A multidisciplinary approach, whereby clinicians from different specialties collaborate and interact as a team, has become increasingly important in the treatment of head and neck cancer (HNC) in order to provide effective, timely, and evidence-based management of these complex and heterogeneous tumors.

Members of the multidisciplinary team may vary per institution, depending on available resources and clinicians, but a team typically includes head and neck surgeons, radiation and medical oncologists, specialists in medical imaging, nurses, and social workers.

One of the benefits of a multidisciplinary approach to HNC is that allows for patients to be offered an increasing array of treatment options from a team of specialists who keep abreast of the latest developments within their respective fields.

&ldquo;I consider [the multidisciplinary team] an absolute necessity to manage patients with head and neck cancer. These tumors affect vital areas of anatomy. Speech, swallowing, communicationall of those are affected,&rdquo; said Everett E. Vokes, MD, Giant of Cancer Care for Head and Neck Cancer, John E. Ultmann Professor, chair, department of medicine, and physician-in-chief at the University of Chicago. &ldquo;The fact is that these days, we can treat many patients with voice-preserving approaches that were pioneered many years ago, and are [now] standard of care at our institution for virtually all anatomic sites.&rdquo;

Vokes added that such approaches &ldquo;should always be considered for patients with oropharyngeal disease, larynx cancer, and certainly nasopharynx cancer.&rdquo; His HNC multidisciplinary team consists of surgeons, radiation oncologists, medical oncologists, pathologists (particularly for some of the rarer histologies and human papilloma virus [HPV]-related disease), a dental/oral surgeon team, radiologists, and nurses.

&ldquo;The surgeon is frequently first,&rdquo; Vokes said, &ldquo;to stage the patient, to carefully evaluate the location, and sometimes to do some treatment. Similarly, for patients who have early-stage disease, there has to be a discussion about&hellip;surgery [versus] radiation.&rdquo; He noted that, for advanced-stage disease, chemoradiation (chemotherapy in combination with radiotherapy), possibly with surgical salvage, or sometimes surgery first followed by chemo radiotherapy, are options that can be considered. Given the range of possible interventions, he stressed that consultation with the multidisciplinary team is especially important. &ldquo;There&rsquo;s no way to do this without sitting down, looking at the scans together, and talking about what everybody thinks is going on with the patient.&rdquo;

Surgery is one of the most critical components of HNC treatment, and advances in surgical techniques now allow for a greater number of treatment options.

Radiation oncologists and medical oncologists on the team also collaborate to provide the latest nonsurgical treatment modalities for HNC, including image-guided and intensity-modulated radiotherapies and chemoradiation.

In the context of multidisciplinary team care, use of these therapies can be optimized to allow for more conservative surgeries and improved survival, with better preservation of functional status by sparing damage to normal tissues and other critical structures.

While surgery remains the mainstay of treatment for many patients, those with poor performance status, advanced age, or comorbidities may be treated with radiation therapy or chemoradiation.

Reconstructive surgery specialists are also important members of the team, to provide the latest options for restoring form and function to patients and to introduce the team to other cutting-edge technologies, such as tissue engineering, that may be used to generate replacements for mucosal tissue.

Because patients with HNC will frequently present with advanced-stage tumors (stage 3 and 4), initial staging is an integral part of treatment planning, and effective follow-up for recurrence and metastasis is also important for these patients.

Advanced techniques, such as combined positron emission tomography/computed tomography (PET/CT), have become widely used for initial staging and screening for metastatic disease, and experienced radiologists who are familiar with the latest techniques in imaging are an essential part of the HNC multidisciplinary team.

Molecular diagnostics is a burgeoning area of interest in the management of HNC. In the near future, the pathology team and/or specialists in molecular biology will likely be consulted to assess and report to the team the presence or absence of key mutations and/or gene rearrangements that have recently been identified through large-scale initiatives, such as The Cancer Genome Atlas (TCGA). Whole genome sequencing of >300 squamous cell carcinoma specimens in TCGA has recently identified mutations in genes involved in squamous epithelial differentiation, as well as established oncogenes and tumor suppressor genes, as potentially important drivers of oncogenesis in HNC.

These will add to previously identified molecular targets in HNC, including the epidermal growth factor receptor (EGFR) and HPV-driven pathways.

Molecular information will also become increasingly important to the team as targeted therapies aimed at a specific mutations or genetic alterations become available and are shown to confer survival benefit for specific types of HNCs.

Although limited data are available, some evidence suggests that multidisciplinary care can improve outcomes in HNC. Friedland and colleagues compared outcomes and survival between HNC patients managed with or without a multidisciplinary team (MDT) in a retrospective 12-year analysis.

The investigators found that, when analyzed individually, there was no difference in survival between the MDT (n = 395) and non-MDT (n=331) groups for patients with stage 1, 2, or 3 disease; however, a significant benefit in 5-year survival was noted for patients with stage 4 disease who were managed by the MDT (hazard ratio [HR] = 0.69;

Evidence suggests that multidisciplinary care can improve outcomes in HNC.

Surgery is one of the most critical components of HNC treatment, and advances in surgical techniques allow for a greater number of treatment options.

Radiation and medical oncologists also collaborate to provide nonsurgical treatment modalities for HNC.

In the near future, the pathology team and/or specialists in molecular biology may be consulted to assess and report the presence or absence of key mutations and/or gene rearrangements that have recently been identified.

With advances in technology, smaller community hospitals and areas with limited medical resources to create telemedicine multidisciplinary teams.

There were also some notable differences in treatment modalities, with MDT patients having a greater use of synchronous chemotherapy (

<.001) and non-MDT patients having a greater use of radiotherapy only (

Important sources of bias in the study were that MDT patients were younger (&asymp;2 yrs) and were more likely to have advanced disease, which could have impacted the findings.

A multidisciplinary approach has been found to be important when using chemoradiation for patients with advanced-stage HNCs. In a retrospective, single-center study of patients with squamous cell carcinoma and stage 3 or 4 disease (N = 17), female gender, single marital status, and stage 4 disease were found to be predictors for increased use of adjunctive nursing and social services, whereas distance from the center, as expected, was a negative predictor for use of these services.

Recognizing these treatment utilization patterns is an important step to guide resource allocation for the team and to help better assess the needs of HNC patients.

Lastly, whereas large hospitals and established cancer centers clearly have the most available resources to generate multidisciplinary teams for HNC and other cancers, with advances in technology, there may also be options for smaller community hospitals and areas with limited medical resources to create telemedicine multidisciplinary teams.

Using video conferencing approaches, all relevant information pertaining to a case can be presented; one study found that among 80 HNC patients who could be evaluated using both teleoncology and in-person approaches, 91% had the same TNM classification and treatment plan, suggesting that telemedicine can safely be used to manage HNC patients.

The availability of such approaches and the increasing use and appreciation of MDTs in general will continue to improve care and quality of life for patients with HNC.

Varkey P, Liu YT, Tan NC. Multidisciplinary treatment of head and neck cancer.

Friedland PL, Bozic B, Dewar J, Kuan R, Meyer C, Phillips M. Impact of multidisciplinary team management in head and neck cancer patients.

Machiels JP, Lambrecht M, Hanin FX, et al. Advances in the management of squamous cell carcinoma of the head and neck.

Perri F, Muto P, Aversa C, et al. Integrated therapeutic approaches in head and neck cancer: the importance of multidisciplinary team management.

Tantiwongkosi B, Yu F, Kanard A, Miller FR. Role of (18)F-FDG PET/CT in pre and post treatment evaluation in head and neck carcinoma.

Mountzios G, Rampias T, Psyrri A. The mutational spectrum of squamous-cell carcinoma of the head and neck: targetable genetic events and clinical impact [published online ahead of print 2014 April 8].

Junn JC, Kim IA, Zahurak ML, et al. Multidisciplinary service utilization pattern by advanced head and neck cancer patients: a single institution study.

Stalfors J, Edstr&ouml;m S, Bj&ouml;rk-Eriksson T, Mercke C, Nyman J, Westin T. Accuracy of tele-oncology compared with face-to-face consultation in head and neck cancer case conferences.

Articles

Clinical Articles

A multidisciplinary approach has become increasingly important in the treatment of HNC in order to provide effective, timely, and evidence-based management of these complex and heterogeneous tumors.

Multidisciplinary Approach to Head and Neck Cancers May Improve Outcomes

Lori J. Wirth, MD, medical director, Center for Head and Neck Cancers, Massachusetts General Hospital, assistant professor, Harvard Medical School, discusses areas of unmet need in the field of thyroid cancer.

Read about molecular markers and the diagnosis of thyroid cancer > >

Unmet Needs in the Treatment of Thyroid Cancer

Ezra Cohen, MD, professor of medicine, UC San Diego Moores Cancer Center, discusses immunotherapy in head and neck cancer.

View more about novel approaches to the treatment of head and neck cancers > >

Immunotherapy in Head and Neck Cancers

Although prognostic biomarkers have become increasingly important in the treatment of many types of cancer, no such markers have yet been identified and validated for thyroid cancer. In order to guide treatment decisions, molecular testing will undoubtedly become an important part of thyroid cancer treatment as targeted therapies, such as sorafenib, become available and are shown to confer a benefit in patient survival.

There is evidence that molecular testing may be of benefit far earlier in the course of treatment, at the diagnostic stage. &ldquo;The word &lsquo;evolution&rsquo; really comes to mind,&rdquo; said Virginia LiVolsi, MD, professor of pathology and laboratory medicine at the University of Pennsylvania, explaining that a series of published articles reported how

mutation testing was going to be predictive of more aggressive behavior in differentiated papillary thyroid cancer (PTC).

Lori J. Wirth, MD, on Unmet Needs in the Treatment of Thyroid Cancer

Wirth is a professor at Harvard Medical School.

In her recent presentation at the 2014 Annual Meeting of the American Head and Neck Society (AHNS), LiVolsi described how molecular testing for genetic alterations such as

mutation and RET/PTC translocation has begun to influence diagnosis with fine needle aspiration biopsy (FNAB) specimens, which are typically categorized pathologically according to the 6-category Bethesda classification.

She noted that there are essentially 2 main questions that one would want to ask regarding molecular testing for a patient with indeterminate cytology by FNAB: &ldquo;Is it neoplastic or not?&rdquo; and &ldquo;If neoplastic, is it benign or malignant?&rdquo;

In the case of a specimen that is atypical, suspicious, and categorized pathologically as a category 3 or 4, for example, results from molecular testing could have an impact on the overall diagnosis and management plan, according to LiVolsi. &ldquo;If you do testing for molecular markers commonly found in malignant thyroid cancer, and found such a markerthe most notable being BRAF&mdash;you could be 99% sure, almost as close to certain as you could be, that this was indeed a papillary carcinoma.&rdquo;

With this type of result, initial therapy would be that used for an unequivocally known papillary carcinoma, which in most cases would be a total thyroidectomy, with or without the central node compartment, she explained. Using this information, &ldquo;You could then assure the patient that he or she does indeed require a total thyroidectomy, without need of doing a separate surgical procedure,&rdquo; LiVolsi said.

For patients with higher categories of suspicion for malignancy (category 5 or 6), LiVolsi explained that they would already be candidates for a total thyroidectomy, and there could be some debate about whether or not molecular testing would be helpful. She noted that for clinicians who believe that positive testing for

indicates a more aggressive lesion, this might lead to a more aggressive initial surgical approach, such as removal of the central compartment and evaluation of the lateral nodes. &ldquo;When I say more aggressive lesion, I don't mean that the lesion is going to metastasize to the lungs tomorrow. I mean that there might be a greater risk of local recurrence,&rdquo; LiVolsi added.

LiVolsi also described how pathologists now have at least 2 multigene molecular tests that can begin to answer these questions, including an RNA-based test that divides lesions into benign or not benign categories using sample-derived RNA and a panel of 167 genes. This test has a 95% negative predictive value, which could reassure patients that a lesion was in fact a benign lesion that could be watched, without surgical intervention.

A second molecular test is used to determine whether or not a lesion has a molecular signature known to be malignant; this is a DNA-based test that detects the presence of multiple mutations and translocations and has a high positive predictive value that could be used to inform clinicians of the need for aggressive intervention if any such mutations and/or translocations are found. Such information might also be used in the future to guide the use of targeted therapies that are aimed at a specific genetic lesion.

LiVolsi noted recent developments, such as results from The Cancer Genome Atlas for PTC, which will also factor into the role of molecular testing in the near future. That study will soon be published by Giordano and colleagues and describes results of whole-genome sequencing for some 500 PTC cases. The findings have identified 2 main families at the molecular level, and a third family classified as &ldquo;Other.&rdquo;

The first family, the BRAF family, is predominantly papillary carcinoma, with either classic type histology or the tall cell variant. These tumors have multifocality in the gland and tend to metastasize to the lymph node; with the exception of the tall cell variant, they tend to be quite indolent.

Molecular testing will become an important part of thyroid cancer treatment as targeted therapies, such as sorafenib, become available and are shown to confer a benefit in patient survival.

Molecular testing may be of benefit far earlier in the course of treatment, at the diagnostic stage.

mutation and RET/PTC translocation has begun to influence diagnosis with FNAB specimens.

Pathologists now have at least 2 multigene molecular tests, including an RNA-based test that divides lesions into benign or not benign categories using sample-derived RNA and a panel of 167 genes.

A second molecular test may determine whether or not a lesion has a molecular signature known to be malignant; this test has a high positive predictive value that could be used to inform clinicians of the need for aggressive intervention.

Several questions remain unanswered, including what type of molecular testing should be done; which FNAB specimens should be tested; which surgical specimens should be tested; and how such information will be used by the surgeon.

The second family, the RAS family, tends to be papillary carcinoma as defined by nuclear changes and follicular pattern, encapsulated or partly encapsulated, with less multifocality in the gland and less risk for lymph node metastases. However, &asymp;20% of these cancers have vascular invasion and capacity for spread to distant sites, such as the lungs and bone.

According to LiVolsi, the third family, &ldquo;Other,&rdquo; is &ldquo;all over the map&rdquo; with many different mutations and epigenetic changes. Although fewer samples corresponding to this group were studied overall, LiVolsi noted that this group has the most potential for future study that is likely to be of diagnostic or prognostic import.

The use of molecular testing in thyroid cancer diagnosis is not without controversy. For example, while some studies support the role of

mutations, such as V600E, in promoting aggressive tumor behavior,

others have suggested that when factors such as extrathyroidal invasion, lymph node metastases, histologic subtype, and distant metastases are taken into account, BRAF (V600E) status was no longer independently associated with mortality.

Other chromosomal translocations, such as the thyroid transcription factor PAX8/peroxisome proliferator-activated receptor gamma (PPAR&gamma;) fusion, originally thought to be specific for follicular patterned thyroid lesions,

have also been found to be expressed in nonlesional tissues and follicular adenomas and thus may have limited utility as a diagnostic marker.

LiVolsi said there are several currently unanswered questions, including what type of molecular testing should be done (eg, isolated markers vs a panel of genes); which FNAB specimens should be tested (eg, all FNAB vs only indeterminate FNAB); which surgical specimens should be tested (eg, all PTC vs extraglandular or metastatic PTC); and how such information will be used by the surgeon (eg, lobectomy vs total thyroidectomy). She also noted that follow-up for most markers is, in most cases, only on the order of approximately 3 years; for PTC, longer follow- up will be needed. According to LiVolsi, such studies will need to be conducted retrospectively; for example, by using archived formalin fixed paraffin embedded (FFPE) specimens.

Lastly, the predictive value of these molecular markers versus classical predictors of tumor size, stage, and lymph node invasion also remains to be evaluated.

Brose MS, Nutting CM, Jarzab B, et al, on behalf of the DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.

Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer.

Xing M. BRAF V600E mutation and papillary thyroid cancer.

Cappola AR, Mandel SJ. Molecular testing in thyroid cancer: BRAF mutation status and mortality.

Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected].

. 2000;289(5483):1357-1360. Erratum in: Science. 2000;289(5484):1474.

Gustafson KS, LiVolsi VA, Furth EE, Pasha TL, Putt ME, Baloch ZW. Peroxisome proliferator-activated receptor gamma expression in follicular-patterned thyroid lesions. Caveats for the use of immunohistochemical studies.

Although prognostic biomarkers have become increasingly important in the treatment of many types of cancer, no such markers have yet been identified and validated for thyroid cancer.

Molecular Markers Emerge in the Diagnosis of Thyroid Cancer

A better understanding of the molecular pathways that confer resistance to radioactive iodine (RAI) in the treatment of differentiated thyroid cancer has led to success in targeting the vascular endothelial growth factor (VEGF) and the VEGF receptor pathways. Other signaling pathways may also be involved in RAI resistance and represent additional potential targets. A newer promising approach is to restore sensitivity to RAI through the mitogen-activated protein kinase (MAPK) pathway by the use of a MAPK kinase (MEK) inhibitor.

In about 5% of patients being treated for thyroid cancer, thyroid cells can no longer take up RAI. For these patients, the long-term prognosis has been grim, with a 10-year survival rate of about 10%. &ldquo;We&rsquo;ve long struggled [with] how to treat them,&rdquo; said Everett Vokes, MD, chair, department of medicine, and professor of medicine and radiation oncology, University of Chicago Medical Center.

Martin Schlumberger, MD, on Results of the SELECT Trial in Thyroid Cancer

Schlumberger is a professor at University Paris-Sud.

Although typically slow growing, RAI-refractory thyroid tumors usually metastasize to the lungs and bone, eventually causing death.

&ldquo;Thyroid cancers have several known and well-described molecular characteristics,&rdquo; said Vokes, including increased expression of VEGF and VEGF receptor-1, VEGF receptor-2, and VEGF receptor-3. A multityrosine kinase inhibitor (TKI) of VEGF receptors 1-3 can shrink RAI-resistant thyroid tumors, result in responses, and prolong progression-free survival (PFS), according to Vokes.

In November 2013, the United States Food and Drug Administration (FDA) approved sorafenib, a multitargeted kinase inhibitor of VEGF receptor-1 and -2, for the treatment of metastatic differentiated thyroid cancer that is refractory to RAI. This approval was based on results from a clinical trial known as DECISION (Lancet 2014;384:319-328), in which 417 patients with RAI-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed in the prior 14 months were randomized to sorafenib, 400 mg twice daily, or placebo.

Progression-free survival, the primary endpoint, was significantly longer in patients assigned to sorafenib compared with placebo: 10.8 months versus 5.8 months (P <.0001), respectively, an advantage that was observed in subgroups based on age, the extent of disease, sites of metastases, or genetic biomarkers. Mutations in

were not associated with longer PFS in the sorafenib arm.

The objective response rates were 12% in the sorafenib group and <1% in the placebo group. There were no complete responses and overall survival was not significantly different between the two groups at the time of the analysis; the high rate of crossover from the placebo to the sorafenib arm (about 70%) at disease progression may have obscured any difference in overall survival, said Vokes.

Sorafenib was associated with more serious adverse events, as expected, but because RAI-refractory thyroid cancer is usually slow growing, sorafenib may not have to be used immediately, said Vokes.

A second multikinaseTKI to show substantial activity in this population is lenvatinib, which inhibits VEGF receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor alpha, RET, and c-kit. At the 2014 Annual American Society of Clinical Oncology meeting, a phase III study known as SELECT was presented. The 392 patients in the trial had measurable disease that had progressed within the past year. They were randomized to oral lenvatinib or placebo in a 2:1 ratio, and patients randomized to placebo were eligible for crossover to levantinib upon disease progression.

The median PFS was 18.3 months in the lenvatinib arm versus 3.6 months in the placebo arm (

<.0001). Sixty five percent of patients in the lenvatinib arm had an objective response, including 4 with complete response, compared with just 2% of the placebo arm. The crossover design may again have prevented a difference in overall survival, said Vokes.

There were 20 treatment-emergent deaths in the lenvatinib arm, 6 of which were deemed to be treatment-related by investigators, compared with 5 in the placebo arm, and significant side effects required dose reduction, dose interruption, and drug discontinuation in 68%, 82%, and 14% of patients randomized to lenvatinib, respectively.

A major distinction between the DECISION and SELECT trials is that patients enrolled in SELECT could have received other VEGF receptor inhibitors prior to enrollment, whereas those patients were excluded from participating in DECISION, said Vokes.

Better understanding of molecular pathways that confer resistance to RAI in the treatment of DTC has led to success in targeting the VEGF and the VEGF receptor pathways. November 2013, the FDA approved sorafenib, a multitargeted kinase inhibitor of VEGF receptor-1 and -2, for the treatment of metastatic DTC that is refractory to RAI based on results from the DECISION trial.

A second multikinase TKI to show activity in this population is lenvatinib, which inhibits VEGF receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor alpha, RET, and c-kit.

A multicenter, phase II trial of the oral multikinase inhibitor cabozantinib in a second-line setting in patients with differentiated thyroid cancer that progressed while on a prior VEGF receptor inhibitor is being conducted.

Another approach to treating refractory patients is to administer a drug that can restore sensitivity to RAI.

gene is another promising line of investigation, said Jonas de Souza, MD, assistant professor of medicine, section of hematology/oncology, also at the University of Chicago Medical Center. Mutations in

can lead to chronic activation of thyroid cancer protein products. In this category, dabrafenib and vemurafenib act to disrupt

signaling and may one day represent other options for RAI-resistant thyroid cancer.

The list of potential targeted agents for iodine-refractory disease is extensive, according to de Souza. &ldquo;As we learn more about the biology of the disease, including

mutations and downstream signaling mechanisms, the list will keep growing. And I strongly believe that the future does lie in precision medicine, and different patients will receive different combinations of drugs, either in combination or sequentially, based on their tumor profiles.&rdquo;

Under the direction of Manisha H. Shah, MD, at Ohio State University, Columbus, the International Thyroid Oncology Group (ITOG) is conducting a multicenter, open-label, phase II trial of the oral multikinase inhibitor cabozantinib in a second-line setting in patients who have had differentiated thyroid cancer that progressed while on a prior VEGF receptor inhibitor. Cabozantinib was selected because of its activity against both Met, an angiogenic protein thought to be critical in causing failure of VEGF receptor targeted therapy, and the VEGF receptor itself.

Patients with RAI-refractory differentiated thyroid cancer often have an absence of iodine receptor expression. Another approach to treating refractory patients, therefore, is to administer a drug that can restore sensitivity to RAI, according to Vokes. Preclinical work conducted at Memorial Sloan Kettering Cancer Center in New York City and others showed that genetic alterations in

can activate MAPK pathway signaling to prevent iodine uptake.

&ldquo;We believe that the cell&rsquo;s ability to absorb radioiodine is controlled by the MAPK pathway,&rdquo; said de Souza.

This discovery led to the hypothesis that a MEK inhibitor might restore thyroid cell sensitivity to RAI. This was indeed the case when the selective MEK1 and MEK2 inhibitor selumetinib was used in an early phase study of patients with metastatic thyroid cancers (

The trial, led by Alan Ho, MD, at Memorial Sloan-Kettering, enrolled 20 patients, all of whom received selumetinib twice daily for 4 weeks. In 12 of the 20 patients, uptake of iodine was restored as verified by positron emission tomography. Four of 9 patients with

mutations had increased uptake of iodine following treatment with selumetinib. In the 8 patients who resumed treatment with RAI, there were 5 partial responses and 3 patients had stable disease, and the responses were durable (&ge;6 months).

A better understanding of the molecular pathways that confer resistance to RAI in the treatment of differentiated thyroid cancer has led to success in targeting the VEGF and the VEGF receptor pathways.

Thyroid Cancer: Targeted Agents Show Promise Following Radioactive Iodine Resistance

Martin Schlumberger, MD, Institut Gustave Roussy, Villejuif Cedex, professor of oncology, University Paris-Sud, France, discusses the takeaway points for a community oncologist from the SELECT trial.

Learn more about targeted agents and radioactive iodine resistance > >

Results of the SELECT Trial in Thyroid Cancer

Targeted therapies, including tyrosine kinase inhibitors (TKIs), are increasingly being investigated in head and neck cancers, including recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) and advanced thyroid cancers.

&ldquo;I think targeted therapies in head and neck cancer have actually been more of a promise than a real achievement, with the exception of thyroid cancer, where they have made a lot of contribution,&rdquo; noted Everett E. Vokes, MD, Giant of Cancer Care recipient for Head and Neck Cancer, John E. Ultmann Professor, chair, department of medicine, and Physician-in-Chief at the University of Chicago, citing the recent success of therapies like sorafenib in radioiodine (RAI)-refractory differentiated thyroid cancer (DTC).

&ldquo;For squamous cell cancers of the head and neck, you had a lot of promise when cetuximab came around,&rdquo; Vokes said, noting that this epidermal growth factor receptor (EGFR)-targeted treatment, added to chemotherapy or sometimes radiation, can be used for patients with SCCHN and recurrent disease.

&ldquo;Beyond that, targeted therapies are really more of an investigational interest [for SCCHN] at this point,&rdquo; he said. &ldquo;We are still struggling to define the relevant driver mutations, and how to best target them.&rdquo;

Ezra Cohen, MD, on Immunotherapy in Head and Neck Cancers

Cohen is a professor at UC San Diego Moores Cancer Center.

However, Vokes acknowledged the potential of major groundbreaking initiatives, such as The Cancer Genome Atlas. &ldquo;The Cancer Genome Project has been very helpful&rdquo; he said, noting the recent identification of several relevant mutations in SCCHN.

&ldquo;We will see, in the next few years, whether that can hopefully be translated into clinical achievement.&rdquo;

This article highlights some recent, mostly phase II findings in SCCHN and thyroid cancer.

In a review of 5 clinical trials of various EGFR-targeted TKIs, including erlotinib, lapatinib, or gefitinib, Cohen et al concluded that, in combined analysis, older age, better performance status, and the occurrence of adverse events (AEs), such as rash, diarrhea, and stomatitis, were predictors of better progression-free survival (PFS) and overall survival (OS).

In a phase II trial, de Souza and colleagues assessed the use of lapatinib in 2 cohorts of patients with RM-SCCHN: those who had not received prior anti-EGFR therapy (arm A) and those who had received prior anti-EGFR therapy (arm B).

This trial showed lapatinib to be largely inactive in both sets of patients as monotherapy, with stable disease (SD) observed as the best response in 41% and 17% of subjects in arms A and B, respectively, and no observed partial response (PR) or complete response (CR).

A small study of foretinib, a multikinase inhibitor that predominantly targets the mesenchymal epithelial transition (MET) receptor, also showed SD as the best response in RM-SCCHN patients, with minor tumor shrinkage observed in 7 of 14 patients (50%). Study authors left open the possibility for further study of foretinib as combination therapy.

Figitumumab, an antibody inhibitor of the insulin-like growth factor receptor (IGF-1R), has also been evaluated as a monotherapy in RM-SCCHN patients.

This phase II study showed no significant activity of figitumumab in this population, and the trial was closed prematurely.

In a phase II study of cutaneous squamous cell carcinoma (CSCC) patients (N=23; n=22 evaluable for response and toxicity), induction therapy with gefitinib resulted in an overall response rate (ORR) of 45.5%, with 18.2% CR and 27.3% PR; the 2-year PFS, disease-specific survival, and OS rates were 63.6%, 72.1%, and 72.1%, respectively, and the treatment was well tolerated.

The authors concluded that EGFR TKIs should be further evaluated for the treatment of CSCC, and that, although none were identified in the study, biomarkers could help identify patients most likely to respond.

Similarly, the pan-human EGF receptor TKI dacomitinib has also demonstrated activity as a first-line therapy for patients with RM-SCCHN in a single-arm phase II study of 69 patients.

Among 63 evaluable patients in the study, an ORR of 12.7% was observed (0 CR, 8 PR), and 57.1% of patients had SD, with 14.3% experiencing SD for 24 weeks or greater; high-grade treatment-related AEs were predominantly diarrhea, acneiform dermatitis, and fatigue.

The multikinase inhibitor vandetanib, which targets RET as well as the vascular endothelial growth factor receptor (VEGFR) and EGFR signaling pathways, has demonstrated activity in locally-advanced or metastatic hereditary medullary thyroid cancer (MTC), for which no therapy had previously been available.10 In this study, a disease control rate (PR or SD for >24 weeks) was observed in 22 of 30 patients (73%), with PR observed in 6 patients (20%), and median PFS was >27 months, indicative of clinically relevant tumor control. These rates were achieved with a largely manageable AE profile.

Despite recent success of therapies like sorafenib in radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) and cetuximab, an EGFR-targeted treatment added to chemotherapy or radiation in patients with SCCHN and recurrent disease, most targeted therapies for head and neck cancers require further investigation.

Some agents in clinical trials for the treatment of RM-SCCHN include lapatinib, foretinib, gefitinib, and dacomitinib.

Some targeted therapies under investigation for thyroid cancer include vandetanib and cabozantinib.

Similarly, cabozantinib is a TKI with activity at MET, VEGFR2, and RET that has also been shown to have activity in MTC in a phase I dose escalation trial (N=85) including 37 patients with MTC.11 A confirmed objective response was achieved in 10 patients among 35 evaluable patients (29%), and 17 patients (49%) had tumor shrinkage of 30% or greater; SD of at least 6 months or a confirmed PR was seen in 25 patients (68%). Overall, the results showed this agent to have activity along with an acceptable toxicity profile in this population of MTC patients that was inclusive of those with somatic RET mutations.

The recently reported results of the landmark DECISION trial should also be mentioned, as they have provided, for the first time, a therapeutic option for patients with RAI-refractory, advanced DTC. In this phase III trial, the multikinase inhibitor sorafenib was shown to significantly prolong PFS (10.8 vs 5.8 months; hazard ratio [HR] = 0.59;

<.0001), and ORR was also significantly improved compared with placebo (12.2% vs 0.5%;

= 0.14), the endpoint was likely confounded by crossover allowance (from placebo to open-label sorafenib) upon progression. Benefits of sorafenib in this important population were attained at the expense of a largely manageable AE profile that was consistent with prior studies of this agent.

Markovic A, Chung CH. Current role of EGF receptor monoclonal antibodies and tyrosine kinase inhibitors in the management of head and neck squamous cell carcinoma.

Cohen EE, Halpern AB, Kasza K, Kocherginsky M, Williams R, Vokes EE. Factors associated with clinical benefit from epidermal growth factor receptor inhibitors in recurrent and metastatic squamous cell carcinoma of the head and neck.

de Souza JA, Davis DW, Zhang Y, et al. A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck.

Seiwert T, Sarantopoulos J, Kallender H, McCallum S, Keer HN, Blumenschein G Jr. Phase II trial of single-agent foretinib (GSK1363089) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

Schmitz S, Kaminsky-Forrett MC, Henry S, et al. Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: clinical activity and molecular response (GORTEC 2008-02).

Lewis CM, Glisson BS, Feng L, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck.

Abdul Razak AR, Souli&egrave;res D, Laurie SA, et al. A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck.

Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.

Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer.

Targeted therapies, including TKIs, are increasingly being investigated in head and neck cancers, including RM-SCCHN and advanced thyroid cancers.