Recent innovations in head and neck oncology: a report from the ICHNO

Abstract

The International Conference on Innovative Approaches in Head and Neck Oncology is a biennial joint meeting under the auspices of the European Society for Radiotherapy and Oncology, the European Head and Neck Society and the European Society of Medical Oncology. The conference focuses on recent developments in head and neck oncology. The main topics of this year were new insights in the epidemiology of head and neck cancer, the emerging role of human papillomavirus in head and neck cancer, update on randomized trials and new management approaches. The format of the meeting included invited key note lectures, interactive symposia, updates on large randomized trials, proffered paper sessions, poster presentations and tumor boards. The meeting was very well balanced, with abundant information and opportunities for interdisciplinary interaction.

The International Conference on Innovative Approaches in Head and Neck OncologyBarcelona, Spain7–9 February 2013

The International Conference on Innovative Approaches in Head and Neck Oncology (ICHNO) aims to bring together leaders in the field of head and neck oncology and a multidisciplinary audience in order to provide a forum for the dissemination of the most relevant and cutting edge innovations, to enhance professional exchange of information between investigators and to offer a podium for multidisciplinary networking among clinicians and researchers.

The format of the meeting includes invited key note lectures, interactive symposia, updates on large randomized trials, proffered paper sessions, poster presentations and tumor boards.

This year’s conference specifically covered the following topics:

• • New insights into the epidemiology of head and neck cancer;

• • The emerging role of human papillomavirus (HPV) in head and neck cancer;

• • Update on randomized trials;

• • New management approaches.

New insights into the epidemiology of head & neck cancer

Gemma Gatta (Department of Preventive and Predictive Medicine, Istituto Nazionaledei Tumori in Milan, Italy) presented an introductory key note lecture on the most recent European data on epidemiology of head and neck cancer. In Europe, head and neck cancer represented 4% of all malignancies in 2008. The age-adjusted incidence of head and neck cancer for men was highest for lip- and oral-cavity and larynx (seven and six per 100,000/year, respectively) and lowest for nasopharynx (0.6 per 100,000/year). The male/female incidence ratio was 4:4. According to the European project on rare cancers (RARECARE), the incidence of each head and neck subsite is below the rare cancer threshold. Therefore, international joint efforts are pivotal to accrue sufficient numbers of patients for prospective clinical trials.

In Europe, survival data are available from the EUROCARE project. For patients diagnosed in 2000–2002, the survival rate was 72, 44 and 36% at 1, 5 and 10 years, respectively. These numbers show the tremendous impact on survival in this patient cohort not only according to the primary tumor, but also in terms of second primary tumors and comorbidities. The main risk factors are tobacco and alcohol consumption. The relative risk according to recent meta-analyses for current smokers is 7 for larynx and pharynx and 3.4 for oral cavity. The relative risk for heavy drinkers is 4 for tongue, 8 for oropharynx and 9 for hypopharynx. With these numbers in mind, prevention would certainly be the most efficient way in the fight against head and neck cancer.

The emerging role of HPV in head & neck cancer

One of the main topics of the conference was the role of high-risk HPV in head and neck squamous cell carcinomas (HNSCCs). Over the last three decades, infection with HPV became an established risk factor for the development of HNSCCs. In the USA, a striking 225% increase in incidence of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) was observed between 1984 and 2004, whereas the incidence of HPV-negative OPSCC decreased by 50% in the same time period.

Xavier Castellsagué (Cancer Epidemiology Research Program in Barcelona, Spain) outlined in his key note lecture that HPV infection is acknowledged worldwide as the most common sexually transmitted disease. A recent study by de Martel et al. revealed the enormous global burden of cancer associated with infection [1]. In this study, it was estimated that 16.1% of the 12.7 million cases of new cancers diagnosed in 2008 were attributable to infections. This percentage has been shown to be more pronounced in less developed areas of the world (22.9%) than in more developed zones (7.4%). The most prominent infectious agents were Helicobacter pylori, hepatitis B and C viruses and HPV, accounting for 1.9 million new cancer cases, mainly of the stomach, the liver and the cervix uteri. Fortunately, only a small fraction of HPV infections persists and proceeds to cancer. In the cervix, more than 80% of HPV infections will be cleared within 6–20 months. While the natural course of cervical HPV infections is comparatively well studied, the according data in oral HPV infections is still lacking. Risk factors for HPV-associated oral cancer are lifetime number of sexual partners, young age of first sexual intercourse and oral sex. The group of the Cancer Epidemiology Research Program in Barcelona analyzed the prevalence of HPV infection in more than 3500 tumor samples from all over the world. Castellsagué stressed that the mere detection of HPV DNA by PCR in the tumor tissue does not allow declaring HPV as the causative agent. The combination with additional transformation factors such as overexpression of p16 or cyclin D1 or underexpression of p53 and pRb or the detection of HPV-RNA is mandatory. In this large-scale study, the overall prevalence of HPV for all sites in HNSCC was 11.7%, for oral cavity 8%, for pharynx 21.1% and for larynx 4.5%. Within the pharynx, the predominant site was the oropharynx with 23.6%, in particular, the tonsil with 53.9% and the base of tongue with 33.3% HPV-positive tumors. The most common virus type was HPV-16 with a low rate of concomitant infections with other oncogenic HPV types. Castellsagué closed with the remark that HPV-related cancer accounting for approximately 15,000 new male and 325,000 new female patients per year represents a pandemic preventable by vaccination.

Ruud Brakenhoff (Department of Head and Neck Surgery at the VU University Medical Centerin, Amsterdam, The Netherlands) gave his lecture on how to detect the HPV status. The prevalence of HPV-positive OPSCC varies substantially between studies, ranging from 20 to 90%. This may reflect a true difference in prevalence between different geographic and cultural regions, but is more likely related to differing HPV detection methods and different time periods of investigation. The most commonly applied technology is HPV DNA detection by PCR as assays are universally available, reliable and applicable on formalin-fixed paraffin-embedded tissue. Due to their very high analytical sensitivity, these assays generally overestimate the actual prevalence rates. As a consequence, various test algorithms combining additional surrogate markers of HPV infection have been investigated in order to increase the accuracy of HPV testing. A previously defined test algorithm for HPV detection consisting of p16 immunostaining followed by high-risk HPV DNA detection by GP5⁺/6⁺ PCR on the positive cases [2] was validated by performing HPV-E6 RT-PCR on according frozen samples as standard of reference. The test algorithm showed a high accuracy of 98%, a sensitivity of 96% and a specificity of 98%. Using the validated algorithm in The Netherlands, the proportion of HPV-positive samples significantly increased from 5% in 1990 to 29% in 2010.

Besides the epidemiological role of HPV in HNSCC and the variability in detection methods, the impact of HPV positivity on prognosis and therapeutic decision was discussed in several panels and tumor boards. Current treatment strategies for OPSCC comprise surgery with adjuvant radiochemotherapy (RCT) or primary RCT for advanced stage cancer and single-modality treatment with either surgery or radiotherapy for early stages. For early-stage (T1/2, N0) OPSCC 5-year locoregional control and disease-specific survival rates both vary between 90 and 100%, respectively for both modalities alone, independent of risk stratification. However, functional outcome data demonstrate better long-term results with respect to speech and swallowing capacity with surgery-based treatment strategies, particularly if transoral approaches were used for the resection. Several retrospective and prospective studies in HPV-positive OPSCCs have consistently reported an improved prognosis independent from the treatment modality. Recently, a recursive partitioning model for patients with OPSCC has been proposed based on the Radiation Therapy Oncology Group (RTOG) 0129 study by Ang et al. [3]. This landmark study on OPSCCs treated by primary RCT was able to separate patients into a low-, intermediate- and high-risk group for overall survival (OS) based on HPV status, smoking and tumor stage.

According to a study by Huang and O’Sullivan (Princess Margaret Hospital in Toronto, ON, Canada), the temporal regression of initial gross cervical lymph nodes following primary RCT appeared to be prolonged in HPV-positive compared with HPV-negative HNSCCs, but it was more reliably achieved beyond 24 weeks. This finding may have implications for the timing for postradiation imaging. With regard to the favorable prognosis in HPV-positive tumors, efforts towards deintensification of treatment seem reasonable. The aim would be to maintain the current survival rates, while reducing early and, in particular, late toxicity in this patient cohort. With the lack of supporting evidence in mind, several speakers concluded that deintensification strategies should be applied with caution and within prospective trials, in particular, in high-stage HPV-positive patients or HPV-positive smokers.

Update on randomized trials

Larynx preservation trials

Renè Leemans (VU University Medical Center, Amsterdam, The Netherlands) reported on behalf of the EORTC Head and Neck Cancer Cooperative Group on the 10-year results of the two EORTC larynx preservation trials EORTC 24851 and EORTC 24954.

In the first trial, patients with previously untreated laryngeal and hypopharyngeal squamous cell carcinoma (SCC) eligible for total laryngectomy (TL) were randomized to conventional treatment by TL plus radiotherapy (RT) or the experimental arm with induction chemotherapy (ICT) consisting of cisplatin and 5-fluorouracil (5-FU; PF) followed by RT in complete responders or TL plus RT in the others. In the experimental arm, the 5- and 10-year survival rates with a functional preserved larynx were 22 and 9%, respectively. There was no difference in terms of survival and disease control between the two arms. The conclusion of this trial was that ICT-based larynx preservation was also feasible for hypopharyngeal cancer.

The second trial compared ICT-based larynx preservation with an alternating schedule of chemoradiation (PF at weeks 1, 4, 7 and 10 and 20 Gy RT on weeks 2–3, 5–6 and 8–9) in 450 patients with laryngeal and hypopharyngeal SCC. The 5- and 10-year survival rates with a functional preserved larynx were 31 and 19% in the ICT arm and 35 and 18% in the alternating arm, respectively. There was no significant difference in terms of survival, disease control and larynx preservation. The conclusion of the trial was that both protocols were feasible for larynx preservation.

Arlene Forastière (Johns Hopkins University School of Medicine, MD, USA) summarized the long-term results of Intergroup RTOG 91-11: a comparison of three treatments to preserve the larynx. Patients with stage III or IV laryngeal SCC (excluding T1 and high-volume T4) were randomized to induction PF followed by RT in partial/complete responders and laryngectomy in nonresponders or concomitant cisplatin/RT (P/RT) or RT alone. From 1992 to 2000, 547 patients were enrolled. Median follow-up was 10.8 years (range: 0.7–17). Laryngectomy free survival was similar for induction and concomitant treatments and significantly worse for RT alone. Locoregional control and larynx preservation were significantly superior for concomitant treatment compared with induction or RT alone. There were no significant differences in OS. It was hypothesized that the higher number of deaths not due to treatment or cancer in the concomitant group might explain the absence of a survival advantage.

Yoann Pointreau (Centre Jean Bernard, Clinique Victor Hugo at Le Mans, France) gave an update on the GORTEC 2000–2001 and TREMPLIN trial. Inclusions for both trials were laryngeal and hypopharyngeal SCC stage III or IV. The GORTEC 2000–2001 trial compared ICT with PF versus ICT with docetaxel and PF (TPF). Only responders were randomized for RCT. The 3-year larynx preservation rate in 213 patients was significantly superior in the TPF arm (70.3 vs 57.5%; p = 0.03). Functional assessment with voice handicap index and quality of life questionnaires in a subset of patients showed good function with regard to voice and swallowing.

In the TREMPLIN trial, all patients received ICT with TPF and were then randomized to either RT with concomitant cisplatin or RT with concomitant cetuximab. The trial enrolled 153 patients, and 116 were randomized. The intent-to-treat analysis revealed no significant differences in laryngeal preservation at 3 months (95 vs 93%), larynx function preservation (87 vs 82%) and OS at 18 months (92 vs 89%). Acute and late toxicity was more common in the concomitant cisplatin arm.

Trials on EGF receptor targeting & biological modifiers

Jan Vermorken (University Hospital, Antwerp, Belgium) reported on the EXTREME and the SPECTRUM trials. Both trials were in recurrent/metastatic HNSCC and both trials tested the addition of an anti-EGF receptor monoclonal antibody to platinum/5-FU. In the EXTREME trial, the chimeric IgG1 antibody cetuximab was used, and in SPECTRUM, the fully human IgG2 antibody panitumumab was used. Only the EXTREME trial was able to demonstrate a significant survival benefit [4]. Cohorts of both studies were retrospectively analyzed for HPV. In the EXTREME trial, 10.9% of tumors were HPV positive, while in the SPECTRUM trial, 22.3% of tumors were HPV positive. Patients with HPV-positive tumors seemed to have a better outcome in both trials, and in the SPECTRUM trial, the HPV-negative patients seemed to benefit most from the addition of panitumumab. The presenter honestly remarked that results have to be interpreted with caution, as the analysis in both prospective trials was performed retrospectively. In conclusion, in the recurrent/metastastic situation, the role of HPV has still to be defined by further studies.

Jordi Giralt (Hospital Universitario Valld’Hebron, Barcelona, Spain) presented the CONCERT trial. Patients with stage III, IVA or IVB HNSCC of all sites (excluding nasopharynx) were randomized 2:3 to either open-label concomitant cisplatin RT versus concomitant cisplatin RT with the addition of panitumumab (CONCERT1) or concomitant cisplatin RT versus concomitant panitumumab RT (CONCERT2).

In CONCERT1, 150 patients were enrolled. The 2-year local regional control (LRC) rate was not significantly different, with 61% for chemoradiotherapy (CRT) and 68% for panitumumab plus chemoradiotherapy. The addition on panitumunab to cisplatin-based CRT did not show an increase in efficacy, but was associated with an increase in toxicity.

In CONCERT2, 151 patients were included. The 2-year LRC rate was 51% for PaRT and 61% for CRT (not significant). There was also a trend in progression-free survival (PFS) and OS for better outcome in the CRT arm.

Trials with biomarker analysis

Johannes Kaanders (Radboud University Medical Center, Nijmegen, The Netherlands) presented a talk on biomarkers of proliferation and hypoxia entitled ‘How well can they predict response to ARCON’. It is well known that tumor cell repopulation during radiation and hypoxia of tumor tissue and environment is an important mechanism of radiation resistance in HNSCCs. The aim of ARCON was to counteract both mechanisms by the application of accelerated RT in combination with the inhalation of carbogen and administration of nicotinamide. The Dutch ARCON trial enrolled 345 patients with advanced stage larynx SCC, who were randomized to ARCON or accelerated RT alone. LRC rate was reported to be high in both arms with a significant improvement of regional control in the ARCON arm, but exclusively in hypoxic tumors. Subsequent analysis of proliferation and hypoxia-related biomarkers by immunohistochemistry (EGF receptor expression, CA-IX and pAKT) revealed conflicting results. Stratification of patients before treatment according to biomarker profiles would be desirable for individualized treatment. The complexity of tumor biology and its dynamic interaction with the microenvironment makes this goal difficult to reach.

Kian Ang (MD Anderson Cancer Center, Houston, TX, USA) reported on the update of the RTOG 0522 trial, a randomized Phase III trial of concurrent accelerated RT and cisplatin versus concurrent accelerated RT, cisplatin and cetuximab for stage III and IV HNSCC. There was no significant difference in PFS, locoregional failure and distant metastases between the two arms. The addition of cetuximab to cisplatin-based concurrent RT does not increase the efficacy of treatment.

Trials on optimization of radiotherapy & radiochemotherapy

Volker Budach (Charite University in Berlin, Germany) presented the results of the ARO 04-01 trial of concurrent 72 Gy HART/cisplatin/5-FU versus HART/mitomycin/5-FU in advanced HNSCCs. Inclusion criteria were stage IV, SCC of the oropharynx and hypopharynx and Karnovsky performance status of >80%. The hyperfractioned RT schedule has been previously described [5]. Cisplatin was applied for six weekly cycles and mitomycin for two cycles. Median follow-up was 54 months for both arms. There was a difference in metastasis free survival in favor of cisplatin, which just reached statistical significance, but no difference in terms of OS, PFS, local control, RC and LRC. Eight parameters (dysphagia, mucositis, dermatitis, xerostomia, pain, weight, leukopenia and creatinine) were assessed for acute toxicity. Only creatinine level reached a statistical significant difference with elevated levels after cisplatin. Late toxicity was assessed with nine parameters (dysphagia, xerostomia, edema, osteoradionecrosis, plexopathia, Lhermitte’s syndrome, tracheostomia and PEG) without revealing a significant difference between the two arms.

Bjorn Zackrisson (University of Umea, Sweden) reported on the 5-year results of the ARTSCAN randomized trial on accelerated RT. Between 1998 and 2006, the Swedish ARTSCAN group performed a RCT in 750 patients with HNSCC of all sites (excluding T1/2 glottis). Patients were randomized to RT with conventional fractionation (2 Gy/day, 5 days/week for 7 weeks, total dose 68 Gy) versus accelerated fractionation (AF; 1.1 Gy+ 2 Gy/day, 5 days/week for 7 weeks, total dose 68 Gy). The 2-year results were previously published [6]. The 5-year results confirm the 2-year results with no difference in terms of OS and LRC between the two arms. AF showed a significant increase in acute toxicity, but not in late toxicity. In this study, an AF schedule was not superior to conventional fractionation.

New management approaches

Transoral surgery for OPSCC

In a debate in favor of and against transoral robotic surgery (TORS) as the standard of care in surgical resection of OPSCC, Christian Simon (University Hospital in Lausanne, Switzerland) voted for the motion and Terry Jones (Liverpool, UK) was supposed to vote against the motion. Simon outlined transoral laser microsurgery (TLM) and TORS as two possibilities of transoral approaches. The differences between the two techniques are the mode of visualization (microscope vs 3D endoscope with various angles), strategy of resection (piece meal vs en bloc) and the number of hands in the field (two vs four). According to Simon, these differences are in favor of robotic surgery; but according to the literature, both techniques provide equivalent results with respect to oncological and functional outcome. The NCCN guidelines allow both approaches, surgery and radiotherapy, for the treatment of early-stage OPSCC, and the techniques are considered equally effective. In the USA, two Phase II studies aiming to provide additional data on TORS/TLM are currently underway. The ultimate goal would be a comparative Phase III study of RT versus transoral surgery for early OPSCC. Jones was also emphasizing the advantages of transoral surgical resection with respect to late morbidity in comparison with primary RT in early-tumor stages. He presented data showing that TLM followed by adjuvant RT confers at least as good a survival outcome for HPV-positive and HPV-negative OPSCC as CRT does for HPV-positive OPSCC but with marked improvements in swallowing outcome.

Sentinel node biopsy for early oral SCC

The role of sentinel node biopsy (SNB) in the early stages of oral SCC was presented by Sandro J Stoeckli (St Gallen, Switzerland). Since the appearance of lymph node metastases still represents the most important adverse prognostic factors in HNSCC, accurate staging is crucial. The management of the clinically and radiologically negative neck in patients with T1/T2 oral SCC is still a matter of debate, though most centers favor elective neck dissection. As only approximately 30% of patients harbor occult disease in the neck, most of the patients have to undergo elective neck dissection with no benefit. The SNB concept has been validated and successfully implemented in different centers around the world [7]. In the largest prospective single-institution cohort in Switzerland, SNB was highly accurate in detecting the sentinel lymph nodes (SNs) with a detection rate of 99%, which was comparable with other studies [8]. As in previous studies, the true status of the neck was most accurately determined by thorough histopathologic examination of the small number of SNs with routine application of step serial sectioning and immunohistochemistry. With the application of SNB in 38% of clinically N0, occult disease in form of micrometastases, macrometastases and isolated tumor cells was found. The negative predictive value for a negative SNB achieved 96%. The ultimate regional control rate of 96% for SN-negative patients underlines the accuracy and oncological safety of SNB. In multivariate analysis, extracapsular spread and SNB positivity achieved adverse prognostic significance for OS, disease free survival and disease-specific survival. SNB allows for an individualized and minimally invasive treatment of the neck without compromising the outcome. Therefore, this concept has the potential to become the new standard of care in the future.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.