Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. A prospective randomized trial of methotrexate versus cisplatin in the treatment of recurrent squamous cell carcinoma of the head and neck Controlled trial of methotrexate and Bacillus Calmette-Guérin therapy for advanced head and neck cancer. Comparison of methotrexate and cisplatin for patients with advanced squamous cell carcinoma of the head and neck region: a Southwest Oncology Group Study. Chemotherapy for head and neck cancer. Comparison of cisplatin + vinblastine + bleomycin versus methotrexate A randomized trial of the combination of cis‐platinum, oncovin and bleomycin (COB) versus methotrexate in patients with advanced squamous cell carcinoma of the head and neck Cisplatinum and Bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: a randomised factorial phase III controlled trial Results of randomised phase II studies comparing S16020 with methotrexate in patients with recurrent head and neck cancer. A phase III randomised trial of cisplatinum, methotrextate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Liverpool Head and Neck Oncology Group. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. Randomized comparison of cis-diamminedichloroplatinum versus cis-diamminedichloroplatinum, methotrexate, and bleomycin in recurrent squamous cell carcinoma of the head and neck [A randomized study comparing cisplatin alone or combined in the palliative treatment of carcinoma of the head and neck. Analysis of a series of 209 patients]. Chemotherapy for head and neck cancer. A randomized comparison of high-dose infusion methotrexate versus standard-dose weekly therapy in head and neck squamous cancer. High-dose versus low-dose cisplatin in advanced head and neck squamous carcinoma: a randomized study. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. Platinum-based chemotherapy plus cetuximab in head and neck cancer. First safety and response results of a randomized phase III study with liposomal platin in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). Randomized phase III trial (GORTEC 98-03) comparing re-irradiation plus chemotherapy versus methotrexate in patients with recurrent or a second primary head and neck squamous cell carcinoma, treated with a palliative intent. A controlled study of combined methotrexate, BCG, and INH therapy for squamous cell carcinoma of the head and neck. Quality of life scores as prognostic factors of overall survival in advanced head and neck cancer: analysis of a phase III randomized trial of pemetrexed plus cisplatin versus cisplatin monotherapy. A randomized phase III study of cisplatin with or without methotrexate for recurrent squamous cell carcinoma of the head and neck. A Northern California oncology group study A randomized trial of cisplatin (CACP) + 5‐fluorouracil (5‐FU) infusion and CACP + 5‐FU bolus for recurrent and advanced squamous cell carcinoma of the head and neck Treatment of recurrent head and neck cancer with cisplatin and 5-fluorouracil vs. the same plus bleomycin and methotrexate. Comparison of methotrexate and sequential methotrexate-5-fluorouracil for patients with recurrent squamous cell carcinoma of the oral cavity. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected].
We report the results of a r and omised phase II trial of docetaxel tested as a single agent in patients with recurrent head and neck cancer using methotrexate as a control arm to vali date the results . Eligibility criteria included : histologically-confirmed squamous cell carcinoma , measurable disease , adequate haematological , renal and hepatic functions , no prior chemotherapy for recurrent cancer , signed informed consent . 40 mg/m2 methotrexate was given as a short weekly bolus i.v . injection , and 40 mg/m2 docetaxel was administered as a one hour weekly infusion . A total of 57 patients were r and omised based on a ratio of 2/1:37 and 20 patients received docetaxel and methotrexate  , respectively . Patient characteristics included 49 males and 8 females ; the median age was 59 years ( range : 43 - 82 years ) . Twenty-eight patients had a local-regional relapse and 29 had distant metastasis , the median disease-free interval was 7.9 months ( range : 0 - 165 months ) . For patients treated with docetaxel , the following grade 3 - 4 toxicities occurred : neutropenia ( 12.5 % ) with febrile neutropenia in one patient ( 1 % ) , anaemia ( 19 % ) mucositis ( 9 % ) and ungueal toxicity ( 9 % ) . In the methotrexate arm , the grade 3 - 4 toxicities were : anaemia ( 15 % ) and mucositis ( 5 % ) . The response rate was significantly higher in the docetaxel arm with 27 % ( 95 % confidence interval ( CI ) : 21.7 - 32.3 % ) of objective responses versus 15 % ( 95 % CI : 11.2 - 18.8 % ) in the methotrexate arm . Overall survival and time to progression were super-imposable between the docetaxel and methotrexate treatments . Docetaxel given as a weekly infusion has a high activity in patients with head and neck cancer . A phase III trial is needed to test if this translates into a survival benefit for docetaxel use A prospect i ve r and omized study was conducted to determine the relative effectiveness , toxicity and tolerance of methotrexate ( MTX ) versus cisplatin ( DDP ) in patients with recurrent head and neck squamous cell carcinoma . Forty‐four patients were r and omized to receive either MTX , 40 mg escalated to 60 mg/m2 IV push weekly , or DDP , 50 mg/m2 6 hour infusion days 1 and 8 every 4 weeks . All patients had objective ly measurable disease and a performance status greater than 60 % ( Karnofsky scale ) . All had been treated with surgery and /or radiotherapy . No patients had prior chemotherapy . Prior treatment , performance status , and site of primary disease were comparable in both groups . Complete and partial objective responses were achieved in 23.5 % of the MTX group and 28.6 % of the DDP group ( P = 0.51 ) . Median duration of response was 84 days in the MTX group and 92 days in the DDP  group . Median survival of patients was 6.1 months with MTX and 6.3 months with DDP  . Mucositis was noted in 38 % of patients in the MTX group ( P = 0.001 ) compared to none in the DDP group . Vomiting occurred in 87 % of patients in the DDP group ( P < .0001 ) compared to 10 % of patients in the MTX group . This study demonstrates that in the treatment of recurrent head and neck squamous cell carcinoma , MTX and DDP are equally effective , although MTX appears to be better tolerated . Cancer 52:206‐210 , 1983 Thirty-eight patients with advanced , inoperable squamous cell carcinoma of the head and neck were r and omized to receive methotrexate alone or methotrexate with Bacillus Calmette-Guérin . The response rates with methotrexate ( 3 of 19 ) and methotrexate plus B. Calmette-Guérin ( 4 of 16 ) were similar , as was the duration of response and survival of the two groups . The results of in vitro immunological studies of lymphocytes were assessed . Marked weight loss , poor performance status , and distant metastases were the most important prognostic factors . The presence of anergy was significantly correlated with weight loss . This study also indicated that a large tumor burden is a frequent occurrence in advanced head and neck cancer and may account for the lack of efficacy of B. Calmette-Guérin One hundred eligible patients with inoperable , locally advanced or metastatic squamous cell carcinoma of the head and neck region following prior therapy were r and omized to receive i m methotrexate ( 50 patients ) or iv cisplatin ( 50 patients ) . Methotrexate produced a complete plus partial response rate of 16.0 % and cisplatin produced a partial response rate of 8.0 % , with median duration s of response of 18 and 8 weeks , respectively . The corresponding median survival times were 20 and 18 weeks . Methotrexate responders survived 60 weeks , versus 17 weeks for nonresponders . The corresponding survival times for cisplatin-treated patients were 38 and 18 weeks . Good pretreatment performance status had a significantly positive effect on survival ( P = 0.04 ) , but prior therapy did not . Toxicity secondary to either agent occurred with the expected frequency . The two agents examined showed comparable antitumor activity in patients with squamous cell carcinoma of the head and neck who had not previously received chemotherapy One hundred ninety‐one patients with recurrent or metastatic squamous cell carcinoma of head and neck origin were allocated at r and om to chemotherapy with conventional‐dose weekly intravenous methotrexate or the combination of cisplatin , vinblastine , and bleomycin . Methotrexate induced responses in 16 of 98 patients ( 16 % ) , whereas 22 of 92 ( 24 % ) responded to the combination regimen ( P = not significant ) . Remission duration ( 20.2 weeks methotrexate ; 15.1 weeks combination ) was similar on both arms , as was survival ( 31.4 weeks methotrexate ; 29.0 weeks combination ) . Therapy was relatively well‐tolerated on both treatment arms , although methotrexate  produced more mucositis and the combination more gastrointestinal and renal toxicity . Response to chemotherapy and disease confined to the locoregional area were associated with somewhat longer survival . Combination chemotherapy as given in this study did not improve any observed parameter , and the results of treatment were poor in both arms A prospect i ve r and omized trial was conducted at Wayne State University , Detroit , Michigan , to compare the efficacy of the combination of high‐dose cis‐diamminodichloroplatinum , Oncovin ( vincristine ) and bleomycin ( COB ) to that of weekly methotrexate ( MTX ) in the induction and maintenance of remission in patients with previously treated advanced squamous cell carcinoma of the head and neck .  Complete response ( CR ) was observed in 11.1 % of patients treated with COB and in 8.3 % of patients treated with weekly methotrexate . The overall response rate ( PR + CR ) was 33.3 % to methotrexate versus 40.7 % to COB . This difference was not significant , nor was the survival of patients treated by either modality . Important variables affecting survival in this study proved to be good performance status ( ⩾70 ) and response to therapy . Nausea and vomiting were the more common side effects of COB ( 56 % ) , while hematologic toxicity was more frequent and more severe in the methotrexate arm ( 75 % ) . Combination chemotherapy with COB is not more effective in producing response or prolonging survival than weekly methotrexate in patients with advanced head and neck carcinoma when both regimens are compared in a r and omized study Summary A phase III 2x2 factorial trial of cisplatinum and bleomycin in 116 patients with recurrent or advanced squamous cell carcinoma of the head and neck is reported . Thirty percent of patients proved to be unfit for chemotherapy , and of those treated progression of tumour was the commonest “ response ” . However , 25 % of patients achieved a partial or complete response , with no significant difference in response rates between the treated arms . The median number of courses received was 1 ( range 0–6 ) and the commonest causes for discontinuation of treatment were renal toxicity and death .  Bleomycin  reduced survival , but not significantly so , whereas cisplatinum  prolonged median survival significantly by 10 weeks . Significant predictors of survival , in addition to treatment by cisplatinum , were age , performance status , N status , number of courses and response of the tumor BACKGROUND The purpose of this study was to carry out two r and omised phase II trials of S16020 , a new olivacine derivative , tested as a single agent in patients with recurrent head and neck cancer , using methotrexate as the control arm to vali date the results . PATIENTS AND METHODS S16020 at either 80 or 100 mg/m2 was administered as a 3-h infusion every 3 weeks . Methotrexate , 40 or 50 mg/m2 , was given by bolus injection , weekly for a minimum of 6 weeks . In total , 36 patients were entered in the r and omised studies ( 25 in an initial study , 11 in a confirmatory study ) of whom 24 received S16020 and 12 received methotrexate . RESULTS A scheduled interim analysis showed one patient having a non-confirmed objective response with S16020 and three patients having a confirmed objective response with methotrexate . In the methotrexate group , there were no patients with severe non-haematological toxicity . With S16020 , there was a high incidence of severe non-haematological toxicities , including asthenia , oedema of the face , oedema and pain at the tumour sites and erythematous rash ; consequently , both studies were stopped . CONCLUSIONS Both studies were stopped due to the poor anticipated benefit/risk ratio for S16020 , although time to progression and overall survival time were similar in both treatment arms We describe a phase III trial on 200 patients with end stage squamous cell carcinoma of the head and neck . The patients were r and omised to one of four treatment arms : cisplatinum alone , methotrexate alone , cisplatinum + 5-FU and cisplatinum + methotrexate . There was no significant difference in the response rates , but the survival of the cisplatinum arm was significantly better than that of the methotrexate arm . The survival of patients receiving cisplatinum as a single agent was longer than that of patients receiving cisplatinum in combination with methotrexate or 5-FU , but not significantly so . Nausea/vomiting and anaemia were significantly more common in the cisplatinum arms than in the methotrexate arm , but the toxicity of combination regimens was not significantly greater than that of cisplatinum used as a single agent PURPOSE To determine whether combination chemotherapy is superior to single agents for recurrent/metastatic head and neck cancer , we compared the efficacy and toxicity of cisplatin ( CP ) and fluorouracil ( 5-FU ) , alone and in combination in a phase III trial . PATIENTS AND METHODS Two hundred forty-nine patients with recurrent head and neck cancer were r and omized to one of three treatments :  CP ( 100 mg/m2 ) and 5-FU ( 1 g/m2 x 4 ) , CP , or 5-FU every 3 weeks . RESULTS The overall response rate to the combination ( 32 % ) was superior to that of CP ( 17 % ) or 5-FU ( 13 % ) ( P = .035 ) . Response was associated with good performance status ( PS ) but not with primary site , site of recurrence , histology , prior irradiation , or relative dose intensity . Median time to progression was less than 2.5 months , and there was no significant difference in median survival ( 5.7 months ) among the groups . By multivariate analysis , patients with better PS and poorly differentiated tumors had superior survival . Hematologic toxicity and alopecia were worse in the combination arm . CONCLUSION Although the response rate to the combination of CP plus 5-FU was superior to that achieved with single agents , survival did not improve Summary Fifty-seven patients with recurrent squamous-cell carcinoma of the head and neck area were r and omized to two different chemotherapeutic regimens . Thirty patients received cis-platinum ( DDP ) alone and 27 patients received a combination of DDP , methotrexate , and bleomycin .  All 57 patients had undergone previous radiation and /or ablative surgery . Of the 30 patients receiving DDP alone , one patient showed a complete response and three a partial response ( 13 % ) . Amongst the 27 patients receiving DDP , methotrexate , and bleomycin , three showed a partial response ( 11 % ) ; there were no complete responders in this group . Major toxicity in the DDP alone group was renal . Renal toxicity and myelosuppression complicated the DDP , methotrexate , and bleomycin group . In summary , the combination of DDP , methotrexate , and bleomycin is no more effective than the use of DDP alone in recurrent squamous-cell carcinoma of the head and neck Two hundred and nine patients , with locoregional or metastatic recurrences of head and neck epidermoid carcinoma , were r and omized to receive a palliative chemotherapy .  The chemotherapy regimens were delivered every 3 weeks , and consisted in ( 1 ) cisplatin , 80 mg/m2 given alone ( CDDP regimen ) , or ( 2 ) in combination with vincristine , 1 mg , methotrexate 10 mg/m2 d 1 , 2 , 3 , and bleomycin 10 mg/m2 , d 1 , 2 and 3 ( 1040 regimen ) . Short-term results were better for patients treated by the 1040 regimen , with a 30 % response rate ( including 4 complete responses ) vs 15 % with the CDDP regimen ( P = 0.01 ) . A superiority of combination chemotherapy was found for all tumoral sites , but was particularly significant for pulmonary and cutaneous metastases , in previously un irradiated areas ( P = 0.001 ) . Tolerance was significantly better with the CDDP regimen ( P = 0.001 ) ; severe side effects , affecting mainly general status , digestive tract and bone marrow were encountered in 5 % of the patients in the CDDP group , vs 21 % in the 1040 group , with one death related to pancytopenia . The median duration of remissions was not statistically different in the 2 groups , as well as the 2 years overall survival . Among responders , the survival was slightly better in those treated with CDDP alone ; moreover , the quality of long term results was found highly correlated with a good initial general status , and with low levels of side effects . Those results confirm recent data of the literature , and lead to the following conclusions : ( 1 ) combination chemotherapy with CDDP give a better response rate than CDDP alone , ( 2 ) response rate does n't influence overall duration of survival , ( 3 ) tolerance to treatment is crucial to preserve quality of life , and thus , ( 4 ) palliative chemotherapy in head and neck cancer should be efficient but also as short of intensity as possible This overview of the role of chemotherapy in head and neck cancer is based on clinical trials conducted at The Princess Margaret Hospital and on a critical review of the literature . For recurrent or metastatic squamous cell carcinoma , no drug or combination has been found superior to methotrexate , which in large series gives transient responses in about 25 % of patients . Reports of higher rates of response have not correlated with increased survival , and response rates from many series have been inflated by the use of poor and variable criteria of response or by inappropriate exclusion of patients . Chemotherapy may lead to high rates of response when used initially as part of combined modality treatment with radiation and /or surgery , but longterm benefit has not yet been demonstrated . Chemotherapy should not be considered part of st and ard management for recurrent or metastatic head and neck cancer , and should be used as part of primary treatment for loco-regional disease only in the context of large , well design ed clinical trials Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospect ively controlled study comparing high-dose infusion methotrexate with leucovorin against st and ard-dose methotrexate without leucovorin .  Patients were stratified for prior treatment and hematogenous metastases prior to r and omization . Patients received either methotrexate ( 1,500 mg/m2 ) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly . Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity . After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly . One patient was ineligible and four had inadequate follow-up to assess response ( less than two weeks ) . Forty-two patients were evaluable for survival and 37 for response .  Six of 19 patients ( 32 % ) treated with high-dose infusion responded ( one complete response ) and four of 18 patients ( 22 % ) receiving st and ard dosage responded ( P = .52 ) . Treatment with high-dose methotrexate result ed in an improved duration of disease control over st and ard dosage with the respective median times to progression of 11 weeks and five weeks ( P = .04 ) . These differences were most marked in good performance status patients ( P = .007 ) and those without hematogenous dissemination ( P = .02 ) . Toxicity , however , was also significantly worse in the high-dose treatment group ( P = .01 ) and survival was identical between treatments ( 4.2 months ) . The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival . Good performance status patients may benefit from more aggressive therapy From November 1981 to February 1983 , 64 patients with advanced head and neck squamous carcinoma were r and omly treated with either high-dose ( 120 mg/m2 ) or low-dose ( 60 mg/m2 ) cisplatin . Of the 62 eligible patients , 59 were evaluable : the response rate observed in patients receiving high-dose and low-dose cisplatin was 16.1 % and 17.8 % , respectively . Survival was superimposable in the two treatment arms . No evidence of dose dependency of cisplatin activity in advanced head and neck squamous carcinoma was noted in this r and omized trial PURPOSE The Southwest Oncology Group ( SWOG ) conducted a r and omized comparison of cisplatin plus fluorouracil ( 5-FU ) and carboplatin plus 5-FU versus single-agent methotrexate ( MTX ) in patients with recurrent and metastatic squamous-cell carcinoma ( SCC ) of the head and neck . The primary objective was to compare separately the response rates of each combination regimen to st and ard weekly MTX . PATIENTS AND METHODS Two hundred seventy-seven patients diagnosed with SCC of the head and neck were r and omized to one of three treatments : ( 1 ) cisplatin 100 mg/m2 intravenously ( IV ) on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 21 days ; ( 2 ) carboplatin 300 mg/m2 IV on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 28 days ; and ( 3 ) MTX 40 mg/m2 IV given weekly . RESULTS All three treatment regimens were well tolerated . However , both hematologic and nonhematologic toxicities were significantly greater with cisplatin plus 5-FU compared with MTX ( P = .001 ) . Toxicity from carboplatin plus 5-FU was intermediate compared with the other regimens . The complete and partial response rates were 32 % for cisplatin plus 5-FU , 21 % for carboplatin plus 5-FU , and 10 % for MTX . The comparison of cisplatin plus 5-FU to MTX was statistically significant ( P less than .001 ) , and the comparison of carboplatin plus 5-FU to MTX was of borderline statistical significance ( P = .05 ) . Median response duration s and median survival times were similar for all three treatment groups . Logistic regression models showed that only treatment assigned was associated significantly with response ( P = .001 ) . Cox proportional hazards models indicated that only performance status was associated significantly with survival ( P less than .01 ) . CONCLUSIONS We conclude that combination chemotherapy result ed in improved response rates but was associated with an increased toxicity and no improvement in overall survival . Therefore , new treatments that may alter the course of disease in recurrent head and neck cancer patients still need to be identified PURPOSE To determine the response rate , survival and toxicity of infusional cisplatin plus fluorouracil ( CF ) versus cisplatin plus paclitaxel ( CP ) in patients with incurable squamous cell cancer of the head and neck , with the hypothesis that CP is superior . PATIENTS AND METHODS Two hundred eighteen patients with locally advanced , recurrent , or metastatic disease were r and omly assigned to CF ( cisplatin 100 mg/m2 day 1 and fluorouracil 1,000 mg/m2/24 hours by continuous intravenous infusion day 1 through 4 ) or CP ( cisplatin 75 mg/m2 day 1 and paclitaxel 175 mg/m2 over 3 hours on day 1 ) . Cycles were repeated every 3 weeks until progression or a minimum of 6 cycles with complete response or stable disease . The primary outcome was overall survival . Secondary outcomes included response rate and toxicity . RESULTS No significant difference in overall survival or response rate was seen . Estimated median survival was 8.7 months in the CF group and 8.1 month in the CP group . Objective response rate ( complete response plus partial response ) was 27 % in the CF group and 26 % in the CP group . Toxicity was similar between groups , with the most frequent including myelosuppression , thrombocytopenia , anemia , nausea , vomiting , and stomatitis . A total of 12 deaths occurred ( CF , seven ; CP , five ) during treatment ; eight from infection , two from hemorrhage , one from cardiac causes and one from unknown causes . Gastrointestinal and hematologic toxicities were more common in the CF group , whereas neurotoxicity was equivalent between groups . CONCLUSION This phase III , r and omized , multicenter trial showed no difference in survival between patients treated with CF or CP BACKGROUND Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck . We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck . METHODS We r and omly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin ( at a dose of 100 mg per square meter of body-surface area on day 1 ) or carboplatin ( at an area under the curve of 5 mg per milliliter per minute , as a 1-hour intravenous infusion on day 1 ) plus fluorouracil ( at a dose of 1000 mg per square meter per day for 4 days ) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab ( at a dose of 400 mg per square meter initially , as a 2-hour intravenous infusion , then 250 mg per square meter , as a 1-hour intravenous infusion per week ) for a maximum of 6 cycles . Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects , whichever occurred first . RESULTS Adding cetuximab to platinum-based chemotherapy with fluorouracil ( platinum-fluorouracil ) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab ( hazard ratio for death , 0.80 ; 95 % confidence interval , 0.64 to 0.99 ; P=0.04 ) . The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months ( hazard ratio for progression , 0.54 ; P<0.001 ) and increased the response rate from 20 % to 36 % ( P<0.001 ) . The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia ( 19 % and 13 % , respectively ) , neutropenia ( 23 % and 22 % ) , and thrombocytopenia ( 11 % in both groups ) . Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group ( P=0.02 ) . Of 219 patients receiving cetuximab , 9 % had grade 3 skin reactions and 3 % had grade 3 or 4 infusion-related reactions . There were no cetuximab-related deaths . CONCLUSIONS As compared with platinum-based chemotherapy plus fluorouracil alone , cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck . ( Clinical Trials.gov number , NCT00122460 . BACKGROUND Cisplatin is one of the most active chemotherapeutic agents used in the treatment of advanced squamous cell carcinoma of the head and neck ( SCCHN ) . However , its clinical efficacy is limited by its renal and hematotoxicity profile . In a r and omized , multicenter phase III trial , we replaced conventional cisplatin by a liposomal formulation of cisplatin ( lipoplatin ) and compared the safety and efficacy profiles of patients in the two treatment arms . PATIENTS AND METHODS Main inclusion criteria were : histologically confirmed SCCHN , age between 18 - 75 years with sufficient renal function . Main endpoints for this interims analysis were hemato- and nephrotoxicity . First response data were collected . RESULTS Forty-six patients were evaluable for outcome and toxicity . Grade III and IV hematotoxicity were more frequent in the cisplatin arm ( 31.7 % vs. 12 % ) , with grade IV leucopenia occurring in 22.2 % . However , 16 % of the patients in that treatment arm experienced grade III anemia compared to only 9.5 % treated with the cisplatin regimen . A total 4 % of the patients in the lipoplatin arm developed grade IV neuropathy , whereas in the cisplatin arm , 19 % developed grade III neuropathy and none developed grade IV . The renal toxicity profile of both drugs also showed marked differences . In the cisplatin arm , 23.8 % of patients suffered grade III toxicity . In contrast , no grade III or IV renal toxicity occurred in patients treated with lipoplatin . The efficacy results showed 38.8 % objective partial remission in the cisplatin arm vs. 19 % in the lipoplatin arm . However 64 % of the patients achieved stable disease while being treated with lipoplatin/5-fluorouracil ( 5-FU ) , vs. 50 % in the cisplatin/5-FU arm . CONCLUSION Liposomal cisplatin seems to reduce both the renal and hematological toxicity to a clinical ly relevant extent as compared to conventional cisplatin . The clinical benefit rate is similar for both regimens PURPOSE This r and omized phase III trial investigated the potential benefit of concurrent re-irradiation , fluorouracil and hydroxyurea versus methotrexate for patients treated with palliative intent for recurrent or second primary head and neck squamous cell carcinoma ( HNSCC ) in previously irradiated area . PATIENTS AND METHODS Patients with recurrent HNSCC or a second primary not amenable to curative-intent treatment were r and omized to the R-RT arm ( concurrent re-irradiation , fluorouracil and hydroxyurea ) or to the Ch-T arm ( methotrexate ) . The primary endpoint was overall survival ( OS ) . Due to a very slow accrual , the trial was closed after inclusion of 57 patients . RESULTS Fifty-seven patients were included . All patients died in the two arms with a maximal follow-up of 5years . Although four complete responses were achieved in R-RT arm , ( none in Ch-T arm ) re-irradiation did not improve OS  compared with methotrexate ( 23 % versus 22 % at 1year , NS ) . Sixteen patients experienced clinical grade ⩾3 late toxicities ( > 6months ) , 11 in R-RT arm and five in Ch-T arm . CONCLUSIONS Premature discontinuation of the trial did not allow us to draw firm conclusions . However , there was no suggestion that concurrent re-irradiation , fluorouracil and hydroxyurea improved OS compared to methotrexate alone in patients treated with palliative intent for a recurrent or second primary HNSCC In a r and omized prospect i ve study of patients with advanced squamous cell carcinoma of the head and neck , treatment with MTX plus BCG and with MTX plus BCG plus INH produced no better response rate or survival time than treatment with MTX alone OBJECTIVES We examined the prognostic factors ( clinical , demographic , and health-related quality of life [ HRQoL ] ) of overall survival ( OS ) and progression-free survival ( PFS ) in patients with recurrent/metastatic head and neck cancer ( HNC ) who were treated with pemetrexed plus cisplatin versus cisplatin in a phase III , multinational , r and omized trial . MATERIAL S AND METHODS Five subscales of the Functional Assessment of Cancer Therapy-Head and Neck Cancer ( FACT-H&N ) , modified to score from 0 to 100 , measured HRQoL at baseline and during treatment . Univariate and multivariate Cox proportional hazards models were used on data pooled from both treatment arms to assess the effect of baseline prognostic factors on OS and PFS . RESULTS Of 795 patients r and omized , 704 completed a baseline FACT-H&N and were included in the analysis . Age ( < 65 versus ⩾65 ; HR=0.74 , 95 % CI : 0.61 - 0.90 ) , race ( Caucasian versus non-Caucasian ; HR=0.83 , 95 % CI : 0.70 - 0.98 per table ) , Eastern Cooperative Oncology Group performance status ( ECOG PS ; 0/1 versus 2 ; HR=0.44 , 95 % CI : 0.35 - 0.56 ) , prior surgery/radiotherapy in the last 6months ( no versus yes ; HR=0.74 , 95 % CI : 0.61 - 0.90 ) , and primary site of disease ( oral cavity versus other ; HR=1.37 , 95 % CI : 1.15 - 1.63 ) were significantly prognostic of OS in univariate models , as were baseline scores on four FACT-H&N subscales ( physical well-being , emotional well-being , functional well-being , additional concerns-H&N ; HRs=0.82 - 0.94 ; all P⩽0.002 ) . In multivariate models , significant prognostic factors were age ( HR=0.78 ) ; race ( HR=0.76 per table ) ; ECOG PS ( HR=0.56 ) ; prior surgery/radiotherapy ( HR=0.76 ) ; and baseline scores of the FACT-H&N subscales of physical well-being , social/family well-being , and additional concerns-H&N ( HRs=0.89 - 0.94 ; all P⩽0.014 per table ) . CONCLUSIONS The results suggest that baseline HRQoL scores are prognostic indicators of OS in recurrent/metastatic HNC in addition to other known clinical and demographic indicators . HRQoL might be considered as a stratification factor in r and omized clinical trials of recurrent/metastatic HNC Eighty patients with recurrent squamous cell cancer of the head and neck were r and omized to cisplatin ( 80 mg/m2 ) every 3 weeks or cisplatin plus weekly methotrexate ( 250 mg/m2 ) with leucovorin . The overall response rate to cisplatin was 18 % , with 10 % complete responses . The overall response to the combination was 33 % with 18 % complete responses ( P = 0.11 ) . There was no difference in response duration , time to progression , or survival . There was no difference in renal toxicity between the 2 arms ( creatinine > 2 mg/dl in 6 % of the patients ) . There was significantly more leukopenia ( 64 % ) , thrombocytopenia ( 18 % ) , anemia ( 18 % ) , and mucositis ( 33 % ) in the combination arm . This combination of two of the best agents for head and neck cancer did not improve response , but result ed in added toxicity One of the most active chemotherapeutic regimens for treatment of advanced and recurrent head and neck cancer is cisplatin ( CACP ) + 5‐fluorouracil ( 5‐FU ) infusion with a response rate of 90 % in advanced , previously untreated patients and 70 % in patients with recurrent disease . Forty‐four patients from two Wayne State University‐affiliated hospitals were entered into a r and omized trial of CACP ( 100 mg/m2 ) day 1 and 24‐hour infusion of 5‐FU ( 1000 mg/m2 ) days 1 through 4 versus CACP ( 100 mg/m2 ) day 1 and bolus 5‐FU ( 600 mg/m2 ) day 1 and day 8 . Thirty‐eight patients were evaluable for three induction courses . Response for the infusion arm was 72 % ( 4/18 complete response [ CR ] + 9/18 partial response [ PR ] ) . Response for the bolus arm was 20 % ( 2/20 CR + 2/20 PR ) . The difference in response was statistically significant by chi‐square analysis ( P < 0.01 ) . Seventy percent of the patients on the bolus arm experienced leukopenia with several episodes of grade s 3 and 4 leukopenia . In addition , 50 % of the patients on the bolus arm experienced thrombocytopenia . Stomatitis was more frequent on the infusion arm but it was mild and reversible . The complete responders on either arm have a median survival of 120 + weeks ; partial responders , 30 weeks . Cisplatin + 5‐FU infusion produces a superior response as initial chemotherapy for three courses compared with CACP and 5‐FU bolus A prospect i ve r and omized trial of 62 patients with recurrent squamous cell carcinoma of the head and neck was conducted to compare the effectiveness of our st and ard chemotherapy program with that of our test regimen . The st and ard chemotherapy regimen consisted of cisplatin 80 mg/M2 on day 1 followed by 5-fluorouracil 800 mg/M2 days 2 through 6 . Our test regimen consisted of the same two drugs plus 15 U bleomycin on day 1 and methotrexate 100 mg/M2 on day 16 followed in 24 hours with 15 mg leucovorin every 6 hours for six doses . One patient in each arm of the study was not evaluated . Among 29 patients receiving the two-drug regimen , there was 1 complete response and 10 partial responses ( 38 % response rate ) . Among 31 patients receiving the four-drug regimen , there were 3 complete responses and 16 partial responses ( 61 % response rate ; two vs. four-drug regimen , P = .06 ) . The failure-free survival in the four-drug group was better than the two-drug group , median 4.5 vs. 2.3 months ( P = .02 ) . The overall survival for both groups was the same ( median of 7.8 months ) . A detailed analysis of toxicity did not reveal any important differences between the two regimens . The addition of bleomycin and methotrexate to our cisplatin and 5-fluorouracil regimen result ed in an increase in effectiveness without adding toxicity Forty-eight fully assessable previously treated patients with biopsy-proven recurrent squamous cell carcinoma of the oral cavity were r and omized to receive either methotrexate ( MTX ) , 40 mg/m2 iv push weekly , or sequential MTX and 5-fluorouracil ( 5-FU ) ( MTX 150 mg/m2 iv for 1 h ; 1 h after the end of MTX , 5-FU 600 mg/m2 iv for 2 h ; 24 h later , leucovorin rescue 10 mg/m2 iv and the same dose was given orally every 6 h 4 times ; the treatment was repeated every 10 days ) . There were 1 complete response ( CR ) and 5 partial responses ( PR ) in the MTX group ; median remission duration = 84 days . There were 3 CR and 11 PR in the MTX-5-FU group ( overall response 14/24 , 58.3%--p less than 0.05 ) ; median remission duration = 125 days . Median survival was 6.2 months in the MTX group and 8.1 months in the MTX-5-FU group . There was no difference in mucositis between the two groups , and a prevalence of leukopenia and moderate gastro-intestinal toxicity in the MTX-5-FU group PURPOSE To compare survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck ( SCCHN ) treated with gefitinib 250 or 500 mg/day or st and ard methotrexate . PATIENTS AND METHODS Four hundred eighty-six patients with recurrent SCCHN were r and omly assigned to oral gefitinib 250 mg/day , gefitinib 500 mg/day , or methotrexate 40 mg/m(2 ) intravenously weekly . Primary end point was overall survival , secondary end points were objective response rate ( ORR ) , safety , symptom improvement , and quality of life ( QOL ) . Exploratory end points included association of efficacy with epidermal growth factor receptor gene copy number and other biomarkers . RESULTS Neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate ( hazard ratio [ HR ] , 1.22 ; 95 % CI , 0.95 to 1.57 ; P = .12 ; and HR , 1.12 ; 95 % CI , 0.87 to 1.43 ; P = .39 , respectively ) . In the gefitinib 250 mg/day , 500 mg/day , and methotrexate groups , respectively , median overall survival was 5.6 , 6.0 , and 6.7 months ; ORRs ( Response Evaluation Criteria in Solid Tumors ) were 2.7 % , 7.6 % and 3.9 % , with no statistically significant difference between either gefitinib arm and methotrexate . No unexpected adverse events were observed , except for tumor hemorrhage-type events with gefitinib ( 8.9 % , gefitinib 250 mg/day ; 11.4 % , gefitinib 500 mg/day ; 1.9 % , methotrexate ) . QOL improvement rates ( Functional Assessment of Cancer Therapy-Head & Neck total score ) were 13.4 % , 18.0 % , and 6.0 % for gefitinib 250 mg/day , 500 mg/day , and methotrexate , respectively . CONCLUSION In patients with recurrent or metastatic SCCHN , while responses with gefitinib were seen , neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate . With the exception of tumor hemorrhage-type events with gefitinib , the adverse event profiles were generally consistent with those previously observed
BACKGROUND Cytotoxic chemotherapy remains a st and ard treatment option for patients with recurrent or metastatic squamous cell carcinoma of the head and neck ( RMSCCHN ) , but its effectiveness is debatable .
We hypothesized palliative chemotherapy efficacy has decreased due to intensification of primary treatment , and investigated this by examining time trends of objective response rates ( ORRs ) in published reports of r and omized trials ( RCTs ) .