Patterns of Failure for Resected Advanced Head & Neck Cancer Treated by Concurrent Chemotherapy and Radiation Therapy: An Analysis of RTOG 9501/Intergroup Phase III Trial
Reviewer: Roberto Santiago, MD
Last Modified: October 8, 2002
Presenter: Jay Cooper Presenter's Affiliation: New York University Medical Center, New York, NY Type of Session: Plenary
The most common failure after grossly or microscopically complete surgical resection and post-operative radiation therapy for advanced cancers of the head and neck is local-regional recurrence.
This study evaluates whether patients with completely resected advanced squamous carcinomas of the head and neck treated with adjuvant radiotherapy (RT) would have a local-regional control benefit from the addition of cisplatin (CDDP) chemotherapy.
Secondary endpoints addressed by the study include the anatomic pattern of first failure and the time course of local-regional relapse.
Materials and Methods
Between 9/95 and 4/00, 459 patients status post resection of squamous carcinomas of the head and neck deemed at high-risk for local-regional recurrence were enrolled in a randomized phase III clinical trial.
The following factors were used to define the patients as high risk: 2 or more involved lymph nodes, extra-capsular disease and/or microscopically involved mucosal margins of resection.
Forty three patients were ineligible.
Primary tumor sites included the oral cavity, oropharynx, larynx, and hypopharynx.
Eligible patients had KPS of at least 60.
Following gross total resection, 231 patients were randomly assigned to RT alone (60-66 Gy /30-33 fractions/ 6-6.6 weeks) and 228 patients were randomly assigned to identical RT plus CDDP (100 mg/m2 i.v. on days 1, 22 & 43).
The patients were stratified according to age (<70 vs >70) and the features mentioned above associated to high risk for local-regional recurrence.
Approximately 94% of patients in each arm were less than 70 years old.
Most had KPS between 80 and 90.
Oropharynx was the most common primary site.
Most patients had T4N2 tumors.
Central review confirmed good compliance with the protocol.
The mean RT dose was in excess of 60 Gy and 61% completed 3 cycles of chemotherapy.
With a median follow-up of 37 months, the 2-year L-R control rate is 71% for those assigned to RT and 76% for the RT plus CDDP group (p=0.16). The risk of local-regional recurrence began to favor combined therapy only after six months of follow-up had passed. No local-regional recurrences were observed after 36 months of follow-up.
Local-regional recurrence as the first site of treatment failure decreased from 25% in the group receiving RT only to 17% in the group receiving concurrent therapy (p=0.041, crude incidence).
Distant metastasis as the first site of failure occurred in 22% and 15% respectively (p=0.076, crude incidence).
Ninety-six patients were alive at 3 years. Neither the 2-year actuarial disease-free nor overall survival was significantly improved by the chemotherapy.
The chemotherapy arm experienced significantly more severe toxicity at any time of follow up that the RT alone arm.
Death from the index cancer was significantly reduced by the addition of chemotherapy when compared to adjuvant RT alone (76% vs. 62%, p<0.05). However, none of the patients treated by RT experienced protocol-related fatal toxicity, whereas 4% of the patients treated with concurrent chemoradiotherapy did.
The concurrent addition of single agent cisplatin chemotherapy to post-operative radiation therapy (without any subsequent adjuvant chemotherapy) did not significantly reduce the overall incidence of local-regional recurrences.
It did reduce local-regional recurrences as the first evidence of treatment failure as well as distant recurrences.
The experimental arm was associated with more severe toxicity as well as treatment related mortality.
Unfortunately, neither the actuarial disease-free survival nor the overall survival was significantly improved by the chemotherapy.
The findings also suggest that three-year follow-up may be adequate to assess the ultimate rate of local-regional recurrence when concurrent chemotherapy and radiation therapy are used post-operatively.
The poor outcome in this patient population and the contrast between the results of this negative trial and the results of a recent EORTC trial evaluating a similar therapeutic approach fuel the interest in adding chemotherapy to adjuvant radiotherapy.
Differences between the two trials that could have influenced the diverging results included:
1. more positive margins of resection in the EORTC trial
2. less oropharyngeal cancers in the EORTC trial
3. Longer time required to deliver the radiotherapy in the EORTC trial
Among the questions that remain unanswered are:
Is the benefit seen in the EORTC trial just the result of a compensation for poor surgery?
Is the RTOG study at a disadvantage because of higher proportion of relatively better prognosis patients (more oropharyngeal cancers)?
Was the adjuvant RT alone arm in the RTOG trial better that expected? If so, was it because RT was delivered over a shorter time?
Only 61% completed chemotherapy as planned in the RTOG trial. Also, there was a marked increase in severe toxicity and treatment related deaths in the chemotherapy arm of the RTOG trial.
Is there a safer way to integrate these? modalities in the adjuvant setting?
At this time, the addition of chemotherapy to radiation therapy should still only be done as part of a clinical trial in the post-operative setting. The toxicity of this combined approach is significant while the results do not appear to be improved in patients treated in this trial.
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