Japanese Journal of Clinical Oncology Advance Access originally published online on June 26, 2008
Japanese Journal of Clinical Oncology 2008 38(7):459-463; doi:10.1093/jjco/hyn052
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© The Author (2008). Published by Oxford University Press. All rights reserved
A Phase II Study of Weekly Paclitaxel and Epirubicin in Recurrent or Refractory Squamous Cell Carcinoma of the Head and Neck
1 Division of Oncology and Hematology, Buddhist Tzu Chi General Hospital, Hualien
2 Department of Oncology, Buddhist Tzu Chi University, Hualien, Taiwan
For reprints and all correspondence: Chi-Cheng Li, Division of Oncology and Hematology, Buddhist Tzu-Chi General Hospital, 707, Sec.3, Chung-Yang Rd. Hualien, Taiwan. Email: kevinlcc1234{at}yahoo.com.tw
Received March 11, 2008; accepted May 27, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: The combination of taxanes and anthracyclines has been proved to be active for treatment of many cancers. We conducted a phase II study to determine the response and toxicity of paclitaxel and epirubicin (TE) in patients with incurable squamous cell carcinoma of the head and neck (SCCHN).
Methods: Patients with metastatic or recurrent SCCHN and adequate hematologic, renal and hepatic function and a Karnofsky performance status 
60% were enrolled. Prior chemotherapy and/or radiotherapy were permitted with 4-week interval. The regimen was paclitaxel 60 mg/m2 and epirubicin 20 mg/m2, on Days 1, 8 and 15, as an intravenous infusion, repeated every 28 days. Patients with disease progression or unacceptable toxicity were excluded from the study.
Results: The current study was intended to treat 43 patients but closed at the planned interim analysis due to early evidence of insufficient efficacy than expectation. Fifteen patients with a median age of 52 years (range, 37–72 years) were accrued. Previously, most patients had received radiotherapy and chemotherapy, and a majority (87%) of patients had treatment-free interval of <6 months. Median Karnofsky performance status was 70% (range, 60–90%). There was one clinical response (7%) and another three (20%) had stable disease. Median overall survival time was 4.5 months. The most common major toxicity was infection (47%), which caused four treatment-related mortalities. Grade 3–4 neutropenia occurred in five patients, but other toxicities were mild and manageable.
Conclusions: In the population with majority of refractory disease of SCCHN, the response rate to TE was lower than expected. Such dose schedule is not recommended unless in chemotherapy naïve patients or in combination with newer agents.
Key Words: paclitaxel • epirubicin • squamous cell carcinoma • head and neck • platinum refractory
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Squamous cell carcinoma of the head and neck (SCCHN) is a major public health problem that frequently causes devastating consequences to the functions, economics and cosmetic appearance of its victims, as well as death. In Taiwan, it is currently ranked sixth in cancer-related mortality and remains a challenging clinical problem worldwide. Sixty percent of primary SCCHN recurs after aggressive standard therapy and 5–25% develops distant metastases (1,2).
Chemotherapy is the main therapy for patients with recurrent or primarily disseminated disease, when local treatment with curative intent is no longer possible. Prognosis for recurrent or metastatic disease is universally poor, and there is no internationally accepted standard regimen for treatment. A number of single-agent chemotherapies have been tested in the past, including methotrexate, bleomycin, cisplatin, carboplatin, 5-fluorouracil, ifosfamide, paclitaxel, docetaxel, vinorelbine, gemcitabine, topotecan and doxorubicin/epirubicin. In general, 10–30% of patients achieve a partial response lasting 3–4 months (3).
One promising compound is the paclitaxel, which promotes stabilization of microtubules during cell division, by blocking mitosis at G2/M phase with subsequent apoptosis in sensitive cells. Some reports indicate that paclitaxel is an active single agent, with overall response rates ranged from 24 to 40% in patients with incurable locally advanced, recurrent or metastatic SCCHN (4–7). Epirubicin (4'-epi-doxorubicin) is an anthracycline antibiotic, which differs from doxorubicin for its epimerization of the hydroxyl group at the 4' position. In comparison with doxorubicin, epirubicin is associated with less myelosuppression, nausea and vomiting and cardiotoxicity at equimolar doses (8). Epirubicin is frequently substituted for doxorubicin as a single agent or in combination regimens as therapy across a broad range of cancers. The combination of doxorubicin or epirubicin and paclitaxel is proved to be very active in the treatment of advanced breast cancer, with an overall response rate in the range of 76–80% and a complete response rate of 18–28% (9,10). Several studies also suggested a role for epirubicin when used as a component of combination chemotherapy in the treatment of locally advanced or metastatic SCCHN (11,12).
These observations prompted us to investigate the efficacy of epirubicin in combination with paclitaxel (TE) in patients with advanced SCCHN. Although the combination of epirubicin and paclitaxel achieves high response rates in advanced breast cancer, considerable toxicity occurs (10). Weekly paclitaxel was proved to be more effective and less toxic than every 3-week administration for breast cancer (13,14). Weekly schedule was also preferred for the toxicity monitoring and management. Weekly paclitaxel 80 mg/m2 and epirubicin 25–35 mg/m2 provide high response rate, around 51–72%, even in second-line therapy of breast cancer, but the dose reduction or granulocyte colony-stimulating factor (G-CSF) prophylatic usage became necessary due to severe hematotoxicity (15,16). We chose a smaller individual dose of paclitaxel (60 mg/m2) and epirubicin (20 mg/m2) weekly in our treatment protocol than have been used in the previously published studies to avoid severe treatment-related toxicities and necessity of G-CSF prophylaxis. The aim of this study was to find a regimen offering an acceptable toxicity profile with a comparable or improved survival in recurrent SCCHN.
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PATIENTS AND METHODS |
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Patient Selection
Patient eligibility criteria included histologically confirmed SCCHN that recurred after previous chemotherapy, radiotherapy and/or surgery, or which presented with distant metastases at the time of initial diagnosis; measurable disease; performance status 60% or more according to Karnofsky performance status scale; age 18–75 years; adequate bone marrow (WBC
4000/ml, absolute neutrophil count 1500/ml and platelet 100 000/ml), liver and renal function (liver transaminases 
3 times upper normal limit if no liver metastasis and five times upper normal limit if liver metastasis is present; total bilirubin 2 mg/dl if no liver metastasis and 5 mg/dl if liver metastasis is present; serum creatinine 2.0 mg/dl); no brain parenchymal or leptomeningeal metastases; and no other previous or concurrent malignancy. Patient was excluded if previous chemotherapy regimen containing taxanes or anthracyclines. Patients considered at risk of having cardiac complications from paclitaxel or epirubicine (history of congestive heart failure, taking antiarrhythmic medication or recent myocardial infarct) were also not eligible. Previous radiotherapy or chemotherapy for adjuvant therapy or relapsed disease is allowed if treatment was completed at least 4 weeks before the enrollment into this study. The study protocol was approved by local ethics committee. All patients were fully informed about the study protocol and given written consent in accordance with institutional guidelines.
Study Design
This was an open-label, non-randomized, single-arm and phase II clinical trial. Simon two-stage design was used to calculate the sample size for the current phase II trial. Thirteen patients were recruited for the first stage. A planned interim analysis was conducted after the first 13 patients were followed up for >12 weeks. Recruitment was not suspended before the first 13 patients were followed up for 12 weeks. If at least four responders were observed in the first stage, additional 30 patients were recruited in the second stage. This design provides a 95% probability of early stopping if the true response rate is 20%, and an 80% probability of trial continuation if the true response rate is 40%.
Treatment Schedule
The regimen consisted of paclitaxel 60 mg/m2 and epirubicin 20 mg/m2 delivered as an intravenous infusion over 30 min on Day 1, 8 and 15. Patients were premedicated with dexamethasone, diphenhydramine and cimetidine to reduce the risk of anaphylaxis. Antiemetics were administered at the discretion of the treating physician. Paclitaxel and epirubicine regimen were repeated every 28 days, after recovery of the patient's blood count, and dose modifications or delays in administration were applied on the basis of nadir counts and toxicities of the last cycle. Treatment was maintained for a maximum of six courses, and chemotherapy was discontinued in case of disease progression or major toxicities.
Response and Toxicity Evaluation
Tumor response assessments were performed after every two cycles of treatment. Criteria of complete response, partial response, stable disease and progressive disease were based on the standard definitions of the WHO. Survival was calculated from the start of chemotherapy until death, and surviving patients were censored at the date of last follow-up. The distribution of survival time was constructed by the Kaplan–Meier method. Adverse events were monitored throughout the study. Toxicity grading was based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 2.0).
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RESULTS |
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A total of 15 patients were enrolled in this phase II trial from July 2005 to January 2007. Patient accrual was permanently closed in January 2007 due to the lack of activity in the interim analysis of the first 13 patients accrued to the trial. The patient characteristics of all enrolled patients are listed in Table 1. The median age of study participants was 52 years (range, 37–72 years), all of who were male. The primary tumor sites were: oral cavity, seven (47%); hypopharynx, seven (47%) and oropharynx, one (7%). All patients had previously received radiotherapy treatment and a majority of patients received previous surgery (80%) and chemotherapy (73%). Thirteen patients (87%) had relapse or progression to previous treatment within 6 months. The median Karnofsky performance status was 70% (range, 60–90%).
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Totally, 83 infusions were administered and evaluated. The median number of chemotherapy infusions was 6 (range, 1–18 infusions), i.e. two treatment cycles. A dose reduction was performed in 8 (9.6%) infusions with 25% reduction for both drugs. The dose reductions were decided all because of neutropenia. Chemotherapy was interrupted for up to 2 weeks in case of greater than Grade 3 adverse reactions. Seven patients received less than two cycles due to rapid disease progression (n = 4) or treatment-related mortalities (n = 3), which did not meet the time of first evaluation. Only one patient had partial response with response rate of 7% according to an intention to treat principle in all enrolled patients. Stable disease was observed in three patients (20%), whereas other patients had progressive disease despite the treatment or die before first evaluation of response. The median survival duration was 4.5 months (range 0.8–15) for the whole cohort (Fig. 1).
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The major adverse reactions to this regimen are listed in Table 2. The main major toxicity was infection, which occurred in 7 of 15 patients (47%). Grade 3–4 neutropenia occurred in 5 of 15 patients (33%) and most of them recovered soon after G-CSF usage. Two of them developed neutropenic fever and successfully treated as infection with strong empirical antibiotics and G-CSF. No one died due to infection secondary to neutropenia. No Grade 3–4 cardiac toxicity was observed. Four (27%) treatment-related mortality was noted in this cohort and all of them die of infection despite no preceding neutropenia. Three of them died due to pulmonary infection and the last one died due to sepsis. Other non-hematological toxicities were mild and manageable.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Palliative chemotherapy has demonstrated survival advantages over best supportive care for advanced SCCHN patients, (3) and the most commonly used agents are cisplatin or carboplatin, generally in combination regimens with infusional fluorouracil or a taxane. Only approximately one-third of patients will respond to first-line platinum-based therapy, and the median overall survival time can be expected to be approximately 6–9 months (3). However, there is no standard treatment in the relapsed or refractory patients. The rate of response to second-line chemotherapy was shown to be largely dependent on the therapy regimen given and on the treatment-free interval between initial and subsequent treatment. Patients with advanced SCCHN have limited alternative therapeutic options once they progress on platinum-based chemotherapy, and response rates are generally poor (3–10%) (17,18). The overall survival time was 56 days with best supportive care and remained short as 3.3–4.6 months despite 25% of disease control rate with aggressive intervention. Although the initial designation of this trial is not to focus on refractory disease, most patients (10 of 11 patients with previous chemotherapy) had failure of platinum-containing regimen within 6 months (median, 2.4 month; range, 1.1–9). The other four chemotherapy naïve patients also had short-interval radiotherapy previously. The overall response of 7%, clinical benefit of 27% and median overall survival of 4.5 months are all comparable with a recent phase II report of taxane in relapse/refractory disease (18).
Epirubcin and paclitaxel had been tested for advanced ovarian cancer after failure of platinum-containing regimens, which resulted in 44% response (19). The synergistic antitumor activity of anthracyclines and paclitaxel had previously been suggested in breast cancer, and synergism was enhanced at higher fractions (20). But the interest of adding epirubicin to paclitaxel had not been documented in SCCHN. So, we designed a phase II clinical trial of weekly epirubicin and paclitaxel for treating patients of SCCHN. However, this trial was terminated at interim analysis due to failure of achieving expected response. There are four possible explanations. First, a high percentage of treatment-refractory disease presented in this trial. Only two patients had treatment-free interval more than 6 months. The short interval to previous treatment may represent not only the refractoriness of chemotherapy but also the rapid growth of tumor. Secondly, four patients die before the first evaluation due to rapid disease progression. Usually, patients with life expectance <3 months will not be included in clinical trials. But, this may be representative for our daily practice in refractory SCCHN instead of selection bias for completing a good-response phase II trial. Thirdly, a high percentage of relative poor performance was presented in this study population. More than half of the patients had performance status of 70% or less. Many studies demonstrated significantly higher risk of death in patients with Karnofsky performance status <80% or 90% when they were receiving chemotherapy (21–23). Fourthly, the treatment-related mortality was relatively high in this trial; especially, the three early treatment-related mortalities due to infection had greatly decreased the response rate on intent-to-treat basis and overall survival time. However, the response rate was still low (12.5%) even in per-protocol population. The last three of these factors would confound each other and all affected by the first one. The selection bias of refractory patients may be the main reason why this trial failed to achieve the expected response. Hence, we proposed that this report should be regarded as a study for platinum refractory or treatment refractory SCCHN despite initial design.
Suboptimal chemotherapy dosing still should be considered in this trial. Although the treatment-related mortality is as high as 27%, the Grade 3 and 4 neutropenia was 33% without prophylaxis with G-CSF. This is lower than 70–91% severe neutropenia in other studies of taxanes achieving high response without G-CSF support (5,18,19). And no patient in this trial with Grade 3 or 4 neutropenia died of infection. The dose was also lower than the common weekly regimens which consisted of paclitaxel 80 mg/m2 and epirubicin 25–35 mg/m2 in treating metastatic breast cancer (15,16,24). Most mortalities of infection in this study were pulmonary infections, the commonest terminal event in head and neck cancer (25). These mortalities maybe related to advanced diseases and poor performance status rather than the complications of chemotherapy-induced immunosupression and/or myelosupression. However, dose escalation may need more intensive supportive care and dedicated patient selection. The combination with targeted agent may be considered to increase the response with acceptable toxicities in patient of refractory SCCHN (26).
In conclusion, this study of TE in patients with refractory SCCHN has failed to demonstrate promising response in accordance to previous evidence of anti-neoplastic activity form the combination of taxane and anthracycline. Such dose schedule is not recommended unless in chemotherapy naïve patients or in combination with newer agents.
Conflict of interest statement
None declared.
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References |
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