Source: www.medscape.com
Author: Zosia Chustecka

In patients with head and neck cancer who do not undergo surgery, chemotherapy with nonplatinum agents given concurrently with radiotherapy offers clear benefits for recurrence and survival, say the authors of one of the largest and longest randomized trials carried out in this patient group.

Event-free survival in patients who received concomitant chemoradiation was double that seen in patients who received radiotherapy alone or in those who received chemotherapy after radiation (with or without concurrent chemotherapy). Overall survival was also nearly doubled, although this result was not statistically significant.

These benefits persisted for 10 years, the researchers note in their report published online October 27 in the Lancet Oncology.

The results come from the UK Head and Neck (UKHAN1) trial, headed by Jeremy Tobias, FRCP, from the Department of Clinical Oncology, University College Hospital, London, United Kingdom.

Chemoradiation as a treatment option for head and neck cancer is still rather controversial, Dr. Tobias told Medscape Oncology, and there are some physicians who would consider using radiation alone. “I think this study has gone quite a long way toward showing that chemotherapy given simultaneously with radiation is useful,” he said. The benefits were “so striking that they trump any additional toxicity,” he added.

However, chemotherapy given after radiation did not confer any benefit, and it increased toxicity. Also, there was no benefit from the addition of chemotherapy to radiation in patients with head and neck cancer who had undergone surgery.

Details of the Long-Term Results
The UKHAN1 study started 20 years ago, and involved 966 patients with locally advanced head and neck cancer; most participants were from the United Kingdom, but some were from Turkey and Malta.

The majority of these patients (n = 713) had not undergone surgery. They were randomized to receive 1 of 4 treatments: radiotherapy alone, radiotherapy with simultaneous nonplatinum chemotherapy (i.e., concurrent chemoradiation), radiotherapy followed by chemotherapy, or radiotherapy with simultaneous chemotherapy followed by chemotherapy alone.

Chemotherapy was either methotrexate alone or a combination of vincristine, bleomycin, methotrexate, and fluorouracil. Toxicity did not differ substantially between these 2 options, the researchers note.

The median survival was 4.7 years in the concurrent chemoradiation group, compared with 2.3 to 2.7 years in the other 3 groups. However, this difference in overall survival did not reach statistical significance (P = .09), probably because the numbers were too small, the researchers explain.

The corresponding median event-free survival was 2.2 years in the concurrent chemoradiation group, compared with 1 year in the other groups (P = .005). The researchers estimate that for every 100 patients treated with concurrent chemoradiation, there were 11 fewer events in the 10 years after treatment than in the other treatment groups. Events included recurrence, death, and diagnosis of a new tumor.

Dr. Tobias said that the increase in overall survival, although not statistically significant, is “clinically important,” and that the increase in time to an event such as a local recurrence, which was significant, is of “immense importance” in this group of patients. The location of these tumors means that a recurrence can necessitate radical surgery, which can then leave the patient without speech or normal swallowing function, which can be “catastrophic,” he said.

Treatment with chemotherapy at the same time as radiation increased toxicity. Significant toxicity was reported by 28% of patients in the concurrent chemoradiation group, compared with 11% in the group receiving radiotherapy alone, 12% in the group receiving radiotherapy followed by chemotherapy, and 36% in the group receiving concurrent chemoradiation followed by chemotherapy. The most common toxicity during treatment was mucositis.

The authors note that the acute toxicity rates reported for the nonplatinum chemotherapy used in this trial (28%) is much lower than that reported in other trials with platinum-containing chemotherapy (41% to 77%).

Platinum compounds, particularly cisplatin, are commonly used in these patients, but Dr. Tobias said that he is “not convinced that this is backed by evidence” and suggested that nonplatinum chemotherapy offers an alternative for patients who are unfit for cisplatin. “It appears to work as well and has substantially lower toxicity, and these drugs are inexpensive,” he noted.

No Benefits Seen After Surgery
A small subgroup of patients (n = 253) in the UKHAN1 trial had undergone radical surgery and were randomized to 1 of 2 treatment options: radiotherapy alone or concurrent chemoradiation.

In this group, there was no significant difference in outcomes between the 2 treatment groups. Overall survival was 5 years for radiotherapy alone and 4.6 years for concurrent chemoradiation, and event-free survival was 3.7 and 3 years, respectively. Significant toxicity was reported by 9% of patients receiving radiotherapy alone and by 20% of those receiving concurrent chemoradiation.

“Adding chemotherapy to radiotherapy was not effective in patients who had undergone surgery previously,” the researchers conclude. It had no significant effect on outcomes, but doubled the acute toxicity.

Recent Meta-Analysis Update
A recent update of ahuge meta-analysis of chemotherapy in head and neck cancer concluded that concurrent chemoradiation should now be the routine treatment of choice for all patients with nonsurgically treated head and neck cancer (Radiother Oncol. 2009;92:4-14). That updated analyzed data from 93 trials and 17,346 patients, including some older data from the UKHAN1 trial, and had a median follow-up of 5.6 years.

These latest results from the UKHAN1 trial (with a median follow-up of 10 years) confirm the conclusion from that updated meta-analysis, Dr. Tobias and colleagues note.

However, they also show that a long-term benefit in terms of recurrence and deaths can be achieved with nonplatinum agents that are inexpensive, relatively easy to deliver, and have lower toxicity than platinum therapies, they add.

“With this particular group of patients, characteristically with multiple comorbidity and relatively low compliance to chemotherapy, the inability to tolerate platinum-based regimens is often a serious barrier to radical chemoradiation,” they write. “Because this is a high-risk and generally unfit patient group, many of whom are excessive users of alcohol and tobacco throughout treatment, the availability of a relatively simple, inexpensive, and low toxicity chemoradiation regimen considerably improves the likelihood of completing treatment, essential for improving the chance of cure.”

Note:
1. This trial was funded by the Cancer Research UK. None of the authors have disclosed any relevant financial relationships.

Source:
Lancet Oncol. Published online October 27, 2009. Abstract