Phase I/II Trial of Outpatient Docetaxel, Cisplatin, 5-Fluorouracil, Leucovorin (opTPFL) as Induction for Squamous Cell Carcinoma of the Head and Neck (SCCHN) Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: a phase I-II feasibility study. Phase II trial of docetaxel, cisplatin, fluorouracil, and leucovorin as induction for squamous cell carcinoma of the head and neck. Docetaxel: an active drug for squamous cell carcinoma of the head and neck. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group.
The purpose of this study was to establish the maximum tolerated dose ( MTD ) of docetaxel in an outpatient docetaxel ( T ) , cisplatin ( P ) , 5-fluorouracil ( 5-FU ) ( F ) , and leucovorin ( L ) ( opTPFL ) regimen and to obtain preliminary assessment of opTPFL efficacy . Thirty-four patients with stage III or IV squamous cell carcinoma of the head and neck were treated with opTPFL . Docetaxel was escalated from 60 to 95 mg/m2 in combination with 100 mg/m2 cisplatin intravenous bolus , and 2,800 mg/m2 5-FU continuous infusion and 2,000 mg/m2 leucovorin continuous infusion with prophylactic growth factors and antibiotics . Patients who achieved a complete ( CR ) or partial ( PR ) response to three cycles received definitive twice-daily radiation therapy . A total of 97 cycles were administered to 34 patients . The major acute toxicities were neutropenia and mucositis . The MTD of docetaxel was 90 mg/m2 . Seventy-seven of 97 cycles of were administered on an outpatient basis . The overall clinical response rate to opTPFL was 94 % , with 44 % CRs and 50 % PRs . The MTD of opTPFL is 90 mg/m2 docetaxel . Outpatient administration of opTPFL is tolerable , feasible , and does not alter the ability to administer definitive radiation therapy on schedule BACKGROUND A r and omized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil ( TPF ) with cisplatin and fluorouracil ( PF ) , followed by chemoradiotherapy . METHODS We r and omly assigned 501 patients ( all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were c and i date s for organ preservation ) to receive either TPF or PF induction chemotherapy  , followed  by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week . The primary end point was overall survival . RESULTS With a minimum of 2 years of follow-up ( > or =3 years for 69 % of patients ) , significantly more patients survived in the TPF group than in the PF group ( hazard ratio for death , 0.70 ; P=0.006 ) . Estimates of overall survival at 3 years were 62 % in the TPF group and 48 % in the PF group ; the median overall survival was 71 months and 30 months , respectively ( P=0.006 ) . There was better locoregional control in the TPF group than in the PF group ( P=0.04 ) , but the incidence of distant metastases in the two groups did not differ significantly ( P=0.14 ) . Rates of neutropenia and febrile neutropenia were higher in the TPF group ; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group . CONCLUSIONS Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy . ( Clinical Trials.gov number , NCT00273546 [ Clinical Trials.gov ] . ) BACKGROUND Phase 2 studies suggest that the st and ard regimen of cisplatin and fluorouracil ( PF ) plus docetaxel ( TPF ) improves outcomes in squamous-cell carcinoma of the head and neck . We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced , unresectable disease . METHODS We r and omly assigned eligible patients between the ages of 18 and 70 years who had stage III or stage IV disease and no distant metastases to receive either TPF ( docetaxel and cisplatin , day 1 ; fluorouracil by continuous infusion , days 1 to 5 ) or PF every 3 weeks for four cycles . Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy . The primary end point was progression-free survival . RESULTS A total of 358 patients underwent r and omization , with 177 assigned to the TPF group and 181 to the PF group . At a median follow-up of 32.5 months , the median progression-free survival was 11.0 months in the TPF group and 8.2 months in the PF group ( hazard ratio for disease progression or death in the TPF group , 0.72 ; P=0.007 ) . Treatment with TPF result ed in a reduction in the risk of death of 27 % ( P=0.02 ) , with a median overall survival of 18.8 months , as compared with 14.5 months in the PF group . There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia , nausea , vomiting , stomatitis , and hearing loss in the PF group . The rates of death from toxic effects were 2.3 % in the TPF group and 5.5 % in the PF group . CONCLUSIONS As compared with the st and ard regimen of cisplatin and fluorouracil , induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck . ( Clinical Trials.gov number , NCT00003888 [ Clinical Trials.gov ] . ) BACKGROUND We performed a prospect i ve , r and omized study in patients with previously untreated advanced ( Stage III or IV ) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation . METHODS Three hundred thirty-two patients were r and omly assigned to receive either three cycles of chemotherapy ( cisplatin and fluorouracil ) and radiation therapy or surgery and radiation therapy . The clinical tumor response was assessed after two cycles of chemotherapy , and patients with a response received a third cycle followed by definitive radiation therapy ( 6600 to 7600 cGy ) . Patients in whom ther was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy .  RESULTS After two cycles of chemotherapy , the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent . After a median follow-up of 33 months , the estimated 2-year survival was 68 percent ( 95 percent confidence interval , 60 to 76 percent ) for both treatment groups ( P = 0.9846 ) . Patterns of recurrence differed significantly between the two groups , with more local recurrences ( P = 0.0005 ) and fewer distant metastases ( P = 0.016 ) in the chemotherapy group than in the surgery group . A total of 59 patients in the chemotherapy group ( 36 percent ) required total laryngectomy . The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease . CONCLUSIONS These preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients , without compromising overall survival PURPOSE To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel , cisplatin , and fluorouracil ( FU ; PCF ) versus st and ard cisplatin and FU ( CF ) , both followed by chemoradiotherapy ( CRT ) , in locally advanced head and neck cancer ( HNC ) . PATIENTS AND METHODS Eligibility criteria included biopsy-proven , previously untreated , stage III or IV locally advanced HNC . Patients received either CF ( cisplatin 100 mg/m2 on day 1 plus FU 1000 [ corrected ] mg/m2 continuous infusion on days 1 through 5 ) or PCF ( paclitaxel 175 mg/m2 on day 1 , cisplatin 100 mg/m2 on day 2 , and FU 500 mg/m2 continuous infusion on days 2 through 6 ) ; both regimens were administered for three cycles every 21 days . Patients with complete response ( CR ) or partial response of greater than 80 % in primary tumor received additional CRT ( cisplatin 100 mg/m2 on days 1 , 22 , and 43 plus 70 Gy ) . RESULTS A total of 382 eligible patients were r and omly assigned to CF ( n = 193 ) or PCF ( n = 189 ) . The CR rate was 14 % in the CF arm v 33 % in the PCF arm ( P < .001 ) . Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm ( log-rank test , P = .006 ; Tarone-Ware , P = .003 ) . PCF patients had a trend to longer overall survival ( OS ; 37 months in CF arm v 43 months in PCF arm ; log-rank test , P = .06 ; Tarone-Ware , P = .03 ) . This difference was more evident in patients with unresectable disease ( OS : 26 months in CF arm v 36 months in PCF arm ; log-rank test , P = .04 ; Tarone-Ware , P = .03 ) . CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients ( 53 % v 16 % , respectively ; P < .001 ) . CONCLUSION Induction chemotherapy with PCF was better tolerated and result ed in a higher CR rate than CF . However , new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment PURPOSE To determine the safety profile and activity of the combination of docetaxel , cisplatin and 5-fluorouracil ( 5-FU ) in chemotherapy-naive patients with squamous cell carcinoma of the head and neck ( SCCHN ) . PATIENTS AND METHODS Patients with locally advanced unresectable SCCHN were treated with docetaxel and cisplatin both as a 1-h infusion on day 1 followed by a continuous infusion of 5-FU for 5 days . Cycles were planned every 3 weeks up to four cycles , whereafter the patients were treated with locoregional radiotherapy . Two dose levels were studied . Doses in level I were 75 mg/m(2 ) of docetaxel , 75 mg/m(2 ) of cisplatin and 750 mg/m(2)/day of 5-FU ; in level II the cisplatin dose was escalated to 100 mg/m(2 ) . Following chemotherapy , all patients were to receive curative radiotherapy according to the st and ards in the different institutions . RESULTS Twenty-five patients were treated at dose level I with 86 cycles ( median four ; range one to four ) , and 23 at dose level II with 84 cycles ( median four ; range two to four ) . The median relative dose intensity was 0.99 ( range 0.86 - 1.04 ) at level I and 0.94 ( range 0.79 - 1.02 ) at level II . The response rate in the intention-to-treat population was 64 % [ 95 % confidence interval ( CI ) 42.5 % to 82 % ] in level I and 78.3 % ( 95 % CI 56.3 % to 92.5 % ) in level II ; all were partial responses . The maximum tolerated dose was reached at level II with renal toxicity , nausea , stomatitis and thrombocytopenia as principal dose-limiting toxicities . The median survival of the 48 patients was 18.5 months . The survival at 12 , 18 , 24 and 30 months was 69 , 54 , 41 and 31 % , respectively . CONCLUSIONS The combination of docetaxel , cisplatin and 5-FU associated with prophylactic ciprofloxacin is feasible and active in patients with SCCHN . Dose level I is recommended for phase III testing PURPOSE To evaluate the toxicity and efficacy of a 4-day regimen of docetaxel , cisplatin , fluorouracil , and leucovorin ( TPFL4 ) in patients with locoregionally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . PATIENTS AND METHODS Thirty previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status of 2 or less were treated with TPFL4 . Postchemotherapy support included prophylactic growth factors and antibiotics . Patients who achieved a complete response ( CR ) or partial response ( PR ) to three cycles of TPFL4 received definitive twice-daily radiation therapy . The primary end points were toxicity and response to TPFL4 .  RESULTS Eighty-five cycles were administered to 30 patients . The major acute toxicities to TPFL4 were mucositis and nausea . One patient died of neutropenic sepsis during therapy . Additional major toxicities were neutropenia , anorexia , nephropathy , neuropathy , and diarrhea . Fourteen percent of all cycles were associated with hospitalization for toxicity . The overall clinical response rate to TPFL4 was 93 % , with 63 % CRs and 30 % PRs . Primary tumor site clinical and pathologic response rates were 93 % and 68 % , respectively . CONCLUSION TPFL4 has an acceptable toxicity profile in good-performance-status patients . Modification of the 5-day TPFL regimen ( TPFL5 : shorter chemotherapy infusion time , earlier intervention with growth factors and antibiotics ) led to fewer episodes of febrile neutropenia and hospitalization . Response rates to TPFL justify further evaluation of combinations of these agents in the context of formal clinical trials PURPOSE We conducted a phase II study design ed to evaluate the activity , safety , and tolerability of docetaxel ( Taxotere : Rhône-Poulenc Rorer Pharmaceuticals Inc , Collegeville , PA ) in patients with advanced , incurable , or recurrent squamous cell carcinoma of the head and neck ( SCCHN ) who had not received prior palliative chemotherapy . PATIENTS AND METHODS Thirty-one patients with measurable , locoregional , or metastatic SCCHN were treated with docetaxel , administered at a dose of 100 mg/m2 as a 1-hour intravenous ( i.v . ) infusion once every 21 days on an outpatient basis . All patients were premedicated with dexamethasone , diphenhydramine , and cimetidine . Prophylactic administration of growth factors or antiemetics was not permitted . RESULTS Thirty-one patients were treated . Twenty-nine patients were assessable for  response  and 30 for toxicity .  Four of 31 patients ( 13 % ) achieved complete response ( CR ) , nine ( 29 % ) achieved partial response had stable disease ( SD ) and seven ( 23 % ) experienced progression of disease ( PD ) . The major response rate was 42 % ( 95 % confidence interval [ CI ] , 24 % to 60 % ) . The median duration of responses was 5 months ( range , 2 to 14 ) . The principal toxicity was leukopenia , which occurred with rapid onset and brief duration . Sixteen patients ( 53 % ) experienced nadir fever , and 13 required dose reduction . Hypersensitivity reactions occurred in four patients . Grade 3 peripheral neuropathy occurred in two patients ; grade 2 or 3 fatigue occurred in six ( 20 % ) and 10 ( 33 % ) , respectively . Minimal edema ( grade 1 ) occurred in five patients ( 17 % ) . Clinical ly significant mucositis , diarrhea , or dermatitis were not observed . CONCLUSION Docetaxel has major activity against SCCHN . It appears to be well tolerated in this group of patients and can be safely administered on an outpatient basis . Premedication with dexamethasone , cimetidine , and diphenhydramine is associated with a reduced incidence of significant edema , hypersensitivity reactions , and dermatologic toxicities PURPOSE The Head and Neck Intergroup conducted a phase III r and omized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer . PATIENTS AND METHODS Eligible patients were r and omly assigned between arm A ( the control ) , single daily fractionated radiation ( 70 Gy at 2 Gy/d ) ; arm B , identical radiation therapy with concurrent bolus cisplatin , given on days 1 , 22 , and 43 ; and arm C , a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy , 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle . Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and , if necessary , as salvage therapy on all three treatment arms . Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test . RESULTS Between 1992 and 1999 , 295 patients were entered on this trial . This did not meet the accrual goal of 362 patients and result ed in premature study closure . Grade 3 or worse toxicity occurred in 52 % of patients enrolled in arm A , compared with 89 % enrolled in arm B ( P < .0001 ) and 77 % enrolled in arm C ( P < .001 ) . With a median follow-up of 41 months , the 3-year projected overall survival for patients enrolled in arm A is 23 % , compared with 37 % for arm B ( P = .014 ) and 27 % for arm C ( P = not significant ) . CONCLUSION The addition of concurrent high-dose , single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival , although it also increases toxicity . The loss of efficacy result ing from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery BACKGROUND The st and ard treatment for advanced ( stage III and IV ) head and neck squamous cell carcinoma ( i.e. , surgery with postoperative radiotherapy  in operable patients and radiotherapy alone in inoperable patients ) has had poor results . A series of r and omized trials of induction chemotherapy have up to now failed to demonstrate an improvement in survival . PURPOSE This trial was design ed to determine whether intensive induction chemotherapy administered before loco-regional treatment would improve survival of patients with advanced disease . METHODS Patients had previously untreated , advanced nonmetastatic ( stages III and IV ) squamous cell carcinoma of the oral cavity , oropharynx , hypopharynx , and paranasal sinuses . The study design was a r and omized , multi-institutional , phase III trial . Eligible patients ( n = 237 ) were r and omly assigned to receive either initial chemotherapy ( cisplatin and infusional fluorouracil ) followed by loco-regional treatment ( group A , n = 118 ) or loco-regional treatment alone ( group B , n = 119 ) . For operable patients ( group A , n = 34 ; group B , n = 32 ) , loco-regional treatment included resection followed by adjuvant radiotherapy . For inoperable patients , radical irradiation was performed with a planned dose of 65 - 70 Gy to involved areas . A dose of 45 - 50 Gy was also planned to the uninvolved neck or postoperatively . The statistical ( log-rank ) test was performed no earlier than 2 years after the r and omization of the last patient . RESULTS Seventy-one patients ( 60 % ) in group A and 67 patients ( 56 % ) in group B were considered free of disease after they completed the treatment sequence . The analysis of time to distant metastases showed an advantage for group A patients . ( Respective 2- and 3-year values for inoperable patients were 15 % and 24 % for group A versus 36 % and 42 % for group B , P = .04 ; only one operable group A patient had distant metastases after 49 months versus 26 % [ 2 years ] and 31 % [ 3 years ] for operable group B patients , P = .01 . ) For inoperable patients , the combined treatment was significantly associated with an increase in complete remission rate ( group A , 44 % ) as compared with radiotherapy alone ( group B , 30 % ) ( P = .037 ) . Inoperable patients also benefitted from induction chemotherapy in terms of disease-free survival ( 49 % and 34 % for group A versus 28 % and 26 % for group B ; P = .06 ) and of overall survival ( 30 % and 24 % for group A versus 19 % and 10 % for group B ; P = .04 ) . CONCLUSIONS When all 237 r and omly assigned patients were analyzed , there were no significant differences in the two treatment strategies in loco-regional failure or in disease-free or overall survival , although the development of distant metastases was reduced . For operable patients , the only benefit from neoadjuvant chemotherapy was a significant reduction in the incidence of distant metastases . For inoperable patients , neoadjuvant chemotherapy improved local control , decreased the incidence of distant metastases , and improved the complete remission rate and overall survival . IMPLICATION S Confirmatory studies with effective chemotherapy regimens delivered for an adequate number of cycles are required BACKGROUND Docetaxel ( Taxotere ) is a new cytotoxic agent acting as a promoter of tubulin polymerisation with broad spectrum antitumor activity in pre clinical testing . Phase I clinical trials have shown promising activity of docetaxel in patients with breast , ovarian and lung carcinomas . The objective of this open multicentre phase II study was to determine the efficacy and tolerability of this agent in patients with head and neck cancer . PATIENTS AND METHODS Patients with proven advanced and /or recurrent squamous cell carcinoma of the head and neck without prior chemotherapy for advanced disease were eligible for this trial . Docetaxel was given at a dose of 100 mg/m2 as a 1 hour infusion every 3 weeks . Dose reductions were performed according to hematological and non-hematological toxicities . No pre-medication was given to prevent hypersensitivity reactions . RESULTS Fourty-three patients entered this trial : 39 patients were evaluable for toxicity and 37 patients were evaluable for response . Sixty-five percent of the patients had locoregional disease , 28 % had metastatic disease , and 7 % had both . Twenty-five percent of the patients had previously received neo-adjuvant cisplatin-based chemotherapy . A total of 166 docetaxel courses were administered . The most frequent side-effects associated with docetaxel were alopecia ( 90 % of the patients ) , asthenia ( 69 % of the patients ) and short lasting neutropenia ( grade 3 - 4 neutropenia in 61 % of the courses ) . Fifty-four percent of the patients experienced skin toxicity , 23 % experienced hypersensitivity reaction , and 31 % developed peripheral edema . Ten partial and 2 complete responses were observed , yielding a response rate of 32 % ( 95 % confidence interval 17%-47 % ) . CONCLUSION Docetaxel is an active drug in patients with advanced squamous cell carcinoma of the head and neck
Background : Head and neck cancer , mostly squamous cell carcinoma , ranks sixth among the most common cancers .
Despite progress in treatment in recent years , survival remains poor .
Since induction chemotherapy has been associated with survival benefit , it is a reasonable treatment option .
The st and ard protocol up to recently has been cisplatin and 5-flourouracil .
The addition of taxanes to the st and ard induction protocol has shown superiority in terms of the overall response rate .
Nevertheless , not all trials demonstrated survival benefit .
We aim ed to evaluate the effect of taxane added to the st and ard protocol of induction therapy .