Molecular targeting agents in the context of primary chemoradiation strategies

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1 CLINICAL REVIEW Molecular targeting agents in the context of primary chemoradiation strategies Simon Laban, MD, 1 * Chia Jung Wang, MD, 1 Adrian Münscher, MD, 1 Silke Tribius, MD, 2 Philippe Schafhausen, MD, 3 Rainald Knecht, MD, PhD 1 1 Department of Head and Neck Surgery and Otolaryngology of the University Medical Center Hamburg Eppendorf, Martinistr. 52, Hamburg, Germany, 2 Department of Radiation Oncology of the University Medical Center Hamburg Eppendorf, Martinistr. 52, Hamburg, Germany, 3 Department of Oncology and Hematology of the University Medical Center Hamburg Eppendorf, Martinistr. 52, Hamburg, Germany. Accepted 29 September 2011 Published online 20 January 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Demands for organ preservation and increasing knowledge in molecular tumor biology have lead to the development of molecular targeting agents. These substances have also been incorporated into concomitant and sequential chemoradiation protocols. Methods. This study was conducted using a systematic literature review. Results. In head and neck squamous cell carcinoma (HNSCC), the inhibition of epidermal growth factor receptor (EGFR) signaling as a central step in carcinogenesis, progression, and metastasis is the predominant approach. Although EGFR targeting substances are commonly used, the specific influence of molecular targeting therapies on patient outcome remains unclear. In this review, results from recent clinical trials in the area of primary chemoradiation in the combination with EGFR targeting agents are discussed. Conclusion. Encouraging results from recent trials need to be confirmed in larger patient cohorts and cost-effectiveness analyses have to be undertaken. Phase III studies need to confirm these results before, time and again, new phase II studies are initiated. VC 2012 Wiley Periodicals, Inc. Head Neck 35: , 2013 KEY WORDS: chemoradiation, molecular targeting agents, EGFR, head and neck cancer, target therapy In the last 15 years, increasing knowledge in the field of tumor biology and molecular biology in general brought forth new treatment strategies taking advantage of the deregulated cell cycle in cancer cells. The general idea of molecularbased cancer therapy is the targeting of aberrant signaling pathways that are overexpressed or otherwise functionally abnormal in neoplastic cells in comparison to physiologic tissue cells. This way, the harm to normal cells shall be minimized whereas tumor cells are thought to be intensively affected. Therefore, these substances usually have a moderate profile of adverse events in comparison with traditional chemotherapeutic agents. Some of these so-called molecular targeting agents have taken the step into clinical application in different kinds of tumors. In head and neck cancer, the epidermal growth factor receptor (EGFR) and its related downstream signaling pathways have been shown to be widely overexpressed. The overexpression has been associated with carcinogenesis, tumor progression, and decreased survival in preclinical and clinical analyses. 1,2 Therefore, this pathway has a central role in head and neck cancer. That is why the majority of molecular targeting agents in this field affect EGFR signaling or related pathways. The most important substances have been presented and described in another review. 3 In order to reduce treatmentrelated toxicities of multimodality cancer treatment and at *Corresponding author: S. Laban, Department of Head and Neck Surgery and Otolaryngology of the University Medical Center Hamburg Eppendorf, Martinistr. 52, Hamburg, Germany. s.laban@uke.uni-hamburg.de the same time intensify the therapeutic effect, molecular targeting substances are incorporated into concurrent and sequential chemoradiation protocols in an increasing manner. A groundbreaking phase III study in the context of primary chemoradiation with cetuximab, a monoclonal antibody against EGFR, was performed by Bonner et al 4 and published in the New England Journal of Medicine in In locally advanced head and neck squamous cell carcinoma (HNSCC), the addition of cetuximab to radiotherapy improved overall and progression-free survival. This study laid the ground for intense efforts to evaluate molecular targeting agents in the clinical setting. This review focuses on the latest and most relevant steps and studies in the area of primary chemoradiation strategies incorporating molecular targeting agents. METHODS A systematic review of the literature was performed using the PubMed database. Studies on concomitant and sequential chemoradiation incorporating molecular targeting substances of the EGFR pathway were screened. Phase II and III studies and good phase I studies were analyzed and included into the review. REVIEW Molecular targeting agents in concomitant chemoradiation Radiotherapy þ Cetuximab for Squamous Cell Carcinoma of the Head and Neck. In 2010, updated survival data and a subgroup analysis for the above-mentioned study by Bonner 738 HEAD & NECK DOI /HED MAY 2013

2 MOLECULAR TARGETING AGENTS IN PRIMARY CHEMORADIATION et al 5 was published. Four hundred twenty-four patients were included in the 2 treatment arms. Two hundred thirteen patients were treated by high-dose radiotherapy alone (for details on fractionation please refer to the original publication 4 ) whereas the remaining 211 patients received weekly cetuximab (initial dose of 400 mg/m 2, then 250 mg/m 2 weekly) added to high-dose radiotherapy. The mean 5-year overall survival (OS) was 29.3 months in the cohort treated with radiotherapy alone in contrast to 49 months in the combination treatment arm with a 5-year survival rate of 36.4% versus 45.6% (hazard ratio, 0.73; 95% confidence interval, ; p ¼.018). An analysis of several pretreatment characteristics was performed regarding OS. Characteristics that favor the addition of cetuximab to radiation therapy were oropharyngeal primaries, T1 to T3 tumors, alternative radiotherapy fractionation (twice daily or concomitant boost vs once daily), N1 to N3 (vs N0), Karnofsky performance score 90%, male sex, 50% of EGFR-positive cells and age below 65 years. In case of a Karnofsky performance score of 60 to 80 or age above 65 years, results were in favor of radiation alone. For another subgroup analysis, patients who received the combined therapy of cetuximab and radiation were stratified according to the maximum of acneiform rash that developed during treatment (mild ¼ grade 0 1; prominent ¼ grade 2 4). Median OS in the group with mild skin reactions was 25.6 months in contrast to 68.8 months in the group with prominent rash (hazard ratio, 0.49; 95% confidence interval, ; p ¼.002). Compared to the data of the cohort treated with radiation alone, patients who had mild skin reactions during radiotherapy in combination with cetuximab seem not to have had a benefit from the addition of the EGFR antibody. At the same time, the additional effect of cetuximab added to radiotherapy alone was even higher in the cohort with prominent rash, and so were the survival data. These results imply that the development of cutaneous reactions to cetuximab treatment has a major positive impact on the patient s prognosis. Patients who did not develop such a rash did not benefit from the addition of cetuximab. These facts underline the need for a priori markers that can identify patients who will really benefit from this combination treatment. This way, not only could response rates and survival data could be improved, but unnecessary use of this still quite expensive antibody treatment be reduced. The prognostic value of the development of the above-mentioned skin reactions has been reported in several other tumor entities before. 6,7 On the other hand, the observation of severe cutaneous toxicities in patients treated with cetuximab led to the initiation of a survey in the European Organization for the Research and Treatment of Cancer with the aim to gain data about the incidence of grade 3 or higher skin toxicity. 8 Questionnaires were sent to 111 institutions throughout Europe for this purpose. Unfortunately only 28 institutions of these 111 provided their data. According to this survey, 35 of 71 patients available for evaluation experienced cutaneous reactions higher than grade 3. This rate lies much higher than the reported incidence by Bonner et al 4 of 17% grade 3 to 5 rash. The high rate of such severe reactions though is likely to be impaired by a selection bias due to the low participation in the survey (28 of 111 institutions). It is possible that only groups who experienced a high rate of severe toxicities reported their data whereas others with lower rates did not. In general, severe treatment-related toxicities are worrisome, because they may lead to dose reductions, treatment discontinuation, or even abruption. This may impact the patients outcome. The cutaneous reactions noticed in treatments incorporating EGFR-inhibiting agents, therefore, seem to be both a blessing and a curse. Up to now, the detailed pathomechanism leading to the expression of the papulopustular rash remains unknown. Because not only EGFR-targeting antibodies, but tyrosine kinase inhibitors as well, led to this cutaneous phenomenon, it is likely that the rash is not primarily an immunogenic reaction, but is somehow rooted in the inhibition of the EGFR pathway itself with the immunologic reactions being secondary epiphenomena. Lacouture 9 published a review about the pathohistological mechanism of the cutaneous skin reactions. These are often described as acneiform although they do not share central clinical and histological features of acne. Lacouture postulates that the blockade of the EGFR signaling results in a disturbance of physiologic cell differentiation, proliferation, migration, and survival. 9 Whereas under normal conditions the main area of phosphorylated EGFR expression in the skin is the basal cell compartment, EGFR inhibition leads to a reduction of EGFR phosphorylation and premature differentiation of basal cells. The disruption in the skin s arrangement of layers and the disturbed EGFR signaling are supposed to lead to a release of cytokines resulting in leukocyte invasion and inflammation. Finally, the skin turns hypotrophic due to premature differentiation and increased apoptosis leaving the skin dry and vulnerable. This hypothesized model based on pathohistological and cell culture experiments is a first step in the elucidation of the mechanism of skin toxicity. The development of skin toxicity seems to be a surrogate parameter for a genetic or epigenetic asset of the patient. Still the central question remains unsolved: which marker can predict an early occurrence of said skin reactions? Another startling fact is that high EGFR expression is associated with decreased survival in patients treated with EGFR-inhibitors even though one would expect the contrary. 5 This may lead to the assumption that in patients with a high EGFR expression, the administered standard dose of cetuximab, as mentioned above, may not be sufficient. The cutaneous toxicity could, therefore, also be a saturation effect. The detailed elucidation of the pathomechanism of the papulopustular rash could be the key to finding a marker that can predict a patient s response to an EGFR-targeted therapy approach and at the same time make the therapy more efficient and cost-effective. Clinical trials focusing on the identification of such markers need to be initiated. Also, trials taking into account the individual EGFR expression intensity for the dosing of EGFR-inhibitors are worthwhile. Cetuximab combined with primary chemoradiation Another interesting approach is the use of EGFRtargeting antibodies like cetuximab in the context of primary chemoradiation combined with traditional chemotherapeutics. In 2006, a group from the Memorial Sloan- Kettering Cancer Center published a phase II study on HEAD & NECK DOI /HED MAY

3 LABAN ET AL. such a combination. 10 Patients received 6 weeks of radiotherapy with a fractionation of 1.8 gray (Gy) per day and a concomitant boost of 1.6 Gy per day in week 5 and 6 adding up to a total dose of 70 Gy. Two cycles of cisplatin (100 mg/m 2, week 1 and 4 of radiotherapy) were given and chemotherapy was amplified by weekly cetuximab (400 mg/m 2 loading dose week 1, 250 mg/m 2 weekly). The 3-year OS rate was 76%, the 3-year progression-free survival rate 56%, and the 3-year locoregional control rate was 71%. Due to a series of serious adverse events, this study was abolished early. With these data in mind, in 2010, a feasibility study with a doseescalation scheme for cisplatin was published. 11 Patients with unresectable HNSCC were treated with a hyperfractionated accelerated radiotherapy (2 Gy per day for 3 weeks, followed by 1.4 Gy twice daily for another 3 weeks up to 70.6 Gy), weekly cetuximab (400 mg/m 2 loading dose week 1, 250 mg/m 2 weekly), and a reduced cisplatin dose applied in a dose escalation algorithm between 20 mg/m 2 and 40 mg/m 2. Fifteen patients were available for assessment: 5 of 15 patients (33%) had a complete response (CR) whereas 8 of 15 patients (53%) had a partial response (PR) which adds up to an overall response rate (ORR) of 13 of 15 patients (87%). Doselimiting toxicities were not reported and the maximum tolerated dose was not reached. 11 Another study with this combination of agents was Eastern Cooperative Oncology Group 3303 which was first presented at the American Society of Clinical Oncology (ASCO) meeting Sixty-one patients with unresectable HNSCC, of which 98% had stage IV disease, were treated with normofractionated radiation therapy (2 Gy/day, 5 times/week for 7 weeks up to 70 Gy), cetuximab (400 mg/m 2 loading dose day 14, then 250 mg/m 2 weekly), and 3 cycles of 75 mg/m 2 cisplatin (days 1, 22, and 43). Maintenance therapy with cetuximab was possible in 41 of 61 patients. Fourteen of 61 patients (23%) had CR, 15 of 61 patients (25%) had PR, whereas 19 of 61 patients had stable disease and 3 of 61 patients progressed during therapy. Ten of 61 patients were not available for assessment. This intense treatment regimen resulted in considerable toxicity: 1 treatment-related death due to neutropenic fever occurred and 97% experienced at least 1 grade 3 or higher toxicity. Most frequent toxicities included neutropenia (26%), fatigue (23%), papulopustular rash (28%), and radiation dermatitis (15%). At the 2010 ASCO meeting, the group published an analysis of prognostic molecular markers. 13 Longer OS and progression-free survival was found in human papillomavirus (HPV)-positive tumors and high EGFR expression was associated with poor OS and progression-free survival. Up to now, no analysis was published that evaluated the prognostic relevance of the maintenance therapy with cetuximab that was performed in a part of the patient cohort. Lapatinib added to chemoradiation A different idea is the incorporation of small molecule tyrosine kinase inhibitors into chemoradiation protocols. The dual tyrosine kinase inhibitor lapatinib which targets EGFR and Human Epidermal growth factor Receptor-2 (HER-2) was introduced into a traditional chemoradiation protocol by an international group from the United Kingdom, France, Hungary, Peru, and India. First results were presented at the ASCO meeting in They performed a prospective phase II trial with normofractionated radiation therapy (2 Gy/day, 5 days a week, for 7 weeks up to 70 Gy), 3 cycles of cisplatin (100 mg, days 1, 22, and 43), and daily oral lapatinib (1500 mg) or placebo, followed by daily maintenance therapy with oral lapatinib (1500 mg) or placebo. The primary endpoint of this study was the complete response rate (CRR) 6 months after chemoradiation. Sixty-seven patients with locally advanced HNSCC were included into the study. Eighteen percent of the patients had stage III, the remainder had stage IV disease. Patients were randomized to either the lapatinib group (33 patients) or the placebo group (34 patients). The rate of grade 3 or 4 toxicities did not differ significantly in the 2 groups, with the exception of higher rates of cutaneous reactions and diarrhea in the lapatinib cohort. The mean radiation dose (70 Gy in both groups) and the mean cisplatin (260 mg total in the lapatinib cohort vs 280 mg in the placebo group) dose was not affected significantly. The CRR 6 months after radiation therapy was 53% in the lapatinib group and 36% in the placebo group. Follow-up data are not yet available. These results show a promising CRR in the lapatinib group. With the addition of lapatinib, only 1 parameter was changed in comparison to the standard chemoradiation protocol. The planning of this study, therefore, allows an abstraction of the results. Drawing conclusions for clinical purposes will be facilitated. It remains to be seen in the future if the OS, progression-free survival, and local control will be superior to the standard chemoradiation treatment. Molecular targeting agents in sequential chemoradiation (induction chemotherapy) In the last decades, numerous sequential chemoradiation strategies have been evaluated in phase II and III studies. Currently, the most common and best examined administration scheme is a triple therapy with docetaxel (T), cisplatin (P), and 5-fluorouracil (F; 5-FU) labeled TPF, that proved to be superior to PF alone in clinical phase III studies. 15,16 In recent years, promising results from the incorporation of EGFR targeting substances into the TPF regimen in preclinical animal models 17 have led to the initiation of clinical trials to evaluate this combination of agents. Adding cetuximab to TPF A group from the Dana Farber Cancer Institute in Boston published a phase I study in 2009 to determine the maximum tolerated dose of 5-FU in a treatment scheme that integrated the monoclonal EGFR antibody cetuximab into TPF, thus labeled C-TPF. 18 Three dosages of 5-FU were evaluated in a dose escalation study. Three 21-day cycles of C-TPF were given in the following manner: 400 mg/m 2 cetuximab loading dose, then 250 mg/m 2 cetuximab weekly, 100 mg/m 2 cisplatin (days 1, 22, and 43), docetaxel 75 mg/m 2 (days 1, 22, and 43), and 5-FU as a continuous infusion (days 1 4 of every cycle) in 3 different doses (arm 1: 700 mg/m 2 /day; arm 2: 850 mg/ 740 HEAD & NECK DOI /HED MAY 2013

4 MOLECULAR TARGETING AGENTS IN PRIMARY CHEMORADIATION m 2 /day; arm 3: 1000 mg/m 2 /day). After completion of induction chemotherapy, patients received definitive chemoradiation. Patients were assigned to the treatment arms in a dose escalation scheme. Dose-limiting toxicities were defined as grade 3 nonhematological toxicity and were considered to be a direct result of the therapy, grade 4 febrile neutropenia, grade 4 neutropenia lasting longer than 7 days, or grade 4 thrombocytopenia. In arm 3, the rate of dose-limiting toxicities was 4 of 12 patients, whereas 3 of the last 6 patients included experienced dose-limiting toxicities. Because of this high rate in the last 6 patients, the prior dose stage (850 mg ¼ arm 2) was declared the maximum tolerated dose. At this dose level, the rate of dose-limiting toxicities was 3 of 13. Therefore, this dose level was recommended for future trials on C-TPF. The ORR in the 28 patients that were available for analysis was 100% with a pathologic complete response of 16 of 20 biopsied patients (80%). These results are comparable to previous results of the group with TPF induction chemotherapy and subsequent chemoradiation. 16 It remains to be seen if the results of C-TPF in regard to survival data, toxicities, and response rates in a large cohort of patients compare favorably with results from past TPF trials. The group based their addition of cetuximab on prior studies with TPF and, with the change in dosing of 5-FU, changed only 1 additional parameter in the treatment setting. This way, the results of a future trial will be easily comparable to the standard TPF chemoradiotherapy trials of the group. Replacing 5-fluorouracil with cetuximab (TPE) Another treatment concept in the setting of induction chemotherapy is the complete replacement of 5-FU in the TPF scheme with cetuximab. This regimen was labeled TPE, the E originating from the brand name of cetuximab: Erbitux (Bristol Myers Squibb Company, Princeton, NJ). In this context, we would like to report about a phase II clinical trial initiated by a group from the University of Pittsburgh. First results of this trial were presented at the ASCO meeting in 2007 and again in 2008, 2009, and In 2010, they published their data in the Journal of Clinical Oncology. 23 Thirty-nine treatment naive patients with locoregionally advanced head and neck carcinoma (stage III IVB, American Joint Committee of Cancer, 6th edition) were included into the study. The primary site was predominantly oropharynx (23 of 39), whereas other sites were larynx, hypopharynx, oral cavity, and nasopharynx. Thirty-six of 39 patients had stage IV disease and 32 of 39 patients had N2 to N3 status in the neck. Six tumors were considered technically or functionally unresectable. The induction chemotherapy consisted of 3 cycles of docetaxel 75 mg/m 2 (day 1 of each cycle), cisplatin 75 mg/m 2 (day 1 of each cycle), and cetuximab with a loading dose of 400 mg/m 2 on day 1 of cycle 1, continued weekly at 250 mg/m 2. Subsequently, patients received normofractionated radiotherapy (2 Gy/day, 5 days a week for 7 weeks up to a dose level of 70 Gy) with concomitant cisplatin (30 mg/ m 2 weekly) and cetuximab (250 mg/m 2 weekly). All patients were radiated with intensity modulated radiation therapy. This chemoradiation protocol was labeled XPE. After completion of this regimen, patients received a maintenance therapy with weekly cetuximab at the common dose level of 250 mg/m 2 for another 6 months. The primary endpoint of the study was the response rate of this combined treatment protocol. Response rates were measured after TPE and 8 weeks after XPE in 3 different ways: radiographically according to Response Evaluation Criteria of Solid Tumors (RECIST 1.0), by clinical examination, and by positron emission tomography (PET). Furthermore, HPV status was tested and EGFR expression was measured as described in detail in the publication. 23 After all 37 patients were available for evaluation of response after TPE, 33 for evaluation after XPE and all patients were evaluable for toxicity. One patient was excluded from the study after a grade 3 hypersensitivity reaction after the first administration of cetuximab and was not evaluable for response or survival. The response rates were reported as follows: 2 of 37 patients had a CR after TPE, 30 of 37 patients had PR, and the remaining 5 patients had stable disease measured by RECIST criteria. This resulted in a CRR of 2 of 37 (5%) and an ORR of 32 of 37 (86%). The CRR differed largely if compared between the different methods of evaluation. For example 2 of 37 had CR according to RECIST criteria whereas 12 of 35 patients were considered to be in CR by clinical examination and 6 of 28 patients by PET/CT. After XPE, 8 of 33 patients had overall CR and the remaining 25 of 33 had PR using RECIST criteria. In contrast to this, by clinical examination or PET/CT, the CR rate was 25 of 32 and 20 of 32, respectively. This observation is often noted in induction chemotherapy studies incorporating RECIST criteria for response evaluation. There are large disparities between response rates in imaging studies if residual disease is measured according to RECIST in comparison to clinical examination or evaluation by PET/ CT. Furthermore, response rates in the primary site and in the neck often differ with the response rates in the neck being the restricting factor. This is usually attributed to faulty criteria for the evaluation of neck masses or to different susceptibility to therapy. In this study, in 3 patients with residual neck disease, an elective neck dissection was performed and two thirds of the specimens were pathohistologically tumor free (pn0). With a median follow-up of 36 months, progression-free survival was 70% at 2 and 3 years with an OS of 84% and 72%, respectively. HPV status and EGFR expression showed no significant effect on progression-free survival or OS. The only significant correlation in regard to survival was, again, the grade of cutaneous reactions: the higher the grade of dermatitis the higher were progression-free survival (p ¼.0088) and OS (p ¼.0117). Disease in 12 patients progressed: local only (n ¼ 3), regional only (n ¼ 3), local and regional (n ¼ 2), distant only (n ¼ 3), and locoregional and distant (n ¼ 1). Nine patients have died, whereas 7 patients died from progression of disease, 1 patient from myocardial infarction, and 1 patient from an unknown cause. The survival data are very good in comparison to TAX 324 by Posner et al 16 (TPF cohort: OS at 2 years 67%; at 3 years 62%; progression-free survival at 2 years 53%; and at 3 years 49%), but premature conclusions should be withheld until a direct comparison between TPF and TPE is possible or TPE has been used in a comparable number of patients in a phase III study. HEAD & NECK DOI /HED MAY

5 LABAN ET AL. Paclitaxel, carboplatin, and cetuximab Another combination of substances being tested in clinical trials at the moment is the combination of paclitaxel (P), carboplatin (C) and cetuximab (C) which has been labeled PCC and was embedded into a sequential chemoradiation strategy. Concerning PCC, we would like to report about 2 studies that were published in the year ,25 One was performed at MD Anderson Cancer Center in Houston, Texas. 24 Forty-seven treatment-naïve patients with advanced HNSCC were included into this prospective phase II trial. The main inclusion criterion was N2b or higher N classification, so all kinds of T classifications were included. The most frequent primary site was oropharynx (87%). The treatment design was an induction chemotherapy with weekly paclitaxel (135 mg/ m 2 ), weekly carboplatin (area under the curve [AUC] 2) and weekly cetuximab (250 mg/m 2 after a loading dose of 400 mg/m 2 day 1 of cycle 1) followed by a riskadapted local therapy consisting of radiation alone (T1, T2; n ¼ 23), chemoradiation (T3, T4; n ¼ 23), or surgery (non-responder; n ¼ 1). Radiation for T1 tumors was performed in 30 fractions up to a total dose of 66 Gy, whereas T2 to 4 tumors were radiated in 40 to 42 fractions with concomitant boost up to a total dose of 70 to 72 Gy each over a time period of 6 weeks. Response rates were measured clinically and radiographically, whereas evaluation was performed separately in the primary tumor region and in the neck. The worse response of these 2 was noted in the overall response evaluation. In the primary tumor, 30 patients (70%) had CR and 13 patients (30%) had PR. In the neck region, 10 patients (22%) had CR, 34 patients (74%) had PR, and 2 patients (4%) had stable disease. Combined into the overall assessment, this means: 9 of 47 patients had CR, 36 of 47 patients had PR, and 2 of 47 patients had stable disease. These results were compared to historic data from previous studies of the group because there was no control group. OS after 1 year was 95% and 3-year OS was 91% with a progression-free survival of 94% after 1 year and 87% after 3 years in the PCC regimen with risk adapted definitive local therapy. A subgroup analysis for HPV status showed an OS and progression-free survival of 100% after 3 years for patients who are HPV-positive. The addition of cetuximab to paclitaxel and carboplatin induction chemotherapy was expected to increase the CR rate to 50% from historically reported 35%. 26 This goal could not be achieved. This might be due to a selection bias, because the historic patient collective consisted of only 67% >N2b rated patients. The second study on PCC was performed at the Johns Hopkins University in Baltimore by the group around Langer et al. 12 First results were presented at the ASCO meeting in The difference between this study s treatment regimen and the regimen used by Kies et al 24 was a different paclitaxel dose and a different treatment after induction chemotherapy. Sixty-three patients with resectable HNSCC, of which 21 patients had stage III and the remaining 42 patients had stage IV disease, were treated with 6 cycles of the following induction protocol: weekly cetuximab with an initial dose of 400 mg/m 2, then 250 mg/m 2 weekly, paclitaxel (90 mg/m 2 ), and carboplatin AUC2. All patients were planned to receive a definitive chemoradiation treatment after induction with weekly cetuximab (250 mg/m 2 ), paclitaxel (30 mg/m 2 ), carboplatin AUC1, and radiotherapy. In week 8, patients who had clinical complete remission underwent biopsy, and in week 14, patients with suspected residual disease underwent biopsy to obtain pathohistological information. If the biopsy in week 14 was negative, chemoradiation was completed up to a total dose of 68 to 72 Gy. In case of pathohistological evidence of residual disease, salvage surgery was performed. Of 74 patients planned for inclusion into the study, 70 patients completed induction chemotherapy and 68 patients also completed chemoradiation, but only 63 patients were available for analysis. After induction chemotherapy, 41 of 63 patients (59%) had a clinical CR which was pathohistologically affirmed (pcr) in 24 patients (59% pcr). A rebiopsy was performed in 34 patients in week 14 and 33 of 34 patients had pcr (91%). This resulted in a pcr of 57 of 60 biopsied patients (95%). Thirty-four patients received a neck dissection with 11 of 34 positive biopsies. Primary disease control was 83% after 2 years, OS was 97% after 1 year, 82% after 2 years with a progression-free survival of 82% after 1 year, and 66% after 2 years. At first sight, the response rates and survival data of the 2 studies on PCC induction chemotherapy are surprising, but the different methodology has to be taken into consideration. Kies et al 24 performed a radiographic and clinical assessment that differentiated between primary tumor and neck masses, whereas Wanebo et al 25 performed a clinical examination and tumor biopsy in the primary and planned neck dissection in the case of tumor persistence in the neck. Also, the patient cohorts and the following treatment after induction chemotherapy were different. In regard to survival data, the treatment regimen used by the MD Anderson group seems to be superior, but direct comparison and premature conclusions should be averted because patient selection criteria certainly have an impact on these data. In conclusion, PCC seems to be a treatment regimen that is worthwhile to take a closer examination in a greater patient cohort. Induction chemotherapy with gefitinib Furthermore, we would like to present 2 studies incorporating gefitinib, a tyrosine kinase-inhibitor of EGFR, into a sequential chemoradiation protocol. 27,28 The first of the 2 studies was published in Cancer in and was performed by the Sarah Cannon Research Consortium. Inclusion criteria were a locally advanced, biopsyproven squamous cell carcinoma of the head and neck including all primary sites (oropharynx, larynx, hypopharynx, oral cavity; T4 and/or >N1), carcinoma of unknown primary, and nasopharynx tumors (>T1 N0 M0). The treatment consisted of 2 cycles of induction chemotherapy followed by chemoradiation and maintenance gefitinib. Induction chemotherapy included daily gefitinib (250 mg p.o.), docetaxel (60 mg/m 2 ; days 1 and 22), carboplatin (AUC5; days 1 and 22), and 5-FU (continuous infusion of 200 mg/m 2 /24 hours; days 1 43). One week after completion of induction therapy, chemoradiation was administered with concomitant docetaxel (20 mg/m 2 weekly), daily gefitinib (250 mg p.o.), and radiotherapy of 1.8 Gy per fraction up to a total dose of 68.4 Gy. All patients who had an objective response continued with 742 HEAD & NECK DOI /HED MAY 2013

6 MOLECULAR TARGETING AGENTS IN PRIMARY CHEMORADIATION maintenance gefitinib orally for 24 months or until disease progression. Sixty-four patients were included in the study; 35 of 64 patients had oropharyngeal tumors, 25 of 64 patients had stage III disease, and 34 of 64 patients had stage IV disease. Fifty-six of 64 patients completed induction chemotherapy as planned, whereas 2 patients were excluded from the study before initiation of treatment and received an alternative treatment. Two patients discontinued therapy due to treatment-related toxicity, 2 patients due to intercurrent illness (pneumonia, gastrointestinal hemorrhage), and 2 patients withdrew consent to continue treatment in the study. Three patients did not receive chemoradiation due to treatment-related toxicity (1 of 3), disease progression (1 of 3), and salvage surgery (1 of 3). Fifty patients completed combined modality treatment and 39 patients continued to receive singleagent maintenance with oral gefitinib. After induction chemotherapy, 23 of 56 patients had objective response (8 of 56 patients had CR; 15 of 56 patients had PR), 26 of 56 patients had stable disease, 1 patient progressed, and the remaining 6 patients did not have a restaging after induction. After completion of chemoradiation, 18 of 50 eligible patients had CR and 22 of 50 patients had PR, 7 of 50 had stable disease, and 2 patients progressed during treatment. There was no comment on the remaining 1 patient missing to the 50 patients available for response evaluation. Interestingly, of the 22 patients with PR after chemoradiation, 9 patients reached CR in a follow-up during maintenance with gefitinib. The 3-year OS was 54% and 3-year progression-free survival was 41%. Most common toxicities during induction chemotherapy were neutropenia (19 of 62 >grade 3), oral mucositis (17 of 62 grade 3), and diarrhea (10 of 62 grade 3), whereas during chemoradiation, the most common adverse events were mucositis (31 of 53 >grade 3) and anorexia (13 of 53). One treatment-related death due to mucositis with pneumonia and subsequent respiratory failure occurred. Papulopustular rash >grade 3 was rare with 2 cases during induction, 2 cases during chemoradiation, and 6 cases during maintenance therapy. In comparison to historic data of the group with a protocol without gefitinib, the addition of the tyrosine kinase inhibitor did not have a favorable effect on treatment efficacy, but it seemed to increase toxicity. Because there was no real control group to compare with, the relevance of maintenance gefitinib cannot be discussed. The second study that included gefitinib into a sequential chemoradiation protocol was published in the Journal of Clinical Oncology in The group based their study on a prior induction chemotherapy study investigating an induction chemotherapy with paclitaxel and carboplatin followed by concomitant chemoradiation with paclitaxel, hydroxyurea, and 5-FU in which 2 different chemotherapy dosages and 3 different radiotherapy dose levels were evaluated. 29 The group hypothesized that gefitinib would be a less toxic radiation enhancer than paclitaxel and that maintenance therapy with gefitinib would have a potential to decrease failure rates. Sixty-nine patients with locally advanced squamous cell carcinoma of the head and neck were included into the trial. Thirty-seven of 69 patients had oropharyngeal tumors, 3 of 69 patients had stage III disease, 56 of 69 patients had stage IVa, and 10 of 69 patients had stage IVb disease. The primary endpoint was the CRR measured by RECIST criteria and confirmed by biopsy whenever possible. Incomprehensibly, 10 of 69 patients had organ-preserving surgery before induction chemotherapy and were, therefore, not available for response evaluation. The treatment consisted of 2 cycles of induction chemotherapy with paclitaxel (100 mg/m 2 ; days 1, 8, and 15) and carboplatin (AUC6; day 1) followed by a concomitant chemoradiotherapy (4 to 5 14-day cycles; 5 treatment days with 1.5 Gy twice daily followed by 9 days without radiation; 500 mg oral hydroxyurea (HU) every 12 hours; 5-FU 600 mg/m 2 /day continuous infusion) 1 to 2 weeks after the last paclitaxel dose. Gefitinib therapy was started orally with 250 mg daily on day 1 of induction chemotherapy and was continued daily during chemoradiation and up to 24 months after completion of treatment as a maintenance therapy. After induction, 7 of 59 patients had CR, 46 of 59 patients had PR, and 6 of 59 patients had stable disease. After chemoradiation, 52 of 59 evaluable patients had CR, 5 of 59 patients had PR, and 2 of 59 patients had stable disease. Sixty patients continued with maintenance oral gefitinib. During induction chemotherapy, 20 of 59 patients had grade 3 neutropenia whereas other serious adverse events were rare. During chemoradiation, 59 of 69 patients developed grade 3 mucositis, 23 patients had grade 3 radiation dermatitis, and 14 patients had grade 3 infections with 2 treatment-related deaths due to bacterial sepsis. Furthermore, there was 1 treatment-related death due to a cardiac event and 1 sudden death after planned neck dissection. EGFR-inhibitor related rash grade 3 was only registered in 3 patients. Forty-eight of 60 patients who started maintenance gefitinib completed the full course of 24 months. Four-year OS was 74%, with a progression-free survival of 72%, and 89% disease-specific survival. Patients with oropharyngeal cancers had a significantly better prognosis with >75% OS versus <50% OS in nonoropharyngeal cancers. Oropharyngeal tumors were also associated with a superior progression-free survival in comparison to tumors of other origin. Sixty-eight percent of oropharyngeal tumors were in patients who tested HPV-positive, whereas 15 of 17 patients who were HPV-positive had tumors that were from oropharyngeal origin. EGFR gene copy number as a marker of EGFR overexpression was significantly associated with poor OS and progression-free survival. Acknowledging the high rate of patients with stage IV disease, the survival data are very promising and warrant further investigation, but the high rate of oropharyngeal primaries and effects of HPV infection have to be taken into consideration. A randomized prospective study is needed to evaluate the effect of gefitinib addition to the protocol and, most importantly, the relevance of gefitinib maintenance, which is a costly treatment. The rate of serious adverse events was much higher than expected and the occurrence of 4 treatment-relateddeathshastobecritically remarked. In comparison with the before-mentioned study with gefitinib, 27 results of this treatment combination are much more promising. The rate of EGFR-inhibitor-related skin reactions was quite low in both studies. The impact of the rash on the prognosis was not commented on and probably the incidence was too low to perform such calculations. HEAD & NECK DOI /HED MAY

7 LABAN ET AL. CONCLUSIONS Molecular targeting agents are included in traditional chemoradiation strategies in an increasing manner and, according to a recent publication in Cancer, the use of cetuximab plus radiotherapy analog to the Wong et al 30 study is already a definitive part in HNSCC treatment in the United States with a proportion of approximately 20% of chemoradiation treatments performed. Interestingly, 1 characteristic associated significantly with the choice of cetuximab over cisplatin was higher age. According to Bonner et al s 5 subgroup analysis of 2010, the benefit of cetuximab addition to radiotherapy in patients 65 years of age is questionable. Although the incorporation of molecular targeting agents in chemoradiation protocols is increasing, traditional chemoradiation strategies are still not sufficiently examined. Numerous questions in this area remain unanswered to date. How high is the positive effect of alternative fractionation of radiotherapy or chemotherapy? Are sequential or concomitant chemoradiation strategies superior? Which is the optimal combination of substances? Is there a place for induction chemotherapy in the standard care for patients with HNSCC? The hope to decrease treatment-related toxicities and the goal of a custom-tailored therapy, nevertheless, warrant the use or examination of these new substances. Many studies we summarized above showed encouraging response rates and survival data with decreased toxicity. We are very curious to see some of these treatment strategies being evaluated in large randomized controlled trials. Unfortunately, scientific efforts are quite omnidirectional because there are usually phase II studies based on other phase II studies. The interesting results from these studies call for an evaluation in a larger cohort of patients, a phase III study, but very few ideas make it past this point. If one looked at the scientific output of the research community, one could argue that a lot of effort and money is spent on research evaluating new treatment strategies without a substantial comparison with the treatment standard. Therefore, implications for the clinical routine are missing. Phase II studies allow diverse designs, study planning is less complicated than the planning of phase III studies, and control groups are not necessarily needed. All this makes the drawing of distinct conclusions from the results very challenging. Table 1 and Table 2 illustrate how difficult comparisons between studies can be with the example of response rates and survival data. In these studies, response rates were often, but not always, evaluated using RECIST criteria; in other publications, response rates were not published, leading to missing columns. This does not count for survival data. Some studies have simply not reached survival endpoints and published their data yet. Often several parameters in the protocol are changed simultaneously compared to prior study efforts. Assignment of results to 1 parameter becomes impossible. As an example, in case of unexpected toxicities or increased survival: were they due to an alternative fractionation approach, a change in inclusion criteria, dosage of chemotherapeutics, or can they be attributed to the addition of a new drug? At the same time, there is an enormous diversification of available therapy, drugs, and protocols. Calls for custom- TABLE 1. Overview over response rates and survival data of concurrent chemoradiation studies. Response rates Survival data CR (%) PR (%) SD (%) PD (%) OS PFS Trial Treatment 12.4 vs 17.1* Bonner et al 4,5 RT vs RT þ cetuximab N/A 36.4% (RT) vs 45.6% (RTþcetuximab) (5 y) 25.6 (mild rash) vs N/A 68.8 (prominent rash) Pfister et al 10 RT, cisplatin, cetuximab N/A 76% (3 y) 56% (3 y) Kuhnt et al 11 RT, cisplatin, cetuximab 3/15 (33) 8/15 (53) 0 1/15 (7) N/A 14/61 (23) 15/61 (25) 19/61 (31) 3/61 (4.9) N/A RT, cisplatin, cetuximab maintenance cetuximab Langer et al 12 (ECOG 3303) N/A N/A 53% vs 36% (lapatinib vs placebo) Harrington et al 14 RT, cisplatin þ/ lapatinib þ/ maintenance Abbreviations: RT, radiotherapy; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; OS, overall survival; PFS, progression-free survival; N/A, inapplicable (data not published). Treatment, response rates, and survival data of concomitant chemoradiation studies incorporating molecular targeting agents. Missing data were not published or studies were still ongoing. Discrepancies in regard to parameters measured/ reported complicate comparisons between different studies. * Median PFS in months. Median OS in months. Missing 10 patients to 100% were unavailable for assessment. 744 HEAD & NECK DOI /HED MAY 2013

8 MOLECULAR TARGETING AGENTS IN PRIMARY CHEMORADIATION TABLE 2. Overview over response rates and survival data of sequential or induction chemoradiation studies. Response rates Survival data CR (%) PR (%) SD (%) PD (%) OS PFS Trial Treatment 16/20 (pcr) N/A N/A N/A N/A N/A Haddad et al 18 Cetuximab, docetaxel, cisplatin, 5-FU þ definitive CRT (C-TPF) 72% (3 y) 70% (3 y) 5/37 (after TPE), 0/33 (after XPE) 30/37 (after TPE), 25/33 (after XPE) 2/37 (after TPE), 8/33 (after XPE) Argiris et al Docetaxel, cisplatin, cetuximab (TPE) þ RT, cisplatin, cetuximab (XPE) 9/47 (RECIST) 36/47 (RECIST) 2/47 (RECIST) 0/47 91% (3 y) 87% (3 y) Kies et al 24 Paclitaxel, carboplatin, cetuximab (PCC) þ risk adapted local therapy" N/A N/A N/A 82% (2 y) 66% (2 y) 54% (3 y) 41% (3 y) 15/56 (after induction), 22/50 after CRT 8/56 (after induction), 18/50 (after CRT) Wanebo et al 25 Paclitaxel, carboplatin, cetuximab (PCC) þ definitive CRT Hainsworth et al 27 Gefitinib, docetaxel, carboplatin, 26/56 (after induction), 7/50 after CRT) 1/56 (after induction)*, 2/50 during CRT 5-FU þ CRT with docetaxel, gefitinib þ maintenance gefitinib 0/59 74% (4 y) 72% (4 y) 6/59 (after induction), 2/59 (after CRT) 46/59 (after induction), 5/59 (after CRT) 7/59 (after induction), 52/59 (after CRT) Cohen et al 28 Gefitinib, paclitaxel, carboplatin þ hyperfractionated RT, hydroxyurea, 5-FU, gefitinib þ maintenance gefitinib Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; OS, overall survival; PFS, progression-free survival; N/A, inapplicable (data not published); 5-FU, 5-fluorouracil; RT, radiotherapy; CRT, chemoradiotherapy; pcr, pathologically confirmed CR; RECIST, Response Evaluation Criteria in Solid Tumors. Treatment, response rates, and survival data of induction chemotherapy or sequential chemoradiation protocols incorporating molecular targeting agents. Missing data were not published or studies were still ongoing. Different ways of assessment for response rates complicate comparisons between different studies. * Six patients were not restaged after induction chemotherapy. tailored therapies are omnipresent. Prognostic and predictive markers are being evaluated. As we learn more and more about tumor environment, genetic and epigenetic influences on carcinogenesis, tumor progression, and aberrant cell signaling in tumors, future therapeutic strategies will indeed have to be individualized, accustoming the patient s individual assets and possibly targeting these therapeutically. This diversification might finally lead to molecular-driven therapies rather than entity-based cancer treatment. To achieve this goal, small steps have to be taken, one after another. The discrepancy between a standard treatment and the call for individualized approaches in a custom-tailored manner are an enormous challenge to researchers. This also counts for traditional dosing strategies relating only to body surface area (mg/m 2 ). For molecular targets, this might not be sufficient. After all, the expression level of the target and associated factors, such as downstream pathways and physiological ligands, might have to be taken into account for optimal results. The solution to this problem could be the identification of predictive and prognostic markers that could lead the way for a priori patient assignment to different therapy options such as induction chemotherapy, concomitant radiochemotherapy with or without the use of molecular targeting agents, or surgery plus adjuvant therapy. Currently, many potential biomarkers such as HPV status, EGFR expression, genetic EGFR polymorphisms, Ki67 status, tumor volume, and many more are under investigation. Up to now, robust information and data from prospective randomized controlled trials designed to answer these questions are lacking. To achieve these challenging goals, new protocols need to be compared to an internal standard at least. This way, results from clinical research could have a greater impact on standard patient care and translation into standard clinical application could be accelerated. In an environment in which health costs are constantly rising and health care systems all over the world are challenged heavily by decreasing resources and increasing spending, treatment recommendations have to be based on hard facts. The effects of the addition of molecular targeting agents to chemoradiation protocols have to be justified by better survival data or significantly better quality of life for the patients due to limitation of treatment toxicity. Determining situations in which the use of these agents is warranted has to be linked with socioeconomic evaluations of the additional treatment costs. Cost-effectiveness analyses have not been performed for any of the abovementioned studies yet. But cetuximab in first-line therapy for recurrent and metastatic head and neck cancer as reported in the so-called Erbitux in First-Line Treatment of Recurreat or Metastatic Head and Neck Cancer (EXTREME) study by Vermorken et al 31 was evaluated in regard to cost-effectiveness by a group from the United Kingdom based upon a review of the manufacturer s submission to the National Institute for Health and Clinical Excellence as part of the single technology appraisal process. 32 The group calculated incremental cost-effectiveness ratio, which means the additional cost per quality adjusted life year (QALY) caused by the addition of cetuximab to therapy with an astonishing result: the cost exceeded per QALY gained. The authors HEAD & NECK DOI /HED MAY

9 LABAN ET AL. concluded that even with a very high willingness to pay the addition of cetuximab in the clinical setting of recurrent or metastatic head and neck cancer, it is unlikely to be cost-effective. Another analysis 33 focused on the costeffectiveness of docetaxel to induction chemotherapy with cisplatin and 5-FU as used in the TAX 324 study by Posner et al. 16 In this setting, the cost per QALY gained was only Of course, from these reports, conclusions must not be drawn prematurely, because the 2 cost-effectiveness analyses just mentioned were in completely different settings, 1 having a palliative intent and the other a curative intent, and both did not deal with molecular targeting agents in the context of chemoradiation as this review does. Still, robust data have to be collected on the clinical effectiveness of treatment strategies using molecular targeting agents in chemoradiation protocols and there has to be a serious discussion if the use of these agents is really warranted in such settings in regards to cost effectiveness and clinical outcome of patients. Health care specialists today have a responsibility to be open for new treatment strategies and to keep an eye on rational spending in social health care systems at the same time. Molecular targeting agents will become an integral part of HNSCC treatment, but currently, more information from randomized controlled trials is needed in regards to survival benefits, treatment-related toxicities, predictive and prognostic markers, and sufficient selection criteria for patient assignment. Additionally, cost effectiveness analyses have to be taken into consideration and new treatment strategies also have to be assessed and discussed in a socioeconomic context. 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