Lay Summary: Induction chemotherapy before chemoradiation is becoming standard for many types of head and neck cancer.
The role of chemotherapy and radiation for advanced head and neck cancer has evolved considerably over the last 20 years. The landmark Veterans Affairs’ (VA) laryngeal cancer study,1 initially published in 1991, provided the best initial evidence to support cisplatin-based, induction chemotherapy as part of a larynx preserving treatment approach. The VA investigators randomized patients with stage III or IV laryngeal cancer to primary surgery and postoperative radiation versus three cycles of induction chemotherapy followed by radiation. Laryngectomy was reserved for patients with a less than major response after two cycles of chemotherapy, suspected disease persistence after radiation, or relapse. The chemotherapy/radiation arm yielded survival rates comparable to those achieved with primary surgical management. Two thirds of surviving patients retained their larynx. The similarly designed European Organisation for Research and Treatment of Cancer (EORTC) larynx preservation study, which focused on patients with advanced cancer of the hypopharynx, further supported the principles of the VA trial. Induction chemotherapy followed by radiation with surgery reserved for salvage came to be considered a new standard treatment for patients with locally advanced cancer of the larynx. The standard approach now involves combined chemotherapy and radiation.
Subsequent studies, most prominently the Radiation Therapy Oncology Group (RTOG) study 91-11, which was undertaken in collaboration with the Head and Neck Intergroup and published in 2003, established the use of concurrent chemotherapy with radiation as the superior nonsurgical, larynx preservation strategy. The RTOG study demonstrated that patients with advanced laryngeal cancer receiving concurrent cisplatin and radiation had a better larynx preservation rate (84%) at a median follow-up of 3.8 years compared to that afforded either by radiation alone or by induction cisplatin/fluorouracil followed radiation (rates of 67% and 72%, respectively). This was confirmed by other studies.
Two large, randomized trials — the Veterans Affairs Laryngeal Cancer Study Group trial and a phase 3 trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) — have demonstrated the benefit of induction chemotherapy with PF (100 mg/m2 of cisplatin on day 1 and 1000 mg/m2 of 5-FU by continuous infusion on days 1-5) with respect to organ preservation. In these trials, overall survival rates were similar in patients receiving either induction PF chemotherapy and radiation or surgery and radiation therapy. In patients with more advanced unresectable tumors, PF induction therapy has been shown to produce long-term survival benefits, with overall survival times in a subset of inoperable patients receiving chemotherapy of 21% at 5 years and 16% at 10 years compared with 8% and 6%, respectively, in patients not receiving chemotherapy. In a phase 3 trial of neoadjuvant chemotherapy in patients with oropharyngeal cancer conducted by the French Groupe d’Etude des Tumeurs de la Tete et du Cou (GETTEC), the median overall survival time for patients with both resectable and unresectable tumors was 5.1 years when PF induction chemotherapy was followed by locoregional therapy vs 3.3 years for those who did not receive PF induction chemotherapy (P = .03).
Nonetheless, there have been strong and persistent undercurrents of interest in induction chemotherapy for patients with locoregionally advanced head and neck cancer. The standard neoadjuvant chemotherapy regimen has consisted of a platinum agent and 5-fluorouracil (5-FU), a regimen known as PF. More recently, the addition of a taxane such as docetaxel (or, less commonly, paclitaxel) to the PF regimen (a triple combination known as TPF) is emerging as a more effective and less toxic standard for induction chemotherapy. The potential for induction chemotherapy before concurrent treatment to improve survival, through patient selection or better disease control such as by reducing distant metastases, as well as to enhance larynx preservation while decreasing the morbidity of treatment, is of great interest. However, more data are needed before such sequential approaches, or as appears in this case, chemotherapy alone, can be promulgated as new treatment standards. The VA guidelines state: “Treatment options for stage III and IV (laryngela) patients include surgery plus postoperative radiation and induction chemotherapy followed by radiation”.
There are five large studies ongoing. The DeCIDE trial — Docetaxel Based Chemotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer — a phase 3 trial sponsored by the University of Chicago, is currently recruiting patients with an expected total enrollment of 400. The trial’s primary objective is to determine the effect on overall survival when induction chemotherapy is administered prior to chemoradiotherapy in patients with nodal stage N2 or N3 head and neck cancer. The Paradigm study, a randomized phase 3 trial, is under way internationally, led by the Dana-Farber Cancer Institute. The trial is comparing sequential therapy with TPF/chemoradiation vs cisplatin-based chemoradiotherapy with accelerated concomitant boost radiotherapy for locally advanced squamous cell cancer of the head and neck. Two European randomized trials comparing a sequential treatment approach including TPF induction chemotherapy and chemoradiotherapy vs standard chemoradiotherapy alone for the treatment of head and neck cancer are in progress, and data are anticipated within 2 years. There is also UC 13362B that includes hydroxyurea.
Long-term follow-up data from the TAX 324 clinical trial released in 2011 showed that adding docetaxel to standard cisplatin plus fluorouracil induction chemotherapy (TPF) reduced the risk for death among patients with head and neck cancer by 26% during a 6-year period.
All of these trials likely will provide definitive information about the role of neoadjuvant chemotherapy in the treatment of head and neck cancer and may finally end the long-standing debate.
NCCN recommends both options, depending on the cancer location(Head and Neck, CHEM-A, 1-3). It recommends the TPF regimen for recurrent, unresectable or metastatic disease.
Postop chemoradiation is sometimes warranted because of extracapsular extension and other factors. Postoperative chemo-radiation with cisplatin in such situations is indicated as per the NCCN guidelines on p. 25.
J. H. Lorch et al, Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trialThe Lancet Oncology, Volume 12, Issue 2
, Pages 153 – 159, February 2011
Pignon JP, Ie Maitre A, Bourhis J, MACH-NC Collaborative Group: Meta-analyses of Chemotherapy in Head and Neck Cancer (MACH-NC). Int J Radiat Oncol Biol Phys 2007, 69(2 suppl):S112-114.
Hoebers FJP, Heemsbergen W, Balm AJ, van Zanten M, Schornagel JH, Rasch CR: Concurrent chemoradiation with daily low dose cisplatin for advanced stage head and neck carcinoma.
Radiother Oncol 2007, 85(1):42-47
Browman GP et al. (2001) Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: A systematic review of the published literature with subgroup analysis. Head Neck 23: 579–589
Adelstein DJ et al. (2003) An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21: 92–98
nccn.org, head and neck cancer 2017
Michael Schlumpf et al, Results of concurrent radio-chemotherapy for the treatment of head and neck squamous cell carcinoma in everyday clinical practice with special reference to early mortality. BMC Cancer. 2013; 13: 610