multidisciplinary symposium on head and neck cancer

6
Meeting Highlights 10.1517/14656566.7.4.489 © 2006 Ashley Publications ISSN 1465-6566 489 Ashley Publications www.ashley-pub.com Multidisciplinary Symposium on Head and Neck Cancer 2 December 2005, Philadelphia, PA, USA Mark Agulnik & Lillian L Siu Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Ste 5-210, Toronto, Ontario, M5G 2M9, Canada The Multidisciplinary Symposium on Head and Neck Cancer focused on the emerging data that underlie optimal treatment for head and neck cancers, with a particular focus on squamous cell carcinoma of the head and neck. In- depth discussions showcased the published Phase II and Phase III data on the treatment of locally advanced disease with both induction chemotherapy and concurrent chemoradiotherapy. Molecular targets of interest and rele- vance in this tumour type were identified, as were the agents which target these putative proteins or pathways of carcinogenesis. Preliminary results from trials incorporating molecularly-targeted agents have shown a promis- ing role for these compounds in the management of both locally advanced and recurrent/metastatic squamous cell carcinoma of the head and neck. The Symposium brought a clear message. The management of squamous cell car- cinoma of the head and neck has evolved considerably, and with the advent of newer chemotherapeutic agents and molecularly targeted therapies, this field will continue to expand over time. Keywords: head and neck cancer, squamous cell carcinoma, targeted therapies Expert Opin. Pharmacother. (2006) 7(4):489-494 1. Introduction Head and neck cancer has an annual global incidence of > 500,000 and remains the fifth most common cancer worldwide. Squamous cell carcinoma of the head and neck (HNSCC) represents the majority of these cases [1]. The treatment of non-met- astatic HNSCC has continued to evolve since 1965, and > 70 randomised trials have attempted to establish the most effective therapy for these patients, with the greatest impact on survival advantage. Clearly, in the setting of locally advanced dis- ease, single modality treatment is insufficient, and chemotherapy, radiotherapy and surgery all have valued roles in the treatment of locoregional disease. In the meta- static setting, the optimal treatment remains elusive. With the advent of targeted therapies, the treatment of head and neck cancers will continue to evolve and yield, over time, new standards of care. The Multidisciplinary Symposium on Head and Neck Cancer presented an in- depth review and discussion of the emerging data that underlie optimal therapy for head and neck cancers. Presentations focused on the multidisciplinary care of locally advanced HNSCC with bimodality or trimodality treatment regimens incorporating surgery, radiation and chemotherapy. Sessions focused on the role of concomitant chemoradiotherapy, induction chemotherapy and treatment of recur- rent disease. A second major theme of the meeting involved the presentation of novel molecularly targeted agents currently under clinical investigation, given the important role that these agents will assume in the future treatments of HNSCC. 1. Introduction 2. Concomitant chemoradiotherapy 3. Induction chemotherapy 4. Incorporating targeted agents in the treatment of locally advanced squamous cell carcinoma of the head and neck 5. Treatment of recurrent disease 6. Targeted therapies 7. Expert opinion and conclusion For reprint orders, please contact: [email protected] Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Library of Health Sci-Univ of Il on 10/28/14 For personal use only.

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Page 1: Multidisciplinary Symposium on Head and Neck Cancer

Meeting Highlights

10.1517/14656566.7.4.489 © 2006 Ashley Publications ISSN 1465-6566 489

Ashley Publicationswww.ashley-pub.com

Multidisciplinary Symposium on Head and Neck Cancer2 December 2005, Philadelphia, PA, USA

Mark Agulnik & Lillian L Siu†

†Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Ste 5-210, Toronto, Ontario, M5G 2M9, Canada

The Multidisciplinary Symposium on Head and Neck Cancer focused on theemerging data that underlie optimal treatment for head and neck cancers,with a particular focus on squamous cell carcinoma of the head and neck. In-depth discussions showcased the published Phase II and Phase III data on thetreatment of locally advanced disease with both induction chemotherapyand concurrent chemoradiotherapy. Molecular targets of interest and rele-vance in this tumour type were identified, as were the agents which targetthese putative proteins or pathways of carcinogenesis. Preliminary resultsfrom trials incorporating molecularly-targeted agents have shown a promis-ing role for these compounds in the management of both locally advancedand recurrent/metastatic squamous cell carcinoma of the head and neck. TheSymposium brought a clear message. The management of squamous cell car-cinoma of the head and neck has evolved considerably, and with the adventof newer chemotherapeutic agents and molecularly targeted therapies, thisfield will continue to expand over time.

Keywords: head and neck cancer, squamous cell carcinoma, targeted therapies

Expert Opin. Pharmacother. (2006) 7(4):489-494

1. Introduction

Head and neck cancer has an annual global incidence of > 500,000 and remains thefifth most common cancer worldwide. Squamous cell carcinoma of the head andneck (HNSCC) represents the majority of these cases [1]. The treatment of non-met-astatic HNSCC has continued to evolve since 1965, and > 70 randomised trialshave attempted to establish the most effective therapy for these patients, with thegreatest impact on survival advantage. Clearly, in the setting of locally advanced dis-ease, single modality treatment is insufficient, and chemotherapy, radiotherapy andsurgery all have valued roles in the treatment of locoregional disease. In the meta-static setting, the optimal treatment remains elusive. With the advent of targetedtherapies, the treatment of head and neck cancers will continue to evolve and yield,over time, new standards of care.

The Multidisciplinary Symposium on Head and Neck Cancer presented an in-depth review and discussion of the emerging data that underlie optimal therapy forhead and neck cancers. Presentations focused on the multidisciplinary care oflocally advanced HNSCC with bimodality or trimodality treatment regimensincorporating surgery, radiation and chemotherapy. Sessions focused on the role ofconcomitant chemoradiotherapy, induction chemotherapy and treatment of recur-rent disease. A second major theme of the meeting involved the presentation ofnovel molecularly targeted agents currently under clinical investigation, given theimportant role that these agents will assume in the future treatments of HNSCC.

1. Introduction

2. Concomitant

chemoradiotherapy

3. Induction chemotherapy

4. Incorporating targeted agents

in the treatment of locally

advanced squamous cell

carcinoma of the head and neck

5. Treatment of recurrent disease

6. Targeted therapies

7. Expert opinion and conclusion

For reprint orders, please contact:[email protected]

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490 Expert Opin. Pharmacother. (2006) 7(4)

2. Concomitant chemoradiotherapy

The advantages and disadvantages of concomitant chemo-radiotherapy in the treatment of patients with HNSCC arenumerous (Box 1). The effect of chemotherapy in locallyadvanced, non-metastatic HNSCC remained uncertain untilPignon et al. [2] published a meta-analysis based on individualpatient data of 63 trials of locoregional treatment with orwithout chemotherapy. Survival data of these trials werereviewed and classified, based on the timing of chemotherapyrelative to the timing of locoregional treatment, with 31 trialsevaluating induction chemotherapy, 8 adjuvant chemother-apy and 26 concomitant chemotherapy. The use of concomi-tant chemotherapy yielded an 8% survival advantage(p < 0.0001), whereas the use of induction or adjuvant chem-otherapy did not offer a significant survival advantage or dis-advantage. An update of these results, recently presented,continues to support the initial findings [3]. Since these firstreports, further randomised Phase III trials have evaluatedthe role of concurrent cisplatin chemotherapy. The Head andNeck Intergroup study compared radiation alone (arm A),radiation with concurrent bolus cisplatin (arm B) and a splitcourse of radiation with concurrent infusional fluorouracilplus bolus cisplatin (arm C), in patients with unresectableHNSCC [4]. Findings further confirm that the addition ofconcurrent high-dose single-agent cisplatin to conventionalsingle daily fractionated radiation significantly improvesoverall survival, although with increased toxicity. The efficacyis lost when radiation is split, as in arm C of the study. TheRadiation Therapy Oncology Group (RTOG) and the Headand Neck Intergroup conducted a randomised trial to investi-gate three radiotherapy-based regimens in patients withlocally advanced laryngeal cancer: induction bolus cisplatinplus infusional fluorouracil followed by radiotherapy, radio-therapy with concurrent bolus cisplatin and radiotherapyalone [5]. Survival data were similar for all three arms of thestudy, given that this study was powered to assess for laryn-geal preservation rather than survival, and that salvage laryn-gectomy could be offered to patients with resectable diseasewho did not respond to primary treatment or had subse-quently relapsed. Concurrent cisplatin and radiation signifi-cantly improved organ preservation compared with either theinduction chemotherapy arm or the radiation alone arm,with 88, 75 and 70%, respectively, of patients possessing anintact larynx at 2 years. Calais et al. [6] within the Grouped’Oncologic Radiothérapie Tête et Cou (GORTEC) groupconducted a randomised Phase III multi-centre clinical trialcomparing radiation alone with radiation and concomitantinfusional carboplatin plus fluorouracil. When added to radi-ation, this chemotherapy combination produced a survivaladvantage, with 3-year overall actuarial survival rates of51 versus 31% favouring the combined modality arm. How-ever, acute toxic effects, specifically mucositis, moist desqua-mation of skin, nutritional status and haematological toxicitywere markedly worse with the addition of chemotherapy.

Concurrent chemotherapy delivered in synchrony withradiation has been shown by randomised controlled studies toimprove survival among patients with locally advanced, unre-sectable HNSCC, and to enhance organ preservation ratesamong resectable cases. Despite these benefits with concomi-tant chemoradiotherapy, several unresolved issues remain:

• Is single-agent cisplatin the optimal concomitantchemotherapy?

• Can the toxicities and long-term functional implications ofconcomitant chemotherapy be curtailed?

• With changes in failure patterns due to better locore-gional control and survival, what strategies can be used toovercome the increasing emergence of distant metastases?

• Will additional chemotherapy or the incorporation oftargeted therapy further enhance outcomes?

Ongoing research is required to identify the optimal con-current chemotherapy regimen, minimise both acute andlong-term toxicities, and successfully integrate additionalchemotherapy and/or targeted agents.

3. Induction chemotherapy

Although induction chemotherapy alone did not confer a sur-vival advantage when added to locoregional treatment inHNSCC [2], there are growing interests in combining induc-tion chemotherapy with concurrent chemoradiotherapy tomaximise therapeutic benefit. The effects of such a strategy onthe therapeutic index remain under investigation at present.In a recently published Spanish study, induction chemother-apy with cisplatin plus infusional fluorouracil was comparedwith paclitaxel, cisplatin plus infusional fluorouracil, followedby concurrent cisplatin and radiotherapy in both arms. Theprimary end point was the overall complete response rate toinduction chemotherapy, with the goal to define the optimalregimen for future evaluations [7]. Although this study demon-strated that the triplet induction chemotherapy regimen ofpaclitaxel, cisplatin plus infusional fluorouracil was better tol-erated, resulted in a higher complete response rate and a trendto longer overall survival, it did not confirm a role for induc-tion chemotherapy, as the comparator arm did not entail theexistent standard of care with concurrent chemoradiotherapyalone. This finding that the addition of a taxane to inductionchemotherapy may have a favourable therapeutic profile isfurther substantiated in a Phase III trial led by The EuropeanOrganization for Research and Treatment of Cancer(EORTC) [8]. In this trial, induction chemotherapy withdocetaxel, cisplatin plus infusional fluorouracil producedimproved rates of response, progression-free survival (PFS)and overall survival, and was better tolerated, when comparedwith cisplatin plus infusional fluorouracil, followed byradiotherapy alone in both arms.

Three Phase III clinical trials are currently in the planningphase or active-accrual phase to definitively evaluate the role ofinduction chemotherapy. The Paradigm Study will evaluate

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three cycles of docetaxel, cisplatin plus infusional fluorouracilfollowed by concurrent chemoradiotherapy with carboplatingiven weekly, versus concurrent chemoradiotherapy with highdose cisplatin given every 3 weeks. The University of Chicagohas proposed a Phase III sequential trial with both trial armsreceiving identical concurrent therapy of hydroxyurea, docetaxeland infusional fluorouracil with twice daily radiation, given forfive cycles every other week. The investigational arm will first betreated with induction chemotherapy consisting of cisplatin,docetaxel and infusional fluorouracil. The Southwest Oncologygroup (SWOG) has proposed a similar trial as the Paradigm

Study; however, both arms of the study will receive the identicalconcurrent therapy with high-dose cisplatin. Adequate Phase IIdata exist to justify the therapeutic value of induction chemo-therapy. Through these well planned, large, randomisedPhase III clinical trials, a final evaluation of the added benefitover concurrent therapy alone should be elucidated.

4. Incorporating targeted agents in the treatment of locally advanced squamous cell carcinoma of the head and neck

In a potential landmark study, Bonner et al. [9] reported theresults of a Phase III randomised trial comparing definitiveradiotherapy with or without the anti-EGFR monoclonalantibody, cetuximab, where a 3-year relapse-free survival andoverall survival were superior in the combined therapy arm.Toxicities observed were comparable between the two armswith the exception of skin rash, which is a class effect ofEGFR inhibitors. The implications from the findings of thisimportant study are significant as current interests includehow to optimally incorporate molecularly targeted agents intoconcurrent chemoradiation regimens, in the primary therapysetting. For instance, a current Phase III clinical trial is beingproposed by the RTOG to add cetuximab to chemoradio-therapy versus chemoradiotherapy alone for stage III and IVdisease that is not metastatic.

5. Treatment of recurrent disease

Although progress has been achieved in recent years in thetreatment of locally-advanced HNSCC, the management ofrecurrent or metastatic disease remains a challenge. Severalrandomised controlled trials have evaluated combinationchemotherapy with different platinum-based doublets versusmonotherapy in patients with recurrent or metastaticHNSCC (Table 1) [10-13]. Although response rates variedamong different arms of the trials, with a range of 10 – 40%,there was no statistically significant change in median survivalwith any specific systemic chemotherapy regimens. Mediansurvival was in the range of 6 – 9 months for chemotherapy-naive patients, and worse in those patients who had receivedprior chemotherapy. All regimens, aside from single-agenttherapy, were associated with substantial toxicities. The effectsof palliative chemotherapy on patients’ health-related andoverall quality of life have not been well studied.

In Phase II clinical trials, several triplet cytotoxic combi-nation regimens and non-platinum-based doublets havebeen evaluated, but no Phase III trials have tested these regi-mens. A Phase III clinical trial is currently being planned toevaluate the combination of cisplatin/fluorouracil versus cis-platin/ docetaxel. For patients who progressed after beingtreated with platinum-based chemotherapy, several drugshave shown modest activity in Phase II clinical trials, includ-ing methotrexate, vinorelbine, gemcitabine, irinotecan anddocetaxel [14-19]. Newer chemotherapeutic options that need

Box 1. Concomitant chemoradiotherapy: advantages and disadvantages.

Advantages

• Both chemotherapy and radiotherapy are independently active treatment modalities in this disease

• Chemotherapy may potentiate radiotherapy and improve local control

• Chemotherapy may decrease micrometastatic disease• Concomitant treatment shortens overall treatment

duration

Disadvantages

• Concomitant use of two treatment modalities produces greater toxicity than either modality alone

• Toxicities may result in a compromise of dose intensity by: i) chemotherapy dose reductions; ii) using single agents rather than combination chemotherapy treatments; or iii) giving split course radiation

Table 1. Randomised control trials for the treatment of recurrent/metastatic squamous cell carcinoma of the head and neck.

Ref. n Regimen ORR (%) Median survival in months

Forastiere et al., 1992 [11]

227 Cis/5-FUCarbo/5-FUMTX

322110

6.65.05.6

Jacobs et al., 1992 [13]

249 Cis/5-FUCis5-FU

321713

5.56.16.6

Forastiere et al., 2001 [10]

210 Cis/P 200 mg/m2

Cis/P 135 mg/m2

35

36

7.6

6.8

Gibson et al., 2005 [12]

218 Cis/5-FUCis/P 175 mg/m2

3026

8.78.1

5-FU: Fluorouracil; Carbo: Carboplatin; Cis: Cisplatin; MTX: Methotrexate; ORR: Overall response rate; P: Paclitaxel.E

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492 Expert Opin. Pharmacother. (2006) 7(4)

to be evaluated include premetrexed, oxaliplatin and newtaxane formulations. Other options include the use of molec-ularly targeted therapies as single agents and in combinationwith conventional chemotherapy.

6. Targeted therapies

The only published Phase III randomised clinical trial incor-porating a targeted therapy in the treatment of recurrent ormetastatic HNSCC is from the Eastern Cooperative Oncol-ogy Group (ECOG). This trial enrolled 117 evaluablepatients, and compared cisplatin/placebo versus cisplatin/cetuximab in recurrent or metastatic disease [20]. For patientstreated with cetuximab/cisplatin, compared with those treatedwith cisplatin alone, objective response rates were 26 versus10% (p = 0.03), and median PFS and overall survival wereprolonged at 4.2 versus 2.7 months (p = 0.09), and 9.2 versus8.0 months (p = 0.21), respectively. Although response rateswere significantly improved with the addition of cetuximab tocisplatin, the differences in PFS and overall survival betweenthe two arms were not statistically significant.

Aside from cetuximab, other anti-epidermal growth factorreceptor strategies have been employed using the small mole-cule tyrosine kinase inhibitors gefitinib and erlotinib. Cohenet al. [21,22] have reported on the single-agent activity of gefit-inib at both 250 and 500mg/day. At a dose of 500 mg/day, theobserved response rate was 10.6% and the disease control ratewas 53%, whereas at a dose of 250 mg/day only a 1.4%response was observed and the disease control rate was 34%.Soulieres et al. [23] evaluated erlotinib in patients with recurrentor metastatic disease, and of 115 patients enrolled, the overallobjective response rate was 4.3%, and disease stabilisation wasmaintained in 38% of patients for a median duration of16.1 weeks. Correlative studies may provide further insightinto the understanding of the mechanisms of action of thesedrugs, and potentially assist in a selection process to matchpatients with drugs they are likely to benefit from. Agulniket al. [24] have presented their correlative studies of erlotinib inrecurrent or metastatic HNSCC. Multidimensional scalingmodels, which grouped markers to increase statistical power,showed a clear clustering of molecular markers in pairedtumour samples (n = 9) from patients who had disease controlversus the patient that had progressive disease, which mayimply that tumour molecular biology may be able to selectpatients who are likely to respond to treatment.

Beyond targeting EGFR, other preliminary trials haveevaluated antiangiogenic or multi-targeted drugs. A Phase IIstudy [25] of sorafenib – a potent inhibitor of multiple recep-tor tyrosine kinases and serine-threonine kinases, includingRaf isoforms, VEGF receptor-2 and platelet-derived growthfactor receptor-β – in patients with recurrent or metastaticHNSCC and nasopharyngeal cancer, has shown a partialresponse in 1/23 and stable disease in 9/23 patients. To max-imise the therapeutic potential of molecularly targetedagents, current strategies are directed towards the evaluationof molecular combinations. For instance, a randomisedPhase II study is being proposed by the University of Chi-cago to compare bevacizumab, a monoclonal antibodyagainst VEGF, given in combination with chemotherapyversus bevacizumab and erlotinib in patients with recurrentor metastatic HNSCC.

7. Expert opinion and conclusion

Improvements in survival, organ preservation and quality of liferemain the most important goals in the treatment of patientswith HNSCC. New therapeutic strategies that have been devel-oped to achieve these goals have been presented at the Multi-disciplinary Symposium on Head and Neck Cancer. In the lastdecade, a clear survival advantage has been demonstrated bythe use of concurrent chemoradiotherapy in the treatment oflocally advanced HNSCC, and this development has led to apractice change. Although there is intense focus on the use ofinduction chemotherapy followed by concurrent chemother-apy, the toxicity of this strategy must be weighed against itspotential therapeutic gain, and randomised trials against con-current chemoradiotherapy alone are needed. The addition ofconcurrent chemotherapy to radiotherapy has improved locore-gional control in the setting of locally advanced disease, butdistant metastases remain a common cause of treatment fail-ures. Advances in systemic therapy are important to better con-trol distant failures and in the management of recurrent orde novo metastatic HNSCC. In the era of targeted therapeutics,single-agent response rates of molecularly targeted agentsremain low in the range of 5 – 15%. It would be rational toconsider molecular combinations or to incorporate their useinto standard regimens. Strategies to best combine targetedtherapies with each other, chemotherapy or chemoradiotherapyare likely to make some much needed advances in thetreatment of HNSCC in the next decade.

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25. CHEN E, WINQUIST E, AGULNIK M et al.: A Phase II study of Sorafenib (BAY 43-9006) in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) and nasopharyngeal cancer (NPC). Eur. J. Cancer (2005) 3:297.

AffiliationMark Agulnik1 & Lillian L Siu†2 MD, FRCPC†Author for correspondence1Clinical Fellow, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada2Staff Medical Oncologist, Associate Professor, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Ste 5-210, Toronto, Ontario, M5G 2M9, CanadaTel: +416 946 2911; Fax: +416 946 6546;E-mail: [email protected]

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