Presenter: E.E.W. Cohen Presenter's Affiliation: University of Chicago Type of Session: Scientific
At the University of Chicago, a series of sequential phase II trials have established induction carboplatin and paclitaxel x 2 cycles followed by concurrent chemotherapy and radiation (CTRT) with paclitaxel, 5-FU, and hydroxyurea (HU) (TFHX) as the standard therapy for locally advanced head and neck cancer at that institution.
This regimen has yielded 3-year overall survival (OS) of 70% and 3-year progression-free survival (PFS) of 80-90%
There are few fatal toxicities with this regimen, but they have found:
Grade 3/4 neutropenia: 33%
Neuropathy (any grade): up to 33%
Grade 3/4 mucositis: 76%
Paclitaxel dose reduction: 40%
Epidermal growth factor receptor (EGFR) inhibition has resulted in additive or synergistic effects when given with chemotherapy and radiation in preclinical studies, and have been shown to have activity in recurrent and metastatic head and neck cancers.
In an effort to reduce the toxicity from therapy, this study was designed to explore the replacement of paclitaxel in the standard regimen at the University of Chicago with gefitinib, a small molecule, tyrosine kinase inhibitor of EGFR.
Materials and Methods
Eligible patients had squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma
All patients were stage IVa, IVb, or stage III base or tongue or hypopharyngeal tumors.
All patients were ECOG performance status (PS) 0-2 and had intact organ function. Organ-preserving surgery was allowed.
Patients who did not undergo surgery received two cycles of induction chemotherapy with carboplatin/paclitaxel.
This was followed by concurrent chemotherapy and radiation (CTRT) consisting of 5-FU (d1-5), HU (bid d1-5) on a week on/week off schedule repeated every 2 weeks, gefitinib (250mg qd d1-14), and radiotherapy (RT) (150 cGy bid)
Gefitinib 250mg qd was maintained after therapy for 2 years total.
70 patients consented for the trial, but 1 withdrew consent prior to initiation of any therapy.
Median age was 59; 70% were male; 70% had ECOG PS of 0, 24% were never smokers, and 16% had organ-preserving surgery prior to CTRT.
The most common primary site was oropharynx (56%).
37/70 patients were stage T1-2; 21/70 were stage T4.
56/70 patients were stage N2a or higher.
Of the 59 patients who underwent induction chemotherapy, partial response (PR) = 75% and complete response (CR) = 14%.
For the concurrent CTRT:
Median RT dose = 72 Gy
96% treated with Intensity-Modulated Radiation Therapy (IMRT)
78% received CTRT without any treatment delay.
Grade 3/4 neutropenia = 16%
Grade 3/4 mucositis = 84%
Grade 3/4 dermatitis = 33%
34% had diarrhea (no grade 4)
46% had rash (no grade 4)
14% had grade 1 neuropathy (no grade 2-5)
36% with grade 3-5 infections with 2 deaths.
2 non-disease related deaths during treatment
6 months post-CTRT, 4 patients required gastrostomy tube feeding and 1 received hyperbaric oxygen therapy for bone exposure.
CR = 89%
PR = 9%
For gefitinib maintenance:
71% continued with gefitinib maintenance
17% have discontinued gefitinib during maintenance
With median follow-up of 14.5 months, 1-year PFS = 85% and 2-year PFS = 82%
1-year OS = 92% and 2-year OS = 89%
Inclusion of gefitinib into concurrent CTRT is feasible and tolerable.
16% grade 3/4 neutropenia
No neuropathy >grade 1
Rates of mucositis and dermitis equivalent to TFHX
The combination of drugs in this study result in a more favorable toxicity profile than TFHX
Maintence gefitinib at 250 mg qd is tolerable
CR and OS rates are thus far encouraging
Current and future studies exploring the roles of induction, EGFR, radiosensitization, and maintenance therapy are underway or planned,.
Clinical/Scientific Implications The above study is an interesting attempt to reduce the toxicity of definitive therapy for head and neck cancer through the substitution of of a traditional chemotherapeutic agent with a targeted therapy. There is good evidence that EGFR inhibition given concurrently with radiation results in improved outcomes in these patients; however the data for giving EGFR with chemoradiation is limited. The substitution of paclitaxel with gefitinib in this trial yields the expected reductions in neuropathy and neutropenia. These can be the most dangerous toxicities in the short-term and most bothersome in the long-term. Although patients given gefitinib had higher rates of diarrhea and rash, these toxicities are generally tolerable. The ability to alter treatment in an attempt to reduce toxicity is a luxury, provided by the fact that outcomes in these advanced patients are so good. It is reasonable to attempt to reduce toxicity in these patients, and the outcome data from this study, while preliminary, seem to show that this regimen may result in equivalent PFS and OS. The results of this study need to be confirmed by a randomized, controlled trial; however, it is clear that the future of head and neck cancer therapy will include a combination of chemotherapy, radiation, and targeted therapies.
Nov 21, 2014 - In a phase III clinical trial, gefitinib was superior to carboplatin-paclitaxel in extending survival for patients with non-small-cell lung cancer, particularly those patients with epidermal growth factor receptor gene mutations, according to a study published online Aug. 19 in the New England Journal of Medicine.