International Journal of Otolaryngology and Head & Neck Surgery, 2013, 2, 240-244
Published Online November 2013 (http://www.scirp.org/journal/ijohns)
http://dx.doi.org/10.4236/ijohns.2013.26050
Open Access IJOHNS
Squamous Cell Carcinoma of the Oropharynx Presenting
with Distant Metastasis to the Ulna
Preetham Achoor Puthukudy*, Musarrat Feshan
Southern Railway HQ Hospital, Chennai, India
Email: *preetham.ap@gmail.com, dr.feshan@gmail.com
Received August 1, 2013; revised September 2, 2013; accepted September 30, 2013
Copyright © 2013 Preetham Achoor Puthukudy, Musarrat Feshan. This is an open access article distributed under the Creative Com-
mons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work
is properly cited.
ABSTRACT
Squamous cell carcinomas are the commonest malignancies of the head and neck. Metastases from stage III and stage
IV tumors occur most commonly in the cervical lymph nodes. The incidence of distant metastases occurring from such
advanced tumors is anywhere between 10% and 40%. Distant metastases occur most commonly to the lungs followed
by the bone and liver. The bone metastasis occurs commonly in the axial skeleton. We report a rather unusual case of
squamous cell carcinomas from the Head and Neck region in a 77-year-old male metastasizing to the ulna. This case is
even more interesting because the presenting symptom was a pathological fracture of the ulna for which he had reported
to the orthopedic department. The immunohistochemistry of the metastatic tumor had shown an unmistakable squamous
cell carcinoma with positive cytokeratin elements within the tumor. He referred to the ENT department where he was
diagnosed with T2N0M1 squamous cell carcinoma of the oropharynx. The patient was treated with internal fixation and
bone cementing for the metastatic lesion, and primarily treated with chemoradiation.
Keywords: Squamous Cell Carcinoma; Oropharyngeal Squamous Cell Carcinoma (OPSCC); Oropharynx;
Distant Metastasis; Ulna; Head and Neck Can cer; Pathological Fracture
1. Introduction
Squamous cell carcinomas are the commonest malignan-
cies of the head and neck accoun ting for over 90% of the
tumors. Distant metastasis from carcinoma arising in the
head and neck is generally considered to be infrequent
and even when it occurs it is mostly from stage III and
stage IV tumors [1,2]. The frequency of distant metasta-
ses does not correlate with the size of the primary lesion,
but correlates with the appearance of cervical node me-
tastases regardless of location in the neck [3]. The com-
monest site of distant metastasis is the lung followed by
the bone and liver [4]. In the bones, the metastasis is
commoner in the axial skeleton—recorded mainly in the
spine, pelvis, sacrum, skull, ribs and clavicle [2]. We
report a rare case of oropharyngeal carcinoma with no
neck nodes where the presenting complaint was a patho-
logical fracture from the distant metastasis in the ulna.
2. Case Report
A 77-year-old male presented with a pathological frac-
ture of the right ulna, after a trivial injury against an
autorickshaw, to the Southern Railway Headquarters Hos-
pital, Ayanavaram, Chennai. He was a chronic smoker
who smoked about 30 - 40 cigarettes per day for many
years but did not have any complaint related to the head
and neck. He attended the orthopedic department of our
hospital with pain, swelling and deformity of his right
forearm (Figure 1). X-Ray showed an osteolytic lesion
(Figure 2). An open biopsy and curettage was done fol-
lowed by Locking Compression Plate (LCP) fixation,
bone cementing with intramedullary K wire fixation.
Subsequently he was referred to the ENT department to
search for a primary which revealed a proliferative mass
in the right vallecula extending to the right aryepiglottic
fold. Both vocal cords were normal and mobile. Biopsy
was taken from the oropharyngeal growth and sent for
HPE. At this stage no neck nodes were palpable.
CT abdomen showed some non-specific irregular wall
thickening in the region of D1 and D2 segments of the
duodenum and in the region of descending colon. CT
chest revealed a few pretracheal and paratracheal lymph
nodes and some evidence of an old pulmonary Koch’s
*Corresponding author.
P. A. PUTHUKUDY, M. FESHAN 241
Figure 1. Right forearm showing deformity due to the
pathological fracture of the ulna.
Figure 2. Pre-op X-ray showing pathological fracture of the
right ulna.
lesion. Radioisotope bone scan showed a central photo-
penic area with an increased skeletal uptake in the right
ulna (Figure 3). Upper GI endos copy was normal.
An open biopsy was performed during the curettage,
LCP and intramedullary K-wire fixation and multiple
tissue material, the largest measuring 4 × 2 × 2 cm, was
sent for HPE. It revealed a bony trabeculae and sur-
rounding fibrocollagenous tissue infiltrated by a malig-
nant neoplasm composed of basaloid cells with hyper-
chromatic nuclei arranged in nests, trabeculae and cri-
briform pattern. Numerous mitotic figures and foci of
Figure 3. Radioisotope bone scan showing a central photo-
penic area with an increased skeletal uptake in the right
ulna.
necrosis were seen. The intervening fibrotic stroma
showed lympho-plasmacytic infiltrate. The tumor was
seen infiltrating into the surrounding muscle. These find-
ings were consistent with a metastatic poorly differenti-
ated carcinoma. Immunohistochemistry of the metastatic
tumor showed that it was positive for cytokeratin, cy-
tokeratin 7 and cytokeratin (high molecular weight); and
was negative for PSA, PSAP, TTF, synaptophysin, CEA,
CDX2 and cytokeratin 20. This is consistent with a
poorly differentiated squamous cell carcinoma. The bi-
opsy report from the oropharyngeal lesion showed mu-
cosa lined by squamous epithelium and a neoplasm com-
posed of atypical cells with hyperchromatic, pleomorphic
nuclei and scanty cytoplasm arranged in sheets and
perivascular pattern. Mitotic figures and foci of necrosis
were also seen.
The clinical staging of the tumor was T2N0M1, Stage
IV disease. Chemoradiation was considered the best op-
tion in this case. Linear Accelerator Radiotherapy was
given along with Chemotherapy with Cisplatin 100 mg
IV every week for 6 weeks. A total dose of 60 Gy was
given over 30 sessions, five days a week for 6 weeks.
The patient completed Chemo radiotherapy but was lost
to follow up.
3. Discussion
Head and neck cancers account for less than 5% of all
cancers. Squamous cell carcinoma is the commonest ma-
lignancy of the head and neck region accounting for al-
most 90% of the tumors [5]. It is also the commonest
malignancy of the oropharynx. Oropharyngeal squamous
Open Access IJOHNS
P. A. PUTHUKUDY, M. FESHAN
242
cell carcinoma, OPSCC, represents 10% - 15% of all
head and neck tumors and has an annual incidence of 10
per million per year in the UK [6]. There is an increasing
prevalence of oral and oropharyngeal cancers in the last
decade, particularly in men aged 35 - 64 years [7]. The
condition is commoner in men, with a sex ratio of 4:1,
and is common in the sixth and seventh decades of life.
The frequency distribution of the primary site carcinoma
in the oropharynx is tonsil or fauc ial pillar 45%, posterior
tongue 40%, soft palate 15% and posterior pharyngeal
wall 5% [8]. The main associated etiological factors are
smoking and alcohol consumption, the effects of which
are cumulative [9]. Dietary deficiencies of vitamin A,
chronic irritants, poor dental hygiene, syphilis and mari-
juana smoking have also been identified as predisposing
factors in upper aerodigestive tract cancers [10]. The
effect of HPV-16 has been profound on OPSCC. It is this
effect which is responsible for the increase in the inci-
dence of OPSCC over the last decade or more, so that
now as much as 50% of OPSCC is thought to be HPV
induced [11].
When present, the initial symptom of an oropharyn-
geal malignancy is often vague and nonspecific, leading
to a delay in diagnosis. Consequently, the overwhelming
majority of such patients has locally advanced tumors
when they present [12]. Other more serious symptoms
that require investigation include sore throat, foreign-
body sensation in the throat, altered voice or referred
pain to the ear, through the glossopharyngeal and vagus
nerves [13] .
Distant metastases are a significant problem in patients
with carcinoma of oropharynx, and happen in approxi-
mately 15% - 20% of all such patients ov er the course of
their disease. The spread is the commonest to the lungs,
in patients with advanced disease, and especially in those
with histologically proven lymph nodes at multiple levels
of the neck or in the lower neck [14]. The overall inci-
dence of clinically detected distant metastasis in head
and neck squamous cancers is 9% - 11% [15]. Among
head and neck cancers, nasopharynx has the highest in-
cidence of distant metastasis while laryngeal cancers
especially those of the vocal cords have the lowest inci-
dence [4].
Distant metastases occur more commonly with larger
primary tumors [4,16,17]. Some studies have noted a
higher rate of distant metastasis from less differentiated
head and neck squamous cell cancers while others have
failed to find any such association [18]. The incidence of
distant metastasis varies significantly from the T and N
stage (T1-2 is 7.87%, T3-4 is 14%, N0-1 is 6.3%, and the
N2-3 is 24%); the N stage has greater influence but Berger
and Fletcher found no connection between the size of the
primary tumor and the development of distant metastases
[3]. Patients with three or more clinical lymph node me-
tastases or low jugular lymph node metastases, bilateral
lymph node metastases, lymph nodes of 6 cm or larger
have a higher incidence of distant metastases [19].
Crile reported in 1923 that 1% of patients with head
and neck cancer developed distant metastases. Clinical
data in recently reported studies indicate an incidence of
5% to 24% whereas autopsy series reports an incidence
of 17% - 47% [1]. Distant metastases were found in
12.3% of patients in a study by Probert et al. in 1974 [2].
As local and regional control of head and neck cancer
has improved, distant metastases have become an in-
creasingly common cause of death [20]. Only a limited
number of studies have reported on the incidence of dis-
tant metastases at presentation. Dennington et al. and
Black et al. have found distant metastases at presentation
in 7% - 12% of patients in advanced stage disease re-
spectively [21,22]. The average time for the development
of distant metastasis is about 10 to 12 months after the
initial diagnosis. Most distant metastases from head and
neck cancers become apparent within the first two years
of the initial diagnosis [23].
The commonest site of distant metastasis was the lung
followed by bone, liver, skin, brain and adrenal gland.
Unexpected sites such as heart, peritoneum, esophagus
and spleen were also seen. In the bone, the commonest
site was the dorsal spine followed by the lumbar spine,
skull, ribs, pelvis and sacrum. Among the long bones,
femur was the only bone recorded to have distant metas-
tasis [2].
Pathologic fracture can be the presenting condition of
patients with metastatic disease. Osteolytic lesions are
predominantly responsible for pathologic fractures. How-
ever, fractures can also occur in mixed or osteoblastic
lesions because tumor-related bone lacks structural in-
tegrity. Higinbotham, in a review of 1800 cancer patients,
found an 8% incidence of pathologic fracture [24]. Breast
carcinoma is the cause of the majority of pathologic
fractures due to metastatic disease. Other malignancies,
each is responsible for 5% - 10% of such pathological
fractures, including kidney, lung, and thyroid carcinoma,
and lymphoma [24]. Of all long bone fractures due to
metastatic disease, 60% involve the femur; the majority
of these (80%) involve the proximal portion [25].
The treatment of a patient with advanced malignant
disease is fraught with a multitude of problems [26,27].
A variety of interrelated factors must be considered when
choosing the appropriate treatment for a patient who
presents with a tumour located in the oropharynx. Ulti-
mately, the treatment must be suited to each patient [28].
Most oropharyngeal tumours are operable, but whether
they are curable by surgery alone is debatable. The sur-
gical principles which continue to be advocated are that
resection must include a margin of 1 - 2 cm of grossly
normal tissue. Oropharyngeal cancers can be resected
Open Access IJOHNS
P. A. PUTHUKUDY, M. FESHAN 243
through three main surgical approaches: the transoral,
transpharyngeal, and the transmandibular approaches. T he
choice of approach depends on the size and location of
the tumour, and whether a concomitant neck dissection is
being planne d and the m e t hod of reconstruct i on [2 9] .
The 1990s saw the introduction and increasing use of
definitive concomitant chemoradiotherapy which offer-
ing better survival compared to radiotherapy [30]. There
is an agreement that T1, T2, and some T3 tumours of the
oropharynx respond well to radiotherapy [31]. Alterna-
tive methods for delivering radiotherapy have been ad-
vocated with the use of interstitial or intracavity implan-
tation of radioactive sources into the tumour [32,33].
The combination of surgery and postoperative radio-
therapy is becoming more popular and there is an appre-
ciable improvement in locoregional disease [34]. With
the additional advantage of concomitant chemoradio-
therapy, the balance has fallen to chemoradiotherapy
over surgery and this has now become the standard of
care for most patients with oropharyngeal squamous cell
carcinoma [35]. Chemoradiotherapy has evolved to be
general in the form of induction chemotherapy with three
cycles of TPF (docetaxel-cisplatin-5 flourouracil) and
then concurrent chemoradiotherapy with platinum [36,
37].
REFERENCES
[1] C. W. Crile, “Carcinoma of the Jaws, Tongue, Cheek, and
Lips,” Surgery Gynecology & Obstetrics, Vol. 36, 1923,
pp. 159-184.
[2] J. C. Probert, R. W. Thompson and M. A. Bagshaw, “Pat-
terns of Spread of Distant Metastasis in Head and Neck
Cancer,” Cancer, Vol. 33, No. 1, 1974, pp. 127-133.
http://dx.doi.org/10.1002/1097-0142(197401)33:1<127::
AID-CNCR2820330119>3.0.CO;2-L
[3] D. S. Berger and C. H. Fletcher, “Distant Metastasis Fol-
lowing Local Control of Squamous Cell Carcinoma of the
Nasopharynx, Tonsillar Fossa, and Base of Tongue,” Ra-
diology, Vol. 100, 1971, pp. 141-143.
[4] M. R. Orlando, L. Robert and F. D. Gilbert, “An Analysis
of Distant Metastases from Squamous Cell Carcinoma of
the Upper Respiratory and Digestive Tracts,” Cancer, Vol.
40, No. 1, 1977, pp. 45-151.
[5] S. Marur and A. A. Forastiere, “Head and Neck Cancer:
Changing Epidemiology, Diagnosis, and Treatment,” Mayo
Clinic Proceedings, Vol. 83, No. 4, 2008, pp. 489-501.
http://dx.doi.org/10.4065/83.4.489
[6] P. J. Bradley, “Management of Squamous Cell Carci-
noma of the Oropharynx,” Current Opinion in Otolaryn-
gology and Head and Neck Surgery, Vol. 8, No. 5, 2000,
pp. 80-86.
http://dx.doi.org/10.1097/00020840-200004000-00002
[7] K. L. Robinson and G. J. Macfarlane, “Oropharyngeal
Cancer Incidence and Mortality in Scotland: Are Rates
Still Increasing?” Oral Oncology, Vol. 39, No. 1, 2003,
pp. 31-36.
http://dx.doi.org/10.1016/S1368-8375(02)00014-3
[8] S. Mak-Kregar, F. J. M. Hilgers, P. C. Levendag, J. J.
Manni, H. Lubsen, J. L. Roodenburg, et al., “A Nation-
wide Study of the Epidemiology, Treatment and Survival
of Oropharyngeal Carcinoma in the Netherlands,” Euro-
pean Archives of Oto-Rhino-Laryngology, Vol. 252, No.
3, 1995, pp. 133-138.
http://dx.doi.org/10.1007/BF00178098
[9] J. S. Tobias, “Cancer of the Head and Neck,” British
Medical Journal, Vol. 308, 1994, pp. 961-966.
http://dx.doi.org/10.1136/bmj.308.6934.961
[10] P. J. Donald, “Marijuana Smoking: Possible Cause of
Head and Neck Cancer in Young Patients,” Otolaryngol-
ogy and Head and Neck Surgery, Vol. 94, No. 4, 1986, pp.
517-521.
[11] M. Romanitan, A, Nasman, T. Ramqvist, H. Dahlstrand,
L. Polykretis, P. Vogiatzis, et al., “Human Papillomavirus
Frequency in Oral and Oropharyngeal Cancer in Greece,”
Anticancer Research, Vol. 28, No. 4B, 2008, pp. 2077-
2080.
[12] M. Pitchers and C. Martin, “Delay in Referral of Oro-
pharyngeal Carcinoma to Secondary Care Correlates with
a More Advanced Stage at Presentation, and Is Associ-
ated with Poorer Survival,” British Journal of Cancer,
Vol. 94, No. 7, 2006, pp. 955-958.
http://dx.doi.org/10.1038/sj.bjc.6603044
[13] J. B. Patrick, “Oropharyngeal Tumors,” In: G. Michael,
Ed., Scott-Browns Otorhinolaryngology, Head and Neck
Surgery, 7th Edition, Hodder Arnold, London, 2008, pp.
2577-2597.
[14] W. J. Goodwin, “Distant Metastases from Oropharyngeal
Cancerm,” Journal for Oto-Rhino-Laryngology and Its
Related Specialties, Vol. 63, No. 4, 2001, pp. 222-223.
http://dx.doi.org/10.1159/000055745
[15] C. R. Leemans, R. Tiwari, J. J. P. Nauta, I. van der Waal
and G. B. Snow, “Regional Lymph Node Involvement
and Its Significance in the Development of Distant Me-
tastasis in Head and Neck Carcinoma,” Cancer, Vol. 71,
No. 2, 1993, pp. 452-456.
http://dx.doi.org/10.1002/1097-0142(19930115)71:2<452
::AID-CNCR2820710228>3.0.CO;2-B
[16] S. Kramer, V. A. Marcial, T. K. Pajak, C. J. MacLean and
L. W. Davis, “Prognostic Factors for Loco/Regional Con-
trol and Metastases and the Impact on Survival,” Interna-
tional Journal of Radiation Oncology • Biology • Physics,
Vol. 12, No. 4, 1986, pp. 573-578.
[17] R. J. Papack, “Distant Metastases from Head and Neck
Cancer,” Cancer, Vol. 53, No. 2, 1984, pp. 342-345.
http://dx.doi.org/10.1002/1097-0142(19840115)53:2<342
::AID-CNCR2820530228>3.0.CO;2-9
[18] G. F. Gowen and G. Desuto-Nagy, “The Incidence and
Sites of Distant Metastasis in Head and Neck Carci-
noma,” Surgery Gynecology & Obstetrics, Vol. 47, 1963,
pp. 603-607.
[19] D. B. Remco, E. D. Elene, B. S. Gordon and R. L. C har l es,
“Screening for Distant Metastases in Patients with Head
and Neck Cancer,” Laryngoscope, Vol. 110, No. 3, 2000,
pp. 397-401.
Open Access IJOHNS
P. A. PUTHUKUDY, M. FESHAN
Open Access IJOHNS
244
http://dx.doi.org/10.1097/00005537-200003000-00012
[20] B. Vikram, E. W. Strong, J. P. Shah and R. Spiro, “Fail-
ure at Distant Sites Following Multi Modality Treatment
for Advanced Head and Neck Cancer,” Head and Neck
Surgery, Vol. 6, No. 3, 1984, pp. 730-733.
http://dx.doi.org/10.1002/hed.2890060305
[21] M. L. Dennington, D. R. Carter and A. D. Meyers, “Dis-
tant Metastases in Head and Neck Epidermoid Carci-
noma,” Laryngoscope, Vol. 90, No. 2, 1980, pp. 196-201.
http://dx.doi.org/10.1288/00005537-198002000-00002
[22] R. J. Black, J. L. Gluckman and D. A. Shumrick, “Scr een-
ing for Distant Metastases in Head and Neck Cancer Pa-
tients,” Australian and New Zealand Journal of Surgery,
Vol. 54, No. 6, 1984, pp. 527-530.
http://dx.doi.org/10.1111/j.1445-2197.1984.tb05440.x
[23] H. C. Karen, F. Paul, W. Raymond and A. H. James,
“Distant Metastases from Head and Neck Squamous Cell
Carcinoma,” Laryngoscope, Vol. 104, No. 10, 1994, pp.
1199-1205.
[24] N. L. Higinbotham and R. C. Marcove, “The Manage-
ment of Pathological Fractures,” Journal of Trauma, Vol.
5, No. 6, 1965, pp. 792-798.
http://dx.doi.org/10.1097/00005373-196511000-00015
[25] F. H. Sim, “Instructional Course Lectures: Meta static B on e
Disease,” In: Instructional Course Lectures, Vol. 49,
American Academy of Orthopaedic Surgeons, Anaheim,
1999.
[26] L. B. Harrison, A. Ferlito, A. R. Shaha, P. J. Bradley and
A. Rinaldo, “Current Philosophy on the Management of
Cancer of the Base of Tongue,” Oral Oncology, Vol. 39,
No. 2, 2003, pp. 101-105.
http://dx.doi.org/10.1016/S1368-8375(02)00048-9
[27] W. Zhen, L. H. Karnell, H. T. Hoffman, G. F. Funk, J. M.
Buatti and H. Menck, “The National Cancer Data Base
Report on Squamous Cell Carcinoma of the Base of
Tongue,” Head and Neck, Vol. 26, No. 8, 2004, pp. 660-
674. http://dx.doi.org/10.1002/hed.20064
[28] K. Sundaram, J. Schwartz, G. Har-El and F. Lucente,
“Carcinoma of the Oropharynx: Factors Affecting Out-
come,” Laryngoscope, Vol. 115, No. 9, 2005, pp. 1536-
1542.
http://dx.doi.org/10.1097/01.mlg.0000175075.69706.64
[29] C. G. Gourin and J. T. Johnson, “Surgical Treatment of
Squamous Cell Carcinoma of the Tongue,” Head and
Neck, Vol. 23, No. 8, 2001, pp. 653-660.
http://dx.doi.org/10.1002/hed.1092
[30] G. Calais, M. Alfonsi, E. Bardet, C. Sire, T. Germain, P.
Bergerot, et al. , “Randomized Trial of Radiation Therapy
versus Concomitant Chemotherapy and Radiation Ther-
apy for Advanced Stage Oropharynx Carcinoma,” Jour-
nal of National Cancer Institute, Vol. 91, No. 24, 1999,
pp. 2081-2086. http://dx.doi.org/10.1093/jnci/91.24.2081
[31] U. Selek, A. S. Garden, W. H. Morrison, A. K. El-Naggar,
D. I. Rosenthal and K. K. Ang, “Radiation Therapy for
Early Staged Carcinoma of the Oropharynx,” Interna-
tional Journal of Radiation Oncology, Biology, Physics,
Vol. 59, No. 3, 2004, pp. 743-751.
http://dx.doi.org/10.1016/j.ijrobp.2003.12.002
[32] L. B. Harrison, “Applications of Brachytherapy in Head
and Neck Cancer,” Seminars in Surgical Oncology, Vol.
13, No. 3, 1997, pp. 177-184.
http://dx.doi.org/10.1002/(SICI)1098-2388(199705/06)13
:3<177::AID-SSU4>3.0.CO;2-4
[33] D. M. Kaylie, K. R. Ste vens, M. Y. Kang, J. I. Cohen, M.
K. Wax and P. E. Anderson, “External Beam Radiation
Followed by Planned Neck Dissection and Brachytherapy
for Base of Tongue Squamous Cell Carcinoma,” Laryn-
goscope, Vol. 110, No. 10, 2000, pp. 1633-1636.
http://dx.doi.org/10.1097/00005537-200010000-00011
[34] A. S. Denittis, M. Machtay, D. I. Rosenthal, N. J. Sanfil-
lippo, J. H. Lee, S. Goldfeder, et al., “Advanced Oro-
pharyngeal Carcinoma Treated with Surgery and Radio-
therapy: Oncologic Outcome and Functional Assess-
ment,” American Journal of Otolaryngology, Vol. 22, No.
5, 2001, pp. 329-335.
http://dx.doi.org/10.1053/ajot.2001.26492
[35] A. Y. Chen, N. Schrag, Y. Hao, A. Stewart and E. Ward,
“Changes in Treatment of Advanced Oropharyngeal Can-
cer. 1985-2001,” Laryngoscope, Vol. 1, No. 17, 2007, pp.
16-21.
http://dx.doi.org/10.1097/01.mlg.0000240182.61922.31
[36] J. P. Pignon, N. Syz, M. Posner, R. Olivares, L. Le Lann,
A. Yver, et al., “Adjusting for Patient Selection Suggests
the Addition of Docetaxel to 5-Fluorouracil-Cisplatin In-
duction Therapy May Offer Survival Benefit in Squamous
Cell Cancer of the Head and Neck,” Anticancer Drugs,
Vol. 15, No. 4, 2004, pp. 331-340.
http://dx.doi.org/10.1097/00001813-200404000-00004
[37] M. R. Posner, D. M. Hershock, C. R. Blajman, E.
Mickiewicz, E. Winquist, V. Gorbounova, et al., “Cis-
platin and Fluorouracil Alone or with Docetaxel in Head
and Cancer,” New England Journal of Medicine, Vol. 354,
No. 6, 2006, pp. 567-578.