Original Article

A Single Group Study into the Effect of Intralesional Tetra-O-Methyl Nordihydroguaiaretic Acid (M4N) in Oral Squamous Cell Carcinoma

Manoj Pandey, Madhvan K Nair and Ru Chih Huang
World Journal of Medical Research 2018, 7:1

Abstract

Background:

Oral squamous cell carcinoma is the most common cancer among males and third commonest among females in India. Conventional treatment is by surgery or radiotherapy either alone or in combination. Survival still remains poor with nearly 50% recurring within 2-years of treatment.

Patients and Methods:

Between November 1999 and April 2000, 21 patients with oral squamous cell carcinoma were recruited. Of these, 3 patients did not complete the intended treatment and were excluded from analysis. After obtaining an informed consent, intralesional tetra-O-methyl nordihydroguaiaretic acid (M4N, currently under development as EM-1421) was injected in doses of 20 mg/day for 3 or 5 days. After completion of this treatment, patients underwent surgical resection of the tumor followed by adjuvant radiotherapy if indicated. Toxicity was monitored by WHO toxicity criteria. Response was recorded as change in surface area, tumor necrosis, pathological response, molecular response complication and recurrences. Overall, disease free and event free survival were calculated using the Kaplan-Meier method and were compared using log-rank testing. Survivin and Cdc2 expression in a preoperative biopsy and postoperative surgical specimen was documented using immunohistochemistry. The survivin and Cdc2 data was analyzed using a Chi square test and the effect of change of survivin and Cdc2 expression on survival was evaluated by the Kaplan-Meier method and log-rank test

Results

Of the 18 patients, 7 (38.9%) had pT2 disease, 4 (22.2%) had pT3 disease while 6 (33.3%) had pT4 disease. 9 (50%) of the patients were node negative while 3 (16.7%) had pN1 disease and 4 (22.2%) had N2b disease. Over a period of 5 years, 4 patients died. Two died (11.1%) of non-tumor related causes. Six (33.3%) patients recurred at primary site, neck node or developed second primary tumors. Two of these (11.1%) died due to second primary tumors at sites distinctly separate from the treated tumor. The other four (22.2%) who relapsed were either salvaged or were on palliative treatment. There were no acute or deferred toxicities in any of the patients. Disease free and overall survival at 5 years was 10/18 (55.6) % and 14/18 (71.7%) respectively. Down-regulation of Cdc2 was observed in 9/18 (50%) and of survivin in 10/18 (55.6%) patients. Tumor stage at presentation (p=0.01) and down regulation of survivin (p=0.01) were found to significantly correlate with disease free survival.

Conclusions

Intralesional tetra-O-methyl nordihydroguaiaretic acid (M4N) appears to be well tolerated using an intralesional dose of up to 100mg (20mg / day) with no evidence of acute or deferred toxicity. M4N has demonstrated significant inhibition of cellular production of Cdc2 and survivin, a potent pro-apoptotic response. This effect translated into tumor necrosis and shrinkage even with this short exposure in association with concomitant surgery and / or radiation.

Key words:

Oral cancer; squamous cell carcinoma; M4N, EM-1421, intralesional administration, cdc2, survivin, apoptosis, caspase, cyclin.

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