Author:

Anna Wagstaff

Minimising the damage from cancer surgery is important in treating cancers of the head and neck, not least because of the role this part of the anatomy plays in speaking and swallowing.

The discovery in 1980 that platinum-based drugs were effective in head and neck cancers, and that sensitivity to cisplatin combination chemotherapy regimens predicted for sensitivity to radiation, opened up new possibilities for avoiding surgery in many patients with locally advanced laryngeal or hypopharyngeal cancers. Important progress towards this goal was made by researchers on both sides of the Atlantic. Key contributions from Europe include the first trial to show the feasibility of preserving a functional larynx in patients with locally advanced cancers of the hypopharynx by using induction chemotherapy followed by definitive radiotherapy as an alternative to surgery with postoperative radiotherapy. European researchers also did some of the earliest work showing the risks and benefits of chemoradiation – adding chemotherapy to radiation therapy using alternating or concurrent schedules – versus radiation therapy alone in advanced non-resectable cancers of the head and neck. This work was followed up by efforts to establish the best way to combine the two treatment modalities in a way that balanced survival benefit with the impact of toxicity on function and quality of life, including a trial that compared the risks and benefits of sequential versus alternating chemo and radiotherapy in patients undergoing larynx preserving treatment for locally advanced, resectable, laryngeal and hypopharyngeal cancers. The subsequent introduction of targeted treatments, and later immunotherapies, reduced the toxicities of non-surgical treatments in significant ways, but so far (2024) have not played an important role in larynx preservation in daily practice.

At the organisational level, it was a European initiative that brought together research groups from Europe and the US at a 2009 international consensus conference to develop guidelines for the design of future trials, including selection criteria of study populations, functional assessments, primary and secondary endpoints, and biomarker studies. That conference sent an important signal to oncologists that discussions about the treatment options of patients with head and neck cancers had to involve at least the three main modalities of surgery, radiotherapy and medical oncology, and helped ensure future trials would build on existing evidence and ask questions that were meaningful to the outcomes that matter to patients.

History

The 1970s saw rapid progress in introducing chemotherapy to the treatment of solid tumours. Head and neck cancers – of which the great majority are squamous cell carcinomas – seemed stubbornly resistant to the growing armoury of agents. Remembering those days, Jean-Louis Lefebvre, a surgeon at the Centre Oscar Lambret in Lille, France, who would go on to lead the first larynx sparing clinical trial for patients with cancer of the hypopharynx, said, “We were the ‘poor parent’ of oncology, because we had surgery, we had radiotherapy, but we didn’t really have effective chemotherapy. The most recent drug we had at that time was bleomycin, but it didn’t make much difference.”

The big change came in 1980, with a presentation at ASCO (the American Society of Clinical Oncology) of data showing that adding cisplatin – an oncology drug developed in the 1970s to treat testicular and ovarian cancers – to a combination chemotherapy regimen made a significant difference to response rates in head and neck tumours. The study, which showed a 67% response rate in a series of 28 patients treated for advanced head and neck squamous cell cancers, had been conducted by a team at Wayne State University, in Detroit Michigan, led by medical oncologist Muhyi Al-Sarraf.

“They showed that, when they used cisplatin, vincristine and bleomycin together, there was a significant tumour response. We had never seen that before,” Lefebvre recalled.

This was followed at the 1982 ASCO conference with a second presentation by Al-Sarraf’s group (the full results were published in 1984), which showed that response to the cisplatin combination regimen strongly predicted for response to subsequent radiotherapy.

“That was a bit of a revolution,” said Lefebvre. “We said, ‘Finally we have a chemotherapy that is effective on the tumour, because in certain cases you see important tumour shrinkage, and there were even some cases where you saw almost nothing left. And, in addition, there seems to be a correlation between the chemo-sensitivity and subsequent radiosensitivity.’”

Though the studies had been done primarily with a view to improving survival for people with incurable head and neck cancers, said Lefebvre, the potential for using the strategy in potentially curable locally advanced head and neck patients, as an alternative to laryngectomy, was quickly recognised in certain quarters on both sides of the Atlantic. “This was the big project, to preserve the larynx.”

In the US, the Veterans Affairs Medical Center set up a Laryngeal Cancer Study Group to lead on this work. In Europe, the clinical research was primarily organised by the Head and Neck group of the European Organisation for Research and Treatment of Cancer (EORTC), which was chaired by Lefebvre. In 1990, recruitment started to an EORTC trial investigating the equivalence of larynx preservation in treating previously untreated operable squamous cell cancers of the hypopharynx, which had traditionally been managed with surgery, usually involving removal of the larynx.

The trial, which was the first larynx preservation trial conducted by the EORTC Head and Neck group, randomised patients to conventional treatment – total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation – or to the experimental treatment – induction chemotherapy (cisplatin + 5FU), followed by definitive radiotherapy in cases where a response to chemotherapy was seen, or to surgery in the absence of such a response. Salvage surgery was performed when patients relapsed after chemotherapy and irradiation.

The preliminary results were presented at ASCO in 1994, and were published in the Journal of the National Cancer Institute in 1996. With a median duration of survival of 25 months in the immediate-surgery arm and 44 months in the induction-chemotherapy arm, the results showed that the experimental strategy did not jeopardise survival, which was the primary endpoint. While treatment failures at local, regional, and second primary sites occurred at approximately the same frequencies in the two arms, failures at distant sites were less frequent in the induction-chemotherapy arm.

The trial also showed positive results for the secondary endpoint of functional larynx preservation, with more than 40% of patients treated in the experimental arm estimated to retain a functional larynx three years after treatment, dropping to 35% at five years. On the basis of these study results, EORTC adopted induction chemotherapy followed by radiation as the new standard treatment to be used as the control arm of future phase III larynx preservation trials.

The EORTC trial results were closely in line with the results of a trial coordinated by the US Veterans Affairs group, which had randomised patients with previously untreated advanced squamous carcinoma of the larynx to a very similar experimental arm of induction chemotherapy followed, where appropriate, with definitive radiotherapy. Initiated in 1985, the results of this trial, published in 1991, showed no difference between the two arms for two-year survival, with 64% of patients in the experimental arm retaining their larynxes (though no data was published about how well those larynxes functioned).

The decision to focus the EORTC trial on the cancers of the hypopharynx was partly to avoid duplicating a trial already underway in the US, but also because France, in particular, had a strong interest, experience and expertise in these cancers due to high incidence rates, said Lefebvre. “We had many hypopharyngeal tumours in France, probably because we have a lot of head and neck cancers – we have a lot of smokers but also a lot of drinkers, which are risk factors for hypopharyngeal cancer. The Americans did not have as many.”

US surgeons, he said, were hesitant to try using the induction-chemo strategy in this group of patients, because they worried about doing salvage surgery in the event of a recurrence. “Salvage surgery of the larynx is easier than salvage surgery of the hypopharynx; there is a lot more mucus, and there is more risk of disunion.”

Despite their greater familiarity, however, and despite the encouraging results coming out of the US, Lefebvre struggled at first to convince his fellow head and neck surgeons to join a trial that many felt could jeopardise patient’s chances by randomising them to a non-surgical treatment. The trial began with only around 100 patients enrolled from two hospitals – Lefebvre’s own hospital in Lille, and the Gustave Roussy in the outskirts of Paris. But “as word spread” others joined, with patients ultimately being enrolled at six French centres, as well as two centres in Italy and one each in Belgium, Netherlands and Switzerland.

Optimising the protocol

The US and European larynx preservation trials changed the prospects for many patients with squamous cancers of the larynx and hypopharynx. They cemented the role of medical oncology as an essential component of multidisciplinary teams treating this set of patients. They also opened up many questions about how to combine the two modalities to greatest effect – questions that were taken up on both sides of the Atlantic, with Europe again making a distinctive contribution. High on the list of questions was whether chemotherapy and radiotherapy would be best given sequentially – as they were in the two larynx preservation trials – or concomitantly – with all the toxicity issues that could be involved – or alternately.

Alternating chemo and radiotherapy

A study initiated in 1989 by the National Institute of Cancer Research in Genova, Italy, compared the standard of care for patients with unresectable squamous-cell head and neck cancers – which was radiotherapy alone – with a novel protocol that alternated four cycles of cisplatin followed by 5FU with three two-week courses of radiotherapy.

The results, published in 1992, showed that alternating chemo and radiotherapy in this group of patients increased median survival from 11.7 to 16.5 months, and increased three-year survival from 23% to 41%. It also showed only a very minor increase in instances of severe mucositis, from 18% with radiotherapy alone to 19% with the alternating protocol.

That experimental protocol was subsequently adopted by the EORTC as an experimental arm to compare with the induction chemotherapy followed (for responders) with radiotherapy, which the EORTC had recently adopted as the standard of care to be used in trials for patients with resectable advanced squamous cells cancers of the larynx or hypopharynx. The phase III trial initiated in 1996, with a primary endpoint of “survival with a functioning larynx”, was carried out as a collaboration between the EORTC’s Head and Neck Group and its Radiation Oncology Group, and was led by Lefebvre. The results, presented at ASCO in 2007, and published in the Journal of the National Cancer Institute 2009, were disappointing; they found that using alternating chemotherapy and radiotherapy in place of sequential chemotherapy and radiotherapy made no difference in terms of larynx preservation, progression free interval, overall survival or acute or late toxic effects.

Concomitant chemoradiotherapy protocols

Two European trials comparing concomitant chemoradiotherapy with radiotherapy alone were presented together at the 2001 meeting of the American Society of Therapeutic Radiology and Oncology (ASTRO). One was run by the French Head and Neck Oncology/Radiotherapy research group GORTEC, led by Gilles Calais, from the Clinique d'Oncologie et de Radiothérapie, at the University Hospital in Tours. This looked at the impact on disease-free survival of adding concurrent chemotherapy to radiotherapy in treating locally advanced oropharyngeal squamous cell carcinoma. Started in 1994, it had already presented preliminary results at the 1998 ASTRO meeting, and had been published in full in the Journal of the National Cancer Institute in 1999.

The other was an EORTC trial, led by Jacques Bernier, a radiation oncologist in Bellinzona in Switzerland, who chaired the EORTC Head & Neck group from 2000 to 2006, for which full results were published in 2004 in the New England Journal of Medicine. This study looked at what concomitant chemoradiation could do in the postoperative setting to improve disease free survival, overall survival, and local control versus radiotherapy alone for patients with locally advanced squamous cell head and neck cancers.

Both trials used similar radiation therapy protocols, with the concomitant chemotherapy arms adding three cycles of carboplatin plus 5FU (in the GORTEC trial) or high-dose cisplatin (in the postoperative EORTC trial) on days 1, 22 and 43.

While the trial results are not directly comparable, as one was in previously untreated patients and the other in the post-operative setting, both reported significant improvement in locoregional control and survival endpoints: GORTEC 3-year disease-free survival was 42% vs 20% (P=0.04) and 3-year overall survival 51% vs 31% (P=0.02); EORTC 5-year progression free survival was 47% vs 36% (P=0.04) and 5-year overall survival 53% vs 40% (P=0.02), notwithstanding the fact that compliance with chemotherapy decreased with the number of courses delivered, with only half of the patients receiving the full protocol. Both studies also reported significantly higher mucosal toxicity in the concomitant therapy arms (GORTEC 71% vs 39%, EORTC: 41% vs 21%).

Both concluded that there was a significant advantage to concomitant chemoradiotherapy compared with radiotherapy alone in managing their respective populations of patients with advanced head and neck cancers.

Publication of the results of a US study, in 2003, added further evidence. This study, conducted by the US Radiation Therapy Oncology Group and Head and Neck Intergroup, and led by Arlene Forastiere of the Sidney Kimmel Cancer Center in Baltimore, focused specifically on larynx preservation in patients with advanced squamous cell cancer of the larynx. It compared three treatment options: the first was induction cisplatin plus infusional 5-FU followed by radiotherapy (the previously established standard of care), the second was concurrent chemotherapy (with high-dose cisplatin), and the third was radiotherapy alone.

That study, which had a primary endpoint of ‘preservation of the larynx’, found that concurrent chemoradiation significantly improved rates of larynx preservation as well as locoregional control compared with the alternative arms; and both arms with chemotherapy (concomitant or sequential) improved disease-free survival. However, overall survival rates were similar in the three groups. Furthermore, the mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatment options. The 10-years update of this study confirmed the beneficial data of concurrent chemoradiotherapy versus the induction arm and the arm with radiotherapy alone with respect to locoregional control and larynx preservation. However, deaths not attributed to larynx cancer or treatment were higher with concomitant chemoradiotherapy – possibly indicating late toxicity.

Adding a taxane

In the meantime, taxanes had arrived on the scene, and a new set of questions had been opening up around the possible benefit of including them in the combination chemotherapy regimen for head and neck cancers. The first trial to evaluate the efficacy and toxicity of adding a taxane (paclitaxel) to the standard induction chemotherapy of cisplatin and 5FU (so-called PPF) in patients with locally advanced squamous cell carcinoma of the head and neck was a Spanish initiative, which was led by Riccardo Hitt at Madrid’s Hospital Universitario 12 de Octubre, and involved 12 institutions in 11 cities across Spain. The efficacy and toxicity results of this extended phase II, which were reported in 2002, prompted the start of a phase III trial, in which the PPF regimen was compared with the standard PF induction chemotherapy (full paper published in 2005). The trial, comprising 382 eligible patients, showed that adding paclitaxel induced a significantly higher complete response rate and was better tolerated than the standard PF regimen. Median time to treatment failure was significantly longer, with a trend to better overall survival (43 vs 37 months).

The data on paclitaxel were promising, but some laboratory data suggested that docetaxel on a concentration basis was more cytotoxic than paclitaxel; moreover, it showed activity in cell lines less sensitive to cisplatin; and preclinical models showed potential synergy between docetaxel and cisplatin and 5-FU. Several European and American investigators studied the combination of docetaxel and cisplatin, and the combination of docetaxel and 5-FU, and ultimately also the so-called TPF regimen (docetaxel, cisplatin, 5-FU). In a phase I–II study, a Belgian/Dutch team led by Jan Vermorken, head of the Medical Oncology Department at the Antwerp University Hospital, defined a TPF dose schedule that seemed feasible and active in the European setting.

The survival benefit from adding docetaxel was confirmed in two further trials, both of which were major collaborations, one led by the EORTC – 24971/TAX 323 – and the other by the Dana Farber Cancer Center in Boston– TAX 324. The results of the two trials were published back to back in 2007 in the New England Journal of Medicine.

The EORTC trial, was led by Vermorken (who had taken over as chair of the EORTC Head and Neck Cancer Group in 2006), and was based on his earlier phase I–II TPF feasibility study. That trial enrolled patients from 37 centres across 15 European countries.

The two studies focused on the survival benefits of adding docetaxel to induction chemotherapy with cisplatin+5FU in patients with advanced squamous cell head and neck cancers. In the EORTC study, which included patients with unresectable disease, responders to the induction chemotherapy (both arms) were then given radiotherapy as a single local therapy. Results, at a median follow up of 32.5 months, showed that adding docetaxel resulted in a significantly improved progression free survival (HR for disease progression or death in the docetaxel group, 0.72; P=0.007) and overall survival (27% reduction in the risk of death; P=0.02). The long-term analysis with a median follow-up of 8.6 years showed that both the progression-free survival (primary endpoint) and the overall survival remained significantly improved.

One remarkable aspect of this European TPF regimen, remembers Vermorken, was that, “despite a short period of more severe neutropenia after each cycle, overall the regimen was less toxic than the standard cisplatin/5FU regimen, with fewer grade 3/4 instances of thrombocytopenia, nausea, vomiting, stomatitis, and hearing loss, and it induced a better quality of life.”

In the US study, which included patients with both resectable and unresectable disease, responders to induction therapy (both arms) went on to receive a more aggressive definitive treatment, using weekly low-dose carboplatin during radiotherapy. Results at three years showed that adding docetaxel significantly improved median overall survival, from 30 months to 71 months (P=0.006).

Again, at long-term follow-up of this study (median follow-up 72.2 months) both overall survival and progression-free survival remained superior with addition of docetaxel to the PF regimen. Both trials clearly indicated that patients who are candidates for induction chemotherapy should be treated with TPF.

These data from randomised studies showing superiority of TPF over PF in patients with variable locally advanced disease settings stimulated GORTEC to start a trial to compare the efficacy and safety of TPF over PF for larynx preservation in patients with untreated stage III or IV larynx or hypopharynx cancer. The study (GORTEC 2000-01) compared three cycles of TPF with three cycles of PF as induction chemotherapy, followed by radiotherapy for responders. The long-term follow-up results (median follow-up 105 months) confirmed that induction chemotherapy with TPF increased larynx preservation and larynx dysfunction-free survival.

The positive results from these trials led to a revival of induction chemotherapy in head and neck cancer, said Vermorken, and strongly influenced the direction of clinical research going forwards, not least in larynx preservation. Lessons learned, in particular from the long-term follow-up data of those trials, and from studies on integrating new treatment modalities such as immunotherapy, will be key to informing further advances in this area, he said.

Making sense of it all

In 2009 an Editorial was published in the Journal of the National Cancer Institute that tried to make sense of the totality of evidence around larynx preserving treatment strategies. The Editorial accompanied publication, in the same issue, of the disappointing results of the EORTC trial looking at the risks and benefits of alternating the administration of chemo and radiotherapy – a protocol that had been chosen in the hope of achieving survival benefits while avoiding the additional toxicity of concomitant administration. The title of the Editorial was: ‘Less toxic larynx preservation: A need for common definitions and metrics’, and its first author was Arlene Forastiere, of the Sidney Kimmel Cancer Center, who had led the three-arm US trial that showed the superior results for larynx preservation rate and rate of loco-regional control from using concurrent chemoradiotherapy. Though not its primary intention, the article throws an interesting light on some differences in perspectives between the European and US researchers regarding the balance between length of life and quality of life, and how that should be reflected in the choice of protocols and endpoints.

While teams on both sides of the Atlantic were looking for “more effective and less toxic approaches,” it was the US that opted to trial the more aggressive protocol giving chemotherapy and radiotherapy at the same time, while Europe went for the slightly less harsh approach of sequential administration. As Forastiere pointed out, in this instance it turned out that the more aggressive protocol was required to get any survival benefit. In an interview conducted at the end of 2010, however, Vermorken queried where the long-term adverse effects of the systemic treatment might not outweigh the benefits of preserving the larynx in some patients. “Now, as we’re seeing the effectiveness of this grow, we’re also beginning to understand that the late side-effects of these non-surgical approaches might strongly influence quality of life and might even be killing some.”

In the same article, Forastiere questioned the EORTC choice of ‘survival with a functional larynx’ as an endpoint, arguing that “it weighs death and the loss of a larynx as equally bad outcomes.” On this particular argument, it was the European approach that carried the consensus. At an international conference convened the following month to develop guidelines for the conduct of phase III clinical trials of larynx preservation in patients with local advanced laryngeal and hypopharyngeal cancer, a gathering of all researchers who had addressed this topic agreed that “the primary endpoint should capture survival and function.”

That conference, held over two days in New York, developed consensus guidelines to align approaches to future phase III clinical trials of larynx preservation in patients with local advanced laryngeal and hypopharyngeal cancer, which were published in April 2009 simultaneously in Head and Neck and the ‘Red journal’ (International Journal of Radiation Oncology, Biology and Physics). In addition to adopting a new primary endpoint of ‘laryngo-oesophageal dysfunction free survival’, it characterised the target trial population and defined functional assessments of speech and swallow, and events to be recorded. It also addressed the issue of correlative biomarker studies.

The conference – co-chaired by Lefebvre from Lille and K Kian Ang from MD Anderson in Houston, Texas – was an important development in aligning future trials to maximise the conclusions that could be drawn from the emerging data. And although it was convened in New York, the key organiser was European, and he was perhaps uniquely placed to ensure an attendance from all the people who needed to be involved and committed to the exercise.

This was Jean-Louis Lefebvre, the French surgeon who had led the first larynx preservation trial for patients with cancers of the hypopharynx. From the earliest days of the larynx preservation story, he had taken a lead in not only helping develop the evidence, but also ensuring it that the ‘head and neck community’ – above all the surgeons – were on top of the latest developments and understood the implications for clinical decision making.

As he pointed out, while the emerging research pointed to the absolute requirement of adopting a multidisciplinary approach, the conferences where these studies were reported and discussed tended to be primarily for medical oncologists or radiation oncologists. “The first publications were presented at ASCO, clearly very few surgeons participate in ASCO – it is a meeting for medical oncologists and researchers, some radiotherapy and few surgeons. We needed other rooms to discuss with surgeons.”

To address this problem, Lefebvre had launched a European Head and Neck Society, which had multidisciplinarity built into the structure of its board. The inaugural meeting was in 2001, in his hometown of Lille. Head and Neck societies from across Europe were invited to attend – but on condition that their delegation included not just a surgeon, but also a medical oncologist and radiation therapist. “That was the challenge,” Lefebvre remembered, “To get them to speak together, to hear the results among themselves.”

The European Head and Neck Society encouraged national groups to affiliate – but again with the precondition that they adopt a similar multidisciplinary structure. “It could not be a surgical head and neck group, or a radiotherapy head and neck group – it had to be multidisciplinary. So, we were able to improve multidisciplinarity and get multidisciplinarity taken into everyday clinical practice.”

When it came to pulling together the New York meeting – co-organised with Kian Ang, a radiation oncologist at MD Anderson – Lefebvre adopted a similar tactic. “We brought together in New York all the structures that had done at least one trial on larynx preservation. And we said to them, ‘We invite you to send a surgeon, a radiotherapist and a medical oncologist. So, they all came together in New York.”

Arguably, Europe was better placed to challenge entrenched professional silos and longstanding practices, because at that time the tradition of organising at a European level was still relatively new, which provided a space for setting up something new, which could respond to the needs of the changing times. In the US, by contrast, two Head and Neck societies had existed since 1958, both entirely dominated by surgeons. In 1998 they agreed to merge to become the American Head and Neck Society, but it remains heavily dominated by surgeons.

Much of the credit for bringing the head and neck community together should also go to Lefebvre himself, who was an evangelist for multidisciplinarity, and understood that surgeons would need some convincing before they would concede an equal role in clinical decision making, particularly for medical oncologists. “In French we say, “prendre son bâton de pélerin”. It is like doing a pilgrimage. The pilgrim is the one who takes up his staff and walks the world to convince people of his beliefs. We had to do that, to explain a lot, educate a lot, convince a lot.”

His efforts were supported by another relative newcomer to the European scene, the European School of Oncology (ESO) – which ran regular courses introducing young oncologists to multidisciplinary approaches to cancer treatment. Lefebvre, together with medical oncologist Vermorken and radiation oncologist Bernier – all leaders of EORTC trials, and all with experience in leading the EORTC Head and Neck cancer Group – led the ESO courses on head and neck oncology during that whole period, helping ensure the new knowledge was rapidly applied to patient care throughout Europe, and stimulating younger generations of doctors to engage in research and innovation, teaching them about the new surgical techniques, latest technologies and novel medical treatment modalities.

Establishing the principles of that multidisciplinary approach continued to pay huge dividends as new treatments, such as EGFR inhibitors and immunotherapies were added to the head and neck armoury. It also opened the way to welcome a host of additional specialists to add their contribution to optimising the treatment and care of this groups of patients, who commonly present with significant comorbidities – cardiac, hepatic, pulmonary – and whose outcomes can be significantly improved with the assistance of good reconstruction, nursing care, dental care, nutritional advice, speech therapy, psychological counselling and more.

“So, we added each time more stuff thanks to multidisciplinarity,” recalled Lefebvre, who retired from his full-time post as head of the Head & Neck department at the Centre Oscar Lambret regional Comprehensive Cancer Centre in 2013, “which is the only way to make real progress in cancer.”