A phase II trial of cisplatin and vinorelbine in patients with recurrent or metastatic squamous cell...

A PHASE II TRIAL OF CISPLATIN AND VINORELBINEIN PATIENTS WITH RECURRENT OR METASTATICSQUAMOUS CELL CARCINOMA OF THE HEADAND NECK

Enrique Espinosa, MD,1 Pilar Zamora, MD,1 Alfredo Milla, MD,2 Serafin Morales, MD,3

Raquel Molina, MD,1 M. Mira, MD,3 Manuel Gonzalez Baron, MD,1

Oncopaz Cooperative Group

1 Servicio de Oncologıa Medica, Hospital La Paz. P° de la Castellana, 261, 28046 Madrid, Spain. E-mail:[email protected] Servicio de Oncologıa Medica, Sanitas Hospitales, Barcelona, Spain3 Servicio de Oncologıa Medica, Hospital Arnau y Vilanova, Lerida, Spain

Accepted 20 May 2002Published online 10 September 2002 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.10172

Abstract: Objective. We assessed the response rate and thetoxicity of cisplatin plus vinorelbine in patients with this condition.

Patients and Method. Forty-two patients were included.Therapy consisted of cisplatin, 100 mg/m2 on day 1, and vinorel-bine, 25 mg/m2 on days 1 and 8, given every 21 days. Therapywas continued up to six courses or progressive disease.

Results. One hundred fifty-nine courses were given (median,three per patient). Dose reduction was applied in 13% of coursesand 43% of patients. Grade 3 to 4 neutropenia appeared in 11%of courses and 35% of the patients. One patient died of febrileneutropenia. Ten percent of patients attained a complete re-sponse, and 23% attained a partial response (overall 33%,95%CI 19%–47%). The median duration of response and mediansurvival were 6 months. Twenty-four percent of patients remainalive at 1 year.

Conclusions. The combination of cisplatin and vinorelbine ismoderately active in patients with recurrent or metastatic carci-nomas of the head and neck and avoids the inconvenience ofprolonged infusions of 5-fluorouracil. © 2002 Wiley Periodicals,Inc. Head Neck 24: 1054–1059, 2002

Keywords: head and neck; recurrent disease; metastatic dis-ease; cisplatin; vinorelbine

Patients with recurrent or metastatic head andneck tumors have a dismal prognosis. Their me-dian survival is 6 months, and their 1-year sur-vival rate is about 20%, despite the use of chemo-therapy. The best therapy for this group ofpatients remains to be defined, because they usu-ally are initially seen in poor physical condition.Ideally, therapy should combine efficacy, conve-nience, and tolerability. Single drugs such asmethotrexate, a platinum compound, or a taxaneobtain response rates of 20% to 30%.1,2 Combina-

Correspondence to: M. Gonzalez Baron

Presented as a poster at the meeting of the American Society of ClinicalOncology, Orlando, Florida, May 2002.

© 2002 Wiley Periodicals, Inc.

1054 Cisplatin-Vinorelbine in Recurrent/Metastatic H&N Cancer HEAD & NECK December 2002

tion chemotherapy produces more responses atthe expense of increased toxicity. The commonlyused combination of cisplatin and a continuousinfusion of 5-fluorouracil obtains responses in30% to 40% of patients and a median survival of 4to 6 months.3–6 However, it requires hospitaliza-tion or the use of an infusion pump.

Vinorelbine, a semisynthetic vinca alkaloid,binds to tubulin and causes the dissolution of mi-totic spindles. It is active in the treatment of lungand breast cancers and has a favorable toxicityprofile; neutropenia is its main side effect. It canbe administered as a short intravenous infusion.A 16% response rate in patients with recurrent ormetastatic head and neck tumors has been re-ported.7

The combination of cisplatin and vinorelbinewas the first novel agent regimen to produce astatistically significant survival benefit over cis-platin plus vindesine in patients with advancednon-small cell lung cancer.8,9 This combinationcan be safely administered as an ambulatory in-fusion in a day-hospital. Considering these data,we decided to perform a phase II trial to assessthe efficacy and tolerability of cisplatin and vi-norelbine in patients with recurrent or metastatichead and neck carcinoma. Efficacy would be mea-sured in terms of response rate and duration ofresponse.

PATIENTS AND METHOD

Patients met all the following inclusion criteria:(1) histologically confirmed head and neck squa-mous cell carcinoma; (2) local relapse not ame-nable to surgery or radiation therapy or meta-static disease; (3) measurable disease; (4) noprevious chemotherapy in the palliative setting;(5) age up to 75; (6) ECOG performance status of0, 1, or 2; (7) life expectancy longer than 3 months;(8) hemoglobin >10 g/dL, leukocytes >3 × 109/L,platelets 100 × 109/L, creatinine <1.5 mg/dL, andbilirubin <2 mg/dL; and (9) written informed con-sent according to local ethical committee’s direc-tives. Tumors from the nasopharynx, paranasalsinuses, and salivary glands were excluded. Cen-tral nervous system infiltration was not allowed,as well as the existence of other malignant dis-eases in the previous 5 years.

Therapy consisted of cisplatin, 100 mg/m2,given as a 4-hour intravenous infusion on day 1and vinorelbine, 25 mg/m2, given as a short intra-venous infusion on days 1 and 8. Courses wererepeated every 21 days in day-hospital facilities.Evaluation was performed after three courses:

therapy would be withdrawn in the case of a pro-gression and continued up to six courses other-wise. We considered that prolonging therapy be-yond six courses could increase toxicity and wouldnot allow us to obtain further responses. Besides,head and neck cancer patients are reluctant tofollow prolonged therapies.

A blood count and a renal chemistry were per-formed on days 1 and 8 of every course. Initialdoses were maintained whenever the neutrophilcount was >1.5 × 109/L and the platelet count was>100 × 109/L. If the count was lower on day 1,chemotherapy was delayed for 1 week, and thenrestarted with a reduction of 25% in the dose ofboth drugs. Granulocyte-colony stimulating fac-tor was not used. Doses were also reduced by 25%in the case of febrile neutropenia or grade 3 to 4thrombocytopenia or grade 3 to 4 mucositis. If re-covery did not occur after a 2-week delay, the pa-tient was withdrawn from the study. Treatmentwas also withdrawn in the case of grade 3 to 4neurotoxicity. In the case of grade 2 neurotoxicity,treatment was delayed until recovery and thenrestarted with a 25% reduction in the doses ofboth drugs. Resuming full doses was not allowedafter reduction because of toxicity.

Sixteen patients were to be included initially.If seven or more responses were seen in thesepatients, the study would continue to include atleast 38 evaluable patients (stopped otherwise).This calculation considered an alpha error of .05and a beta error of .2.10 Toxicity was recorded ondays 1 and 8 of every course of chemotherapy andgraded according to WHO scales.

RECIST criteria were followed to define theradiologic response.11 Clinical response alone wasnot regarded as a response. Time to progressionand survival were measured from the time of in-clusion. The duration of response was measuredfrom the time response was detected until pro-gression.

RESULTS

From September 2000 to March 2001, 42 patientswere included in the study (2 women and 40 men).All of them had recurrent or metastatic disease orboth. Primary treatment consisted of surgery inall of them and surgery plus radiotherapy in 25.Two of them had also received platinum-basedchemotherapy as neoadjuvant therapy. Table 1summarizes the patients’ characteristics.

As a whole, 159 courses of chemotherapy weregiven, with a median of three per patient (range,1–6). Ten patients received six courses. Twenty-

Cisplatin-Vinorelbine in Recurrent/Metastatic H&N Cancer HEAD & NECK December 2002 1055

one courses (13%) were given at reduced doses in18 patients (43%) because of toxic effects in pre-vious courses. After dose reduction, three patientshad a second episode of neutropenia and requiredfurther reduction of doses. Therapy was delayedin 16 courses (10%) and 11 patients (26%). Thecause for dose reduction or treatment delay wasleukopenia in all patients, with three exceptions:one mucositis, one renal toxicity, and one anemia.Two (5%) patients required hospitalization, onebecause of febrile neutropenia and the other be-cause of vomiting. Two patients declined furthertherapy after the second course of chemotherapy,

one because of vomiting and the other because oforthostatic hypotension.

Grade 3 to 4 neutropenia appeared in 18courses (11%) and 15 patients (35%). Three pa-tients had two episodes of neutropenia. One pa-tient (3%) died from febrile neutropenia in thesecond course. He had not experienced neutrope-nia or any other remarkable toxicity in his firstcourse of treatment. Another patient died sud-denly 1 week after the second course of chemo-therapy; he had not experienced fever or othereffects attributable to chemotherapy in the previ-ous days. His family did not consent the autopsy,so that the cause of the death remained unknown.Four patients (10%) had grade 3 nausea/vomiting,two (5%) had grade 3 anemia, and one (3%) hadgrade 3 mucositis. Other minor toxicities were re-versible grade 1 renal toxicity in two patients (onecontinued therapy with carboplatin, and the otherreceived reduced doses of cisplatin), orthostatichypotension in one, and grade 2 peripheral neu-rotoxicity in one. This latter patient experiencedneurotoxicity by the sixth course of treatment, sodoses were not reduced. Table 2 summarizes tox-icity.

Four patients with inoperable local relapse at-tained a complete response (10%). Two of themhad had surgery previously, and the other twosurgery plus radiotherapy. Another 10 patients(23%) obtained a partial response; these re-sponses affected local relapses, the lungs (threepatients), and soft tissues (one patient). Thus, theoverall response rate was 33% (95%CI, 19%–47%). The median duration of response was 6months (range, 1–11 months). The median time toprogression was 3 months (range, 1–14 months),and the median overall survival was 6 months(range, 1–21 months). Twenty-two patients (52%)progressed while on chemotherapy or soon there-

Table 1. Characteristics of the 42 patients included inthe study.

Primary tumorOral cavity 15Larynx 12Oropharynx 7Hypopharynx 6Nasal 1Unknown 1

Previous therapySurgery alone 15 (36%)Surgery + radiotherapy 25 (59%)Surgery + chemotherapy 2 (5%)

Kind of relapseLoc. regional 29 (69%)Metastatic 6 (14%)Both 7 (17%)

Location of metastases (*)Lung 8Bone 3Soft tissue 2Liver 1

ECOG performance status0 1 (2%)1 33 (79%)2 8 (19%)

*Two patients had more than one metastatic location: lung liver and lungbone.

Table 2. Toxicity in 42 patients (159 cycles).

Grade 1 Grade 2 Grade 3 Grade 4

Neutropenia 3 (7%) 10 (24%) 5 (12%)Febrile neutropenia (*) 1 (3%)Nausea/vomiting 25 (59%) 6 (14%) 4 (10%)Anemia 22 (52%) 3 (7%) 2 (5%)Mucositis 2 (5%) 1 (3%)Renal 2 (5%)Orthostatic hypotension 1 (3%)Peripheral neuropathy 1 (3%)Alopecia 25 (59%) 6 (14%)

*Toxic death. Another patient died for unknown reasons.


after. So far, three patients (7%) remain free ofdisease at 11+, 11+, and 12+ months; 15 (36%) arealive with disease, and 24 (57%) have died.Twenty-four percent of patients remained alive at1 year.

DISCUSSION

Patients with recurrent or metastatic squamouscell head and neck tumors have a median survivalof 6 months, so that treatment should be regardedas palliative in this context. Traditionally, chemo-therapy has been used for palliation of symptomsin patients with this condition. Chemotherapydrugs such as cisplatin, carboplatin, methotrex-ate, bleomycin, and 5-fluorouracil have docu-mented responses in 15 to 20 patients. The mostfrequently used regimen is the combination of cis-platin and 5-fluorouracil. This combination hasbeen demonstrated to be more active than eitheragent alone, but a survival advantage has notbeen seen in randomized trials.12 Thirty-threepercent of our patients responded to cisplatin plusvinorelbine; the median duration of response was6 months, and the median overall survival wasalso 6 months. These results are similar to thoseobtained with cisplatin plus infusional 5-fluoro-uracil.

Recently developed chemotherapy drugs haveallowed the use of new combinations in an at-tempt to improve the results of the classicschemes. The taxanes paclitaxel and docetaxelcould increase response rates when combinedwith platinum compounds. For instance, the com-bination of cisplatin and docetaxel yielded a 54%response rate with 15% of complete responses in aseries of 31 patients.13 Sixty-six percent of pa-tients had grade 3 to 4 neutropenia. A 46% re-sponse rate (11% complete responses) wasreported in another study with the same combi-nation.14 Six patients died of treatment-relatedcomplications. Paclitaxel alone obtained a prom-ising 40% response rate in a phase II trial,15 butthe same authors could not improve this percent-age by combining paclitaxel and cisplatin.16 A re-cent phase III trial of cisplatin and 5-fluoruracilversus cisplatin and paclitaxel showed responsesin 22% and 28% of patients, respectively.17 Sur-vival at 1 year was 41% and 30%, and mediansurvival was 8 months and 9 months, respec-tively. Survival figures compare favorably withthose in this series, probably because of the verypoor prognosis of our patients: 19% had an ECOGperformance status of 2, and 59% had previouslyreceived radiotherapy.

Three-drug combinations have also been stud-ied in this context. Paclitaxel, ifosfamide, and ei-ther cisplatin or carboplatin yielded responserates of 58% and 59%, respectively, in two trials,with a 17% rate of complete responses in bothcases.18,19 Again, toxicity was high; almost all pa-tients had grade 3 to 4 neutropenia, and therewas one death caused by febrile neutropenia andsepsis in the study with carboplatin. In anothersmall trial, the combination of cisplatin, doce-taxel, and 5-fluorouracil obtained a 44% responserate.20 Finally, the combination of docetaxel and anonplatinum compound, namely 5-fluorouracil,has not been very successful; the overall responserates were 27% and 24% in two trials.21,22 Fromall these trials, we can conclude that combina-tions of a platinum compound and a taxane obtainsome more responses than the standard cisplatinand 5-fluorouracil but at the expense of consider-able toxicity. It might be reasonable to reservesuch aggressive schemes for first-line treatmentin locally advanced disease, a condition in whichexcellent response rates have been reported,23

and cure is still the objective.An alternative to aggressive schemes would

consist of simple treatments with reduced toxicityand similar efficacy to that of cisplatin and 5-flu-oruracil, because most patients with recurrent ormetastatic tumors do not benefit from chemo-therapy. Besides, they usually are initially seenwith weight loss and may be more prone to haveside effects because of the previous use of radio-therapy or chemotherapy. Infusional 5-fluoroura-cil requires hospitalization or the use of an infu-sion pump, which poses some inconvenience tomost patients. Oral fluoropyrimidines circumventthe problem of a prolonged infusion of 5-fluoro-uracil and have a proven efficacy in the neoadju-vant setting.24–26 A small trial of UFT and leu-covorin reported a 26% response rate in patientswith advanced or metastatic head and neck car-cinomas.27 However, patients with recurrent dis-ease may not swallow properly, which wouldhamper treatment compliance. Pegylated lipo-somal doxorubicin is administered as a short in-travenous infusion and has a favorable toxicityprofile. This drug achieved a 33% response rate ina small trial.28

The combination of vinorelbine and a plati-num compound can be suitable for patients withrecurrent or metastatic squamous cell tumors ofthe head and neck. Kornek et al29 reported resultswith vinorelbine 30, mg/m2, on days 1 and 8, pluscarboplatin, 300 mg/m2, on day 1, given every 3


weeks. Two of twenty-four patients attained apartial response (9.5%), whereas 46% of them ex-perienced grade 3 to 4 leukopenia. The high tox-icity and low efficacy of this regimen could be re-lated to the dose calculation of carboplatin, whichwas adjusted by body surface rather than the areaunder the curve. Also, carboplatin produces morehematologic toxicity than cisplatin. Gebbia et al30

used the combination of vinorelbine, 25 mg/m2, ondays 1 and 8, and cisplatin, 80 mg/m2, on day 1 inpatients with previously untreated or recurrenttumors. In the group of 20 patients with recurrentdiseases, the response rate was 55%, with 15%complete responses. Toxicity was acceptable. Thesame regimen was successfully used in patientswith endometrial carcinoma.31

In this study, cisplatin and vinorelbine ob-tained similar results to those of classic regimens.One third of patients responded to treatment, and10% attained a complete response. That meansthat the regimen does not sacrifice the option ofan objective response. As expected, complete re-sponses were only seen among patients with localrelapse. Toxicity was quite tolerable, consideringthat most patients had received previous radio-therapy. Only two patients needed hospitaliza-tion because of side effects, which means that 95%of our patients had their treatment in day-hospital facilities. Toxicity was quite predictable,mainly consisting of neutropenia and, less com-monly, nausea and vomiting. However, this che-motherapy is not harmless. One of our patientsdied from febrile neutropenia, and another onedied for unknown reasons. In another group ofpatients with previously untreated local disease,we have seen two cases of vinorelbine-related hy-pertension that occurred during the infusion ofthis drug. We have not seen any case of acute painin the tumor as that reported by Gebbia et al.30,31

Toxicity could be decreased by reducing the dosesof both drugs. Cost is also a concern in the pallia-tive setting. Our scheme is acceptable in this re-gard, because it does not include a taxane.

Platinum compounds seem to account for mosttoxic effects in these regimens. New drugs couldpermit the design of active schemes without cis-platin or carboplatin. As stated previously, theassociation of docetaxel and 5-fluorouracil did notoffer any advantage,21,22 but other combinationswith taxanes could be explored in the future. Tax-ane-containing regimens could be cost saving ifthey had high activity and low toxicity. Alterna-tively, the dose of cisplatin in our regimen could

be reduced and a third drug incorporated to de-crease serious side effects and increase efficacy.

Ninety percent of head and neck tumors ex-press high levels of the epidermal growth factorreceptor, which make them suitable for treatmentwith specific inhibitors of this receptor. Trialswith these molecules in patients with advancedhead and neck cancer are ongoing. Because theirtoxicity does not overlap with that of chemo-therapy, the combination of both kinds of drugsmay be of interest.

In summary, the combination of cisplatin andvinorelbine is moderately active and has moder-ate toxicity in patients with recurrent or meta-static tumors of the head and neck. We think thatit compares favorably with combinations of cis-platin and 5-fluorouracil because of its convenientadministration.

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