Chemoradiotherapy versus Radiotherapy in Patients with Advanced Nasopharyngeal Cancer: Phase III Randomized Intergroup Study 0099

Reviewers: John Han-Chih Chang, MD and Kenneth Blank, MD
Source: Journal of Clinical Oncology, Volume 16 Number 4, pg. 1310-1317

Background

Nasopharyngeal carcinomas are rare entities in the United States and comprise less than 1% of all malignancies. It does seem to be much more common in Southern China and Taiwan (18 - 20% of all cancers). Other areas of high incidences are Kenya, Tunisia, Sudan and Uganda. It is 2 - 3 times more common in men than women and occurs with peak incidence at age 50 - 59. Etiology is multifactorial, but studies have related it?s incidence to ingestion of salt-cured foods which contain nitrosamines that distributes over the nasal mucosa. The Epstein-Barr virus (EBV) has also been proposed as an etiological factor since nearly 90% of WHO grade/type 3 patients have high IgA antibody titer to the EBV capsid antigen. Genetics as always plays an important role. The rates of nasopharyngeal malignancy in the Chinese people living in other countries are higher than the general population in which they are residing. The risk of Chinese-Americans is approximately 6 times that of other nationalities in the United States.

Histological classification is done by the World Health Organization (WHO) grading system. Type 1 is a well to moderately differentiated carcinoma with keratin production. Type 2 is a non-keratinizing carcinoma. Type 3 is an undifferentiated carcinoma (also includes lymphoepithelioma).

The standard treatment has been radiation therapy. The results for locally advanced disease (stages III and IV) have been fair. From many single institutional studies, 5 year survival rates range from 30 - 45%, but drops off to 25% by 10 years and 12% by 20 years. Many have explored other avenues of therapy such as chemotherapy. Trials with cisplatin (CDDP) have shown some promising results, but no positive randomized trial on survival has been published until now.

The current article details some of the initial results of the Southwest Oncology Group?s's (SWOG) cooperative intergroup trial 0099 involving the RatiationTherapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG). This phase III randomized trial compared chemoradiotherapy (CTX/XRT) treatment to radiotherapy alone (XRT) for stage III and IV nasopharynx cancer.

Materials and Methods

The two arms of this trial were, as mentioned above, CTX/XRT versus XRT alone. The XRT was Computed Tomagraphy (CT) based treatment planned. Cobalt 60 or higher megavoltage machines were utilized. Treatment volumes included primary tumor site and neck nodes down to the clavicles. Total dose to the tumor and margin was 7000 centiGrays (or rads) in 180 to 200 rad fractions daily. Treatment started day one. The chemotherapy used was CDDP and 5-flourouracil (5FU). CDDP (100mg/m2) was given concurrently with radiation in the CTX/XRT arm day one and every 21 days for 3 cycles. CDDP was reduced to 80mg/m2 and combined with 5FU (1000mg/m2) starting 4 weeks after the last day of radiation and continuing every 21 days for another total of 3 cycles. The only surgery that was performed was either a partial or radical neck dissection for persistent lymph nodes after treatment. The end points for this study were progression free survival (PFS) and overall survival (OS). Accrual goal was for 270 patients.

Results

One hundred and ninety-three patients were enrolled between 1989 and 1995. Only 147 were analyzed secondary to ineligibility reasons for the other 46 detailed in the article. A secondary analysis was performed on an intent-to-treat basis on 185 patients (includes the 38 deemed ineligible for incomplete work ups/evaluations). Ninety-one percent of the patients were stage IV. Most were WHO grade/type 3 (41%) and 2 (35%).

Median follow-up was 2.7 years. Interim analysis had stopped the trial in 1995, because of the overwhelming data in support of improved outcome in the combined modality arm. The hazard ratio between the XRT and CTX/XRT arms was 3.28. This corresponded to median progression free and overall survivals of 15 and 34 months for the XRT arm, respectively, and neither having been reached in the CTX/XRT arm. The actuarial 3 year PFS and OS rates for XRT were 24% and 47%, respectively. For the CTX/XRT arm, they were 69% and 78%, respectively. These were statistically significant with p values of < 0.001 and 0.005.

One hundred and forty-six were evaluated for toxicity. No fatal or grade 5 toxicity were reported. The most severe toxicities seen in the CTX/XRT relative to the XRT alone arm were leukopenia (lowering of white blood cell count), nausea, vomiting, ototoxicity (hearing impairment) and stomatitis (breakdown of mucosa of the oral cavity).

Complete response rates were not statistically significant, but had a difference of 13% (36% versus 49%) favoring CTX/XRT. Failure was seen only locoregionally in 26% of the XRT alone arm and 10% in the CTX/XRT arm. Distant as any component of failure was 35% in the XRT alone arm and 13% in the CTX/XRT arm.

Compliance to chemotherapy was slightly over 50% in this trial. This troublesome figure holds true other combined modality trials involving the head and neck.

Discussion

The results of this trial are in overwhelming support of combined modality for nasopharynx. The PFS and OS results were analyzed for the 185 patients that were mentioned above. The results were identical to the ones for the 147 formally analyzed. The hazard ratios for 3 year PFS and OS were 2.5 and 4.34, respectively, favoring the CTX/XRT arm. As expected, systemic and local toxicities were much greater for the CTX/XRT arm than for XRT alone, but survival benefits seem to far outweigh the detriment.

Lacking were data on compliance to chemotherapy and outcome. This maybe useful in tailoring the chemotherapy. Data on outcome and WHO grade/type was also missing. Despite similar survivals stage for stage, there is an inherent difference in how these patients fail (type 1 and 2 have more locoregional failure while distant disease predominates type 3). The effects of chemotherapy on these patterns of failure may have been useful.