Multiagent Trials - Head and neck cancer

Nearly all possible combinations and combination doses/schedules of methotrexate, cisplatin, bleomycin, and 5-FU and other agents listed in

Table 90-26 have been tried in numerous single-arm studies of recurrent HNSCC. Results have covered a wide range of response rates, including generally low complete response rates, in heterogeneous subsets of patients.

There is a high level of enthusiasm currently for integrating the newer agents into combination chemotherapy for recurrent disease. Results of such approaches have been encouraging. A recent phase II trial of paclitaxel (175 mg/m2 in a 3-hour infusion on day 1), ifosfamide (1,000 mg/m2 in a 2-hour infusion on days 1 through 3) and cisplatin (60 mg/m2 on day 1, repeated every 3 to 4 weeks) achieved positive results in recurrent HNSCC. This trial achieved an overall response rate of 58% (30 of 52), a complete response rate of 47% (9 of 52), and a median survival of 8.8 months. The relatively well-tolerated toxicity included transient grades 3 to 4 neutropenia in 90% of patients (the most frequent moderate to severe toxicity), neutropenic fever in 27%, grade 3 peripheral neuropathy in three patients (none had grade 4), and grade 3 mucositis in only one patient (none had grade 4). There were no deaths due to toxicity.

More recently, the above regimen was modified by the substitution of carboplatin for cisplatin. This regimen produced less neuropathy, gastrointestinal toxicity, and fatigue, and similar overall and complete responserates and survival rates in recurrent disease in comparison with the paclitaxel plus ifosfamide plus cisplatin (TIP) regimen.

A major current direction for new drug development is targeted therapy. This includes epidermal growth factor receptor (EGFR) inhibitors, p53-targeting agents, and farnesyltransferase inhibitors (FTIs), among other agents.

Concomitant Chemoradiotherapy for Recurrent Disease
A very novel approach in the recurrent-disease setting is represented by a phase I study of concomitant chemoradiotherapy with paclitaxel, 5-FU, and hydroxyurea with G-CSF support. This regimen was administered to 55 patients who had failed to respond to prior radiotherapy (n = 25) or surgery, had a coexistent or prior second malignancy, or had unresectable or metastatic disease and less than a 10% probability of a 2-year survival (Brockstein JCO 1998). Twenty such patients were treated at the recommended phase II dose level of hydroxyurea (500 mg orally twice daily for 11 doses), 5-FU (600 mg/m2/d by continuous infusion for 5 days), and paclitaxel (20 mg/m2/d by continuous infusion for 5 days), with twice-daily radiotherapy. Dose-limiting toxicities consisted of myelosuppression, mucositis, dermatitis, and diarrhea. Paclitaxel concentrations of >10 nmol/L were achieved in the plasma of 65% of patients. Complete responses were achieved in 70% of assessable patients. This study showed (1) the feasibility of adding infusional paclitaxel and hyperfractionated radiotherapy to 5-FU, hydroxyurea, and concomitant radiotherapy and (2) the achievement of radiosensitizing levels of paclitaxel in most patients. Based on the regimen’s high locoregional control rate, further investigation in previously untreated patients is justified.

Randomized Studies
A minority of the trials comparing multiagent and single-agent (methotrexate or cisplatin) therapies produced significant differences in response, and the overall single-agent and multiagent median survivals are similar at 5 to 6 months.

Jacobs and colleagues reported a three-arm comparative trial of cisplatin and 5-FU as single agents and in combination. Although no major survival differences occurred, the response rate was highest in the cisplatin/infusional 5-FU combination.

SWOG reported a three-arm randomized phase III study comparing cisplatin/5-FU, carboplatin (300 mg/m2)/5-FU, and single-agent methotrexate in recurrent HNSCC. The response rate and toxicity of cisplatin/5-FU were significantly greater than they were in the methotrexate arm. The carboplatin/5-FU arm did not differ significantly from the two other arms in response or toxicity. Median survival was poor and not significantly different among the three groups. Interpretation of these results is clouded by atypical toxicity patterns. Moderate to severe myelosuppression (leukopenia) was significantly more frequent in the cisplatin arm, suggesting suboptimal dosing of carboplatin.

Five studies compared single-agent cisplatin with cisplatin combinations. Despite promising single-arm studies, cisplatin combinations have not performed better than cisplatin alone in phase III trials. Multiagent survival rates are equivalent to those with single-agent cisplatin. Based on single-agent activity of paclitaxel (discussed above), an ECOG study evaluated high-dose paclitaxel plus G-CSF plus cisplatin versus low-dose paclitaxel plus cisplatin. A total of 210 patients were entered, 199 of which were analyzable (101 in the high-dose arm and 98 in the low-dose arm). This trial was designed to assess a potential dose-response effect of paclitaxel and the activity of paclitaxel plus cisplatin in this population. Primary endpoints were event-free and overall survival. No survival advantage was associated with high-dose paclitaxel, suggesting that there was no paclitaxel dose-response effect. This may be due to the mechanism of action of paclitaxel, which has the ability to cause microtubular aggregation at only 10 um serum concentrations (readily achieved by lower doses). Myelosuppression and infection were the most frequent toxicities, which were expected with the 24-hour paclitaxel infusion schedule. This regimen was poorly tolerated. Grade 4 neutropenia was more frequent in the low-dose arm (71.1%) than in the high-dose arm (60.9%). Approximately 40% of patients withdrew from treatment because of toxicity. Still, median survival was 7.3 months and the 1-year survival rate was nearly 30%, which suggests that paclitaxel and cisplatin may be more efficacious than cisplatin and 5-FU in this setting. These investigators concluded that the true response rate probably was higher but that the large number of patients taken off the study early for reasons of toxicity caused a lowering of the rate. The low- and high-dose paclitaxel (plus cisplatin) regimens of this trial had similar toxicity profiles. Both arms experienced substantial rates of severe myelosuppression leading to life-threatening infection, due to the 24-hour infusion schedule of paclitaxel. These toxicity results of a multicenter trial make this infusion schedule unrecommended for treating recurrent/ metastatic disease. As no dose-response effect was observed, there is no evident need for the more expensive high-dose regimen (including growth factor support).

Conclusions
All the data on traditional agents for recurrent, unresectable, and metastatic disease fail to show that multiagent therapy is more effective than single-agent therapy. Although combination chemotherapy for recurrent or metastatic HNSCC may produce higher response rates than single agents, none of the randomized combination trials (including those comparing cisplatin/5-FU) produced improved survival over single-agent treatment. Single-agent and combination chemotherapy can provide effective palliation for these patients. The choice of regimen was based on the important balance between efficacy and toxicity (quality of life), which must be considered on a case-by-case basis.

The development of new more active drugs and combinations must assume high priority. Although the combination of cisplatin and infusion 5-FU had generally been the regimen of choice for palliation in patients able to tolerate the increased toxicity, the results of large series with long follow-up and of recent phase III trials indicate no advantage over other combinations (in response or survival) or over less toxic single-agent therapy (in survival). There are promising new molecular-targeting and cytotoxic agents, including the taxanes and ifosfamide, and novel approaches, such as gene targeting/therapy, under development.

One of the most promising new drugs in development in head and neck cancer is an EGFR inhibitor. The agent is a chimeric monoclonal antibody to EGFR (C225). ECOG recently reported preliminary C225 results from a phase III trial in recurrent head and neck cancer in patients who had not received prior chemo- therapy. One hundred fifteen patients were randomized to cisplatin plus C225 versus cisplatin plus placebo. Overall response rates were 93% for those receiving cisplating/C225 and 22% for those who received cisplatin alone. The progression-free survival rates were 4.1% and 3.4% in the cisplatin plus C225 arm and cisplatin plus placebo arm, respectively, and median survival rates were 9.2% and 7.96%, respectively. These results indicate favorable trends in response and survival associated with the C225 plus platinum combination. The C225 combination was reasonably well tolerated, with an expected higher rate of rash. A limitation of this study was a statistically under-powered design. However, subset analysis revealed that those with intermediate stage disease had a partial response rate of 11.5% (no complete responses [CRs] reported), but clinical benefit in this group (partial response plus stable disease) was 28%. Another critical study of this antibody is testing C225 in combination with radiotherapy versus radiotherapy alone. This study has completed accrual, but the data have not yet been reported.

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Provided by ArmMed Media
Revision date: July 7, 2011
Last revised: by Tatiana Kuznetsova, D.M.D.