TNM staging, lymph node metastasis, and serum miR-92b expression were self-regulating risk factors for overall survival (OS) and disease-free survival (DFS) in patients with advanced OSCC. MiR-92b is up-regulated in patients with advanced OSCC, which can be used as a marker for induction chemotherapy and prognosis evaluation of advanced OSCC.

Identification of chemoresistance-associated miRNAs in hypopharyngeal squamous cell carcinoma

This study aimed to determine candidate miRNAs that could help to evaluate whether patients with hypopharyngeal squamous cell carcinoma (HSCC) would benefit from docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy. We downloaded the expression profiles of HSCC patients from the Gene Expression Omnibus database. miRNA profiles were analyzed via Principal Components Analysis (PCA), followed by Linear Discriminant Analysis (LDA). The Database Annotation for Visualization and Integrated Discovery tool was utilized for enrichment analysis; STRING and Cytoscape were used for network construction. We detected that hsa-miR-15b-5p, hsa-miR-93-5p, and hsa-miR-130a-3p might act as crucial regulators in chemoresistance of HSCC, and they may play as prognosticators and therapeutic targets in the future.

768P - Paclitaxel in combination with cisplatin and 5-fluorouracil (TPF) induction chemotherapy for locally advanced borderline-resectable esophageal squamous cell carcinoma: A phase II clinical trial

BackgroundThe optimal treatment for locally advanced borderline-resectable squamous cell carcinoma (SCC) of the oesophagus is unclear. This phase II trial assessed the safety and efficacy of paclitaxel in combination with cisplatin and 5-fluorouracil (TPF) induction chemotherapy and subsequent surgery for locally advanced borderline-resectable esophageal SCC (NCT02976909). MethodsPatients with clinical T4 and/or bulky lymphadenopathy that may invade nearby organs were eligible. Treatment started with 2 to 4 cycles of TPF induction chemotherapy (paclitaxel 135mg/m2 on day 1, cisplatin 75mg/m2 on Day 1; 5-fluorouracil 4g/m2 for 120hours continuous infusion from Day 1 to Day 5), followed by surgery if resectable, or by radical concurrent chemoradiotherapy if unresectable. The primary endpoint was pathologically proven complete resection (R0) rate. ResultsFrom November 2016 to December 2018, 47 patients were enrolled. After 2 to 4 cycles TPF chemotherapy, surgery was performed in 27 patients (57.4%), 10 (21.3%) patients received radical concurrent chemoradiotherapy. R0 resection was confirmed in 25 patients (53.2%). Pathologic complete response after chemotherapy was confirmed in 4 patients (8.5%). During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (29.8%), leucopenia (21.3%), febrile neutropenia (4.3%) and stomatitis (4.3%). No serious postoperative complications were observed in patients undergoing surgery. ConclusionsTPF induction chemotherapy followed by surgery as a multidisciplinary treatment strategy showed promising signs of tolerability and short-term efficacy in patients with locally advanced borderline-resectable esophageal SCC. Long-term survival is still being followed up. Legal entity responsible for the studyYuhong Li. FundingGuangdong Esophageal Cancer institute. DisclosureAll authors have declared no conflicts of interest.

Toxicité de la chimiothérapie d’induction par docétaxel, platine, 5-fluorouracile (TPF) pour les cancers des voies aérodigestives supérieures localement évolués en routine clinique : importance du statut nutritionnel

PurposeThe objective of this study was to identify predictive factors of toxicity of docetaxel, platin, 5-fluorouracil (TPF) induction chemotherapy for locally advanced head and neck cancers. Patients and methodsFrom July 2009 to March 2015, 57 patients treated consecutively with TPF were included retrospectively. There were 47 males (83%), the median age was 56 years [40–71 years]. Thirty-eight patients (67%) were treated for inoperable cancer (highly symptomatic and/or high tumor burden) and 19 (33%) were treated for laryngeal preservation. There were 47% stage IVa, 32% stage III and 21% stage IVb. At diagnosis, there were 53% stable weight, 28% grade 1 weight loss, 17% grade 2 weight loss and 2% grade 3 weight loss. ResultsForty-seven percent of patients were in partial response after TPF, 28% in complete response, 7% stable, 2% progressing and 2% discordant response. The possibility of oral feeding without a feeding tube was predictive of a better response (P=0.02). Thirty-nine percent of patients increased weight during TPF, 35% were stable, 18% in grade 1 weight loss, 6% in grade 2 and 2% in grade 3. Six of the patients (10.5%) died during chemotherapy: four from febrile neutropenia, one from pneumopathy and one of unknown cause. Age 57years and older was associated with a higher risk of grade≥3 anemia and thrombocytopenia. There was a higher risk of grade≥3 infection for weight loss at diagnosis (P=0.04) and feeding tube (P=0.05). There was a higher risk of grade≥3 neutropenia for weight loss during TPF (P=0.03). ConclusionInduction chemotherapy by TPF has an strong anti-tumor efficacy (75.5% objective response) but an important morbidity with 10% toxic deaths in our very symptomatic population with a very important tumor burden. Age and nutritional status are important factors to consider.

Personalized TPF induction chemotherapy on the basis of stathmin expression in patients with locally advanced oral squamous cell carcinoma.

6040 Background: A randomized phase 3 trial failed to demonstrate a survival advantage for TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in the overall study population of patients with locally advanced and resectable oral squamous cell carcinoma (OSCC). It is possible that personalized TPF-based induction chemotherapy might improve outcomes in biomarker-defined subsets of patients. Methods: Immunohistochemical staining against stathmin was performed in pre-treatment biopsy specimens in 170 OSCC patients from our randomized trial. Chemoresistance to TPF chemotherapy drugs regulated by stathmin expression was investigated. The anti-cancer activity of TPF chemotherapy drugs alone, a combination of TPF drugs and PI3K-AKT-mTOR pathway inhibitors, and vincristine were investigated using in vitro and in vivo OSCC models. Results: OSCC patients with low stathmin expression benefited from TPF induction chemotherapy in terms of overall survival (HR = 0.102, 95% CI:0.013-0.781, P = 0.028), disease-free survival (HR = 0.070, 95% CI:0.009-0.525, P = 0.010), locoregional recurrence-free survival (HR = 0.070, 95% CI:0.009-0.524, P = 0.010), and distant metastasis-free survival (HR = 0.101, 95% CI:0.013-0.767, P = 0.027). Stathmin overexpression promoted cellular proliferation and chemoresistance to TPF drugs in OSCC (P &lt; 0.05). PI3K pathway inhibitors decreased stathmin expression and phosphorylation, and improved the chemosensitivity to TPF drugs in vitro and in vivo (P &lt; 0.05). Vincristine decreased stathmin expression and phosphorylation, and OSCC lines were significantly sensitive to vincristine in vitro and in vivo (P &lt; 0.01). Conclusions: Our results suggest a potential personalized TPF induction chemotherapy on the basis of stathmin expression in OSCC patients: patients with low stathmin expression in the biopsy samples are suggested to receive TPF induction chemotherapy followed by surgical resection and post-operative radiotherapy. For patients with stathmin overexpression PI3K inhibitor is a good choice to improve the inductive effect of TPF chemotherapy drugs; vincristine is a potential alternative for a chemotherapy drug when a patient is chemoresistant to or unsuitable to receive TPF chemotherapy drugs; however, more clinical trials are warranted to verify this optimization protocol.

Long-Term Survival and Prognostic Factors in Locoregionally Advanced Nasopharyngeal Carcinoma Patients Treated with TPF Induction Chemotherapy followed by Cisplatin-Combined Concurrent Chemoradiotherapy.

Purpose: The objective of this study was to report long-term results of docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and identify prognostic factors for this group of patients.Materials and Methods: From December 2010 to January 2015, 109 patients with locoregionally advanced (III-IVB) NPC were included. Patients were scheduled to complete TPF induction chemotherapy followed by cisplatin based CCRT. Failure-free survival (FFS), overall survival (OS), locoregional failure-free survival (LRFFS) and distant failure-free survival (DFFS) served as clinical outcomes. Kaplan-Meier method, Cox proportional hazards model and receiver operating characteristic (ROC) curves were used for analyzing.Results: With a median follow-up of 60.2 months (range, 7.9-91.6 months), 3-year FFS, OS, LRFFS, and DFFS were 76.8%, 85.1%, 88.3%, and 84.1%, respectively. The highest incidence rate of recurrence and metastasis were in the first year after treatment. Multivariate analyses showed that age, total time of radiation therapy (RTT), and total time of therapy (TTT) were independent prognostic factors for FFS and OS. Body mass index (BMI), RTT and TTT were significant variables predicting DFFS. TTT was the only independent prognostic factor for LRFFS.Conclusion: This study indicated that TPF regimen produced encouraging results in Asian patients with locoregionally advanced nasopharyngeal carcinoma. Toxicity was tolerable and reversible. However, overall treatment time is an important factor that we should take into consideration when make plans of induction chemotherapy related treatment.

Importance of magnesium sulfate supplementation in the prevention of hypomagnesemia and hypocalcemia during chemoradiation in head and neck cancer

In advanced squamous cell carcinoma of the head and neck, concomitant radiotherapy with cisplatin and/or cetuximab is frequently combined with cisplatin-based induction chemotherapy, which can cause severe hypomagnesemia, hypocalcemia, and hypokalemia. The aim of our study was to analyze the effects of magnesium sulfate supplementation on the incidence of hypomagnesemia, hypokalemia, and hypocalcemia during four cycles of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy followed by concomitant radiotherapy (CRT) with cisplatin and cetuximab. Twenty-five patients included in a phase II prospective study received routine magnesium sulfate infusions before each cycle of cisplatin, and additional supplementation based on laboratory findings. During TPF, the incidence of grade 1/2 and grade 3/4 hypomagnesemia was 16% and 4%, respectively; and increased despite magnesium supplementation during CRT to 72% and 8%, respectively. During TPF, a grade 2 and grade 4 hypocalcemia occurred in 8% and 4%, respectively; and during CRT, it reached 36% (grade 1/2). Grade 1 hypokalemia only was observed during TPF (4%) and CRT (8%). The median amounts of supplemented magnesium sulfate during TPF and CRT were 20 mEq and 50 mEq, respectively. It appears that a low incidence of grade 3/4 hypomagnesemia and hypocalcemia in our patients resulted from intensive magnesium supplementation. Thorough measurements of magnesium and calcium during cisplatin-based chemoradiation protocols in patients with head and neck cancer are crucial in preventing the development of grade 3/4 hypomagnesemia and hypocalcemia.

TPF induction chemotherapy followed by concurrent chemoradiotherapy for locally advanced nasopharyngeal carcinoma: Long term results of a Tunisian series

PurposeWe represent in this study the long term results of docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by concurrent chemoradiotherapy in Tunisian patients with locally advanced nasopharyngeal carcinoma. The objective of our study is to analyse the efficacy as well as the toxicity of this therapeutic protocol. Patients and methodsBetween January 2004 and December 2008, 32 patients with locoregional advanced non metastatic disease (T2b or above and/or N1 or above AJCC 2002) were treated in our institution by three cycles of docetaxel, cisplatin and 5-fluorouracil induction chemotherapy every 21 days followed by concurrent chemoradiotherapy. Conventional radiotherapy was delivered using a cobalt 60 machine during 7 weeks with weekly cisplatin (40mg/m2). ResultsTwenty-nine patients (90%) had presented an objective clinical response in lymph nodes after neoadjuvant chemotherapy, with a complete response in 28%. Acute toxicity of docetaxel, cisplatin and 5-fluorouracil induction chemotherapy was dominated by vomiting (59%), asthenia (40.6%), diarrhea (34.4%) and febrile neutropenia (15.6%). The complete response rate after the end of treatment was around 80%. The 5 years overall survival and disease-free survival were respectively 68.2% and 67.5%. ConclusionOur results, in this field of study, are encouraging with acceptable toxicity despite the lack of intensity-modulated radiotherapy technique in our institution during the period of study.

Elevated growth differentiating factor 15 expression predicts long-term benefit of docetaxel, cisplatin and 5-fluorouracil induction chemotherapy in patients with oral cancer.

Our previous phase 3 trial (NCT01542931) failed to demonstrate improved survival when docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy was introduced prior to surgery and postoperative radiotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). The aim of the present study was to investigate the long-term predictive value of GDF15 expression for potential personalized treatment strategies in OSCC. A total of 256 patients with stage III/IVA OSCC from our phase 3 trial were enrolled in the present study. Immunohistochemical staining against GDF15 was performed in the biopsy samples from 230/256 patients. Kaplan-Meier analysis, followed by the log-rank test, and the Cox proportional hazards model were used for outcome analysis using the statistical SPSS 18.0 software package for Windows. Among the 230 patients, low GDF15 expression was detected in 68 patients and high GDF15 expression was detected in 162 patients. With a median follow-up period of 67 months, the patients with low GDF15 expression exhibited a higher survival rate than those with high GDF15 expression, including 5-year overall survival (73.4 vs. 57.7%; P=0.059), 5-year disease-free survival (64.5 vs. 49.2%; P=0.033), 5-year locoregional recurrence-free survival (66.0 vs. 51.5%; P=0.043) and 5-year distant metastasis-free survival (73.4 vs. 56.6%; P=0.038) rates. Furthermore, the cT3/4N0M0 patients with high GDF15 expression benefited significantly from TPF induction chemotherapy, including overall survival (HR=0.233; P=0.02), disease-free survival (HR=0.296; P=0.014), locoregional recurrence-free survival (HR=0.347; P=0.035) and distant metastasis-free survival (HR=0.212; P=0.013) rates. The results of the present study suggested that elevated GDF15 expression may be used as a long-term prognostic biomarker for poor clinical outcomes in patients with locally advanced OSCC. Elevated GDF15 expression in cT3/4N0M0 patients predicts significant long-term benefit of survival from TPF induction chemotherapy.

Value of two-cycle docetaxel, cisplatin, and 5-fluorouracil induction chemotherapy in hypopharyngeal carcinoma.

Various studies have investigated laryngeal function and survival after induction chemotherapy in hypopharyngeal carcinoma, but potential factors to help predict response rates after induction chemotherapy remain unknown. This retro- spective study evaluated which factors are related to an ineffective response to two-cycle docetaxel, cisplatin, and 5-fluoro- uracil (TPF) induction chemotherapy in hypopharyngeal carcinoma to determine potential candidates for this treatment in clinical practice. From Jan 2005 to Dec 2015, 81 patients diagnosed with hypopharyngeal squamous cell carcinoma based on a pathological examination were analyzed. They were administered two-cycle TPF induction chemotherapy, and magnetic resonance imaging was performed before and after induction chemotherapy. The mean survival time was 5.7 years (95% confidence interval, 5.1-6.2 years). The 1, 3, 5 and 6-year survival rates were 98.8%, 80.1%, 64.5%, and 54.2%, respectively. TPF induction chemotherapy was well tolerated; the main adverse effects resolved with symptomatic treatment. A response to TPF induction chemotherapy was associated with lymph node size, tumor grade, invasion region, T stage, and primary tumor. The following issues were significantly associated with an increasing non-response rate to two-cycle induction chemotherapy: increasing lymph node size, moderately differentiated squamous cell carcinoma, invasion of the esophagus along with the thyroid cartilage, and primary tumor in the piriform sinus. Lymph nodes of ≥2.15 cm, moderately differenti- ated tumor grade, or thyroid cartilage invasion were the best cutoff values for patients who did not respond to induction chemotherapy. However, the initial cancer site, cancer stage, and degree of cancer differentiation were not closely related to the efficacy of induction chemotherapy.

Taxane, platinum and 5-FU prior to chemoradiotherapy benefits patients with stage IV neck node-positive head and neck cancer and a good performance status.

The benefit of adding docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy to chemoradiotherapy (CRT) in head and neck squamous cell carcinoma (HNSCC) remains uncertain. We aimed to investigate whether ICT is well tolerated when given with prophylactic treatment against predicted adverse effects and which patients benefit most. A single-centre audit identified 132 HNSCC patients with stage IVa/b neck node-positive disease, prescribed TPF followed by CRT. TPF involved three cycles of docetaxel (75mg/m2 IV) and cisplatin (75mg/m2 IV) on day 1 plus 5-FU (750mg/m2 IV) on days 2-5. Planned CRT was 66Gy in 30 fractions of intensity-modulated radiotherapy with concurrent cisplatin (100mg/m2 IV) at the beginning of week 1 and 4 (days 1 and 22). All patients received prophylactic antibiotics and granulocyte colony-stimulating factor. Median follow-up was 39.5months. 92.4% of patients completed three cycles of TPF; 95.5% of patients started chemoradiotherapy. Grade 3/4 adverse events were low (febrile neutropenia 3.0%), with no toxicity-related deaths. 3-year overall survival was 67.2%; disease-specific survival was 78.7%; locoregional control was 78.3%. Distant metastases rate was 9.8% (3.0% in those without locoregional recurrence). Good performance status (p=0.002) and poor tumour differentiation (p=0.018) were associated with improved overall survival on multivariate analysis. With prophylactic antibiotics and granulocyte colony-stimulating factor TPF was well tolerated with good survival outcomes. TPF should remain a treatment option for stage IV neck node-positive patients with a good performance status. The use of tumour grade to aid patient selection for TPF warrants investigation.

A two-arm multicenter phase II trial of one cycle chemoselection split-dose docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy before two cycles of split TPF followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1)

Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for locally advanced head and neck cancer. This phase II study investigated the effectivity of a split-dose TPF ICT before surgery for locally advanced resectable (stage III/IVA) oral and oropharyngeal cancer. Patients received TPF split on two dosages on days 1 and 8 per cycle (30 mg/m2 docetaxel, 40 mg/m2 cisplatin, 2000 mg/m2 fluorouracil per week). Responders (reduction tumor volume ≥30% after first cycle) received three 3-week cycles and non-responders only one cycle before surgery and postoperative radio(chemo)therapy (RCT). The primary endpoint was progression-free survival rate after 24 months. Secondary endpoints were amongst others overall survival, histopathological response to ICT, toxicity, quality of life and swallowing function. Fifty-four patients (91% stage IVA, 87% male, 72% oropharyngeal cancer, 70% responders) were eligible for a per-protocol analysis. The progression-free survival rate after 24 months was 88.5% for responders and 60.6% for non-responders (P = 0.005). The overall survival rate after 24 months was 97.3% for responders and 73.7% for non-responders (P = 0.032). The rate of histopathological complete remission of the primary tumor was higher in responders (P = 0.015). High-risk classification for postoperative RCT was lower in responders (P < 0.0001). The most common grade 3+ adverse event was neutropenia in 26% of patients during ICT and mucositis in 13% during postoperative RCT. During treatment and follow-up quality of life and swallowing function was not different between responders and non-responders. Patients with oral and oropharyngeal cancer responding to split-dose TPF before surgery and postoperative RCT show good oncological results. The tri-modal treatment regime was well tolerated. ICT using tumor response as criterion for duration of ICT before surgery of oral and oropharyngeal cancer merits additional investigation in a phase III study. NCT01108042.