Head and Neck Department
Centre Oscar Lambret
Around 500,000 new cancers of the oral cavity, larynx and pharynx are diagnosed each year worldwide. Two-thirds of them are diagnosed at an advanced stage. As most of these cancers are squamous cell carcinoma induced by tobacco consumption and alcohol abuse, half the patients also present co-morbidities.
Early stages may be controlled in more than 85% of the cases by single modality treatment (either surgery or irradiation). The most frequent failure is the appearance of metachronous cancers. For these early diseases there is no indication for chemotherapy.
For advanced diseases combined therapies are required. Despite heavy therapies (surgery and postoperative irradiation or definitive irradiation with surgery in reserve for salvage if needed) the global outcome is disappointing, with a five-year survival of around 30%. In addition, when surgery is performed it often consists of quite mutilating procedures. Although modern reconstructive surgery may in selected cases reduce the cosmetic and functional sequels, some mutilations, such as total ablation of the larynx, remain a real concern for quality of life.
For a long period chemotherapy played a marginal role in HNSCC management: it was mainly used for recurrent/metastatic diseases that were not candidates for further surgery or radiotherapy. The appearance of the cisplatin-5 fluorouracil (PF) regimen in the early 1980s had a tremendous impact as it provided impressive response rates in previously untreated patients while chemosensitivity correlated with subsequent radiosensitivity. Chemotherapy was therefore widely integrated in advanced HNSCC treatments with curative intent. A large meta-analysis assessed the five-year survival benefit of chemotherapy added to conventional therapy when compared with this conventional therapy alone. It appeared that either adjuvant or ICT had no significant impact.
On the contrary, CRT provided a significant 8% benefit. However when ICT consisted of PF, there was a significant 5% benefit. ICT after a long period of widespread use was almost totally abandoned in favor of CRT. Its remaining place was in organ preservation protocols, in particular in larynx preservation.
CRT either as the first approach or in the postoperative setting has provided indisputably improved results.[3,5,6]
In parallel, significant improvements were also achieved in surgery (in particular in reconstructive surgery), in definitive radiotherapy with altered fractionation, while targeted therapies appeared promising in a randomised clinical trial. Docetaxel has been assessed in clinical research for advanced HNSCC with interesting results. Large phase III trials with docetaxel have been conducted and published recently.[10–12] Their results definitely reopened the discussion of the place of ICT.
Chemotherapy appeared to be a logical way to improve the outcome of advanced HNSCC either for treatment intensification or for organ preservation. If ICT had no real impact on survival (except for PF ICT), it had a definite role in larynx preservation.4 In clinical trials CRT either as the first approach or in the postoperative setting has provided indisputably improved results.[3,5,6]
But the price to be paid was a noteworthy acute and late toxicity. Acute toxicity (mucositis in particular) is a real concern for HNSCC patients with a frequent poor performance status. Late toxicity (sclerosis, fibrosis in particular) may compromise subsequent surgery or the function of preserved organ.
As a result, in daily practice CRT must be restricted to fit patients and its indications should be balanced when surgery is considered as a possible option in the overall treatment protocol.
Definitive irradiation with either hyperfractionated or accelerated schedules is able, in particular in younger patients and for advanced stages, to yield significantly better survival when compared with conventional radiation therapy. But again the price to be paid is an increased toxicity in addition to possible logistic concerns when these altered fractionations are used on a large scale.
Targeted therapy added to radiation therapy achieved significantly better locoregional control and survival without increasing acute radiation-induced toxicity in one randomised trial8 and is currently being assessed in other phase III trials.
As on one hand the overall toxicity of ICT followed by radiotherapy is certainly lower that with CRT and, on the other hand, new drugs such as taxanes appeared effective in clinical trials, ICT including docetaxel was a logical new step.
The EORTC24971/TAX 323 trial10 compared, in 358 previously untreated and unresectable cases of advanced HNSCC, four cycles of ICT consisting of PF in 181 patients versus TPF in 177 patients prior to subsequent irradiation.
Treatment with TPF resulted in a reduction of 28% in the risk of disease progression or death as compared with PF (p = 0.007) and an absolute increase in three-year survival of 10.9%, while TPF was better tolerated than PF.
The TAX 324 phase III trial11 compared, in 501 patients with previously untreated advanced HNSCC considered unresectable or candidate for organ preservation, three cycles of PF in 246 patients versus TPF in 255 patients prior to CRT consisting of radiotherapy and carboplatin.
Treatment with TPF resulted in a reduction of 30% in the risk of death (p = 0.006) and a 14% increase in three-year survival, again with a better tolerance to treatment.
The GORTEC 2000.0112 phase III trial compared, in 220 patients with previously untreated larynx or hypopharynx cancer amenable to total laryngectomy, three cycles of PF in 108 patients versus TPF in 112 patients prior to irradiation in case of objective response or to total laryngectomy in the other cases. In preliminary results TPF provided a significant 22% improvement in objective response rate and larynx preservation and was better tolerated.
Clearly, TPF ICT has been compared in three randomised trials to be the only ICT regimen (PF) that provided a significant survival benefit in the MACH-NC study, even if lower than the benefit achieved with CRT. These three trials involved different kinds of diseases: unresectable, either resectable or not or resectable.
Even if addressing different questions, these three trials achieved similar conclusions.
Clearly induction chemotherapy must be reconsidered as a valid option for the treatment of advanced HNCCC. When ICT is indicated, then TPF should be the preferred regimen.
Professor Lefebvre is a member of the advisory boards and lecturer for Sanofi-Aventis and Merck Serono.
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2. Ensley JF, Jacobs JR, Weaver A, et al. Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancer of the head and neck. Cancer 1984;54:811-4.
3. Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355:949-55.
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7. Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368:843-54.
8. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567-78.
9. Posner MR, Lefebvre JL. Docetaxel induction therapy in locally advanced squamous cell carcinoma of the head and neck. Br J Cancer 2003;88:11-7.
10. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:11-20.
11. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and flurouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:21-31.
12. Calais G, Pointreau Y, Alfonsi M, et al. Randomized phase III trial comparing induction chemotherapy using cisplatin (P) and fluorouracil (F) with or without docetaxel (T) for organ preservation in hypopharynx and larynx cancer. Preliminary results of GORTEC 2000-01. ASCO meeting 2006, Atlanta: abstract 5506.