A retrospective study of induction chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil followed by concurrent radiotherapy with cetuximab in locally advanced head and neck cancer

A retrospective study of induction chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil followed by concurrent radiotherapy with cetuximab in locally advanced head and neck cancer
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  A retrospective study of induction chemotherapy with docetaxel,cisplatinum, and 5-fluorouracil followed by concurrent radiotherapy with cetuximab in locally advancedhead and neck cancer  Brian Kim, MD ⁎ , Robert O. Dillman, MD, Peter Chen, MD, Russell Hafer, MD,Craig Cox, MD, Neil Barth, MD, R. Matthew Carroll, MD,Louis VanderMolen, MD, Minh Nguyen, MD, JinChu Huang, PhD,Annamarie Minion, MS, Marianne Plunkett, MS, Ralph Mackintosh, PhD  Hoag Memorial Hospital Presbyterian, Newport Beach, CA, USA Received 27 January 2011 Abstract Background:  The objective was to study the results of induction chemotherapy followed by external beam radiation therapy with concurrent cetuximab in the treatment of locally advanced head andneck cancer. Methods:  Seventeen patients with stage III or IV squamous cell carcinomas of the head and neck who received docetaxel, cisplatinum, and 5-fluorouracil followed by radiation therapy withconcurrent cetuximab were retrospectively analyzed. All radiation was delivered with image-guided intensity-modulated radiation treatments. Primary end points analyzed were local control andoverall survival. Results:  With a median follow-up of 17 months, the approximate 2-year local control was 85%, withoverall survival being 91%. At time of last follow-up, only 1 death was observed, with the cause of death unknown. Two local failures were observed, and the patients were under active management for their recurrences at time of last follow-up. No distant metastatic failures were noted amongthe patients. Conclusions:  Induction chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil followed by concurrent radiation with cetuximab provides for excellent locoregional control of disease.Future prospective studies can better establish the efficacy of this treatment regimen to current favored protocols.© 2012 Elsevier Inc. All rights reserved. 1. Introduction Approximately 40 000 to 50 000 new head and neck cancers are diagnosed each year in the United States [1].Approximately 90% to 95% are squamous cell carcinomas of the head and neck (SCCHNs), and 60% present with stage IIIand IV disease [2]. Many advances have been made in themultimodality treatment of SCCHN including the rise in theuse of concurrent chemotherapy as well as advancements inradiation techniques such as the utilization of intensity-modulated radiation treatment (IMRT). These improvementshave contributed in improving locoregional control andoverall survival over the last 2 decades [3-5].However, with distant metastatic disease still being a problem, induction chemotherapy has emerged as a focus of   Available online at American Journal of Otolaryngology – Head and Neck Medicine and Surgery 33 (2012) 93 – ⁎ Corresponding author. One Hoag Drive PO Box 6100 Newport Beach,CA92658-6100,USA. Tel.:+1 9497645528;fax:+1 9497648106.  E-mail address: (B. Kim).0196-0709/$  –  see front matter © 2012 Elsevier Inc. All rights reserved.doi:10.1016/j.amjoto.2011.02.004  study. Other theoretical advantages to induction chemother-apy include high response rates and benefit with regard toorgan preservation. The results of the EORTC 24971 (TAX323) trial have shown benefit to an aggressive inductionstrategy [6]. In this phase III trial comparing docetaxel,cisplatinum, and 5-fluorouracil (TPF) and PF inductionchemotherapy followed by radiation therapy (RT) in patientswith locally advanced unresectable SCCHN, patients inthe TPF group had an improvement in median overallsurvival of 4.3 months and an absolute increase in 3-year survival of 10.9%.In addition to these emerging data, a study demonstratedthe effectiveness of the use of cetuximab (Erbitux, ImcloneSystems, New York, NY, USA), an IgG monoclonalantibody that targets the epidermal growth factor receptor [7]. That phase III study randomizing patients to high-doseRT or high-dose RT plus concomitant cetuximab showedimprovement in locoregional control (median 24.4 vs 14.9months,  P   = .005) and overall survival (median 49.0 vs 29.3months,  P   = .03). Importantly, the addition of cetuximab didnot increase the incidence of adverse events such asmucositis, xerostomia, dysphagia, pain, and weight loss.This is in contrast to the increase in adverse effects typicallyseen with traditional concurrent chemotherapy.Thus far, however, no major trials have explored mergingthe 2 strategies. In theory, the toxicities incurred by anaggressive induction treatment may be offset with theconcurrent use of cetuximab rather than platinum-containingregimens. In this study, we report a series of patientstreated with induction chemotherapy with TPF followed by concurrent radiation with cetuximab to evaluate for clinical efficacy. 2. Materials and methods Seventeen patients treated between 2006 and 2009 withSCCHN were retrospectively identified by chart review ashaving undergone induction chemotherapy with TPFfollowed by concurrent radiation with cetuximab. Thistreatment strategy was up to the sole discretion of thetreating physicians involved, but all used the samechemotherapy regimen.Induction chemotherapy consisted of 3 to 4 cyclesevery 3 weeks of docetaxel (day 1, 75 mg/m 2 ), cisplatin(day 1, 75 mg/m 2 ), and 5-FU (days 1 – 5, 750 mg/m 2 ). The patients received intravenous hydration, granulocyte colony-stimulating factor, and occasionally erythropoietin  α  at thediscretion of the treating medical oncologist. Concomitant cetuximab was planned for 7 to 8 cycles. It was administeredintravenously with infusion times designed to limit anyhypersensitivity reaction (400 mg/m 2 over 2 hours, 1 week  before the start of RT, then 250 mg/m 2 over 1 hour, once per week during the radiation period).Total dose of radiation was targeted to be at least 7000 to7020 cGy, in 180- to 200-cGy fractions, to all areas of initialgross disease before induction chemotherapy. The doseadministered to uninvolved lymph nodes was at least 5000 cGy. Doses were reduced in some patients duringtreatment at the discretion of the attending radiationoncologist. All patients received a noncontrast computedtomographic (CT) scan for treatment planning. Contouringwas performed by the radiation oncologists using fusionstudies as deemed to be necessary by the physician. For IMRT planning, all patients were treated with image-guidedhelicaltomotherapy(TomoTherapy,Inc,Madison,WI,USA).Fortreatment delivery,all patientsreceiveda megavoltage CT before each treatment fraction. Image fusion, where the dailymegavoltage CT is fused to the srcinal kilovoltage treatment  planning CT, was performed by the treating therapists under the guidance of the treating physician. Complete response  (CR) after induction chemotherapywas defined as no disease detected on physical examinationand magnetic resonance imaging or CT –  positron emissiontomography (PET) scan imaging. Anything less than a CR on imaging or physical examination was defined as a  partial response  (PR).  Locoregional control   was defined as noevidence of disease on imaging (magnetic resonanceimaging or CT/PET scan) and physical examination. Timewas measured from the completion of radiation treatment rather than initiation of treatment. Rates of locoregionalcontrol and overall survival were estimated according toKaplan-Meier method. 3. Results Median age at diagnosis was 65 years (15 male and2 female subjects), with all patients presenting with either stage III or IV disease (4 patients with stage III and13 patients with stage IV disease). The majority of cases hadthe primary site of disease in the oropharynx (14 out the17 patients). Location of disease along with the patient characteristics is listed in Table 1.With a median follow-up of 17 months, the approximate2-year locoregional control was 85%, with overall survival Table 1Patient characteristicsMedian age, y 65Sex 15 Male2 FemaleStage III 4Stage IV 13Location 14 Oropharynx1 Larynx1 Hypopharynx,1 Unknown primaryLymph node stage 1 N05 N18 N23 N394  B. Kim et al. / American Journal of Otolaryngology  –   Head and Neck Medicine and Surgery 33 (2012) 93  –  97    being 91% (Fig. 1). At time of last follow-up, only 1 deathhad been reported; and the cause of death is unknown. Twolocal failures were observed (1 at the primary site of diseaseand 1 nodal failure), and the patients were under activemanagement for their recurrences at time of last follow-up.Both patients present with stage IVA base-of-tonguesquamous cell cancers. No distant metastatic failures werenoted among the patients.Complete response after induction chemotherapy wasseen in 5 (29.4%)of 17 patients, whereas a PR was noted inall treated patients. Both local failures were seen in patientswho had achieved a PR after induction therapy. An exampleof a CR on CT-PET scan after induction therapy is shownin Fig. 2.Median total dose of radiation delivered to all areas of gross disease was 7000 cGy. One patient stopped treatment at 6000 cGy because of treatment-related adverse effects;however, at last follow-up, the patient still demonstratedcontrol of disease at 30 months. Of note, that patient demonstrated a CR after induction chemotherapy. Toxicitydata were not collected as part of this study. 4. Discussion Although this is a small series, we believe it is a uniquestudy analyzing a novel sequence of chemoradiotherapy.Questions exist regarding the benefit of induction chemo-therapy followed by concurrent chemoradiation therapy vsconcurrent chemoradiation therapy alone. In addition, thereare questions regarding the efficacy of concomitant cetux-imab therapy in comparison to the more traditional platinum- based concomitant regimens. Future phase III studieswill address these issues; but until then, this study revealsthat a novel approach using induction chemotherapyfollowed by concomitant cetuximab and radiation istolerable and efficacious.Although our sample size is small, some encouragingresultsclearlyexist.Locoregionalcontrolat2yearswas85%.In the landmark phase III trial establishing the superiority of cetuximabplusRTvsRTalone,2-yearlocoregionalcontrolinthecetuximab+RTarmwas50%[7].IntheTAX323trial,at a median follow-up of 32.5 months, the median progression-freesurvivalwas11.0monthsintheTPFgroup[6].Onecouldhypothesize that the improved rates observed in our seriesare due to the combination of aggressive induction chemo-therapy followed by a concomitant treatment regimen, aregimen that the previously mentioned studies did not use.A more similar treatment comparison is the TAX 324 trialwhere patients were randomized to receive either TPF or PF   0 4 8   1   2   1   6   2  0   2  4   2   8   3   2   3   6  4  0 Local Control Survival N = 17 median F/U 22 mos (range 8 -42 mos) Fig. 1. Approximate 2-year locoregional control and overall survival.Fig. 2. Complete response on CT-PET scan after induction therapy.95  B. Kim et al. / American Journal of Otolaryngology  –   Head and Neck Medicine and Surgery 33 (2012) 93  –  97   induction chemotherapy, followed by concomitant weeklycarboplatin therapy and radiotherapy [8]. Estimated progres-sion-free survival at 2 years was 53% in the TPF group. Theestimated 3-year survival rate was 62% in the TPF group.Our series compares favorably to this protocol andhypothetically may be less toxic because of the use of cetuximab rather than carboplatin.With regards to response rates to induction chemother-apy, our study also compares favorably to the TAX 323 trial[6]. In that study, an 8.5% CR and 68% overall responsewere noted after TPF, whereas we observed a 29.4% CR and100% response rate. Itis unclear why our response rates werehigher other than for reasons associated with sampling andstatistical anomaly.A recent retrospective study looked at the tolerance of induction chemotherapy with docetaxel, cisplatin, and 5-FUfollowed by radiotherapy with concomitant cetuximab in46 cases of SCCHN [9]. This study reported high rates of completing all therapy and acceptable toxicity. Although the primary end point of the study was looking at tolerability, it was noted that disease progression was seen in 6.5% of the patients with locoregional response rates after inductionchemotherapy approaching 90% in certain subsets, similar todata observed in our series.As of now, no randomized studies have shown inductionto be superior to chemoradiotherapy alone or vice versa[10,11]. Whether the incorporation of induction regimens before established combined modality treatment regimenswill improve outcomes is actively being studied [12]. Inaddition, newer targeted molecular antibodies such ascetuximab have still not been proven to be more beneficialthan platinum regimens despite the attractiveness of  potentially lower toxicity [13 – 16]. Incorporation of molec-ular markers such as human papilloma virus status into thetreatment strategy will also be crucial in determining anoptimal therapy [17 – 20]. Innovative treatment regimens inthe future incorporating all these modalities may prove to be of most benefit for control of disease and minimizationof toxicities. 5. Conclusions Induction chemotherapy with TPF followed by concur-rent radiation with cetuximab provides for excellent locoregional control of disease. More detailed studies ontoxicity and quality of life will also allow for better evaluation of this regimen. Future prospective studies can better establish the efficacy of this treatment regimen tocurrent favored protocols. Acknowledgment The Ogasawara Foundation for the Promotion of Scienceand Engineering. References [1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer JClin 2008;58:71-96.[2] Seiwert TY, Salama JK, Vokes EE. The chemoradiation paradigm inhead and neck cancer. Nat Clin Pract Oncol 2007;4:156-71.[3] Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapyversus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998;16:1310-7.[4] Jeremic B, Shibamoto Y, Milicic B, et al. Hyperfractionated radiationtherapy with or without concurrent low-dose daily cisplatin in locallyadvanced squamous cell carcinoma of the head and neck: a prospectiverandomized trial. J Clin Oncol 2000;18:1458-64.[5] Denis F, Garaud P, Bardet E, et al. Final results of the 94-01FrenchHeadandNeckOncologyand RadiotherapyGrouprandomizedtrial comparing radiotherapy alone with concomitant radiochemother-apy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69-76.[6] VermorkenJB,Remenar E,vanHerpenC, et al. Cisplatin,fluorouracil,and docetaxel in unresectable head and neck cancer. N Engl J Med2007;357:1695-704.[7] BonnerJA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximabandcisplatinum for squamous-cell carcinoma of the head and neck. N EnglJ Med 2006;354:567-78.[8] Posner MR, Hershock DM, Blagman CR, et al. Cisplatin andfluorouracil alone or with docetaxel in head and neck cancer. N EnglJ Med 2007;357:1705-15.[9] Buiret G, Combe C, Favrel V, et al. A retrospective multicenter studyof the tolerance of induction chemotherapy with docetaxel, cisplatin,and 5-fluorouracil followed by radiotherapy with concomitant cetuximab in 46 cases of squamous cell carcinoma of the head andneck. Int J Radiat Oncol Biol Phys 2010;77:430-7.[10] Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapyand radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091-9.[11] Forastierre AA, Maor M, Weber RS, et al. Long-term results of intergroup 91-11: a phase III trial to preserve the larynx — inductioncisplatin/5FU and radiation therapy versus concurrent cisplatin andradiation therapy versus radiation therapy (abstract 5517). J Clin Oncol2006;24:284s.[12] Adelstein DJ, Moon J, Hanna E, et al. Docetaxel, cisplatin, andfluorouracil induction chemotherapy followed by accelerated fraction-ation/concomitant boost radiation and concurrent cisplatin in patientswith advanced squamous cell head and neck cancer: a Southwest Oncology Group phase II trial (S0216). Head Neck 2010;32:221-8.[13] Wirth LJ, Allen AM, Posner MR, et al. Phase I dose-finding study of  paclitaxel with panitumumab, carboplatin and intensity-modulatedradiotherapy in patients with locally advanced squamous cell cancer of the head and neck. Ann Oncol 2010;21:342-7.[14] Chen C, Kane M, Song J, et al. Phase I trial of gefitinib incombination with radiation or chemoradiation for patients with locallyadvanced squamous cell head and neck cancer. J Clin Oncol 2007;25:4880-6.[15] Cohen EE, Kane MA, List MA, et al. Phase II trial of gefitinib 250 mgdaily in patients with recurrent and/or metastatic squamouscellcarcinomaoftheheadandneck.ClinCancerRes2005;11:8418-24.[16] Cohen EE, Haraf DJ, Kunnavakkam R, et al. Epidermal growthfactorreceptorinhibitorgefitinibaddedtochemoradiotherapyinlocallyadvanced head and neck cancer. J Clin Oncol 2010;28:3336-43.[17] Licitra L, Perrone F, Bossi P, et al. High-risk human papillomavirusaffects prognosis in patients with surgically treated oropharyngealsquamous cell carcinoma. J Clin Oncol 2006;24:5630-6.[18] Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy andsurvival in squamouscell carcinomaof the head andneck. J Clin Oncol2009;27:1992-8.96  B. Kim et al. / American Journal of Otolaryngology  –   Head and Neck Medicine and Surgery 33 (2012) 93  –  97   [19] Ragin CC, Taioli E. Survival of squamous cell carcinoma of the headand neck in relation to human papillomavirus infection: review andmeta-analysis. Int J Cancer 2007;121:1813-20.[20] Ang KK, Harris J, Wheeler R, et al. Human papillomavirus andsurvival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24-35.97  B. Kim et al. / American Journal of Otolaryngology  –   Head and Neck Medicine and Surgery 33 (2012) 93  –  97 
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