Adding tirapazamine to chemoradiotherapy showed no improvement for head and neck cancers

The addition of tirapazamine, a bioreductively activated hypoxia-selective antitumor agent, to cisplatin and radiation did not improve survival in patients with advanced head and neck cancer, according to the findings of a large, international trial. In addition, a secondary analysis of the trial found that poor quality radiotherapy was associated with poor treatment outcomes regardless of the treatment arm.

Researchers conducted a phase 3 trial (Trans-Tasman Radiation Oncology Group [TROG] 02.02, HeadSTART) from 89 sites in 16 countries to compare a tirpazamine-containing regimen with a standard radiation and cisplatin regimen. The trial was started based on promising results from a previously conducted phase 2 trial (TROG 98.02).

The researchers assigned patients with previously untreated stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx to one of two treatment regimens: radiotherapy of 70 Gy in 7 weeks concurrently with either cisplatin 100 mg/m ² on day 1 of weeks 1, 4 and 7 (Arm 1; n=431) or cisplatin 75 mg/m

² plus tirapazamine 290 mg/m² per day on day 1 of weeks 1, 4 and 7, and tirapazamine alone 160 mg/m² per day on days 1, 3 and 5 of weeks 2 and 3 (Arm 2; n=430).

Survival outcomes similar

There was no difference in OS between treatment regimens (HR=1.07; 95% CI, 0.86-1.34). The 2-year OS was 65.7% (95% CI, 61-70) for Arm 1 and 66.2% (95% CI, 62-71) for Arm 2.

There were no differences between arms for 2-year failure-free survival (HR=0.99; 95% CI, 0.81-1.21) or 2-year locoregional failure-free rates (HR=0.89; 95% CI, 0.68-1.17). There was also no difference between treatments for quality of life.

In the experimental arm, muscle cramps, diarrhea and skin rash were more frequent, whereas nausea, renal impairment, hearing loss and anemia were more frequent in the standard treatment arm.

“Given the results of this trial and previous experience, we believe that additional trials targeting hypoxia in head and neck cancer treated with chemoradiotherapy would only be worthwhile if they could be conducted in a well-defined group of patients at high risk of locoregional failure as a result of tumor hypoxia and could be carried out in centers capable of delivering high-quality radiotherapy,” the researchers wrote in the Journal of Clinical Oncology.

According to Kian Ang, MD, PhD, a professor in the department of radiation oncology at The University of Texas M.D. Anderson Cancer Center, the findings of this study will not have an effect on clinical practice because there are already three options for treating patients with locally advanced head and neck cancer.

Ang told HemOnc Today that after this trial was launched, two other treatment options demonstrated positive findings in phase 3 trials. One was radiation plus cetuximab (Erbitux, ImClone), and the other was docetaxel, cisplatin, 5-FU induction chemotherapy followed by radiation with or without carboplatin.

“The take-home message is that with three options available now, a negative findings study will not impact standard of care,” he said.

In a secondary analysis of this trial, researchers reported the effect of radiotherapy quality and protocol compliance on outcome. The analysis included interventional review of 687 plans submitted to the Quality Assurance Review Center.

The Trial Management Committee reviewed plans and radiotherapy documentation for protocol compliance. Secondary review of noncompliant plans was performed to determine the effect on tumor control, as well. There were 820 patients who were evaluable.

Radiotherapy quality vital

In this secondary analysis, the findings highlight the importance of being aware of the quality of radiotherapy, according to Ang.

“Those in the field of oncology should realize that poor quality radiotherapy is equivalent to poor quality surgery; neither can be remedied,” he said during the interview.

About 25% of patients who received treatment were noncompliant for at least one of the criteria. Forty-seven percent of noncompliant plans had deficiencies with a predicted major adverse effect on tumor control.

Major deficiencies were unrelated to primary tumor site (P=.91), T stage (P=.56) or extent of nodal disease (P=.52). Major deficiencies were associated, however, with the number of patients enrolled at the treatment center: 29.8% of patients had a predicted major adverse effect in centers enrolling fewer than five patients vs. 5.4% in centers enrolling at least 20 patients (P<.001).

Among patients who had at least 60 Gy, 2-year OS was 50% for those with major deficiencies vs. 70% for those whose treatment was initially protocol compliant (HR=1.99). Freedom from locoregional failure was also lower among those with major treatment plan deficiencies compared with those with compliant plans (54% vs. 78%; HR=2.37).

“It is sobering to note that the value of good radiotherapy is substantially greater than the incremental gains that have been achieved with new drugs and/or biologicals,” the researchers wrote. – by Christen Cona

For more information:

• Ang KK. J Clin Oncol. 2010;doi:10.1200/JCO.2010.28.3085.
• Peters LJ. J Clin Oncol. 2010;doi:10.1200/JCO.2009.27.4498.
• Rischin D. J Clin Oncol. 2010;doi:10.1200/JCO.2009.27.4449.