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Annals of Oncology Advance Access originally published online on June 21, 2006
Annals of Oncology 2006 17(10):1560-1567; doi:10.1093/annonc/mdl151
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© 2006 European Society for Medical Oncology

head and neck cancer

Paclitaxel and gemcitabine vs. paclitaxel and pegylated liposomal doxorubicin in advanced non–nasopharyngeal head and neck cancer. An efficacy and cost analysis randomized study conducted by the Hellenic Cooperative Oncology Group

G Fountzilas1, P Papakostas2, U Dafni3, T Makatsoris4, M Karina1, A Kalogera-Fountzila1, N Maniadakis5, G Aravantinos6, K Syrigos7, A Bamias8, C Christodoulou9, T Economopoulos10, HP Kalofonos4, A Nikolaou1, N Angouridakis1, G Stathopoulos9, D Bafaloukos11, N Pavlidis12 and J Daniilidis1

1 Aristotle University of Thessaloniki School of Medicine, Thessaloniki
2 ‘Ippokration’ Hospital
3 Laboratory of Biostatistics, University of Athens School of Nursing, Athens
4 University of Patras School of Medicine, Patras
5 University Hospital, Iraklio
6 ‘Agii Anargiri’ Cancer Hospital
7 Oncology Unit, 3rd Department of Medicine, Athens Medical School
8 Department of Clinical Therapeutics, University of Athens School of Medicine
9 ‘Henry Dunant’ Hospital
10 University Hospital ‘Attikon’
11 ‘Metropolitan’ Hospital, Athens
12 University of Ioannina School of Medicine, Ioannina; Greece

Correspondence to: Prof G. Fountzilas, Department of Medical Oncology, ‘Papageorgiou’ Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Macedonia, Greece. E-mail: fountzil{at}med.auth.gr


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
Background: The prognosis of patients with recurrent and/or metastatic head and neck cancer (HNC) is poor. Median survival of these patients following chemotherapy is in the range of 6 to 9 months. In the present randomized phase III trial we compared two new combinations containing new drugs with proven activity in phase II studies with patients with HNC.

Patients and methods: From November 1999 until November 2004, 166 eligible patients with HNC were enrolled in the study. They were treated with paclitaxel 175 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks (group A, 85 patients) or with paclitaxel, as in group A, and pegylated liposomal doxorubicin 40 mg/m2 on day 1 every 4 weeks (group B, 81 patients).

Results: There was no significant difference in response rate (20% versus 29%, P = 0.21), time to disease progression (median; 4.4 months versus 6.0 months, P = 0.09) and survival (median; 8.6 months versus 11.05 months, P = 0.25). Both regimens were generally well tolerated. The most frequently reported side effect, apart from alopecia, was neutropenia. Overall, there was no significant difference in severe toxicity between the two treatment arms.

Conclusions: The present study could not demonstrate a survival benefit with either regimen. Both treatments were well tolerated. Randomized studies comparing each of the two regimens with standard chemotherapy are warranted.

Key words: paclitaxel, doxorubicin, gemcitabine, chemotherapy, head and neck cancer


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 Acknowledgements
 References
 
The prognosis of patients with advanced (locoregionally recurrent and/or metastatic) head and neck cancer (HNC) is poor. Cisplatin-based combinations have been the backbone of chemotherapy in advanced HNC, with median survival in the range of 6 to 9 months irrespectively of the regimen used [1–4]. These unacceptably poor results urged investigators to shift their interest to new generation agents, such as taxanes, gemcitabine, pegylated liposomal doxorubicin hydrochloride (PLD, CaelyxTM Shering-Plough, Kenilworth, NJ) or navelbine. Taxanes, paclitaxel and docetaxel, have recently been introduced in the treatment of advanced HNC and demonstrated significant activity [5, 6]. On the other hand, gemcitabine, a new deoxycytidine analog, has only modest activity as a single agent in advanced HNC [7]. Of note, results concerning the cytocidal effect of the combination of paclitaxel and gemcitabine in vitro have been contradictory, being less than additive in selected human tumor cell lines [8] and synergistic in others [9]. Moreover, PLD has been developed in an effort to increase drug delivery to cancer cells, while reducing some forms of toxicity (myelosuppression, cardiotoxicity, alopecia) compared with its parent compound [10]. In a number of phase I and II trials it was shown that PLD in combination with radiotherapy (RT) was highly active in locally advanced or recurrent HNC [11, 12].

In our continuous effort to identify new, more active, regimens in advanced HNC, our group conducted a series of phase II trials evaluating non-platinum containing regimens. Interesting results were reported in two studies with the combinations of paclitaxel with gemcitabine [13] and paclitaxel with PLD [14]. The overall response rates (ORR) in those studies were 41% and 28%, respectively. Furthermore, median survival was 9 months in the first study and 7 months in the second. In both studies severe toxicities, apart from myelotoxicity, were infrequently recorded.

Motivated by this information we conducted a randomized phase III trial to further evaluate these two new and promising regimens in the treatment of advanced HNC. The primary objective of the study was survival. Secondary objectives were time to progression (TTP), time to treatment failure (TTF), ORR and rates of acute severe toxicities.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 Acknowledgements
 References
 
eligibility criteria
Patients were eligible for the present study (HE 5A/99) if they met the following criteria: (a) histologically or cytologically documented locally advanced or recurrent/metastatic non-nasopharyngeal squamous cell carcinoma (SCC) of the head and neck region; (b) age ≥18 years; (c) performance status (PS) ≤2 on the Eastern Cooperative Oncology Group (ECOG) scale; (d) life expectancy of at least 12 weeks; (e) adequate bone marrow, hepatic and renal function and (f) adequate cardiovascular, pulmonary and nutritional status to tolerate protocol treatment. Adjuvant or neoadjuvant chemotherapy was allowed providing that the elapsed time from completion of chemotherapy to first recurrence was ≥12 months. Prior surgery or RT was allowed. Patients were excluded from the study if they had a history of: (a) prior or synchronous cancer except of completely excised non-melanoma skin cancer or curatively resected in situ cervical cancer; (b) serious infection or other serious underlying medical condition, which could impair the ability of the patient to receive protocol treatment; (c) motor or sensory neuropathy, grade II or higher, according to World Health Organization (WHO) criteria; (d) atrial or ventricular arrhythmias and/or congestive heart failure, even if medically controlled and (e) previous chemotherapy for advanced disease. The clinical protocol and the companion translational research studies were approved by the Hellenic Cooperative Oncology Group Protocol Review Committee and by the Institutional Review Board of ‘Kyanous Stavros’ Hospital and the Bioethics Committee of the Aristotle University of Thessaloniki School of Medicine. A written informed consent was obtained from all patients.

Pretreatment evaluation included medical history, physical examination, chest X-ray, liver ultrasound, CT scan or MRI of involved areas, bone scan, ejection fraction measured by nuclear gated heart scan or echocardiogram, complete blood count (CBC) and complete biochemistry.

CBC and biochemistry were re-evaluated on the first day of each treatment cycle. CBC was repeated on day 8 prior to gemcitabine infusion. A baseline neurological evaluation prior to initiation of paclitaxel was recommended. Assessment of tumor response in patients with measurable or evaluable disease was required by imaging techniques, after the third and sixth cycle and every 3 months thereafter, until disease progression. Response criteria were those adopted by WHO.

treatment
Stratified randomization balanced by center was performed centrally at the HeCOG Data Office in Athens. Patients were stratified according to history of induction chemotherapy or concomitant chemoradiotherapy (Yes versus No) and PS (0+1 versus 2). Patients randomized to group A were treated with gemcitabine 1000 mg/m2 dissolved in 500 ml 0.9% sodium chloride over 30 min infusion on days 1 and 8 immediately followed, on day 1, by paclitaxel 175 mg/m2 over 3-h infusion with standard premedication. Each cycle was repeated every three weeks. Patients randomized to group B received PLD 40 mg/m2 dissolved in 250 ml 5% dextrose over 1-hour infusion on day 1 immediately followed by paclitaxel, as in group A. Each cycle was repeated every 4 weeks. Ondansentron + dexamethasone were used as antiemetics in all patients.

dose modifications
Paclitaxel, gemcitabine and PLD doses were reduced according to hematological and non-hematological side effects. When a dose reduction was required, no dose re-escalation was allowed. The absolute neutrophil count (ANC) had to be ≥1500/µl and the platelet count ≥100 000/µl prior to the beginning of each treatment cycle.

If the ANC was between 1000–1500/µl on day 8, gemcitabine was administered with G-CSF to maintain dose intensity (DI). If the ANC was less than 1000/µl, gemcitabine treatment was postponed for 1 week, and G-CSF treatment was initiated. In that case G-CSF was given prophylactically in all subsequent cycles.

Dose reductions were performed when, despite the use of G-CSF, neutropenia and/or thrombocytopenia had been present for ≥7 days. The standard levels that were used in modifying the dose of paclitaxel were as follows: level 0, 175 mg/m2; level 1, 135 mg/m2; level 2, 100 mg/m2; level 3, 80 mg/m2. Any patient who could not tolerate dose level 3 was taken off the study.

When the ANC was between 500/µl and 1000/µl and/or the platelet count was between 50 000/µl and 99 000/µl the paclitaxel dose was reduced by one dose level. The dose of paclitaxel was reduced by two dose levels in cases that the ANC was less than 500/µl and/or the platelet count was less than 50 000/µl, or in cases of febrile neutropenia with or without documented infection. The dose of paclitaxel was reduced by three dose levels only in the case of severe bleeding. Furthermore, in cases of grade III or IV neutropenia and/or thrombocytopenia, the doses of gemcitabine or PLD were reduced by 25% and 40%, respectively, in all subsequent cycles. When non-hematological toxicity occurred, drug doses were modified as follows; In case of ≥grade II mucositis the dose of paclitaxel was reduced by one dose level, the dose of PLD by 25% and that of gemcitabine by 50%. In cases of more than grade II neurotoxicity or any grade IV toxicity, except of alopecia, the patient was taken off the study. Toxicity criteria were those adopted by WHO.

follow-up
Patients were followed at the clinic by an ENT surgeon and a medical oncologist every 3 months after the completion of the treatment with physical examination, CBC, biochemistry, chest X-ray and specific imaging, as indicated.

statistical analysis
According to the study protocol, a total number of 253 patients were needed to be recruited, at a 5% withdrawal rate, to achieve an 80% power to detect, with a two-sided test, a 3-month difference to a 6-month baseline median survival. Taking into consideration an accrual rate of 60 patients per year, the maximum study duration was estimated to be 4.5 years. An interim analysis based on the O'Brien Fleming boundary values was scheduled when 50% of the endpoints had been reached. The accrual goal was not reached even though recruitment continued for one additional year than originally planned. At the interim analysis, the administrative decision was made to end the study due to the poor accrual rate.

Survival was estimated from randomization date to the date of last follow-up or until the patient's death. TTP was deemed as the time between randomization and progression documented clinically and/or radiologically. Patients who died from the disease without having documented progression, or from any cause during the chemotherapy period or within a month from its completion were considered as events for the estimation of TTP. Time to treatment failure (TTF) was calculated from randomization to the date of treatment discontinuation for any reason, or disease progression, or death from any cause during chemotherapy (or within a month from its completion), whichever occurred first. Results are reported on an intent to treat basis.

Fisher's exact test and chi-square test were used for comparing patients' characteristics, response and toxicity. The Kaplan-Meier method was used to calculate TTP, median follow up, and survival curves, while the log-rank test was used to compare time to event distributions. A prognostic factor analysis was performed with the Cox proportional hazards model. A backward selection procedure with removal criterion P = 0.10, identified the subclass of significant variables among the following: Age (≤64 versus >64), PS (0 versus 1 versus 2), gender (male versus female), site of disease (locoregional only versus distant only versus both locoregional + distant), tumor grade (well or moderately differentiated versus poorly differentiated or undifferentiated), treatment group (P+GEM versus P+PLD) and previous chemotherapy with or without RT (Yes versus No). Exact confidence intervals (CI) were used to determine the 95% upper and lower confidence limits of response rate.

economic evaluation
Health care resources are scarce and should only be deployed for those therapeutic options that provide more value for money. In particular, when a treatment option is more effective and less costly than its alternative it is obvious that it should be preferred. However, when a treatment option is more effective but also more costly than its alternative, then its extra cost must be reasonable and justifiable in relation to its effectiveness. Finally, if the two treatments are equally effective, it is reasonable to prefer the less costly, as it saves money and offers the same health outcome. Hence, a prospective economic evaluation has been carried out from the perspective of the National Health Service (NHS) in Greece. The chosen measure of effectiveness was survival. Treatment cost per patient was estimated on the basis of resource utilization data, collected for the trial, and 2005 unit cost data, which were collected from the database of the University Hospital of Heraklion, and are common amongst most public hospitals. Resource utilization data were analyzed for each patient in relation to chemotherapy and concomitant medications given; the diagnostic and laboratory tests performed; any hospitalisations and resources necessary for the treatment of adverse events; and finally, the follow up visits. It is important to note that the cost of chemotherapy in each cycle is based on the dose given, multiplied by the cost per mg and also on the assumption that there was no drug wasted, since it is common practice that the remaining drug in a vial is used for the next patient. Raw data were tested using typical statistical measures and bootstrapping was employed to deal with uncertainty and to compute cost-effectiveness acceptability curves [15, 16].


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 Acknowledgements
 References
 
From November 1999 until November 2004, 176 patients were enrolled in the study. Four patients with insufficient medical records were excluded from the analysis. Furthermore, six more patients were considered non-eligible (five patients received other than protocol treatment and one patient had a second primary tumor at study entry). Both groups were equally balanced with regard to major patient and tumor characteristics. The progress of patients through the various stages of the trial is shown in Figure 1 according to the Consolidated Standards of Reporting Trials [17].


Figure 1
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  		Figure 1 Consolidated Standards of Reporting Trials.

 
compliance to treatment and toxicity
Important pretreatment patient and tumor characteristics are depicted in Table 1. Larynx was the primary site of disease in half of the patients. Although the eligibility criteria allowed for patients with locally advanced disease, no such patient entered the study. The vast majority of patients presented with a PS of 0 or 1. Selected treatment characteristics are shown in Table 2. Approximately 80% of chemotherapy cycles were administered at full dose. Notably, less than half of the patients completed six cycles of chemotherapy in either group. Significantly, more chemotherapeutic cycles were delivered with a delay in group A (P < 0.001). Also a significant difference was seen in relative DI (RDI) of paclitaxel in favour of group B (P < 0.001). In total, 92 patients (47 in group A and 45 in group B) discontinued treatment permanently. The reasons for treatment discontinuation are shown in Table 3.


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  		Table 1 Selected patient and tumor characteristics

 

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  		Table 2 Selected treatment characteristics

 

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  		Table 3 Reasons for treatment discontinuation (percentages have been calculated according to the number of patients that discontinued treatment)

 
Twenty patients (12%) died during the course of chemotherapy. Fifteen of them died from early progression of the disease, seven after the first cycle of chemotherapy, three after the second, one after the third, three after the fourth and one after the fifth. Moreover, cause of death was a cardiac event in three patients, one patient from group A with a known history of medically controlled heart failure died from acute heart attack after the first cycle, one patient from group B died from myocardial infarction while hospitalized after three cycles of treatment for red blood cell (RBC) transfusion, while one more patient, from group B, died from cardio-pulmonary failure while hospitalized after the third cycle, for febrile neutropenia and grade 4 thrombocytopenia. Finally, one patient from group B died from listerial meningitis after the fourth cycle and one patient from group A committed suicide at home after the third cycle of treatment. Treatment interruption for toxicity was reported in three patients of group A (grade 2 and grade 3 peripheral neuropathy in two of them and non-specified in one) and persistent myelotoxicity in one patient of group B. Most of the patients who decided to withdraw from the study felt that their general condition did not improve considerably to justify continuation of treatment. Comorbid diseases or poor social economical status may also have played a role in taking this decision for some patients.

Severe (grade 3/4) side effects are shown in Table 4. There was no significant difference in the incidence of severe toxicity between the two groups. The most frequently recorded severe side effect was neutropenia (12% in group A versus 16% in group B, P = 0.50). Nausea/vomiting was mild and easily controlled with standard antiemetics. Four episodes of serious infections occurred, all in group A. Severe hand and foot syndrome was noted in three patients in group B, as expected, and was treated with pyridoxine. Febrile neutropenia was reported in six patients (one in group A and five in group B, respectively, P = 0.11). Alopecia was universal.


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  		Table 4 Incidence n and (%) of severe toxicities

 
G-CSF administration was required in 45 patients (25 in group A and 20 in group B) and erythropoietin in 30 patients (15 in each group). The criterion for introduction of erythropoietin was Hb value < 11 g/dl. Two patients in group A were treated with bisphosphonates and four patients with amifostine (one in group A and three in group B) in an attempt to prevent paclitaxel-induced sensory neuropathy. Treatment with antibiotics was given to 30 patients (16 in group A and 14 in group B). Ten patients (six in group A and four in group B) were hospitalized for RBC transfusion and one patient in each group for platelet transfusion. Salvage treatment was given in 60 patients (36%), 30 in each group and included radiation therapy in 15 patients (seven in group A and eight in group B), chemotherapy in 29 (13 in group A and 16 in group B), treatment with gefitinib in 13 (seven in group A and six in group B) or the combination of chemotherapy and radiation in three patients of group A.

response and survival
Overall, 26 patients were not evaluable for response. The main reason was death prior to evaluation (10 in group A and five in group B). In most cases (11 out of 15) cause of death was the disease. Other reasons for non evaluation for response were, toxicity (one patient in group A with non-specified toxicity and one in group B with persistent myelotoxicity) and voluntary withdrawal prior to evaluation (one in group A and six in group B). Finally, one patient in group B moved to another hospital, while another patient refused evaluation although he completed six cycles of treatment.

There was no significant difference in ORR between the two treatment arms (20% in group A versus 29% in group B, P = 0.21) (Table 5). After an overall median follow-up of 39.5 months, 139 patients (84%) had demonstrated tumor progression (73 in group A and 66 in group B) and 139 patients (84%) had died (72 in group A and 67 in group B). Median TTP was 4.4 months (range, 0.07–63.08) in group A and 6.0 months (range, 0.62–59.64) in group B (P = 0.09, Figure 2), while median time to treatment failure was 2.95 months (range, 0.01–63.08) in group A and 3.84 months (range, 0.01–59.64) in group B, (P = 0.14). Moreover, median survival was 8.6 months (range, 0.07–63.08) in group A and 11.05 (range, 0.62–59.64) in group B (P = 0.25, Figure 3). The estimated survival rates were 35% (95% CI 24.8–45.2%) versus 47% (95% CI 36.3–58.3%) at 1 year, 18% (95% CI 9.4–26.6%) versus 20% (95% CI 10.5–28.9%) at 2 years and 12% (95% CI 4–20%) versus 14% (95% CI 5.3–22.5%) at 3 years.


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  		Table 5 Best response

 

Figure 2
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  		Figure 2 Time to disease progression; group A (blue), group B (red).

 

Figure 3
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  		Figure 3 Survival; group A (blue), group B (red).

 
Results of the Cox regression analysis (Table 6) revealed that several prognostic factors, including previous treatment performance status and grade, were related to significantly poorer survival.


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  		Table 6 Multivariate regression (using significance level 0.10)

 
economic analysis
The survival analysis showed no difference between the two treatment arms, therefore the economic analysis was only based on the total treatment cost in each arm. This is a special case of economic evaluation often referred to as ‘cost–minimization’ analysis, because the aim is to find the therapy that minimizes treatment cost and hence health care expenditure [18,19]. The mean total treatment cost in the first group (P+GEM) is {euro}7419 (range: {euro}1044–{euro}13 826; 95% CI {euro}6688–{euro}8150) and in the second group (P+PLD) {euro}11 068 (range: {euro}2350–{euro}19 362; 95% CI {euro}10 038–{euro}12 098). Hence, mainly because of differences in chemotherapy costs, the combination of paclitaxel and gemcitabine costs significantly less (mean: {euro}3649; 95% CI {euro}2386–{euro}4912; P < 0.001) to the NHS than the combination of paclitaxel and PLD in the treatment of advanced non–nasopharyngeal HNC. Approximately 95% of the total treatment cost is due to chemotherapy, hence as long as the price of gemcitabine remains significantly lower than its alternative, the combination of gemcitabine with paclitaxel will remain the preferred option. The cost data analysed are not very skewed, and therefore the bootstrapped results are very similar—and for this reason not presented—which indicates that the differences in the economic analysis data are very robust.


   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
Acknowledgements
 References
 
The primary objective of the present phase III study was to compare the survival of patients with advanced HNC treated with the combination of paclitaxel and gemcitabine or PLD.

We initially planned this study mainly for two reasons. Firstly, to confirm in a randomized study the promising efficacy results and toxicity profile reported for these two regimens in our phase II studies [13, 14]. Secondly, in the case of a confirmation, to select the superior regimen and subsequently compare it with a standard regimen, such as cisplatin and infusional FU (CF) or weekly methotrexate.

Actually, we adopted a similar strategy with that of the ECOG investigators, who compared in a phase III study (E1395) [4] the CF combination with that of cisplatin and paclitaxel (CP) in advanced HNC. In order to select the proper dose of paclitaxel the same group previously conducted a phase III study (E1393) [20] comparing the combination of cisplatin (75 mg/m2) with two dose-levels of paclitaxel, a high (200 mg/m2 in a 24-h infusion) and a lower one (175 mg/m2 in a 24-h infusion). Since no significant difference was identified between the two groups in survival or ORR, the lower dose was selected for the subsequent E 1395 study. Furthermore, the duration of the paclitaxel infusion was shortened to 3 h in the subsequent study [4] since the 24-hour infusion was accompanied by a high incidence of severe hematological toxicity.

In our study, response rates did not differ between the two treatment arms and they were within the range reported in several others studies [1, 4] using the CF combination. Since ORR was not the primary endpoint in the present study there are several limitations in translating the results of response evaluation. First, there were four patients enrolled in the study with non-measurable disease (one in group A and three in group B). Second, a small number of patients were assessed for response clinically and not by imaging techniques even though it was anticipated by the protocol and third, most importantly, there was no central review of imaging material pertinent to tumor response.

The two regimens used in the present study were generally well tolerated. The most frequently recorded severe side effect was myelotoxicity, seen in 14% of patients with the paclitaxel/gemcitabine and in 20% of patients with the paclitaxel/PLD combination. These results appear to be superior to those reported in the E 1395 [4]. Even though indirect comparisons across trials may lead to erroneous conclusions, in this case the difference in the incidence of myelotoxicity was too large to remain uncommented and it should be evaluated in future studies. For example, the incidence of neutropenia in the E1395 study was 67% with the CF and 55% with the CP combination, considerably higher to the 12% seen with the paclitaxel/gemcitabine or to 17% seen with the paclitaxel/PLD combination. Interestingly, in our study severe thrombocytopenia was noticed only in two patients while its incidence was 23% with the CF and 5.5% with the CP regimen. Furthermore, severe sensory neuropathy was observed in 4% to 5% of the patients in the E1395 study, and only in 1% of our patients. Obviously, the latter difference can be attributed to the use of cisplatin in both treatment arms in that study.

There was no significant difference in survival between the two groups. Of note, median survival in our study was 8.6 months with paclitaxel/gemcitabine and 11 months with paclitaxel/PLD, similar to 8.7 months reported with CF or 8.1 months with CP in the E1395 study [4]. It is noteworthy that a considerable number of patients died early during the course of chemotherapy. This observation is consistent with the findings described by others [1, 4, 20]. History of heavy smoking, alcohol abuse and low social-economical status are frequently associated with HNC and contribute to the impaired clinical condition of these patients and the higher probability of dying from comorbid diseases.

Whilst the two treatment arms were equally effective in terms of survival, the combination of paclitaxel and gemcitabine costed substantially less to the NHS than the combination of paclitaxel and PLD in the treatment of advanced non-nasopharyngeal HNC. This was due, almost entirely, to the price difference between gemcitabine and PLD. Hence, as long as gemcitabine is cheaper, its combination with paclitaxel may be preferred on economic grounds as it costs less to the NHS.

In conclusion, the present study could not demonstrate a significant difference in survival between patients treated with the paclitaxel/gemcitabine or the paclitaxel/LPD combination. However, even though the two regimens did not differ in ORR, TTP or survival there may be other factors, such as quality of life (QoL) that could select one of them as the most promising treatment to be compared with the standard CF combination. Unfortunately, at the time of study design, we were not able to collect QoL data from our patients, since there was not a QoL instrument validated in the Greek language for HNC patients. Until a definite randomized phase III study comparing standard chemotherapy with each of these regimens has been conducted, both of them should be considered as experimental treatments and possible therapeutic alternatives for frail patients with HNC that could not tolerate platinum-based chemotherapy.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
References
 
The authors wish to thank Mrs Irini Grimani for statistical analysis. We also thank Mrs Evita Fragou for monitoring the study, Mrs Maria Moschoni for coordinating data management (all at HeCOG Data Office in Athens) and Mrs Stella Dallidou for secretarial assistance.

This work was presented in part at the ECCO-13 Meeting, Paris, October 2005. Supported by a Hellenic Cooperative Oncology Group research grand (HE R 5/99).

Received for publication March 29, 2006. Revision received May 19, 2006. Accepted for publication May 22, 2006.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
1. Jacobs C, Lyman G, Velez-Garcia E, et al. (1992) 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. J Clin Oncol 10:257–263.

2. Forastiere AA, Metch B, Schuller DE, et al. (1992) 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. J Clin Oncol 10:1245–1251.[Abstract/Free Full Text]

3. Clavel M, Vermorken JB, Cognetti F, et al. (1994) Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 5:521–526.[Abstract/Free Full Text]

4. Gibson Michael K. and Yi Li, et al. (2005) 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. J Clin Oncol 23:3562–3567.[Abstract/Free Full Text]

5. Forastiere AA, Shank D, Neuberg D, et al. (1998) Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group Trial (PA 390). Cancer 82:2270–2274.[CrossRef][Web of Science][Medline]

6. Catimel G, Verweij J, Mattijssen V, et al. (1994) Docetaxel (Taxotere): An active drug of the treatment of patients with advanced squamous cell carcinoma of the head and neck. Ann Oncol 5:533–537.[Abstract/Free Full Text]

7. Catimel G, Vermorken JB, Clavel M, et al. (1994) A phase II study of gemcitabine (LY 1880 11) in patients with advanced squamous cell carcinoma of the head and neck. Ann Oncol 5:543–547.[Abstract/Free Full Text]

8. Theodossiou C, Cook JA, Fisher J, et al. (1998) Interaction of gemcitabine with paclitaxel and cisplatin in human tumor cell lines. Int J Oncol 12:825–832.[Web of Science][Medline]

9. Jensen PB, Holm B, Sorensen M. (1997) In vitro cross resistance and collateral sensitivity in seven resistant small-cell-lung cancer cell lines. Preclinical identification of suitable drug partners to Taxotere, topotecan and gemcitabine. Br J Cancer 75:869–877.[Web of Science][Medline]

10. Ranson MR, Carmichael J, O'Byrne K, et al. (1997) Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 15:3185–3191.[Abstract]

11. Stewart JSW, Harrington KJ, Harrison D, Whittaker J. (1999) A phase II study of STEALTH pegylated liposomal doxorubicin (Doxil, Caelyx) and radiotherapy in the treatment of advanced head and neck squamous cell carcinoma (HNSCC). Proc Am Soc Clin Oncol 18:398 (Abstr).

12. Faivre S, Alsabe H, Djafari L, Janot F, Julieron M, Domenge C, et al. (2004) Locoregional effects of pegylated liposomal doxorubicin (Caelyx®) in irradiated area: A phase I–II study in patients with recurrent squamous cell carcinoma of the head and neck. Eur J Cancer 40:1517–1521.[CrossRef][Web of Science][Medline]

13. Fountzilas G, Stathopoulos G, Nicolaides C, et al. (1999) Paclitaxel and gemcitabine in advanced non-nasopharyngeal head and neck cancer: A phase II study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 10:475–478.[Abstract/Free Full Text]

14. Janinis J, Stathopoulos G, Timotheadou E, et al. (2004) Phase I–II study with paclitaxel and pegylated liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the head and neck. Anticancer Drugs 15:479–487.[CrossRef][Medline]

15. van Hout BA, Al MJ, Gordon GS, Rutten FF. (1994) Costs, effects and C/E ratios alongside a clinical trial. Health Econ 3:309–319.[Web of Science][Medline]

16. Efron B and Tibshirani RJ. (1993) An introduction to the Bootstrap. Monographs on Statistics and Applied Probability 57(Chapman and Hall/CRC, Boca Raton FL) pp. 1–430.

17. Moher D. (1998) CONSORT: An evolving tool to help improve the quality of reports of randomized controlled trials. JAMA 279:1489–1491.[Free Full Text]

18. Drummond M, O' Brien B, Stoddart G, Torrance G. (1998) Methods for the Economic Evaluation of Health Care Programmes. (Oxford Medical Publications, Oxford).

19. Cost-effectiveness in health and medicine. (1996) (Oxford University PressIn Gold M, Siegel J, Russell L, Weinstein M (Eds.). , New York).

20. Forastiere AA, Leong T, Rowinsky E, et al. (2001) Phase III Comparison of High-Dose Paclitaxel + Cisplatin + Granulocyte Colony-Stimulating Factor Versus Low-Dose Paclitaxel + Cisplatin in Advanced Head and Neck Cancer: Eastern Cooperative Oncology Group Study E1393. J Clin Oncol 19:1088–1095.[Abstract/Free Full Text]


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