Weekly Docetaxel, Cisplatin, and Cetuximab in Palliative Treatment of Patients with Squamous Cell Carcinoma of the Head and Neck.

LESSONS LEARNED: Chemotherapy for recurrent, metastatic squamous cell carcinoma of the head and neck need not be known for extreme toxicity.The weekly regimen studied here has been demonstrated to be tolerable and effective.
BACKGROUND: The objective of this study was to establish the response rate, progression-free survival (PFS) and overall survival (OS), and safety profile of weekly docetaxel, platinum, and cetuximab (TPC) in patients with relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN).
MATERIALS AND METHODS: Twenty-nine patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group (ECOG) performance status <3 were enrolled in an institutional review board-approved phase II trial. This study permitted prior chemoradiation, radiation, and/or surgery, provided that 3 months had elapsed since the end of the potentially curative treatment. Patients received cisplatin 30 mg/m2 or carboplatin area under the curve (AUC) 2, docetaxel 30 mg/m2, and cetuximab 250 mg/m2 weekly for 3 weeks, followed by a break during the fourth week, for a 28-day cycle. Planned intrapatient dose modifications were based on individual toxicity.
RESULTS: Twenty-seven patients received TPC and were evaluable for response and toxicity. Rates of complete response (CR), partial response (PR), and confirmed PR were 3%, 52%, and 30%, respectively. The overall objective response rate was 56%. Estimated median PFS and OS were 4.8 and 14.7 months, respectively. The rates of grade 3 and 4 worst-grade adverse events (AEs) per patient were 85% and 7%, respectively. Dose density through cycle 4 was preserved for all patients; however, treatment beyond cycle 6 with the TPC regimen proved unfeasible.
CONCLUSION: Weekly docetaxel, cisplatin, and cetuximab is an effective regimen for patients with metastatic or recurrent SCCHN. Response rates, PFS, and OS compare favorably with other combination chemotherapy treatments. Grade 4 toxicity rates observed in this study were substantially lower than those described with regimens using less frequent, higher-dose chemotherapy schedules. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Discussion

The motivation behind this project was our observation that the so‐called EXTREME regimen, which is considered the standard of care by many for these patients, is appropriately named for its extreme toxicity and inconvenience. Our hypothesis was that the exchange of a taxane for infusional fluorouracil (5‐FU) and a more frequent, lower‐dose schedule in a regimen we have named “TPC” would preserve activity while substantially reducing both toxicity and inconvenience. We believe the results of this trial provide preliminary confirmation of this hypothesis. The response rates we observed were numerically superior to two prior benchmark studies, and grade 4 AEs were markedly lower than seen in these same benchmark studies.

Although the field is evolving with the development of immunotherapies and targeted therapies, we assert that regimens such as TPC could be considered instead of the EXTREME regimens in future development of definitive trials likely to involve combinations of immunotherapy and chemotherapy in this patient population [1], [2], [3], [4], [5], [6], [7], [8].

Trial Information

Head and neck cancers

Metastatic/Advanced

None

Phase II

Single arm

Overall response rate

Toxicity

Complete response rate

Progression‐free survival

Tolerability

Deliverability

Safety

Active and should be pursued further

Drug Information

Cisplatin

Small molecule

Platinum compound

30 milligrams (mg) per square meter (m2)

IV

Patients received cisplatin 30 mg/m2 or carboplatin AUC 2, docetaxel 30 mg/m2, and cetuximab 250 mg/m2 weekly for 3 weeks, followed by a break during the fourth week, for a 28‐day cycle. Planned intrapatient dose modifications were based on individual toxicity.

Carboplatin

Small molecule

Platinum compound

AUC 2

IV

Docetaxel

Small molecule

Microtubule‐targeting agent

30 milligrams (mg) per squared meter (m2)

IV

Cetuximab

Antibody

Anti epidermal growth factor receptor (EGFR)

250 milligrams (mg) per square meter (m2)

IV

Patient Characteristics

23

4

All patients with incurable metastatic or recurrent squamous cell carcinoma of the head and neck. Patients who were treated with chemoradiation, radiation, and/or surgery as part of a curative plan were eligible, but this treatment must have been completed 3 months prior to enrollment.

Median (range): 60 (24–80) years

0

Prior therapy clarification: surgery, 14 patients; radiation, 21 patients; chemotherapy (as part of attempted curative chemoradiation plan). Prior agents: docetaxel, 6 patients; cisplatin, 16 patients; 5‐FU, 4 patients; cetuximab, 6 patients; bevacizumab, 1 patient.

Primary Assessment Method

Total Patient Population

29

29

27

27

RECIST, version 1.0

n = 1 (3%)

n = 14 (52%)

n = 5 (19%)

n = 6 (22%)

n = 1 (4%)

4.8 months, CI: 2.7–6.6

14.7 months, CI: 8.3–

Kaplan‐Meier Time Units, months

See Figures 1 and 2 for dose intensity, overall survival, and progression‐free survival data.

Figure 1.

Dose intensity of chemotherapy administered as a percentage of intended dose per cycle. Patients who discontinued for progression of disease or who continued on cetuximab alone after cycle 7 are not represented in this figure. Patients who received cisplatin and carboplatin within the same cycle are counted separately in each bar for each agent, with intensity represented on a prorated basis for each.

Abbreviation: pt, patient.

Figure 2.

Survival graphs. (A): Overall survival. (B): Progression‐free survival.

Abbreviations: CI, confidence interval; OS, overall survival; PFS, progression‐free survival.

Adverse Events

Assessment, Analysis, and Discussion

Study completed

Active and should be pursued further

We set out to conduct a trial of weekly docetaxel cisplatin (or carboplatin) and cetuximab in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN) in order to ask whether this combination of agents dosed on a weekly schedule could preserve response rates while diminishing toxicity in this patient population. We saw a 56% response rate (15/27 patients). Thirty‐three percent (9/27 patients) had the responses confirmed with follow‐up imaging per RECIST. Although this RECIST‐based confirmed response rate was below our planned benchmark, it is worth noting that in the Vermorken and Gibson studies, which are regarded as definitive benchmarks for response to platinum, fluorouracil and cetuximab (PFC) and platinum and paclitaxel (PT), formal RECIST criteria were not used. Therefore, the response rate we observed with docetaxel, platinum, and cetuximab compares very favorably with these latter two studies, that is, 56% compared with 36% and 27% [4], [8]. Our median progression‐free survival and overall survival rates of 4.8 months and 14.7 months compare favorably with both the above randomized control trials and multiple other chemotherapeutic regimens used in this setting [3].

The most remarkable observation we made was a very low rate of high‐grade adverse events. Specifically, there were only two grade 4 adverse events described, both clinically insignificant lymphopenia. This number compares very favorably with prior studies, in which grade 4 adverse event rates ranged typically from 30% to 50% for chemotherapy doublets and triplets administered once every 21 days [4], [8], [12], [13]. Our adverse event (AE) data are consistent with another report of weekly docetaxel and cisplatin in this setting [14]. Although this diminution in high‐grade adverse events is promising, we are uncertain as to whether it can be attributed to the substitution of a taxane for fluorouracil, the weekly dosing schedule, more frequent monitoring, or higher attention to supportive care in this single‐institution study. We view these AE rate reduction results as very promising but preliminary, for it is impossible to say whether such results extrapolate to a larger multi‐institutional experience.

With the emergence of promising new immunotherapy treatments (in particular the recent approvals of nivolumab and pembrolizumab for the treatment of SCCHN in the recurrent metastatic setting) it is difficult to predict what place chemotherapy will occupy in future clinical practice. It is worth remarking that monoclonal antibodies targeting PD‐1 have limited activity in this disease, with a response rate of only 13% in the recently published randomized controlled trial for nivolumab [5]. We suspect that the greatest benefit to the new immunotherapy compounds, either alone or in combination with other immunotherapy compounds, is likely to be realized with treatment plans that integrate immunotherapy and conventional systemic therapy. Regimens less toxic than the EXTREME regimen or standard high‐dose cisplatin will need to be tested in combination with immunotherapy in order to achieve the goal of maximal anticancer activity with a reasonable toxicity profile.

We believe our results seen in this patient population justify further development of this regimen. Given the changing landscape of treatment options in patients with head and neck cancer, it will be necessary to explore more definitive comparisons with the present chemotherapy standards while simultaneously exploring integration with immunotherapy.

Table 1.

Tumor response rates to docetaxel, platinum, and cetuximab

Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Serious adverse events.

Abbreviations: AE, adverse event; alk phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; G‐tube, gastrostomy tube; GI, gastrointestinal; INR, international normalized ratio; UTI, urinary tract infection.

Table 2.

Baseline characteristics

Abbreviations: 5‐FU, fluorouracil.