Accepted 12 April 2006 Published online 13 November 2006 in Wiley InterScience ( DOI: /hed.

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1 ORIGINAL ARTICLE PHASE II ANALYSIS OF PACLITAXEL AND CAPECITABINE IN THE TREATMENT OF RECURRENT OR DISSEMINATED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK REGION Jens D Bentzen, MD, 1 Hanne Sand Hansen, MD 2 1 Department of Radiotherapy and Oncology, University Hospital in Herlev, 2730, Herlev, Denmark. jeben@herlevhosp.kbhamt.dk 2 Department of Oncology, Finsencenter, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark Accepted 12 April 2006 Published online 13 November 2006 in Wiley InterScience ( DOI: /hed Abstract: Background. The aim of this phase II study was to evaluate the antitumor activity and toxicity of a non-platin containing regimen with paclitaxel and capecitabine. Methods. Fifty patients with recurrent or disseminated squamous cell carcinoma were included in the study. The treatment consisted of paclitaxel 175 mg/m 2 once every third week and capecitabine 825 mg/m 2 per oral (p.o.) twice daily (bid) for 2 weeks. Results. The overall response rate according to the World Health Organization (WHO) criteria was 42%. Two patients had a complete response (CR), 19 patients had a partial response (PR), 14 patients had no change (NC), 12 patients had progressive disease (PD), and 3 patients were not evaluable (NE). The median survival time was 8 months. Toxicity was very moderate. Only 10% of 315 delivered treatments had to be given in reduced dose or postponed for a week or more. Conclusions. The toxicity was low and manageable. The overall response rate was comparable to the commonly used cisplatin/5-fluorouracil regimen. VC 2006 Wiley Periodicals, Inc. Head Neck 29: 47 51, 2007 Keywords: paclitaxel; capecitabine; head and neck cancer; squamous cell carcinoma; toxicity Correspondence to: J. D. Bentzen VC 2006 Wiley Periodicals, Inc. The incidence of head and neck cancer in Denmark approaches 1000 patients per year. The primary treatment strategy is accelerated radiotherapy (66 68 Gy/2Gy/fraction, 6 fractions/week) in combination with the hypoxic radiosensitizer nimorazol. Surgery is selected for some of the oral cancers and for salvage treatment. Chemotherapy is mainly used for patients with recurrent or primarily disseminated disease, when local treatment with curative intent is no longer possible. No standard chemotherapy regimen has yet been agreed upon either in Denmark or in the rest of the world. Most regimens tested so far contain cisplatin, a drug that in Denmark often requires hospitalization because of our rather long-lasting prehydration and posthydration regimens, and which has considerable toxicity, especially in this patient population. Cisplatin combined with 5-fluorouracil (5-FU) is probably the most used combination regimen, yielding response rates of about 33%. 1 The aim of this study was to try to find a regimen offering a more favorable toxicity profile com- Paclitaxel and Capecitabine in HNSCC HEAD & NECK DOI /hed January

2 bined with a comparable or improved response rate in comparison to the cisplatin-containing regimens. Paclitaxel (Taxol, Bristol-Myers Squibb, Bromma, Sweden) is an interesting antimitotic drug that is already frequently used in the treatment of several other cancers such as ovarian cancer and breast cancer. The experience with paclitaxel in head and neck cancer is limited, with reported response rates in different combination regimens ranging from 23% to 78%. 2 5 Doses of 135 to 175 mg/m 2 can be given safely as 3-hour infusions every 3 weeks on an outpatient basis. Capecitabine (Xeloda, Roche, Basel, Switzerland) is an oral prodrug to 5-FU. Its activation to 5-FU by thymidine phosphorylase occurs mainly within the tumors. 6 A combination regimen with paclitaxel 175 mg/m 2 every third week and capecitabine 825 mg/m 2 twice daily (bid) days 1 to 14, followed by 1-week rest, has previously been found to be safe in a breast cancer study. 7 MATERIALS AND METHODS Patient Eligibility. Patients were eligible under the following conditions: (1) histologically confirmed recurrent or disseminated squamous cell carcinoma of the head and neck region, not suitable for curative radiotherapy or salvage surgery; (2) measurable disease in minimum 2 dimensions; (3) age 18 to 75 with World Health Organization (WHO) performance status 2; (4) no previous chemotherapy for 1 month; (5) no other severe life-shortening disease or other malignant disease; and (6) adequate bone, liver, and renal function. Patients had to be mentally well and psychologically capable of understanding and adhering to the treatment plan. The protocol was approved by the Ethics Committees of Copenhagen, Denmark. All patients gave written informed consent. Treatment. The treatment plan was as follows: Day 1: Paclitaxel 175 mg/m 2 i.v. over 3 hours. Days 1 to 14: Capecitabine 825 mg/m 2 per dose orally bid (twice daily) for 2 weeks, with 200 ml water taken <30 minutes after a meal. After a 1-week interval without medication, the treatment was repeated. The patients received the following intravenous (i.v.) premedication 30 minutes before administration of paclitaxel: dexamethasone 10 mg, clemastine 2 mg, and nizatidine 100 mg. Statistical Analysis. The criteria for response were based on the WHO definition. 8 Survival curves were generated according to the Kaplan Meier method. 9 Survival was calculated from the start of chemotherapy until death. Surviving patients were censored at the day of their last follow-up visit. Time to progression was calculated from the first day of chemotherapy to the first documentation of progression. RESULTS Table 1. Patient characteristics. Characteristics No. of patients % Total no. of patients Sex Male Female 8 16 Age, y 54.7 (range, 32 73) WHO performance Primary disease site Nasopharynx 9 18 Oropharynx 8 16 Hypopharynx 7 14 Larynx 7 14 Oral cavity Nasal cavity or maxillary sinus 1 2 Other 3 6 Prior therapy None 3 6 Radiotherapy and surgery Radiotherapy alone Surgery alone 1 2 Disease site at study entry Local only Regional only 6 12 Distant metastasis only 6 12 Locoregional Local and distant metastaseis 3 6 Regional and distant metastaseis 1 2 Local, regional, and distant 6 12 Abbreviation: WHO, World Health Organization. Patient Characteristics. Fifty patients were consecutively included in the study between January 2001 and April The patient characteristics are listed in Table 1. The distribution according to the International Union Internationale Contre le Cancer (UICC 1997) TNM classification 10 at the time of the primary diagnosis and at the begin- 48 Paclitaxel and Capecitabine in HNSCC HEAD & NECK DOI /hed January 2007

3 Table 2. UICC TN classification. Initial status N0 N1 N2 N3 Total T T T T T Total Status at time of entrance in study rn0 rn1 rn2 rn3 Total rt rt rt rt rt Total Abbreviations: UICC, Union Internationale Contre le Cancer; TN, tumor node. ning of chemotherapy is shown in Table 2. Twenty-nine of the patients had been treated with radiotherapy as the primary treatment, 2 in combination with operation. Eighteen patients had had primary surgery, 17 of whom had undergone additional postoperative radiation. The 3 patients with primarily disseminated disease had not had any other treatment before the study chemotherapy. Three of the 50 patients had primary distant metastases, all in the lung. Thirty-eight patients had local tumor recurrence or remnant local tumor. Twenty-three patients had regional lymph node metastases. More than one half of the lymph nodes were localized in region 2: 38% in region 3 and 10% in region 4. A total of 42 (84%) ofthe patients had tumor recurrence within the radiation fields. Distant metastases were seen in 16 patients. Ten patients had lung metastasis, 5 had liver metastasis, and 4 had bone metastasis. Five patients had metastasis to >1 distant site; 29 patients started chemotherapy for their first relapse, 11 patients for the second relapse, and 7 patients after 3 to 6 relapses. Response and Survival. Treatment was well tolerated when given on an outpatient basis. A total of 50 patients received 315 series of chemotherapy, 20 patients had >6 series, and 6 patients had >12 series. The response rate according to the WHO criteria was 42% (see Table 3). Two patients had a complete response (CR), and 19 patients had a partial response (PR). Fourteen patients were evaluated as having no change (NC), and 12 patients had progressive disease (PD). Three patients died before they received 3 series and were therefore not eligible for response evaluation (NE), but they where included in the response evaluation (intention to treat analysis). The mean time to progression (TTP) was days (5.2 months). A Kaplan Meier plot of crude survival is shown in Figure 1. The median survival time was 244 days or 8 months. The 2 patients who had CR are still alive with no evidence of disease (NED). Toxicity. The worst registered toxicities are listed in Table 4. Thirteen series of 315 (10%) were administered in reduced dose or postponed for 1 week. One patient did not complete the first cycle. Hair loss and hand-and-foot syndrome were the most common side effects. Only 1 patient experienced grade 4 gastrointestinal toxicity. Hemato- Table 3. Best response: WHO, intention to treat analysis*. Response No. of patients % CR 2 4 PR NC PD NE 3 6 Total Abbreviations: WHO, World Health Organization; CR, complete response; PR, partial response; NC, no change; PD, progressive disease; NE, not evaluable. *Mean time to progression (TTP) in 44 patients was 157 days (5.2 months). FIGURE 1. Kaplan Meier plot of crude survival for the 50 patients. Median survival time, 244 days. Paclitaxel and Capecitabine in HNSCC HEAD & NECK DOI /hed January

4 Table 4. Toxicity observed in 50 patients: WHO criteria. No. of patients (%) by grade Grade 0 Grades 1 2 Grades 3 4 Not evaluated Skin (hand-and-foot syndrome) 20 (40) 20 (40) 6 (12) 4 (8) Alopecia* 2 (4) 24 (grade 1) (48) 19 (grade 2) (38) 5 (10) Allergy 36 (72) 3 (6) 1 (2) 10 (20) Mucositis 31 (62) 11 (22) 3 (6) 5 (10) Nausea 15 (30) 29 (58) 2 (4) 4 (8) Vomiting 29 (58) 15 (30) 2 (4) 4 (8) Diarrhea 17 (34) 26 (52) 3 (6) 4 (6) Infection 17 (34) 22 (44) 8 (16) 3 (6) Neurotoxicity 23 (46) 20 (40) 1 (2) 6 (12) Arthritis/muscle pain 14 (28) 31 (62) 0 (0) 5 (10) Cardiac 32 (62) 2 (4) 0 (0) 16 (32) Urogenital 28 (56) 7 (14) 1 (2) 14 (28) Anemia 15 (30) 32 (64) 0 (0) 3 (6) Leukocytopenia 22 (44) 18 (36) 7 (14) 3 (6) Neutropenia 24 (48) 13 (26) 9 (18) 4 (8) Thrombocytopenia 40 (80) 7 (14) 0 (0) 3 (6) Abbreviation: WHO, World Health Organization. *For alopecia, grade 1 is partial hair loss; grade 2 total hair loss. There is no grade 3 or 4. logic toxicity (neutropenia) was moderate, with only 9 patients experiencing grade 3 and none grade 4 toxicity. There were no toxic deaths. DISCUSSION Studies of combination therapy with paclitaxel and capecitabine for recurrent or metastatic head and neck cancer has not been published before. The combination of taxanes and capecitabine has been used for metastatic mammary cancer and for colorectal cancer. A study by McDonald and Miles 11 has shown a synergistic effect in recurrent mammary cancer of paclitaxel and capecitabine. For metastatic colorectal cancer, a randomized study with paclitaxel and capecitabine versus the Mayo Clinic regimen (5-FU and leucovorin) showed at least equal results. Median time to progression was 140 versus 144 days, and median survival time was 392 versus 391 days. The response showed 27% versus 54% in favor of the paclitaxel and capecitabine regimen. 12 Single agents such as methotrexate, cisplatin, 5-FU, paclitaxel, bleomycin, and ifosfamid are effective with responses ranging from 15% to 33% and 5- to 6-month median survival times in pretreated patients. 13 The most used combination, cisplatin and 5-FU, gives overall response rates on the order of 30% and median survival times of 4 to 6 months. 14,15 The side effects associated with this regimen are considerable, however. In a recent randomized phase III study by the Eastern Cooperative Oncology Group (ECOG), cisplatin (100 mg/m 2 day 1) plus 5-FU (1000 mg/m 2 /24 hours, days 1 to 4) (CF) was compared with cisplatin (75 mg/m 2 day 1) and paclitaxel (175 mg/m 2 day 1) (CP). 5 The estimated median survival times were not significantly different (CF 8.7 months and CP 8.1 months). Response rates were 27% (CF) and 26% (CP). Toxicities were similar between the groups and consisted mainly of myelosuppression, nausea, and stomatitis. Neutropenia was common, with grade 3 and 4 neutropenia in 67% (CF) and 55% (CP). In the present study, we had a very low toxicity, with only 10% of the planned treatments having to be given in a reduced dose and especially a very low frequency of grades 3 and 4 neutropenia. Hand-and-foot syndrome was also a minor problem, probably because the dose in our study was a slightly lower than the dose of capecitabine used in most colorectal trials. The overall response rate in this study was 42% (intention to treat analysis), which is definitely comparable to the cisplatin 5-FU regimen. The mean TTP was 5.2 months and the median overall survival time (Kaplan Meier) was 244 days or 8 months, which is also comparable to the best studies reported so far, including the recent ECOG study. 5 The tested regimen with the combination of capecitabine 825 mg/m 2 bid days 1 to 14 and paclitaxel 175 mg/m 2 day 1 every third week was well tolerated on an outpatient basis and was associated with a very modest toxicity. The combination regimen provides reasonable response rates in comparison with the cisplatin 5-FU regimen. In 50 Paclitaxel and Capecitabine in HNSCC HEAD & NECK DOI /hed January 2007

5 addition, this regimen can easily be administered on an outpatient basis. In our view, this regimen could be a good substitute for the currently applied cisplatin 5-FU regimen. Because of the promising preliminary results, the study is currently being extended to accrue a total of 150 patients to provide a more robust estimate of response rates and survival. REFERENCES 1. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region. A metaanalysis of randomized trials. J Clin Oncol 1996;14: Hitt R, Paz-Ares L, Hidalgo M, et al. Phase I/II study of paclitaxel/cisplatin as first-line therapy for locally advanced head and neck cancer. Semin Oncol 1997;24(suppl 19): Gebbia V, Testa A, Cannata G, Gebbia N. Single agent in advanced squamous cell head and neck carcinoma. Eur J Cancer 1996;32A: Licitra L, Fulfaro F, Grandi C, et al. Phase II study of biweekly/cisplatin. Proc Am Soc Clin Oncol 1996; Gibson MK, Li Y, Murphy B, et al. 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 2005;23: Miwa M, Lira M, Nishida M, et al. Design of a novel oral fluoropyrimidine carbamate, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998;34: Villalona-Calero MA, Blum JL, Jones SE, et al. A phase I and pharmacologic study of and in breast cancer patients. Ann Oncol 2001;12: Miller AB, Hoogstraten B, Staquet M, Winkler A. reporting results of cancer treatment. Cancer 1981;47: Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53: Wittekind C, Wagner G, editors. UICC: TNM Klassifikation maligner Tumoren. 5th ed. Berlin: Springer; McDonald F, Miles D. Xeloda and Taxotere: a review of the development of the combination for use in metastatic breast cancer. Int J Clin Pract 2003;57: Van Cutsem EV, Twelves C, Cassidy J, et al. Oral compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001;9: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia, PA: Lippincott-Raven; p Jacobs C, Lynman V, Velez-Garcia E, et al. A phase III randomized comparison of cisplatin plus fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992; 10: Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin and carboplatin 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 1992; 10: Paclitaxel and Capecitabine in HNSCC HEAD & NECK DOI /hed January