Cycles Of TPF Research Articles

Adding Induction Chemotherapy to Preoperative Concurrent Chemoradiotherapy Does Not Improve the Treatment Results in Locally Advanced Hypopharyngeal Carcinoma: A Randomized Phase II Trial

The role of TPF induction chemotherapy followed by concurrent chemoradiotherapy in the locally advanced hypopharyngeal carcinoma is unclear. Based on the established treatment modality-preoperative concurrent chemoradiotherapy by our institution, we conduct a phase II study to determine the role of induction chemotherapy in locally advanced hypopharyngeal carcinoma. A total of 142 patients with stage III/IVA-B hypopharyngeal carcinoma were randomly assigned (in a 1:1 ratio) to induction chemotherapy followed by preoperative concurrent chemoradiotherapy group (IC+CCRT group) or preoperative radiotherapy alone group (CCRT group), 113 patients were analyzed. The induction chemoradiotherapy regimen consists of Paclitaxel 175 mg/m2, d1, d22; DDP 75 mg/m2, d1, 22 and 5-FU 750 mg/m2, d1-4, 22-25. Concurrent chemotherapy regimen was cisplatin 80mg/m2/d1,22,43. All patients who received preoperative concurrent chemoradiotherapy will be evaluated at DT 53Gy, only primary lesions reaching large PR are recommended for radical concurrent chemoradiotherapy, otherwise planned surgery. We use the Kaplan-Meier method and the log-rank test to analyze. With a medial follow-up of 40.4 month, the 3-year overall survival(OS), progression-free survival(PFS), locoregional control rates(LRC), distant metastasis-free survival(DMFS)and laryngectomy-free survival of the IC+CCRT group (n = 53) and the CCRT group(n = 60) were 55.7% vs 55.1%(P = 0.802), 44.7% vs 56.1%(P = 0.324), 58.4%vs 69.8%(P = 0.198), 75.4%vs77.7%(P = 0.983) and 86.3%vs 85.4%(P = 0.938).Subgroup analysis showed that, the 3-year OS, PFS, LRC, DMFS and laryngectomy-free survival for patients who only received IC+CCRT group (n = 46, who received two cycles of TPF and radical concurrent chemoradiotherapy) and the CCRT group(n = 45, who received the radical concurrent chemoradiotherapy), were 61.1% vs 49.4%(P = 0.314), 50.3% vs 51.3%(P = 0.926), 62.5% vs 68.4%(P = 0.526), 76.3% vs 75.2%(P = 0.717)and 96.0% vs 89.1%(P = 0.236). The 3-year OS, PFS, LRC, DMFS and laryngectomy-free survival were 63.6% vs 50.8%(P = 0.217), 52.8% vs 52.6%(P = 0.813), 63.9% vs 66.6%(P = 0.621), 73.8% vs 76.3%(P = 0.926) and 94.0% vs 84.7%(P = 0.151) in the patients who response to induction chemotherapy (n = 45, who reached PR after two cycles of TPF) and control group(n = 59). The most common failure patterns were locoregional recurrence, followed by distant metastasis, with rate of 26.5% and 18.6%. There was no difference between the two groups. The grade 3+ hematologic toxicities between IC+CCRT vs CCRT were 40.78% vs 5.08% (P<0.001). The major failure pattern of locally advanced hypopharyngeal carcinoma is local regional relapse. Adding induction of chemotherapy to preoperative concurrent chemoradiotherapy could not improve the survival and laryngectomy-free survival of local advanced hypopharyngeal cancer in the cost of higher acute hematology toxicities. Clinical trial information: NCT03558035.

Induction Chemotherapy with Docetaxel, Cisplatin and 5-Fluorouracil (TPF) Followed by Chemoradiotherapy for Locally Advanced Head and Neck Cancer: Can It Achieve Its Potential?

Objective: In view of concerns about toxicity and deliverability of induction chemotherapy and its impact on subsequent chemoradiotherapy, a retrospective review was carried out with patients treated for locally advanced head and neck cancer (LAHNC) in a single centre between 2007-2017. Patients and Interventions: Patients with LAHNC and good performance status receiving induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF) followed by chemoradiotherapy to 70Gy in 35 daily fractions with platinum-based chemotherapy. Main Outcome Measures: Overall and cause-specific survival, rates of locoregional recurrence or distant metastasis, treatment-related toxicity. Results: One hundred and eight patients with LAHNC were treated with 1-4 cycles of TPF (95 receiving two cycles) followed by chemoradiotherapy. The mean delivered dose intensity was 97.6% for all TPF cycles. Median interval from the start of the final cycle of TPF to the start of radiotherapy was 24 days, with 92/103 (89%) starting radiotherapy within 28 days. Median radiation treatment time was 47 days. The mean delivered dose intensity for chemotherapy delivered concurrently with radiotherapy was 97%. There were significantly fewer dose reductions in those receiving platinum/5FU combinations than platinum only regimes (P &lt; 0.0001). For those receiving two cycles of TPF, 90% of patients completed the whole course of treatment within 14 weeks (median overall treatment time 13.1 weeks). There were four treatment-related deaths during induction chemotherapy and none during radiotherapy. Twenty-five developed locoregional failure and 13 distant metastases (both in eight). Actuarial overall survival was 60.7% at five years, with progression-free survival of 77.9% at two years and 74.1% at five years. For oropharynx cancers, overall survival was 70.4% and progression-free survival 80.8% at five years. Conclusion: Although significant toxicity from TPF was observed, with appropriate support, it is possible to complete treatment without undue compromise of subsequent treatment.

Prediction of Therapeutic Effects from One Course of TPF Chemotherapy for Advanced Hypopharyngeal Laryngeal Cancer.

In head and neck cancer, docetaxel, cisplatin and 5-fluorouracil (TPF) is often given in two or three cycles. The purpose of this study was to perform single-cycle TPF for chemoselection in patients with advanced hypopharyngeal laryngeal cancer. The study included 56 patients with stage III/IV advanced hypopharyngeal/laryngeal squamous cell carcinoma. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), TPF response rate, laryngeal sparing, and grade 3 or more adverse events. The median PFS was 34.8 months. The median OS was not evaluable. The response rate was 71%. The median laryngeal preservation period was not estimable. Grade 3 or 4 adverse events were reported in 46 patients. PFS rate in this study may have been improved by selecting surgical treatment for patients for whom chemoradiotherapy seemed less effective. One cycle of TPF in induction chemotherapy appeared effective for chemoselection.

298P - Long-term complication and outcomes after induction chemotherapy with TPF followed by chemoradiotherapy for nasopharyngeal cancer

BackgroundAlthough the acute toxicities during induction TPF in head and neck cancers are well known, there has been little studied about the long term complications including of outcomes in nasopharyngeal cancer (NPC). The purpose of this study is to evaluate the long term complications and survival outcomes in patients with locally advanced NPC treated with induction TPF followed by CRT. MethodsFrom 2004 to 2016, 244 patients were diagnosed as NPC. Among them, 104 patients who completed the 3 cycles of TPF (docetaxel 75 mg/m2 and cisplatin 75/m2 day 1, plus fluorouracil 1000 mg/m2 days 1–4, every 3 wks) followed by CRT were evaluated. During CRT, cisplatin was given as either a weekly or 3 weeks regimen and RT was performed at 65–70 Gy. After completing TPF and CRT, follow up imaging and regular examination was checked by ENT specialist. ResultsThe median follow-up duration was 60 months (range, 13-135). 5Y OS rate and 3Y PFS rate were 88.9±3.7% (95%CI 81.65-96.15) and 80.4±4.5 (95%CI 71.58-89.22). PFS was significantly associated with TNM (p = 0.001), especially N stage (N3, 3Y-PFS 42.9%, p = 0.001). The response after induction chemotherapy and postop CRT were significantly associated with PFS and OS. ENT complications such as hearing impairment, chronic infection, ear drum perforation were shown in 31 patients (30%) and renal impairment (Clcr≤60) was developed in 30 patients (30%). The incidence of both complications was significantly associated with age (>65 years, ENT Cx, p = 0.011, renal Cx, 0.032). However, age was not attenuate response rate or survival. The decreased Clcr before starting RT was associated with long term renal complication, and cumulative cisplatin dose did not affect treatment outcome. In addition, both ENT and renal toxicities were not associated with the radiation dose or cumulative cisplatin dose. ConclusionsTPF followed by CCRT is an effective treatment scheme for advanced NPC. However, long term complications in ENT and decreased renal function were considerable, especially in elderly. Therefore, careful observation and management are required for high risk patients and optimal cisplatin adjustment could be prevent renal complication without affecting the treatment outcomes. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Randomized phase II study with or without induction chemotherapy combined with accelerated high dose radiotherapy and cetuximab in locally advanced unresectable HPV positive squamous cell carcinoma of the head and neck.

6077 Background: Concomitant chemoradiotherapy (CT/RT) is the standard treatment for locally advanced non- resectable squamous cell carcinoma of the head and neck. Acute side effects can be serious and late effects important. Patients with HPV+ tumors carry a better prognosis than other patients. De-escalation studies are explored with respect to RT, dose, fractionation, target volumes, adjuvant pharmacotherapy, with encouraging results. However, several patients still recur locoregionally, also in high dose RT volumes. Some patients have distant metastases, often with massive tumor burden and late during follow up (FU). Purpose of the study: 1.To evaluate the effect of induction chemotherapy (IC) on (a) progression free survival (b) distant metastases as first site of failure (c) locoregional failure (d) pattern of tumor response, spatial and timely, exploring the possibility to reduce RT dose and/or target volume(s) in future protocols. 2. to address the impact of high dose RT for bulky disease, T3/T4 given concurrent with cetuximab (E). Methods: Patients had previously untreated stage III/IV (&gt;80 % st IV; TNM 7th), M0 disease, WHO 0-1, unresectable squamous cell carcinoma of the head and neck, HPV positive as evaluated with p16 and/or PCR. Pts were randomised between 2 arms. Pts in arm A were scheduled for 2 cycles of TPF : T (docetaxel) 75 mg/m2 day 1, P (cisplatin) 75 mg/m2 day 1 and F (fluorouracil) 1000 mg/m2 over 24 hours day 1-4. RT was delivered with IMRT to all pts : 68 Gy in 6 weeks for T1/T2 tumors, 76 Gy in 6.5 weeks for T3/T4 tumors with E given one week before and weekly during RT. Tumor response was evaluated according to RECIST with CT, MRI or PET/CT after IC, at 6-8 weeks, 1 and 2 years FU. Results: From january 2011 to february 2016, 152 consecutive pts were enrolled, 77 in arm A. All pts had oropharyngeal cancer. In arm A, 7 pts had CR after TPF, 19 had PR out of 36 evaluable pts. At 2 years FU 70/77 pts (91%) were alive in arm A, 69/75 (92%) in arm B. Distant metastases as first site of failure was 3 (3.9%) in arm A and 7 (9.3%) in arm B. Adverse events grade 3-4, ever registered, were seen in 71 pts in arm A and 63 in arm B, were transient, most often related to RT. Conclusions: Survival and locoregional control at 2 years was high and similar in both arms. Distant metastases as first site of failure was more than doubled in arm B, not having induction chemotherapy (IC). Clinical trial information: EudraCT number: 2009-013438-26.

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.

Primary prophylactic granulocyte colony-stimulating factor according to ASCO guidelines has no preventive effect on febrile neutropenia in patients treated with docetaxel, cisplatin, and 5-fluorouracil chemotherapy.

The efficacy of primary prophylactic granulocyte colony-stimulating factor (G-CSF) in preventing febrile neutropenia (FN) in patients treated with docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy remains controversial. We compared the incidence of FN in patients treated with and without primary prophylactic G-CSF. We performed a retrospective analysis of 142 patients with locally advanced head and neck or esophageal cancer treated with TPF between January 2009 and March 2017. Among them, 116 patients started TPF without primary prophylactic G-CSF (control group) while 26 patients were given primary prophylactic G-CSF from day 7 of the first cycle of TPF (prophylactic group). The incidence of grade 4 neutropenia during the first cycle of TPF was significantly higher in the control group than in the prophylactic group [58.6% (n = 68) vs. 30.8% (n = 8), p = 0.02]. However, the incidence of FN in the first cycle was not significantly different between the two groups [32 patients (27.5%) in the control group and 8 patients (30.8%) in the prophylactic group (p = 0.62)]. In addition, the mean relative dose intensity throughout all cycles of TPF, as well as the survival time and response after TPF, were also not significantly different between the two groups. Primary prophylactic G-CSF from day 7 of the first cycle of TPF did not reduce the incidence of FN. Our findings suggest that the timing of primary prophylactic G-CSF, as recommended by the American Society of Clinical Oncology guidelines, should be modified to reduce the incidence of FN in TPF.

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.

Prospective, Multicenter, Phase 2 Trial of Induction Chemotherapy Followed by Bio-Chemoradiotherapy for Locally Advanced Recurrent Nasopharyngeal Carcinoma

To evaluate, in a phase 2 study, whether induction docetaxel, cisplatin, and fluorouracil (TPF) followed by weekly docetaxel and cetuximab in concurrence with intensity modulated radiation therapy can improve the treatment outcome for patients with advanced locally recurrent nasopharyngeal carcinoma (rNPC). Thirty-three patients with rNPC (T3-T4, N0-N1, M0) were recruited. Of these, 19 patients (57.6%) had stage rT3 recurrence, and the rest had stage rT4. Eight patients also had rN1 at the time of relapse. Treatment outcomes and safety were evaluated. Among these 33 patients, 1 died after 1 cycle of TPF, 5 patients withdrew from the study during the induction period because of grade ≥3 toxicities; 27 patients completed the whole course of treatment, but 1 died before any assessment could be made. The median follow-up period was 28.5months. The progression-free survival and overall survival at 3years for the whole group were 35.7% and 63.8%, respectively. Among the 26 patients who could be assessed after treatment, the complete response rate was 30.8%, and the locoregional control rate at 3years was 49.2%. Temporal lobe necrosis (TLN) developed in 8 cases. The rates of grade ≥3 hearing loss, soft tissue necrosis, dysphagia, and trismus were 30.8%, 15.4%, 11.5%, and 19.2%, respectively. Overall, 5 patients died owing to acute (1 after cycle 1 TPF and 1 after completion of bio-chemoradiotherapy) or late (2 epistaxis and 1 TLN) treatment-related complications. The proposed salvage treatment regimen for advanced locally recurrent NPC could achieve a better treatment outcome than seen in previous studies. However, poor tolerability of induction TPF and the high rate of TLN limit its applicability outside clinical trials.

The role of interim FDG PET-CT after induction chemotherapy as a predictor of concurrent chemoradiotherapy efficacy and prognosis for head and neck cancer

PurposeInduction chemotherapy (ICT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CCRT) has the advantages of organ preservation and systemic control in head and neck cancer (HNC). Early prediction of CCRT efficacy may help identify patients who will benefit more from surgery than from CCRT. We investigated the role of interim 18-fluoro-2-deoxy-glucose positron emission tomography computed tomography (FDG PET-CT) after ICT to predict the efficacy of CCRT and clinical outcomes.MethodsTumor responses were retrospectively reviewed after CCRT based on the Response Evaluation Criteria in Solid Tumors. FDG PET-CT imaging was performed before and after three cycles of TPF. We examined the associations between the metabolic response (percentage decrease in the maximum standardized uptake value [SUVmax] and total metabolic tumor volume [MTV]) after ICT and complete response (CR) to CCRT, progression-free survival (PFS), and overall survival (OS).ResultsWe studied 43 HNC patients with a median follow-up of 32.7 months. Lymph node (LN) SUVmax and total MTV decreases from baseline after ICT were greater in patients with a CR to CCRT than in non-CR patients (LN SUVmax, 88.8% vs. 62.5%, respectively; total MTV, 99.7% vs. 89.9%, respectively). Decreases in total MTV ≥ 78% and LN SUVmax ≥73% after ICT predicted CR to CCRT and longer OS and PFS.ConclusionsUsing interim FDG PET-CT to measure SUVmax and total MTV after three cycles of ICT may be a useful technique for identifying HNC patients who will benefit from CCRT and predicting survival outcomes.

Dihydropyrimidine dehydrogenase mutation in neoadjuvant chemotherapy in head and neck cancers: Myth or reality?

Purpose:The docetaxel, 5-fluorouracil (5-FU), and cisplatin (TPF) regimen in India is associated with high percentages of Grade 3–4 toxicity. This analysis was planned to evaluate the incidence of dihydropyrimidine dehydrogenase (DPD) mutation in patients with severe gastrointestinal toxicity, to assess whether the mutation could be predicted by a set of clinical criteria and whether it has any impact on postneoadjuvant chemotherapy response.Methods:All consecutive patients who received TPF regimen in head and neck cancers between January 2015 and April 2015 were selected. Patients who had predefined set of toxicities in Cycle 1 were selected for DPD mutation testing. Depending on the results, C2 doses were modified. Postcompletion of two cycles, patients underwent radiological response assessment. Descriptive statistics has been performed. The normally distributed continuous variables were compared by unpaired Student's t-test, whereas variables which were not normally distributed by Wilcoxon sum rank test. For noncontinuous variables, comparison was performed by Fisher's exact test.Results:Out of 34 patients, who received TPF, 12 were selected for DPD testing, and 11 (32.4%, 95% confidence interval [95% CI]: 19.1–49.3%) had DPD mutation. The predictive accuracy of the criteria for the tested DPD mutations was 81.3% (95% CI: 62.1–100%). Of the 11 DPD mutation positive patients, except for one patient, all others received the second cycle of TPF. The dose adjustments done in 5-FU were 50% dose reduction in 9 patients and no dose reduction in one patient. The response rate in DPD mutated patients was 27.3% (3/11) and that in DPD nonmutated/nontested was 39.1% (9/23) (P = 0.70).Conclusion:In this small study, it seems that the incidence of DPD mutation is more common in Indian then it's in the Caucasian population. Clinical toxicity criteria can accurately predict for DPD mutation. Postdose adjustments of 5-FU from C2 onward, TPF can safely be delivered in the majority of patients with DPD heterozygous mutations without decrement in efficacy.

NEOADJUVANT CHEMOTHERAPY FOLLOWED BY CONCURRENT CHEMORADIATION FOR LOCALLY ADVANCED HEAD AND NECK CANCERS

Background: The administration of chemotherapy with radiotherapy in the treatment of patients with locally advanced head and neck carcinoma has been broadly used. For many years, chemotherapy has been administered in the adjuvant or neoadjuvant settings and concurrently with radiotherapy. Objective: To evaluate the role of neoadjuvant chemotherapy before concurrent chemoradiotherapy in treatment of locally advanced head and neck cancers regarding overall survival, progression free survival, toxicity and organ preservation. Patients and Methods: A 40 patients (all of whom had stage III or IVA disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) received 3 cycles of TPF (docetaxel plus cisplatin and fluorouracil) induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin and radiotherapy (70 Gy over 7 weeks) for 5 days per week. Results: With a minimum of 6 months of follow-up (median follow up period 14.3 months), over all response rate was 95% with complete remission in 30 patients (75%), partial response in 3 patients (7.5%), stationary disease in 5 patients (12.5%) and progressive disease in 2 patients (5%). The median overall survival was not reached and 3 years survival was 62.8%. The toxicity associated with this protocol was controlled and no chemotherapy associated deaths recorded. Conclusion: Induction chemotherapy by TPF is a reasonable approach for unresectable locally advanced head and neck squamous cell carcinoma and organ preservation for laryngeal and hypopharyngeal cancer patients. Also, it is of benefit in large tumor volume to decrease the volume of radiotherapy and subsequently its toxicity.TPF induction must be considered as one of the standards for larynx preservation.

A Phase 2 Open Label, Single-Arm Trial to Evaluate the Combination of Cetuximab Plus Taxotere, Cisplatin, and 5-Flurouracil as an Induction Regimen in Patients With Unresectable Squamous Cell Carcinoma of the Head and Neck

Despite treatment, prognosis of unresectable squamous cell carcinoma of the head and neck (SCCHC) is dismal. Cetuximab therapy has proven to increase the clinical activity of radiation therapy and chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile. We designed a phase 2 trial to evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil (TPF) plus cetuximab (C-TPF) as an induction regimen in patients with unresectable SCCHN. A single-arm phase 2 trial was conducted. Eligible patients included those with untreated unresectable SCCHC, World Health Organization performance status of 0 to 1, 18 to 70 years of age. Treatment consisted of four 21-day cycles of TPF (docetaxel, 75 mg/m(2) day 1; cisplatin, 75 mg/m(2) day 1; 5-fluorouracil [5-FU], 750 mg/m(2) day 1-5) and cetuximab, 250 mg/m(2) weekly (loading dose of 400 mg/m(2)). Prophylactic granulocyte colony-stimulating factor and antibiotic support were given. After induction, sequential accelerated radiation therapy with concomitant boost (69.9 Gy) and weekly cetuximab therapy were delivered in the absence of disease progression. The primary endpoint was objective response rate (ORR) to C-TPF. Fifty patients were enrolled across 8 centers. Median age was 54 years; disease was stage IV; oropharynx and hypopharynx were the most common primary sites. Eighty-two percent received 4 cycles of C-TPF, and 86% started sequential treatment based on radiation therapy and cetuximab. ORR after C-TPF was 86% (95% confidence interval [CI]: 73%-94%) and 24% had complete response (CR). With a median follow-up of 40.7 months, median overall survival (OS) was 40.7 months. The 2-year actuarial locoregional control (LRC) rate was 57%. The most common drug-related grade 3 or 4 toxicities during induction were neutropenia (24%), neutropenic fever (24%), and diarrhea (20%). There were 3 treatment-related deaths (6%). C-TPF yields high ORR and CR as induction treatment in unresectable SCCHN. However, hematologic toxicity is too high to recommend this regimen at the current dose.

Neoadjuvant (Na) Chemotherapy (Ct) with Docetaxel, Cisplatin and 5-Fluorouracil (Tpf) Before Concomitant Chemoradiation (Ccr) for Patients (Pts) with Locoregionally Advanced (La) Squamous Cell Carcinomas of the Head and Neck (Scchn): Updated Results of an Intensive Nurse-Led Support Program (Inlsp)

ABSTRACT Aim: 2/3 of the pts with SCCHN present in advanced stages (III and IV). Since 2007, in some centres, the standard of care for LA SCCHN is NA CT with TPF, followed by CCR. This approach has led to improved progression-free (PFS) and overall (OS) survival at the expense of greater toxicity (Tx). In 2012 we started at our institution an INLSP and all consecutive pts were enrolled. We present our updated Tx results. Methods: Pts were treated with Docetaxel 75mg/m2 (day 1), Cisplatin 75mg/m2 (day 1) and 5-Fluorouracil 750mg/m2/day (days 1-5) for 3 cycles, followed by CCR. The clinical records of all pts were retrospectively reviewed and demographical, epidemiological and clinical data were retrieved. We evaluated efficacy using clinical criteria and Tx using Common Terminology Criteria for Adverse Events 4.0. Treatment-related deaths, emergency room visits and hospital admissions were analyzed. Statistical analysis was performed using STATA (R). Results: Between July 2008 and March 2014 147 pts were treated at our institution (88% male). Mean age at diagnosis was 53 years-old. 95% of the pts had ECOG PS 0 or 1. The most common primary tumor locations were oropharynx (48%), hypopharynx (26%) and oral cavity (20%). The majority had stage IVA (52%) or IVB (46%) disease. Tobacco (95.9%) and Alcohol (93.2%) use were the most common comorbidities. 44.2% of the analyzed pts were enrolled on our INLSP. Pts received a mean number of 2.74 cycles of TPF. Overall clinical response rate (cRR) with TPF was 90.5%, with a Complete cRR of 19.1%. Most common adverse events (all grades) were anemia (43.5%) and diarrhea (25.2%). 25.2% of the pts experienced grade 3-4 Tx (mainly neutropenia and diarrhea). Seven pts died as a result of the treatment (4.8%). Pts enrolled on our INLSP experienced fewer grade 3-4 events (18.5 vs 30.5%), treatment-related deaths (4.6 vs 5.1%), emergency room visits (35.4 vs 40.2%) and hospital admissions (30.8 vs 34.1%), but differences were not statistically significant. Conclusions: NA CT with TPF followed by CCR is an effective treatment for pts with LA SCCHN. Tx is important. These pts should be treated at high-volume, experienced institutions. Our RR and Tx rates are comparable to other published series. Our INLSP improves Tx results, even though differences are still nonsignificant. Disclosure: All authors have declared no conflicts of interest.

Induction Chemotherapy with Docetaxel, Cisplatin and Fluorouracil (Tpf) in Locally Advanced Head and Neck Cancer–Single Center Retrospective Analysis

ABSTRACT Aim: Background: Most patients with head and neck cancer (HNC) present with locally advanced disease (stage III and IV). For these patients, the prognosis is poor. Recurrence rates range between 40-60% and overall survival (OS) at 5 years is less than 20%. Although induction chemotherapy is not considered standard treatment, it has a role in irresectable tumors or in organ preservation strategy, avoiding total laryngectomy (larynx and hypofarynx cancer). The three drug regimen, adding taxane to cisplatin and fluorouracil backbone, has shown to be superior in terms of OS and progression-free survival (PFS) in several phase III studies. Methods: Retrospective analysis of a consecutive series of patients with a new diagnosis of locally advanced HNC, with no distant metastases, treated with primary chemotherapy with TPF, from May 2010 until December 2013. After 3 cycles, the response was evaluated with a computerized tomography scan. If there was no response the treatment strategy was modified. The primary end point was OS. Survival was calculated with Kaplan-Meier method considering the time difference between the date of death or last observation and the date of the first cycle of TPF. Toxicity was classified according to Common Toxicity Criteria of Adverse Event (Version 3). Results: A total of 143 patients were included, 93,2% were male, with a median age of 52,8 years (35-76 years). Most of the patients presented with stage IVA disease (67,8%), 19,6% with stage IVB and 12,6% with stage III. The median follow-up time was 23 months. The median overall survival was 22,5 months, with an estimated OS at 24 months of 45%. 80,4% of the patients completed 4 cycles of chemotherapy. The response rate was 70,6%, with 9,1% of total responses. Most of the patients (48,3%) were subsequently treated with concomitant chemo-radiotherapy. Mucositis was the most frequent toxicity (9%). Infection (Grade ≥3) was detected in 3,5% of the patients. The rate of death associated with toxic effects or within 30 days of last cycle was 7,6%. Conclusions: Our survival data are comparable with the phase III studies, strengthening the role of induction chemotherapy in locally advanced head and neck cancer. Disclosure: All authors have declared no conflicts of interest.

Concomitant chemoradiation (CRT) or cetuximab/RT (CET/RT) versus induction Docetaxel/ Cisplatin/5-Fluorouracil (TPF) followed by CRT or CET/RT in patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN). A randomized phase III factorial study (NCT01086826).

6004 Background: Platinum-based CRT is the standard treatment for LASCCHN. CET/RT is superior to RT alone and it is an alternative treatment to CRT. Induction TPF resulted to be superior to cisplatin/5fluorouracil but its efficacy when added to concomitant treatment is to be demonstrated. We designed this open-label multicenter 2x2 factorial study to assess 2 primary endpoints: 1) overall survival (OS) of induction vs. no induction; 2) Grade 3-4 in-field mucosal toxicity of CRT vs. CET/RT (already presented at ASCO 2013). Methods: 421 patients with LASCCHN of the oral cavity, oropharynx, hypopharynx, stage III-IV, ECOG PS 0-1 were randomized to one of four treatment options: Arm A1: CRT (cisplatin/5fluorouracil x 2 concomitant to standard RT fractionation); Arm A2: CET/RT; Arm B1: 3 cycles of TPF followed by the same CRT; Arm B2: 3 cycles of TPF followed by CET/RT. The superiority hypothesis of OS comparison of TPF induction vs. no induction (Arms B1+B2 vs. A1+A2), requires 204 deaths to detect a relative reduction of 33% with 2-sided 5% significance level for the log-rank test and a power of 80%. Results: 415 out of 421 patients (six major violations) were finally analyzed: 207 in induction and 208 in concomitant arm. By march 2014, at a median follow-up of 41.3 months (mos), 243 events for PFS and 201 deaths were observed. Radiological CR was 43.5% in induction and 28% in concomitant arm (p=0.002) Median PFS was 29.7 mos in induction vs 18.5 in concomitant arm with a 3-year PFS of 46.8% vs 36.7% (HR:0.73; 95%CI 0.57-0.94; p=0.015), respectively. Median OS was 53.7 mos in induction vs 30.3 in concomitant arm with a 3-year OS of 57.6% vs 45.7% (HR:0.72; 95%CI 0.55-0.96; p=0.025) respectively. Compliance to concomitant treatments was not affected by induction TPF. Conclusions: Induction TPF followed by CRT or CET/RT significantly improved PFS and OS (independently from the type of concomitant strategy) in LASCCHN patients without compromising compliance to the concomitant treatments. Clinical trial information: NCT01086826.

A phase II-III study comparing concomitant chemoradiotherapy (CRT) versus cetuximab/RT (CET/RT) with or without induction docetaxel/cisplatin/5-fluorouracil (TPF) in locally advanced head and neck squamous cell carcinoma (LASCCHN): Efficacy results (NCT01086826).

6003 Background: This is the first phase III study directly comparing CRT vs CET/RT in LASCCHN. Primary endpoints of this study were to compare: 1) overall survival (OS) of induction vs. no induction arms; 2) Grade 3-4 in-field toxicity of CRT vs. CET/RT. Preliminary toxicity results of concomitant treatments (primary endpoint for this comparison) were reported at the 2012 ASCO meeting. Here we present response rate and survival data for the two concomitant treatments (CRT vs. CET/RT), irrespective of induction chemotherapy. Methods: Untreated patients with unresectable LASCCHN, stage III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: CRT (2 cycles of cisplatin/5fluorouracil concomitant to RT); Arm A2: CET/RT; Arm B1: 3 cycles of TPF followed by the same CRT; Arm B2:3 cycles of TPF followed by CET/RT. Results: A total of421 patients were randomized: 261 received CRT (131 Arm A1+ 130 Arm B1) and 160 received CET/RT (80 Arm A2+ 80 Arm B2). 82% were male; median age was 60y; PS of 0 (79%) or 1 (21%). Stage was III (32%) or IV (68%). Sites of disease were: oral cavity 20%, oropharynx 57%, hypopharynx: 23%. No significant differences were observed in patients’ characteristics distribution. At a median follow-up of 32.9 months, a total of 174 deaths occurred (204 required for final OS analysis). Data on activity and efficacy of CRT and CET/RT are shown in the Table. Conclusions: No significant differences were observed in response rate, progression free survival and OS between CRT and CET/RT. Pts are still being followed-up to assess OS of induction vs. no induction arms. Clinical trial information: NCT01086826. [Table: see text]

Induction chemotherapy (CT) with docetaxel, cisplatin, and fluorouracil (TPF) followed by concomitant cisplatin plus radiotherapy in locally advanced nasopharyngeal cancer (NPC): Results after 06 years.

6075 Background: In squamous cell carcinoma of head and neck cancer, TPF induction CT improved survival over cisplatin plus fluorouracil (Posner MR: NEJM, vol357, Oct 2007). The main objective of this study is to evaluate the activity and safety of TPF in patients (pts) with locally advanced NPC followed by concomitant cisplatin plus radiotherapy (cCTRT). Methods: Pts with undifferentiated NPC were enrolled from December 2006–December 2012 and received 3 cycles of TPF (docetaxel 75 mg/m2 and cisplatin 75/m2 day 1, plus fluorouracil 750 mg/m2 days 1–5, every 4 wks) with G-CSF days 1–5 post CT. CT was followed by cCTRT with cisplatin 40 mg/m2/wk and radiotherapy (65–70 Gy) starting 4–6 wks after the third cycle of CT. The primary endpoint was overall response rate (ORR) after induction CT and after cCTRT. Secondary end points were safety, disease free survival (DFS), and overall survival (OS). Results: 42 pts have been enrolled (26 M/16 F). UICC 1997 classification: n=9 stage II, n=10 stage III, n=23 stage IV. Median age is 37 yrs (range 18–64). Evocative clinical signs are cervical nodes n=20, rhinologic n=13, otologic n=5, and neurologic n=4. All pts were evaluated for safety and 38 for response.TPF well tolerated with main toxicities grade 3–4 (WHO) were neutropenia 36%, thrombocytopenia 32%, anemia 18%, diarrhea 6%, and mucositis 18%. Four pt died from sepsis that was probably treatment-related. ORR was 90% with an 71.4% (n=27) complete response (CR) rate, 23.6% (n=9) partial response (PR), and 5.2% (n=2) stable disease. No pts progressed after induction CT. Main toxicity during cCTRT was neutropenia grade 3–4 in 9%, mucositis grade 3 in 45% and grade 4 in 4%. Late toxicities were xerostomia grade 3 in 50%. At treatment completion, CR and PR rates were 79% and 20%; 2 pts had stable disease. At a median follow up of 72 months (range 7–72), 8% of pts have shown recurrence or progressive disease. DFS and OS rates at 72 months were 65% and 70%, respectively. Conclusions: TPF followed by cCTRT appears to be an active and feasible regimen with a manageable safety profile and may be a promising therapeutic option for pts with high stage NPC.

Induction chemotherapy challenges for head and neck cancer

In The Lancet Oncology, Haddad and colleagues1 present the results of the PARADIGM trial. In this randomised phase 3 study, induction with three cycles of TPF (docetaxel, cisplatin, and fluorouracil), one of the most efficient and popular polychemotherapies, followed by concurrent chemoradiotherapy with either docetaxel or carboplatin was compared with upfront concurrent chemoradiotherapy with bolus cisplatin. PARADIGM aimed to redefine the optimum treatment strategy in locally advanced head and neck carcinoma with 3-year overall survival as the primary endpoint.

Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial

The relative efficacy of the addition of induction chemotherapy to chemoradiotherapy compared with chemoradiotherapy alone for patients with head and neck cancer is unclear. The PARADIGM study is a multicentre open-label phase 3 study comparing the use of docetaxel, cisplatin, and fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin-based concurrent chemoradiotherapy alone in patients with locally advanced head and neck cancer. Adult patients with previously untreated, non-metastatic, newly diagnosed head and neck cancer were eligible. Patients were eligible if their tumour was either unresectable or of low surgical curability on the basis of advanced tumour stage (3 or 4) or regional-node stage (2 or 3, except T1N2), or if they were a candidate for organ preservation. Patients were randomly assigned (in a 1:1 ratio) to receive either induction chemotherapy with three cycles of TPF followed by concurrent chemoradiotherapy with either docetaxel or carboplatin or concurrent chemoradiotherapy alone with two cycles of bolus cisplatin. A computer-generated randomisation schedule using minimisation was prepared and the treatment assignment was done centrally at one of the study sites. Patients, study staff, and investigators were not masked to group assignment. Stratification factors were WHO performance status, primary disease site, and stage. The primary endpoint was overall survival. Analysis was by intention to treat. Patient accrual was terminated in December, 2008, because of slow enrolment. The trial is registered with ClinicalTrials.gov, number NCT00095875. Between Aug 24, 2004, and Dec 29, 2008, we enrolled 145 patients across 16 sites. After a median follow-up of 49 months (IQR 39-63), 41 patients had died-20 in the induction chemotherapy followed by chemoradiotherapy group and 21 in the chemoradiotherapy alone group. 3-year overall survival was 73% (95% CI 60-82) in the induction therapy followed by chemoradiotherapy group and 78% (66-86) in the chemoradiotherapy alone group (hazard ratio 1·09, 95% CI 0·59-2·03; p=0·77). More patients had febrile neutropenia in the induction chemotherapy followed by chemoradiotherapy group (16 patients) than in the chemoradiotherapy alone group (one patient). Although survival results were good in both groups there was no difference noted between those patients treated with induction chemotherapy followed by chemoradiotherapy and those who received chemoradiotherapy alone. We cannot rule out the possibility of a difference in survival going undetected due to early termination of the trial. Clinicians should still use their best judgment, based on the available data, in the decision of how to best treat patients. The addition of induction chemotherapy remains an appropriate approach for advanced disease with high risk for local or distant failure. Sanofi-Aventis.