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Abstract. Background: This study was designed to evaluate

the concomitant use of weekly docetaxel and hyperfractionated

radiotherapy for the treatment of head and neck cancer

(HNC). Patients and Methods: Twenty-five patients with

advanced squamous cell HNC were treated with

hyperfractionated radiotherapy (72 Gy at 1.2 Gy twice per day)and weekly chemotherapy with docetaxel (10 mg/m2). Results:

Toxicity was significant, with grade 2 to 4 mucositis observed in

100% and lymphopenia in 84%. Seventeen patients (68%)

received the full chemotherapy regimen as planned. The initial

overall response rate was 88.0%, while the complete response

rate was 68.0%. At a median follow-up period of 10 months,

the 2-year Kaplan-Meier projected overall survival was 47.3%,

and the cause-specific survival was 81.8%. Conclusion: This

study demonstrated that hyperfractionated radiotherapy with

weekly docetaxel achieved better init ial response than

conventional radiotherapy. In addition, the acute toxicity of

this regimen was within the acceptable limits of severity.

The majority of patients with head and neck squamous cell

carcinoma (HNSCC) present with locoregionally advanced

disease, associated with a poor prognosis despite treatment

by surgical resection, radiotherapy, or both. As a result,

new treatment strategies that incorporate systemic agents,

with the goal of organ preservation and optimal disease

control, have become a major focus of clinical

investigations in head and neck cancer (HNC). A meta-

analysis provided level I evidence of survival benefits

under concurrent chemoradiotherapy (1). Various

chemotherapeutic drugs that have shown activity in the

treatment of HNSCC have been combined with

radiotherapy. Cisplatin is the agent that has been studied

the most, at various doses and schedules (2). On the other

hand, docetaxel is one of the most active agents for

HNSCC (3) and is believed to be a radiosensitizer (4).

Docetaxel has been reported to be an effective anticancer

agent against HNSCC. Response rates of 21-42% werereported following therapy with docetaxel as a single agent

in patients with locally advanced, recurrent and/or

metastatic HNSCC (5). The drug promotes the

polymerization and stabilization of microtubules, thus,

leading to an accumulation of cells at the G2/M boundary,

which is relatively the most radiosensitive phase of the cell

cycle (6-8).When it was first introduced, docetaxel was

administered once every 3 weeks; however, weekly

administration now appears to offer several advantages in

terms of toxicity, especially regarding myelosuppression. In

addition, weekly administration also increases the chance

of enhancing the effect of radiotherapy (9).Hyperfractionated radiotherapy is considered to be one

of the techniques for achieving better treatment results

than with conventional radiotherapy. Theoretically, this

alternative could make it possible to raise the total

radiation dose without increasing the incidence of late

toxicities or prolonging the overall treatment time (10).

Moreover, randomized clinical trials revealed that

hyperfractionated radiotherapy was superior to

conventional radiotherapy for the treatment of HNC,

especially regarding local control (11, 12).

Regarding the effects of combined docetaxel and

radiotherapy, Airoldiet al. conducted a phase I and phase II

study on cases of unresectable HNSCC and concluded thattherapy with carboplatin and docetaxel administered

concurrently with conventional radiotherapy was a feasible

and effective treatment method for unresectable HNSCC

(13). However, to our knowledge, there have been no

studies on chemoradiotherapy with weekly docetaxel and

hyperfractionated radiotherapy for advanced HNC. Under

these circumstances, a study of concurrent docetaxel based

chemotherapy and hyperfractionated radiotherapy was

conducted on HNSCC patients.

3781

Correspondence to: Fumihiko Matsumoto, MD, Ph.D., Department

of Oto-rhino-laryngology, Juntendo University school of Medicine,

2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Tel: +81-3-5802-

1229, Fax: +81-3-5840-7103, e-mail: [email protected]

Key Words: Docetaxel, hyperfractionated radiotherapy, head and

neck cancers.

ANTICANCER RESEARCH26: 3781-3786 (2006)

Concurrent Weekly Docetaxel and HyperfractionatedRadiotherapy for Advanced Head and Neck Cancer

FUMIHIKO MATSUMOTO1, KUMIKO KARASAWA2, SHIN ITOH1, MEGUMI TODA1,

TAKUO HARUYAMA1, MASAYUKI FURUKAWA1 and KATSUHISA IKEDA1

Departments of 1Oto-rhino-laryngology and 2Radiology, Juntendo University School of Medicine, Tokyo

0250-7005/2006 $2.00+.40

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Patients and Methods

Patients. Consecutive patients with histologically proven locally

advanced HNSCC were investigated. All patients had their medical

histories taken and underwent a physical examination including

endoscopic examination, fiberscopy, chest X-ray or chest computed

tomography (CT), CT and magnetic resonance image (MRI) of the

head and neck. The patients had either previously untreated

HNSCC or had been previously treated with radiotherapy and/or

chemotherapy. Patients were staged according to the International

Union Against Cancer staging system the treatment requirements

were based on the Eastern Cooperative Oncology Group (ECOG)

criterion performance status of less than two.

Radiotherapy. Radiotherapy was delivered with 4 MV photons. It

was initially applied to a large field covering the entire primary site,

including the regional lymph node area. After 40.8 Gy, of

prophylactic nodal irradiation was completed, the field was then

reduced to the area of the clinical tumor volume with a margin of

1 cm. In this study, the hyperfractionated radiotherapy consisted of

1.2 Gy per fraction; two fractions per day were delivered more than

6 h apart, 5 days per week. The total dose was 72 Gy. The mean

overall treatment time was 43 days.

Chemotherapy. The patients received six or seven cycles of

chemotherapy given concurrently with radiotherapy every week.

Chemotherapy, which consisted of docetaxel, was given as a weekly2-h bolus of 10 mg/m2 of the body surface area and was

administered 30 min before radiotherapy. The patients receiving

this chemotherapy regimen were hospitalized. The patients were

monitored at least weekly during their treatment, in an effort to

manage treatment-induced adverse effects, particularly mucositis

and myelosuppression.

Evaluation. The initial response was evaluated by either a physical

examination, a fiberscopic examination and CT or MRI at 6 weeks

after the end of chemoradiotherapy. In addition, flurodeoxyglucose

positron emission tomography (FDG PET) was administered in all

patients. A complete response (CR) was defined as the

disappearance of all clinically evident tumors and no new disease.

A partial response (PR) was defined as a >50% reduction in the

sum of the products of perpendicular tumor measurements and no

new disease. Stable disease (SD) was defined as less than a partial

response and progressive disease (PD) was defined as a >25%

increase or new sites of disease. After completion of the therapy,

follow-up evaluations were performed at monthly intervals for the

first year and then every other month for the second year. CT

and/or MRI were performed every 3, 6, 9, 12 months and every 6

months, respectively. The overall and cause-specific survival rates

were assessed using the Kaplan-Meier method starting from the

date of treatment initiation. Toxicity was evaluated according to

National Cancer Institute Common Terminology Criteria for

Adverse Events version 3.0.

Measurement of tumor volume. The tumor volumes were measured

with the Eclipse Treatment Planning System (Varian Medical

Systems, USA) based on the treatment planning CT. The volume

of the primary tumor and metastatic lymph nodes were measured

all together. In cases in which artifacts derived from the dentures

precluded a delineation of the tumor, the physical examination and

diagnostic MRI findings were referred. The sum of the volume of

each node in N2 or N3 disease was then estimated and analyzed.

Results

Patient population. Between March 2003 and November

2005, 25 patients were enrolled in the study. The clinical

characteristics of these 25 patients and their tumors are

detailed in Table I. Nodal metastases were present in 84%

of the patients. Sixty-eight percent of the patients hadadvanced nodal disease (stage N2 or N3), 76% of these had

huge primary tumors (stage T3 or T4). Fourteen patients

had stage IV A, five patients had stage IV B and three

patients had stage III disease.

Toxicity. No fatal treatment toxicity was observed. The acute

toxicities, including mucositis, hematological and non-

hematological toxicities, are summarized in Table II. No

patient developed hypersensitivity reactions, either during or


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Table I.Patient characteristics.

Age; median in years 64.9

Gender

male 23

female 2

Primary siteoropharynx 8

hypopharynx 8

larynx 8

oral cavity 1

T1 T2 T3 T4

N0 0 2 1 1

N1 0 1 2 1

N2 0 2 7 3

N3 1 0 2 2

Table II.Acute toxic effects of treatment.

Grade

2 3 4

Leukopenia 4 2 0

Neutropenia 2 1 0Lymphopenia 7 12 2

Hemoglobinemia 3 0 0

Dry mouth 15 7 0

Mucositis 9 16 0

Dermatitis 10 2 0

Treatment-related pain 14 7 0

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immediately after docetaxel infusion. Oral and pharyngeal

mucositis were the major problems during therapy, as

expected. Although all patients had grade II/III acute

mucositis, no grade IV mucositis was observed. Sixteen out

of 25 patients developed grade III mucositis, thus, requiringmedication for analgesia at the end of treatment until the

regeneration of epithelium. Seventeen patients (68%)

received the full chemotherapy as planned. Five out of 25

patients received seven cycles, 12 patients received six cycles,

1 received five cycles, 4 received four cycles and 3 patients

received three cycles. Patients who demonstrated a severely

deteriorated physical condition and extensive mucositis were

not treated. Two patients did not receive the whole

radiotherapy, because their general condition deteriorated

due to tumor growth. The radiotherapy was completed in the

other patients without interruption.

Response and survival . Table III shows the response rates

(RR) and the CR rate, regarding primary lesions, lymph

node metastases and loco-region at the end of radiotherapy.

Twenty-one out of 25 patients demonstrated CR in the

primary lesion. A clinical CR was achieved in the neck in 14

out of the 21 assessable patients with neck nodes identified

at presentation. The CR rate of the primary lesion was

superior to that of neck metastases. A neck dissection was

performed in 2 out of 8 patients with clinical evidence of

residual adenopathy after chemoradiotherapy. Both patients

undergoing a neck dissection had no residual evidence of

disease in the neck. The cases were stratified by T-stage and

N-stage. Although not statistically significant, the CR ratesfor the T1-3 stage cases were higher than for the T4 cases.

The responses of chemoradiotherapy in N2b or more nodal

disease were worse than for N1 or N2a nodal disease, but

the difference was not statically significant either. These

results are detailed in Table IV.

Among the 17 patients with CR, recurrence occurred in

seven patients. The lymph node was the most common

location of recurrence (in 4 patients). The primary site was

involved in 2 patients and distant metastases were observed

in 3 patients. The cases were stratified according to the

primary lesion. Although not statically significant, the initial

response in the hypopharynx was worse than in the other

lesions. Eight patients evaluated in this study died; five from

disease progression or metastasis while the remaining three

of intercurrent diseases, including secondary cancer. The 2-year overall and cause-specific survival rates of all patients

were 47.3% and 81.8%, respectively. The relationship with

the initial response and tumor volume is shown in Table V.

Discussion

Radiotherapy and chemotherapy may be combined in

several ways in the treatment of head and neck carcinomas.

The two treatments may be given simultaneously or with an

alternating scheme. Radiotherapy may be delivered with

conventional fractionation or with an accelerated or

hyperfractionated regimen. Several randomized studies

suggested an improvement in the survival with concurrentchemoradiotherapy (14-18). Radiotherapy with concurrent

chemotherapy could be considered as the standard of care

for the treatment of stage III and IV head and neck

carcinomas, when nonsurgical treatment is planned.

Docetaxel is one of the active agents for head and neck

malignancy. It has been used as a multi-agent chemotherapy

in an induction setting. In three phase II studies of

docetaxel-based regimens as induction therapy for patients

with locally advanced HNSCC, the overall response rates

Matsumotoet al: Weekly Docetaxel with Hyperfractionated Radiotherapy

3783

Table III. Clinical response of the primary site and the lymph nodes.

CR PR SD CR Response

rate rate

Primary site 21 2 2 84.0 92.0

Neck lymph node(n=21) 13 5 3 61.9 85.7

Overall 17 5 3 68.0 88.0

CR=complete response; PR=partial response; SD=stable disease.

Table IV. Complete response by T classification and N classification.

Primary CR rate Lymph node CR rate

T1 0% N1 100%

T2 100% N2a 100%

T3 91.7% N2b 57.1%

T4 71.4% N2c 50%N3 40%

CR=complete response.

Table V. Clinical response regarding tumor volume.

Tumor volume (cm3) (mean)

CR 54.5

(2.9-305.6)

PR 36.6

(15.8-62.2) p

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ranged from 93 to 100%, with CR rates of 40-63%. The

primary toxicities were neutropenia and febrile neutropenia

(19-21). Although it was an effective method, these

regimens were not planned with concurrent chemo-

radiotherapy due to associated acute toxicity. It was recently

noted that neutropenia could be remarkably reduced by

weekly administration. This method was used with

concurrent chemoradiotherapy and it was considered to be

theoretically effective. There are advantages in using a

weekly schedule. First, a putative radiosensitizing effect of

docetaxel can be better exploited by repeated applications.

Others used docetaxel predominantly for radiosensitizing

effects and applied a low dose every week before the

radiotherapy session (22, 23). Second, this application is

practicable and well-tolerated with respect to such

chemotherapy-related side-effects as hematotoxicity,

neurotoxicity and nausea. The rather high rate of acute

mucosal toxicity (100% grade II or III) was caused by our

policy of avoiding treatment breaks in radiotherapy, withintensified supportive care. For this reason, most patients

were hospitalized during therapy. Several studies on chemo-

radiotherapy with weekly docetaxel for head and neck

carcinoma have been published, but, to our knowledge,

there are no previous studies on chemoradiotherapy with

weekly docetaxel and hyperfractionation for the treatment

of advanced HNC.

Many reports have suggested that dose escalation

achieves an improved local control in radiotherapy for

various malignancies (24, 25). Advances in biology have led

to alterations in fractionated radiation therapy, including

hyperfractionated radiotherapy, which has been performedsince the 1980s to escalate the total dose without

prolonging the overall treatment time. Furthermore, some

randomized trials recently revealed the clinical

effectiveness of altered fractionated radiotherapy for

treating head and neck carcinomas, especially in their local

control (11, 12). Fu et al. (11) reported the 2-year local

control rate of hyperfractionation at 1.2 Gy per fraction

totalling 81.6 Gy to be 54.4%, a statistically significant

improvement over the conventional fractionation at 2 Gy

per fraction totalling 70 Gy, which was 46.0%. In their

study, further investigations were performed to compare

two altered fractionated radiation therapies, accelerated

fractionation according to the protocol of Wanget al. (26)

and concomitant boost fractionation, with conventional

fractionation. This comparison revealed only the

concomitant boost fractionation to be superior to

conventional fractionation. However, the concomitant

boost fractionation had more severe late toxicity than that

of conventional fractionation. These findings suggested that

hyperfractionated radiotherapy was one of the best altered

fractionated radiation therapies. However, no trials of

hyperfractionation with weekly docetaxel have studied its

effectiveness in the head and neck region according to sub

sites. Akimoto et al. reported that altered fractionated

radiotherapy was significantly superior to conventional

radiation therapy, even regarding the overall survival rate

of patients with hypopharyngeal carcinoma, although their

altered fractionated radiotherapy was accelerated

hyperfractionation, which caused more severe late toxicity

than hyperfractionated radiotherapy (27).

The results of the present study show that concurrent

chemo-radiotherapy using hyperfractionated radiotherapy

combined with low-dose weekly docetaxel produced an

overall response rate of 89.3% and a CR rate of 60.7%.

Fujiiet al. (28) reported the results including 60 Gy/30 fx of

radiotherapy with 10 mg/m2 of weekly docetaxel for stage

III/IV head and neck carcinoma. The response rate and CR

rate were 96.9% and 50%, respectively. Biete et al. used

weekly docetaxel 20 mg/m2with conventional radiotherapy.

The overall response rate was 88% and CR rate was 44%

(29). Our response and CR rates were comparable to thoseof other reports. However, the CR rate in the hypopharynx

was worst in the primary sites, and no significant site-

specific differences in radiocurability were observed among

the three sites. In addition, there were more patients with

advanced nodal disease (N2b or more) among the

hypopharynx patients.

Regarding primary lesions, the CR rate was 84.0% and

regarding lymph node metastasis was 61.9%. It is more

difficult to control neck node metastases than a primary

lesion. In this study, the initial response in N1 and N2a

stage were better than for N2b or more, but the difference

was not statistically significant. Multiple neck nodemetastases were difficult to initially control in this protocol.

Large neck node metastases, especially with central

necrosis, usually showed no CR after chemoradiotherapy.

Hence, we recommend an elective neck dissection for initial

N2b-3 stage, when such lymph nodes are determined to be

resectable. There were four patients who had clinical

evidence of residual adenopathy with a complete response

of the primary site. A neck dissection was performed in 2 of

these patients with clinical evidence of residual adenopathy

after chemoradiotherapy. Neither patient was observed with

pathologically viable tumor cells.

As Dubben et al. (30) empirically stated, the tumor

volume is regarded as the most reliable predictor of tumor

control after RT. The importance of the tumor volume for

local control after RT was also reported for various head

and neck cancers (31, 32). Although Bentzen and Thames

(33) stated that patient-to-patient variability in

radiocurability and other factors also make the volume

effect less pronounced than would be expected from a

simple proportionality between them, the significance of

other factors predictive of tumor radiosensitivity still

remains controversial and radiocurability, in comparison to


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the tumor volume has not been quantitated. The data from

the present study were not sufficient to indicate that the

tumor volume correlated with the treatment outcomes for

patients undergoing targeted chemoradiotherapy. However,

the mean tumor volumes in the CR and PR groups were

significantly small. As a result, recommending this regimen

to patients who initially presented with a huge tumor

remains controversial.

Some patients developed grade 2 or higher hematological

toxicity. Six out of 25 patients developed grade 2 or higher

leukopenia and three out of the 25 developed grade 2 or

higher neutropenia. The most common hematological

toxicity was lymphopenia. Recent publications reported

weekly applications of concomitant docetaxel and

radiotherapy, which seemed to cause less neutropenia (9,

34). Lymphopenia was severe and caused pneumonia in

other studies with weekly docetaxel at more than 20 mg/m.

Docetaxel-induced interstitial pneumonia was also

reported to increase by simultaneous lymphopenia. In thisstudy, lymphopenia was mild. Only fourteen patients

developed grade 3 or more lymphopenia. The lymphopenia

did not disturb the schedule of chemoradiotherapy, but the

mechanism of this toxicity is unclear. Although no grade 4

mucosal toxicity was observed, grade 3 mucosal toxicity

occurred in 64.0% of the patients, similar to other

reported data (35-37). Calais et al. , (35) reported the

results of a phase II study including 70 Gy/35 fx of

radiotherapy with 20 mg/m2 of weekly docetaxel for stage

III/IV oropharyngeal carcinoma. The rate of grade 3 and 4

mucositis was 84%. In eight patients, six or seven cycles of

chemotherapy with weekly docetaxel were not tolerablewith concomitant hyperfractionated radiotherapy because

of severe mucositis. However, no acute mucositis severe

enough to cause an interruption of the radiation therapy

occurred. We were therefore cautious and did not treat any

patients who had a reduced physical condition or extensive

mucositis. Aggressive follow-up care, hospitalization,

prompt nutritional intervention and analgesia all played a

critical role in maintaining the dose intensity of this

treatment regimen and were in large part responsible for

the success achieved. Two patients did not receive the whole

protocol radiation therapy and died during this therapy.

However, the reason for death was not toxicity. Their

general condition rapidly deteriorated due to tumor growth.

The 2-year overall survival and cause-specific survival

rates were 47.3 and 81.8%, respectively. Needless to say, the

median follow-up duration of 8 months was not sufficient to

allow for a reasonable evaluation of the long-term

outcomes. However, our results seemed to be comparable

to those of weekly docetaxel concurrent chemotherapy and

radiation therapy. Although the patients evaluated in this

study may have deceased for many different reasons, the

overwhelming cause of death in this cohort was either

distant metastatic disease or second primary neoplasms, and

not due to a locoregional tumor. Other investigators who

used similar aggressive locoregional treatments have made

this same observation, and attention must now be focused

on the prevention of such distant metastases. Appropriate

intervention might include the use of additional multi-agent

chemotherapy given as either induction or adjuvant

treatment, or the use of other, nonchemotherapeutic

systemic approaches. However, the complexity of these

treatment regimens and their effect on patient compliance

remain a significant concern.

In conclusion, this study demonstrated that hyper-

fractionated radiotherapy with weekly docetaxel achieved a

better initial response. The acute toxicity of this regimen

was also within the acceptable limits of severity. Based on

the small number of patients and the short observation

period of this study, we could not conclude that the

docetaxel regimen offers any substantial survival or organ-

sparing benefits.

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Received June 1, 2006

Accepted July 10, 2006


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