RTOG Protocol No: 9505	Protocol Status:
	Opened:	April 24, 1995

Title:

Evaluation of Tumor Angiogenesis Measured with Microvessel Density (MVD) as a Prognostic Indicator in Nasopharyngeal Carcinoma.

Patient Population:

- Patients with squamous cell carcinoma of the nasopharynx treated with radiotherapy ± radiosensitizer (misonidazole or SR-2508) in RTOG's protocols 79-13, 79-15, 83-13, and 85-27 are eligible.
- Non-RTOG protocol patients with primary squamous cell carcinoma of the nasopharynx treated with radiotherapy alone between 1975 and 1996 with a minimum of two years of followup information available will also be eligible. Slides and blocks must be available.
- Patients with a diagnosis of squamous cell carcinoma of the nasopharynx whose initial treatment plan included chemotherapy which was administered according to the combined modality arm of intergroup nasopharynx study INT 0099 are eligible provided that there has been compliance with each issue in Section 3.3 of the protocol.
- Patients who expired within two years of initial treatment are eligible, provided adequate information is available.
- The following information must be available on each patient: initial TNM Classification, details and dates of the initial treatment regimen, disease status at two years or at death (if survival is less than 2 years), slides and blocks of the tumor specimen obtained at diagnosis (prior to commencement of any treatment).
- Study-specific informed consent must be obtained from living patients.

Objectives:

1. To evaluate MVD as an independent prognostic factor in patients with nasopharyngeal carcinoma (NPC) and treated with radiation therapy alone by correlating MVD with incidence of distant metastasis, local-regional control, disease-free survival and overall survival.

2. To evaluate MVD as an independent prognostic factor in patients with nasopharyngeal carcinoma (NPC) who have been treated with radiation therapy and chemotherapy according to the intergroup trial INT0099/RTOG 88-17 by correlating MVD with incidence of distant metastasis, local-regional control, disease-free survival and overall survival.

3. To correlate MVD with WHO histopathological type of nasopharyngeal carcinoma.

Schema:

A retrospective analysis of tumor samples from patients previously treated on select RTOG studies.

Study Chairs:	Karen K. Fu, M.D.	Patients Entered as of:
	Noel Weidner, M.D.	3/15/00	193

Reference: Hammond E, Weidner N, et al. Prognostic Value of Intratumoral Microvessel Density in Nasopharyngeal Carcinoma: Results of RTOG Study 95-05. US/Canadian Pathology, Chicago, IL, 2002.

Background: Tumor angiogenesis is important for growth & spread of cancer cells. Intratumoral microvessel density (iMVD), a measure of tumor angiogenesis, is a reported prognostic factor in patients with solid tumors from many sites, including the head & neck. In Radiation Therapy Oncology Group (RTOG) study 9505 we studied iMVD in patients with nasopharyngeal carcinoma.

Design: Among 166 eligible patients, iMVD was evaluable in 123. After highlighting microvessels with CD34 immunostaining, iMVD was determined in the microvessel hot spots of nasopharyngeal carcinoma biopsies. Results were correlated with tumor stage, overall survival, and time to distant metastasis.

Results: iMVD ranged from 9 to 243 (median=70); 34% had iMVD less than 60, our hypothesized cutpoint. Significantly more N2-3 patients had iMVD greater than or equal to 60 (p=0.04). No statistically significant difference existed between the 2 groups (iMVD less than 60 vs. iMVD greater than or equal to 60) for either overall survival (p=0.23) or time to distant metastases (p=0.16); however, a trend favored patients with lower iMVD values in both cases. Patients with iMVD greater than or equal to 60 died at a rate 1.35 times faster (95% confidence interval 0.82, 2.20), and developed metastases at a rate 1.73 (0.81, 3.73) times faster than patients pts with MVD less than 60. Multivariate analysis was used to evaluate whether adding iMVD added any predictive power in addition to the T- and N-stage. In overall survival, iMVD was not a significant predictor; however, the hazard ratio (HR) of 1.27 (0.76, 2.12) was very similar to what we saw in univariate analysis (1.35). Similar results were seen in time to distant metastases [HR=1.55 (0.59, 2.86)]. Finally, inter-observer variability in measuring iMVD on small biopsy fragments (kappa=0.24, only fair agreement) suggests that reproducibly can be suboptimal & contribute to inconclusive correlations.

Conclusions: Patients with higher iMVD values presented with higher stage disease; and, they may might die 27% faster & develop metastases 55% faster than ptspatients with lower MVD values. Although a trend appeared to be emerging for survival & distant metastases, these differences were not found statistically significant