Eur Arch Otorhinolaryngol DOI 10.1007/s00405-015-3673-y
CASE REPORT
Long-term remission of locally recurrent oropharyngeal cancer after docetaxel-based chemotherapy plus cetuximab Petr Szturz1,2 • Pol Specenier1,3 • Carl Van Laer3,4 • Danielle Van Den Weyngaert3,5 Bob Corthouts6 • Laurens Carp7 • Eric Van Marck8 • Olivier Vanderveken3,4 • Jan B. Vermorken1,3
•
Received: 28 December 2014 / Accepted: 25 May 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Background In recurrent head and neck squamous cell carcinoma ineligible for resection or irradiation, treatment aims primarily at symptom control and quality of life enhancement with an expected outcome of 6–12 months. Methods In 2005, a male patient, born in 1944, with a second local recurrence of human papillomavirus negative tonsil cancer was enrolled in the EXTREME trial, and randomized to platinum/5-fluorouracil/cetuximab arm resulting in partial remission with progression-free survival of 12 months. The second-line systemic therapy comprised Deceased: E. Van Marck. & Petr Szturz
[email protected] Jan B. Vermorken
[email protected] 1
Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
2
Department of Internal Medicine, Hematology and Oncology, School of Medicine, University Hospital Brno and Masaryk University, Brno, Czech Republic
3
Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
4
Department of Otorhinolaryngology and Head and Neck Surgery, Antwerp University Hospital, Edegem, Belgium
5
Department of Radiotherapy, University Radiotherapy Antwerp, Antwerp, Belgium
6
Department of Radiology, Antwerp University Hospital, Edegem, Belgium
7
Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium
8
Department of Pathology, Antwerp University Hospital, Edegem, Belgium
5 cycles of 3-weekly docetaxel/cisplatin/5-fluorouracil regimen plus weekly cetuximab. Results As confirmed on imaging and repeated biopsies, complete response was achieved with disease-free survival of 8 years and follow-up period of 12 years. Severe acute toxicities during the taxane-based chemotherapy plus cetuximab included grade 4 anorexia and grade 3 febrile neutropenia. Conclusions Poor tumor differentiation, no weight loss, oropharyngeal location, white race, and particularly the induced complete response were most likely the key favorable prognostic factors in the reported patient. The possibility of a synergistic interaction between taxanes and cetuximab should be further explored. Keywords Tonsil cancer Positron emission tomography Taxanes Targeted therapy Epidermal growth factor receptor inhibitor
Introduction Despite advances in primary management of newly diagnosed oropharyngeal cancers, about 40 % of patients develop recurrent diseases most of which are difficult to salvage [1]. In case of a relapsed tumor deemed unsuitable for surgery or irradiation, only palliative strategies like best supportive care, cytotoxic chemotherapy or targeted therapy could be offered with an expected prognosis of 6–12 months [2]. Traditionally, a platinum-based combination has been regarded as the cornerstone of systemic treatment in this particular setting, however, without any proven survival advantage over single-agent methotrexate [3]. Although several phase II studies of three-drug
123
Eur Arch Otorhinolaryngol
regimens with taxanes (paclitaxel or docetaxel) suggested higher response rates, the observed unfavorable safety profile precludes their application in frail patients [4, 5]. Moreover, data from the pertinent phase III studies comparing them with platinum/5-fluorouracil doublets are still lacking in contrast to monoclonal antibodies, where the landmark EXTREME (Erbitux in first-line treatment of recurrent or metastatic head and neck cancer) trial presented clear evidence of cetuximab/platinum/5-fluorouracil superiority [6]. That has changed clinical practice and established a new standard first-line systemic treatment option for patients with locoregionally recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). For second-line systemic treatment, no similar recommendations exist and patients should preferably be invited to participate in clinical trials. In this paper, we report on efficacy and feasibility of two successive biochemotherapy regimens in a case of repeatedly relapsing oropharyngeal cancer leading to a long-term disease-free survival of 8 years. The lasting complete remission has been confirmed both on radiological and scintigraphic imaging modalities, as well as on several subsequent histological verifications.
Case report In May 2002, a 57-year-old male patient presented with a sore throat in the left tonsil area lasting for the past 6 months. Antibiotics proved not effective and in July 2002, based on a computed tomography (CT) finding of a nodule in the left tonsil with no associated lymphadenopathy, he underwent bilateral tonsillectomy. Pathological evaluation revealed a moderately differentiated SCCHN on the left side classified as T1(pT2)N0M0 according to the American Joint Committee on Cancer staging system (6th edition) (Fig. 1a, b). Due to positive microscopic resection margins, postoperative external radiotherapy was delivered to the tumor site and cervical lymph nodes in 33 fractions at a dose of 66 Gy, and to the spinal and supraclavicular lymph nodes at a dose of 50 Gy. The patient’s other medical history was characterized by arterial hypertension, paratyphoid, sinusitis, stomach ulcers, status post appendectomy and anal fistula for which he also had been operated. As a never-smoker, he admitted casual alcohol consumption. One year later, in July 2003, a biopsy-proven local recurrence of human papillomavirus (HPV) negative poorly
Fig. 1 Histological findings, hematoxylin-eosin staining. (1) Moderately differentiated SCCHN, July 2002, magnifications 9100 (a) and 9200 (b). (2) Poorly differentiated SCCHN, May 2006, magnifications 9100 (c) and 9200 (d)
123
Eur Arch Otorhinolaryngol Fig. 2 Local recurrence of tonsil SCCHN documented as an asymmetric, heterogeneously enhancing mass (37.8 by 28.4 mm) on T1-weighted MRI image after intravenous gadolinium administration (a, see red asterisk) with increased FDG uptake on PET axial (b) and coronal (c) scans in May 2005
differentiated SCCHN was observed on a follow-up CT examination and a positron emission tomography (PET) scan with 18F-fluorodeoxyglucose (FDG). A radical tumor resection with radical neck dissection could be performed (which revealed submandibular lymph node involvement) with free resection margins. However, in April 2005, a second local recurrence of poorly differentiated SCCHN was histologically confirmed in a swelling visible on endoscopy. At that time, the patient’s major complaints included gradually increasing pain in the tongue and left lower jaw accompanied by dysphagia, trismus and burning mouth syndrome. Magnetic resonance imaging (MRI) showed an expanding mass of 3 cm in diameter in the left tonsil region corresponding with abnormal FDG uptake on PET examination (Fig. 2). Clinical and radiological investigations were negative for distant metastases. After evaluation by the multidisciplinary head and neck oncologic team, the tumor was considered ineligible for surgery or reirradiation. Consequently, the patient entered the EXTREME study and was randomized to the investigational arm consisting
of 3-weekly PF chemotherapy (cisplatin at a dose of 100 mg per square meter of body-surface area on day 1 plus 5-fluorouracil at a dose of 1000 mg per square meter on days 1–4) combined with weekly cetuximab (at an initial dose of 400 mg per square meter, then 250 mg per square meter) [6]. After finishing the planned 6 cycles, a partial response (response evaluation criteria in solid tumors guideline version 1.0) was assessed by a restaging MRI and then weekly single-agent cetuximab continued, in accordance with the protocol. Except for a grade 3 stomatitis, acute side effects of the combination regimen were mostly low to moderate in severity (Table 1). Interestingly, during the cetuximab maintenance period, the patient developed punctate keratitis of his left eye manifesting with a decreased visual acuity, which has been reported earlier [7]. In May 2006, MRI indicated disease progression and the cetuximab monotherapy was discontinued. Biopsy verification along with a dual modality FDG-PET/CT examination were obtained (Figs. 1c, d, 3a). Considering the
123
Eur Arch Otorhinolaryngol Table 1 Observed acute toxicity during the systemic treatment Treatment
PF-C (cisplatin, 5-fluorouracil plus cetuximab)
Cetuximab monotherapy
TPF-C (docetaxel, cisplatin, 5-fluorouracil plus cetuximab)
Time period
9/5/2005–6/9/2005
13/9/2005–3/5/2006
14/6/2006–16/9/2006
Side effects
Grade (common terminology criteria version 2.0)
Nausea
1
0
1
Anorexia
2a
1
4d
Constipation
1
0
0
Diarrhea Stomatitis
0 3b
0 0
2 0
Skin rash
1
1
1
Alopecia
0
0
2
Febrile neutropenia
0
0
3
Infection
2
0
1e c
c
Sensory neuropathy
1
1 ?2 ?0
2
Dizziness
1
0
2f c
Fatigue
2
1
Hearing
2
2c
2c
Nail changes
0
1
0
a b c
2
Weight loss from 100 to 90 kg During the second cycle Consequence of the PF-C treatment
d
Tube feeding, weight loss from 86 to 81 kg
e
With neutropenia
f
Hypotension 75/60 mm Hg
patient’s good general condition, acceptable toxicity and efficacy of the previous systemic treatment and a platinumfree interval of 9 months, he was enrolled in a feasibility in-house study of 3-weekly TPF-C regimen starting in June 2006 (docetaxel and cisplatin, both at doses of 75 mg per square meter on day 1, 5-fluorouracil at a dose of 750 mg per square meter on days 1–5, and cetuximab at a dose of 250 mg per square meter on days 1, 8, and 15 after an initial loading dose of 400 mg per square meter on day 1 of the first cycle). Premedication before chemotherapy comprised oral dexamethasone 8 mg twice a day for 3 days, starting on day -1. Despite standard supportive care strategies including antibiotic prophylaxis (ciprofloxacin 500 mg every 12 h on days 5–15), the toxicity was substantially higher than during the EXTREME trial. A decline in performance status by one level to World Health Organization (WHO) grade 2 was accompanied by an overall deterioration in the patient’s health status leading to an early termination of the treatment after 5 out of 6 planned cycles (Table 1). Nevertheless, interim PET/CT following the second cycle showed partial remission (Fig. 3b) and after a total of 5 cycles, restaging MRI
123
documented tumor resolution with only residual fibrotic changes. The complete remission was confirmed by FDGPET/CT imaging in December 2007 (Fig. 3c). During the follow-up period, the patient experienced several serious medical conditions (right radical nephrectomy for stage pT1N0M0 renal cell carcinoma in 2009; cholecystitis with open cholecystectomy complicated by liver abscesses, iatrogenic pancreatitis with renal insufficiency for which he underwent intermittent hemodialysis, endoprosthesis for saccular abdominal aortic aneurysm, and myocardial infarction with a stent placement in 2013), yet he managed to recover maintaining a satisfactory quality of life. Although follow-up PET/CT scans demonstrated a mildly increased FDG accumulation in the left oropharyngeal region, this finding has remained stable since November 2011 and three repeated biopsies suggested infectious intercurrences with no evidence of malignancy. In September 2014, 8 years after biochemotherapy cessation and 12 years after the primary diagnosis, periodical clinical and laboratory check-up documented a sustained disease-free status with persistent late toxicity in the form of hearing loss and sensory neuropathy, both grade 2.
Eur Arch Otorhinolaryngol Fig. 3 Triplets of PET/CT fusion sagittal scan (lower image), PET/CT fusion axial scan (upper left) and PET axial scan (upper right) showing disease progression prior to TPF-C regimen (a, May 2006), partial remission after 2 treatment cycles (b, July 2006) and sustained disease-free status during the follow-up period (c, December 2007). See red arrows for metabolic active tumor mass
Discussion Recurrent head and neck cancer in patients who are unable or unwilling to undergo salvage resection or radiotherapy remains a challenging clinical scenario. Generally, in patients with good to moderate functional status (WHO grades 0–2), systemic treatment with either cytotoxic chemotherapy, targeted agents or a combination thereof is recommended, primarily aiming at symptom control and a better quality of life. Since the 1977 report of Wittes and colleagues on cisplatin activity against SCCHN and a subsequent 1985 phase III study of Morton et al. demonstrating a 10-week improvement in median overall survival with cisplatin over best supportive care, it has been recognized as a pivotal agent in the recurrent or metastatic setting [8, 9]. Single-agent conventional chemotherapy (cisplatin, methotrexate, 5-fluorouracil, or bleomycin) and taxanes yield mostly short responses in 15–30 % and 20–43 % of cases, respectively. Cytotoxic combination regimens in the form of doublets or triplets further enhance the response rate but at a cost of increased toxicity. In addition, no substantial survival benefit beyond the median estimates of 6–9 months has been shown in randomized phase III clinical trials [10].
Cetuximab is a chimeric immunoglobulin type G1 monoclonal antibody targeting the extracellular domain of epidermal growth factor receptor (EGFR), which competitively antagonizes natural ligand binding and stimulates antibody-dependent cellular cytotoxicity (ADCC). Furthermore, it exhibits additive antitumor effects with cisplatin [11]. The relevance of EGFR inhibition in SCCHN is underscored by a highly prevalent overexpression of this molecular target. In a group of platinum-refractory patients with recurrent or metastatic tumors, a 2007 phase II study demonstrated the intrinsic activity of cetuximab, reporting a 13 % response rate and a 46 % disease control rate [12]. In 2008, the phase III trial EXTREME found a significant enhancement in median overall survival (from 7.4 to 10.1 months, p = 0.04) with the addition of cetuximab to the first-line platinum/5-fluorouracil doublet [6]. Based on the long-term follow-up data, 31 (14 %) patients in the cetuximab arm compared with 25 (11 %) in the chemotherapy alone arm lived more than 2 years. At 5 years, 8 patients (6 and 2, in both arms, respectively) were still alive including the one described in this case report [13]. In the reported patient, to achieve such a remarkable treatment result with the TPF-C regimen, chemoresistance given by the recurrent disease setting and augmented by the
123
Eur Arch Otorhinolaryngol
first-line PF-C application had to be overcome. Docetaxelcontaining combinations represent the cornerstone of induction therapy in locoregionally advanced SCCHN, while raising response rates in recurrent and metastatic tumors [4, 10, 14]. According to a recently published metaanalysis of five randomized trials consisting of 1772 patients with locally advanced SCCHN, the risk of death was reduced by 21 % with the addition of a taxane to cisplatin/5-fluorouracil induction chemotherapy translating into a 7.4 % absolute survival benefit at 5 years [14]. In a cohort of 19 patients with locally advanced and/or recurrent SCCHN, Janinis et al. prospectively tested a TPF schedule (docetaxel 80 mg per square meter on day 1, cisplatin 40 mg per square meter on days 2 and 3, and 5-fluorouracil 1000 mg on days 1–3, repeated every 28 days) resulting in an overall response rate of 44 %, a median time to progression of 7.5 months, and a median overall survival of 11 months. Notably, the prophylactic use of granulocyte colony-stimulating factor contributed to the manageable hematologic toxicity profile with 15 % febrile neutropenia rate and no treatment-related deaths [4]. However, about twice as high incidence of febrile neutropenia occurred in the most potent taxane/platinum-based triplets with ifosfamide, where no hematopoietic growth factors were permitted (response rates up to 95 %) [10]. Furthermore, phase II trials with well-tolerated taxane/platinum combinations plus cetuximab demonstrated response rates over 50 % compared to 36 % reached in the EXTREME trial with platinum/5-fluorouracil plus cetuximab [6, 15, 16]. In 2007, Buentzel et al. presented data on 23 primary platinum-resistant subjects with recurrent SCCHN who received a 3-weekly chemotherapy comprising carboplatin (200 mg per square meter) and paclitaxel (200 mg per square meter) plus weekly cetuximab (250 mg per square meter after an initial 400 mg per square meter dose) producing an objective response rate of 56 % with one case of complete remission. Median time to progression and overall survival were 5 and 8 months, respectively [15]. In 2012, Guigay et al. reported on a 54 % response rate with one case of complete remission achieved by first-line docetaxel/cisplatin/cetuximab triplet in 54 patients with recurrent or metastatic SCCHN. After four 3-weekly cycles of the combination regimen (docetaxel and cisplatin, both 75 mg per square meter on day 1, and weekly cetuximab 250 mg per square meter after an initial 400 mg per square meter dose), maintenance therapy with single-agent cetuximab continued until disease progression or unacceptable toxicity. Median progression-free survival and overall survival were 7.1 and 15.3 months, respectively [16]. Therefore, the already proven efficacy of platinum doublet plus cetuximab in our patient was enhanced by the addition of docetaxel, yielding a partial
123
response after 2 cycles and a complete response after 5 cycles, thus showing its therapeutic potential. So what are the prognostic factors relevant in the recurrent and metastatic settings for patients receiving chemotherapeutic or targeted agents? A multivariate analysis from two randomized Eastern Oncology Cooperative Group (ECOG) phase III trials (E1393 and E1395) revealed the following independent favorable predictors for overall survival: poor tumor cell differentiation, ECOG performance status of 0, weight loss 5 % or less in the previous 6 months, primary tumor location other than the oral cavity or hypopharynx, and no prior radiotherapy. Additionally, favorable predictors of 2-year survivorship were poor tumor cell differentiation, ECOG performance status of 0, no prior radiotherapy, white race, and at least a partial response to chemotherapy which was regarded as a major influence on survival. Noteworthy, 6 (1.5 %) patients were still alive at 5 years and all of them had locally recurrent disease at study baseline [17]. High levels of EGFR and its ligand (transforming growth factor alpha) have been related to dismal outcome [18, 19]. Recently, a retrospective analysis of the EXTREME trial identified p16 and HPV status as further prognostic factors, however, no predictive value for improved outcome with cetuximab addition was found [20]. Moreover, circulating tumor cells and immunohistochemical expression levels of ERCC1 and RASSF1A may serve as novel experimental prognostic biomarkers [21, 22]. There are conflicting results concerning the significance of EGFRvIII mutation as well as its prevalence among SCCHN cases [23–25]. Importantly, none of the above mentioned indicators has ever been prospectively validated in a large randomized trial. In our patient, in accordance with the published data, poor tumor cell differentiation, weight loss of less than 5 % preceding the treatment initiation, location of the tumor in the oropharynx, white race and the induced complete response have most likely played an important role in the therapy success and maintenance of the long-lasting remission. Although aggressive supportive care measures managed to deal with grade 3 febrile neutropenia and grade 4 anorexia maintaining the prescribed dose density, the experienced acute adverse effects of the TPF-C regimen were unacceptably serious leading to an early treatment termination. This observation, in retrospect, is explainable because later studies have shown that full-dose TPF-C regimen cannot be given safely even as an induction chemotherapy regimen in patients with locoregionally advanced SCCHN [26]. However, TPF-C at lower doses (in particular of the 5-fluorouracil) might be feasible in that setting [27] and, as mentioned earlier, taxane/platinum combinations plus cetuximab without 5-fluorouracil seem to be viable (and surprisingly active) options for the
Eur Arch Otorhinolaryngol
treatment of patients with recurrent or metastatic disease [15, 16]. Moreover, besides cytotoxicity, taxanes induce other biological effects, especially in the immune system, showing among others enhancement of natural killer (NK) cell activity, which is intriguing within the context of the important ADCC effect of cetuximab [28]. These observations suggest the possibility of a special interaction between taxanes and cetuximab that needs to be further explored. A randomized trial has been ongoing in France, Germany and Spain since 2014, which compares the PF-C regimen used in the EXTREME trial with docetaxel/cisplatin/cetuximab schedule (GORTEC 2014-01 trial).
Conclusions A highly active cytotoxic combination of the TPF regimen plus targeted agent cetuximab proved to be effective in a patient with inoperable radioresistant recurrent SCCHN. Although the overall prognosis of such patients is poor, based on this case report and available literature data, it could be hypothesized that a certain subset of patients presenting with favorable prognostic factors may be successfully salvaged using this modality. As the drug induced toxicity may be life-threatening, dose adaptation of the cytotoxic backbone is unavoidable and the contributing role of 5-fluorouracil needs to be further explored. Finally, future trials should prospectively verify the relevance of the suggested prognostic and predictive markers and new indicators should be sought for a precise definition of the long-term survivors from SCCHN. Acknowledgments The authors acknowledge the contribution of Professor Martin Lammens (Department of Pathology, Antwerp University Hospital, Edegem, Belgium), who provided histological micrographs. Conflict of interest Professor Vermorken has participated in advisory board of Merck. Ethical standards All patients in the Department of Medical Oncology of the Antwerp University Hospital are treated in accordance with the ethical standards of the institute, which are in agreement with the 1964 Helsinki declaration and its later amendments. This patient participated in trials that were agreed upon by the Ethics Committee of the Institute. The patient is in full agreement with reporting the course of his disease in the literature.
References 1. Layland MK, Sessions DG, Lenox J (2005) The influence of lymph node metastasis in the treatment of squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx: N0 versus N?. Laryngoscope 115:629–639 2. Brockstein BE (2011) Management of recurrent head and neck cancer: recent progress and future directions. Drugs 71:1551–1559
3. Forastiere AA, Metch B, Schuller DE et al (1992) Randomized comparison of cisplatin 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 10:1245–1251 4. Janinis J, Papadakou M, Xidakis E et al (2000) Combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in previously treated patients with advanced/recurrent head and neck cancer: a phase II feasibility study. Am J Clin Oncol 23:128–131 5. Shin DM, Khuri FR, Glisson BS et al (2001) Phase II study of paclitaxel, ifosfamide, and carboplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma. Cancer 91:1316–1323 6. Vermorken JB, Mesia R, Rivera F et al (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127 7. Specenier P, Koppen C, Vermorken JB (2007) Diffuse punctate keratitis in a patient treated with cetuximab as monotherapy. Ann Oncol 18:961–962 8. Wittes RE, Cvitkovic E, Shah J, Gerold FP, Strong EW (1977) CIS-Dichlorodiammineplatinum(II) in the treatment of epidermoid carcinoma of the head and neck. Cancer Treat Rep 61:359–366 9. Morton RP, Rugman F, Dorman EB et al (1985) Cisplatinum and bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: a randomised factorial phase III controlled trial. Cancer Chemother Pharmacol 15:283–289 10. Vermorken JB, Specenier P (2010) Optimal treatment for recurrent/metastatic head and neck cancer. Ann Oncol 21(Suppl 7):vii252–vii261 11. Fan Z, Baselga J, Masui H, Mendelsohn J (1993) Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53:4637–4642 12. Vermorken JB, Trigo J, Hitt R et al (2007) Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 25:2171–2177 13. Vermorken JB, Remenar E, Hitt R et al (2014) Platinum-based chemotherapy (CT) plus cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck cancer (R/MSCCHN): 5-year follow-up data for the extreme trial. J Clin Oncol 32(suppl; abstr 6021) 14. Blanchard P, Bourhis J, Lacas B et al (2013) Taxane-cisplatinfluorouracil as induction chemotherapy in locally advanced head and neck cancers: an individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group. J Clin Oncol 31:2854–2860 15. Buentzel J, de Vries A, Micke O (2007) Experience with cetuximab plus paclitaxel/carboplatinum in primary platinum-resistant recurrent head and neck cancer. J Clin Oncol 25(suppl; abstr 6077) 16. Guigay J, Fayette J, Dillies AF et al (2012) Cetuximab, docetaxel, and cisplatin (TPEx) as first-line treatment in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Final results of phase II trial GORTEC 2008-03. J Clin Oncol 30(suppl; abstr 5505) 17. Argiris A, Li Y, Forastiere A (2004) Prognostic factors and longterm survivorship in patients with recurrent or metastatic carcinoma of the head and neck. Cancer 101:2222–2229 18. Rubin Grandis J, Melhem MF, Gooding WE et al (1998) Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90:824–832
123
Eur Arch Otorhinolaryngol 19. Santini J, Formento JL, Francoual M et al (1991) Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck 13:132–139 20. Vermorken JB, Psyrri A, Mesı´a R et al (2014) Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial. Ann Oncol 25:801–807 21. Grisanti S, Almici C, Consoli F et al (2014) Circulating tumor cells in patients with recurrent or metastatic head and neck carcinoma: prognostic and predictive significance. PLoS One 9:e103918 22. Park Y, Kim DS, Park KH et al (2012) RASSF1A and ERCC1 expression levels might be predictive of prognosis in advanced, recurrent, and metastatic squamous cell carcinoma of the head and neck treated with docetaxel and cisplatin. Onkologie 35:673–682 23. Sok JC, Coppelli FM, Thomas SM et al (2006) Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res 12:5064–5073
123
24. Chau NG, Perez-Ordonez B, Zhang K et al (2011) The association between EGFR variant III, HPV, p16, c-MET, EGFR gene copy number and response to EGFR inhibitors in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Head Neck Oncol 3:11 25. Boeckx C, Weyn C, Vanden Bempt I et al (2014) Mutation analysis of genes in the EGFR pathway in Head and Neck cancer patients: implications for anti-EGFR treatment response. BMC Res Notes 7:337 26. Vermorken JB, Remenar E, van den Weyngaert D et al (2012) Feasibility of cetuximab plus sequential platinum-based therapy (TPF/CRT) in advanced squamous cell head and neck cancer (SCCHN): a randomized phase II study of the EORTC Head and Neck Cancer Group. Eur Arch Otorhinolaryngol 269:1311–1410 (abstract OP42) 27. Haddad RI, Tishler RB, Norris C et al (2009) Phase I study of C-TPF in patients with locally advanced squamous cell carcinoma of the head and neck. J Clin Oncol 27:4448–4453 28. Tsavaris N, Kosmas C, Vadiaka M et al (2002) Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. Br J Cancer 87:21–27
