Annals of Oncology Advance Access originally published online on September 6, 2007
Annals of Oncology 2007 18(11):1856-1860; doi:10.1093/annonc/mdm346
© 2007 European Society for Medical Oncology
head and neck cancer |
Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data
1 Department of Medical Oncology, University Hospital Antwerp, Edegem
2 Department of Radiotherapy, Campus Middelheim, ZNA Hospital Network, Antwerp
3 Department of Otolaryngology, University Hospital Antwerp, Edegem
4 Epidemiology and Community Medicine, Center for Cancer Prevention, University of Antwerp, Edegem
5 Department of Medical Oncology Campus Middelheim, ZNA Hospital Network, Antwerp, Belgium
* Correspondence to: Dr P. Specenier, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel: +32 3 8214014; Fax: +32 2 2694547; E-mail: pol.specenier{at}uza.be
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Abstract |
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Background: Radiotherapy (RT) with concurrent chemotherapy is the current standard of care for patients with unresectable locally advanced squamous cell carcinoma of the head and neck (SCCHN). Gemcitabine (GEM) is a potent radiosensitizer and in addition has activity as an anticancer agent in SCCHN.
Patients and methods: Twenty-six patients with locally far advanced SCCHN were enrolled in a chemoradiation feasibility study between November 1998 and September 2003. Use was made of conventionally fractionated RT and GEM 100 mg/m2, which was given within 2 h prior to radiotherapy on a weekly basis starting on day 1 of RT. Response was assessed according to WHO criteria, toxicity according to NCI-CTC version 2.
Results: The patients received a median of 7 (2–8) weekly cycles of gemcitabine and a median cumulative RT dose of 70 Gy (66–84.75). Hematologic toxicity was mild, but non-hematologic toxicity was severe: grade 3–4 stomatitis occurred in 85% of patients, dermatitis in 69%, pharyngitis/esophagitis in 81% and 80% of the patients needed a feeding tube during treatment. All 22 evaluable patients responded (50% complete, 50% partial). Median follow up of the surviving patients is 46 months. Median disease-free and overall survival is 13 months and 19 months, respectively; 27% of the patients are alive without evidence of recurrence beyond 3 years.
Conclusions: Conventionally fractionated RT in combination with GEM 100 mg/m2 weekly is feasible and highly active in the treatment of locally advanced SCCHN. In particular, long-term local control rate is promising. Acute mucosal toxicities are significant but manageable. Long-term toxicity interferes with normal food intake.
Key words: chemoradiation, gemcitabine, head and neck cancer, squamous cell carcinoma
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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For a long time definitive radiation therapy has been the standard treatment for locally advanced unresectable squamous cell carcinoma of the head and neck. High local and regional failure rates typically translated in 3-year survival rates of less than 25% and 5-year survival rates of less than 10%, leaving significant room for improvement [1–3]. Administration of mostly cisplatin-based chemotherapy, concomitantly with radiotherapy, improved locoregional control and survival in many studies, albeit at the cost of an increased hematologic and non-hematologic toxicity [4–9].
2',2'-difluoro-2'-deoxycytidine (dFdC, gemcitabine, Gemzar) has several properties which make it a good candidate for incorporation into chemoradiation regimens in the treatment of advanced head and neck cancer. It has an attractive toxicity profile and, in particular, it causes no significant mucosal toxicity on its own [10–15]. It has activity against head and neck cancer when used as a single agent or in combination with other cytotoxic agents, and it appears to be a very potent radiosensitizer at low concentrations in vitro and in vivo [16–20].
Eisbruch et al. pioneered the concomitant use of low-dose, weekly gemcitabine with standard radiation therapy in head and neck cancer patients and showed a high activity but also severe mucosal reactions leading to de-escalation of the initial dose from 300 to 100 mg/m2 [18] and subsequently even to 10 mg/m2 [19]. His preliminary data presented in 1997 [18] instigated this phase II feasibility study.
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patients and methods |
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study design
This was a phase II, single-institution feasibility study of the combination of weekly gemcitabine concomitantly with radiotherapy in patients with head and neck cancer.
eligibility criteria
To be eligible patients were required to have histologically confirmed locally advanced squamous cell carcinoma of the head and neck for which surgery was not considered appropriate after careful evaluation by a multidisciplinary dedicated team of head and neck surgeons, radiation oncologists and medical oncologists, either because of unresectability or for organ preservation. Staging procedures included clinical examination, endoscopy and CAT scan. Other requirements for eligibility were written informed consent, age 
18 years, performance status of 
2 according to WHO, life-expectancy of at least 12 weeks, adequate bone marrow, renal and liver function. Prior radiotherapy or chemotherapy were not permitted. However, prior surgery of the neck was permitted. Exclusion criteria were known central nervous system involvement, congestive heart failure or angina pectoris, uncontrolled hypertension and arrhythmia requiring medication, history of significant neurological or psychiatric disorders and active infection.
In accordance with the Declaration of Helsinki, IHCH-GCP guidelines and applicable local laws, all patients provided signed, informed consent. The Ethics Committee of the University of Antwerp approved the protocol.
treatment
Treatment consisted of weekly gemcitabine at a dose of 100 mg/m2 prior to conventionally fractionated radiotherapy (planned cumulative dose 70 Gy, five fractions/week, fraction dose 2 Gy). Gemcitabine was started on the same day as the radiotherapy and was administered (dissolved in 150 ml NaCl 0.9%) over 30 min within 2 h before radiotherapy. Gemcitabine was given for the duration of radiotherapy. In case of interruption of the radiotherapy due to toxicity, gemcitabine was withheld until restart of radiotherapy. Metoclopramide 20 mg and dexamethasone 8 mg or methylprednisolon 40 mg were given prophylactically by the i.v. route 30 min before the start of the gemcitabine.
efficacy and safety evaluation
Patients were evaluated for response according to the criteria of the World Health Organization. Response was evaluated by clinical examination, endoscopy and CAT scan. Toxicities were evaluated according to the National Cancer Institute Common Toxicity Criteria version 2. Acute toxicities were scored weekly during radiation.
study objectives
The primary objective of this study was to study the feasibility of the combination of weekly gemcitabine, at the dose described earlier, concomitantly with radiotherapy in patients with head and neck cancer. Secondary objectives were to study the safety profile and to assess the anti-tumor activity of the combination. After the end of treatment patients were followed for early and late toxicity, local and distant disease control and survival.
statistics
Data were summarized using number of patients and percentages. Overall survival and disease-free survival were calculated using the Kaplan–Meier method. Statistical Package for the Social Sciences (SPSS 13).
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results |
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patient population
Twenty-six patients with squamous cell cancer of the head and neck were enrolled in the study between November 1998 and September 2003.
Patient characteristics are shown in Table 1. Primary tumor and Nodol status of these patients is shown in Table 2. The majority of patients (80%) had inoperable disease. A minority had potentially resectable disease but required mutilating surgery, i.e. laryngopharyngectomy (3/26) or laryngectomy (2/26). Two patients were kidney transplant survivors for several years.
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treatment and toxicity
The patients received a median of seven cycles (range 2–8) of gemcitabine and a median cumulative radiation dose of 70 Gy. Radiation dose was 70 Gy in 21 patients. Radiation was stopped at a cumulative dose of 66 Gy in two patients and at 68 Gy in one patient, either for toxicity or for practical reasons. Two patients received a higher dose (77.6 Gy and 84.75 Gy, respectively). Both patients had progressing tumor while on treatment and went on with two daily fractions of 1.2 and 1.5 Gy , respectively. Median treatment duration was 50 days (range: 37–56 days). One patient refused further gemcitabine after two cycles and continued with radiotherapy alone. This patient remained in the survival analysis. Hematologic toxicity was mild: one episode of grade 3 neutropenia occurred in one patient and grade 3 anemia occurred in another. We observed no grade 3 thrombocytopenia. Non-hematologic toxicities were more severe. Skin and mucosal toxicity is shown in Figure 1. Grade 3–4 toxicities included oral mucositis in 22 of the 26 patients (85%), dermatitis in 18 (69%), pharyngitis and/or oesophagitis in 21 (81%). Feeding tubes were not routinely inserted before treatment but at physician's discretion during treatment in 21 of the 26 patients (81%). Weight loss of more than 5% of the initial body weight occurred in 16 (62%) patients; 8 (31%) patients lost more than 10% of their initial body weight.
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Twenty-one patients needed hospitalization for at least one night. The mean and median duration of hospitalization for the 26 patients was 13.6 and 5 days (range 0–76), respectively.
None of the 15 patients alive without disease after 1 year was dependent on a feeding tube. Figure 2 shows the late toxicity that was scored after recovery of the acute toxicities (at least 3 months after the end of treatment). In patients who had a recurrence, late toxicity was scored before the recurrence. Seven patients are still alive with a minimum follow-up of 3 years.
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Over time, xerostomia in these patients remained unchanged. Six patients are able to eat softened food; only one patient can eat normally, without any restrictions.
response and outcome
Response was evaluable in 22 patients. All evaluable patients responded, i.e. with a radiological and/or clinical complete response in 11 (50%) and a partial response in 11 (50%). Lymph node resection was performed before the chemoradiation in one patient and a radical neck dissection was performed after chemoradiation in five patients. Four of these dissection specimens still contained tumor. Nine patients (35%) relapsed locally. Distant metastasis and a second primary occurred in 11 patients (42%) and 1 patient (4%), respectively. All recurrences were observed within 2 years after primary diagnosis. Median follow up of the surviving patients is 46 months. Median disease-free and overall survival is 13 months and 19 months, respectively. Twenty-seven percent of the patients are alive without evidence of recurrence beyond 3 years.
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discussion |
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The data we present are mature, as treatment in the last patient was completed more than 3 years before analysis. The median follow-up time for the surviving patients is 46 months.
As expected, the hematologic toxicity of weekly low-dose gemcitibine combined with standard radiotherapy was low. We encountered only one episode of grade 3 neutropenia and one episode of grade 3 anemia in two patients. No treatment delays or interruptions were due to hematologic toxicity. This is in line with the results of others who studied the concomitant use of gemcitabine and radiation in patients with head and neck cancer [19, 21].
Radiation therapy alone or chemoradiation typically causes significant mucositis in patients treated for head and neck cancer [2]. In an extensive review of the literature, Trotti et al. [22] reported an overall incidence of mucositis (any grade) of 80% in patients treated with radiotherapy whatever schedule was used. Grade 3–4 mucositis occurred more frequently in patients treated with altered fractionations (57%) or with chemoradiation (43%), than in those treated with conventionally fractionated radiation alone (34%).
Despite the use of feeding tubes in 80% of our patients, weight loss of more than 10% occurred in 30% of the patients, suggesting that an earlier start of tube feeding might be necessary for most patients.
In our study we used a conventional fractionation schedule (70 Gy, five fractions/week, fraction dose 2 Gy). We can only speculate on toxicity and local control if gemcitabine would have been combined with altered fractionation schedules [23] or more advanced radiation techniques such as IMRT [24, 25].
Despite the severe mucosal reaction, median treatment time was 50 days, which is not significantly longer than the planned treatment duration of 49 days. This is important as prolonged overall treatment time is a well-known factor that has a negative impact on the outcome of locally advanced squamous cell head and neck cancer due to tumor cell repopulation [26–29].
Historically locoregional relapse in patients with locally advanced head and neck tumors was far more frequent than distant relapse and even in contemporary series, which use intensive regimens, local disease control only equals distant disease control at best [1]. In our population there were more distant metastases than local failures, which is no surprise as gemcitabine at the dose used in this study is mainly a radiosensitizer but is not expected to show much anti-tumor activity on its own.
Most patients had permanent grade 1 or 2 xerostomia and skin fibrosis. Swallowing difficulties were common even after recovery of the acute mucosal toxicities but none of our disease-free survivors after 1 year remained dependent on a feeding tube.
Only one of the seven long-term survivors (i.e. beyond 3 years) was able to take normal food, all the others only softened food. Late dysphagia and long-lasting feeding-tube dependency is not uncommon after chemoradiation for advanced head and neck cancer, and is not unique for the combination with gemcitabine [30–32].
The optimal dose and timing of administration of gemcitabine in combination with radiation in head and neck cancer have still to be determined. The final analysis of the phase I study by Eisbruch et al. suggests that a dose somewhere between 10 and 50 mg/m2 might be the optimal dose when administered weekly concurrently with radiotherapy in the treatment of head and neck cancer [19]. Long-term follow up data on efficacy and toxicity, are however not available.
Twice weekly administration was reported to result in a higher therapeutic ratio, compared to weekly administration in a murine model, and proved feasible and promising in human pancreatic cancer and non small cell lung cancer and in inoperable feline squamous cell oral tumors [33–36]. Therefore, a future trial exploring the therapeutic value of a low dose of gemcitabine twice weekly combined with contemporary radiation techniques seems worthwhile to perform.
Cisplatin-based chemoradiation is currently considered standard treatment for locally advanced stage squamous cell carcinoma. In squamous cell carcinoma of the uterine cervix the addition of gemcitabine to concurrent cisplatin and irradiation conferred an improved tumour control over cisplatin alone, albeit at the cost of an increased toxicity [37]. Benasso et al. combined gemcitabine and cisplatin in an alternating chemoradiation schedule in unresectable head and neck cancer. Data of locoregioal control rate compared favourably with those from the database of patients treated with alternating cisplatin–fluorouracil and radiation within controlled clinical trials at the same institution. However, toxicity was substantial and probably prohibitive for widespread adoption of this regimen in the medical community [38]. Hence the question if weekly low-dose gemcitabine could be safely combined with cisplatin and conventional radiation in squamous cell carcinoma of the head and neck (SCCHN) remains unanswered.
Addition of the Epidermal Growth Factor Receptor (EGFR) blocking chimeric monoclonal antibody cetuximab (Erbitux) to radiotherapy improved locoregional control but not distant disease-free survival in a recently published randomized phase III study in locally advanced head and neck cancer without increasing mucosal toxicity (39).
It is important to mention that preclinical data in nude mice bearing a human squamous cell head and neck cancer cell line suggest that the combination of gemcitabine with the EGFR tyrosine kinase inhibitor gefitinib act synergistically when combined with radiation therapy [40]. We are unaware of clinical or preclinical data on the combination of radiation data with gemcitabine and cetuximab, something that needs further attention.
In conclusion, standard radiation therapy in combination with gemcitabine 100 mg/m2 weekly is feasible and highly active in the treatment of locally advanced squamous cell carcinoma of the head and neck. Acute mucosal toxicities are significant but manageable. However, late toxicity is more problematic. Particularly, normal food intake did not recover in the majority of patients. Long-term local control rate is promising. More data are needed about optimal dose and schedule of gemcitabine (alone or in combination with other cytotoxic agents) when combined with contemporary radiation techniques and about its integration in the management of locally advanced head and neck cancer with radiation and anti EGFR therapies.
Received for publication May 6, 2007. Revision received June 4, 2007. Accepted for publication June 5, 2007.
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