Abstract. Metastatic cancer is a life-threatening illness with a predictably fatal outcome, thereby representing a major unmet medical need. In 2003, Rexin-G™ became the world's first targeted injectable vector approved for clinical trials in the treatment of intractable metastatic disease. Uniquely suited, by design, to function within the context of the human circulatory system, Rexin-G is a pathotropic (disease-seeking) gene delivery system bearing a designer killer gene; in essence, a targeted nanoparticle that seeks out and selectively accumulates in metastatic sites upon intravenous infusion. The targeted delivery of the cytocidal gene to primary tumors and metastatic foci, in effective local concentrations, compels both cancer cells and tumor-associated neovasculature to self-destruct, without causing untoward collateral damage to non-target organs. In this study: i) we report the results of three distinctive clinical studies which demonstrate the initial proofs of concept, safety, and efficacy of Rexin-G when used as a single agent for advanced or metastatic cancer, ii) we introduce the quantitative foundations of an innovative personalized treatment regimen, designated the 'Calculus of Parity', based on a patient's calculated tumor burden, iii) we propose a refinement of surrogate end-points commonly used for defining success in cancer therapy, and iv) we map out a strategic plan for the accelerated approval of Rexin-G based on the oncologic Threshold of Credibility paradigm being developed by the Food and Drug Administration.
Pretreatment absolute granulocyte (less than 6,000/cu mm), lymphocyte (greater than 1,500/cu mm), and monocyte (300 to 900/cu mm) counts are three independent indicators of good prognosis for patients with metastatic gastric cancer. There tests improve the prediction of survival significantly compared with estimates based on ambulatory status alone. If the patient is completely ambulatory, median survival (MS) is 27.6 weeks, and it improves further to 37.6 weeks if results of two hematology tests indicate a good prognosis. If the patient is partially ambulatory, MS is 16.2 weeks; however, if results of two blood tests indicate a good prognosis, MS is 25.7 weeks, and if two tests indicate a poor prognosis, MS is only 11.1 weeks. The model corrected a false assessment of a poor prognosis for 56% of all patients.
The Gastrointestinal Tumor Study Group (GITSG) has since 1975 included protocols for monitoring carcinoembryonic antigen (CEA) levels in its colorectal cancer adjuvant trials. Among the 563 patients on the colon cancer study (GI 6175) and the 207 patients on the rectal cancer study (GI 7175), one third had preoperative CEA determinations and more than 90% had some postoperative CEA monitoring. Colon cancer patients whose preoperative CEA was greater than 5 ng/ml had a greater probability of recurring than those whose values were lower (33% versus 18% recurrence with 21 months minimum follow-up; p < 0.05). The prognostic value of preoperative CEA was apparent only in patients with Dukes' C1 colon tumors. Preoperative CEA values were not of prognostic significance among the rectal adenocarcinoma patients. Although elevated levels of CEA after resection of either colon or rectum cancers were strongly associated with subsequent tumor recurrence, no single CEA value, arbitrarily defined as "elevated", provided an adequate screening test with both high sensitivity and high specificity. Postoperative CEA elevations were more strongly predictive of recurrence when part of a steadily rising trend. In the colon cancer study, the median monthly increase in CEA for disease-free patients was estimated to be zero, and for the relapsed patients 5.8%. The corresponding estimates for patients on the rectal cancer protocol were zero and 7.8%. Only 36 of the 344 disease-free patients on the colon protocol and 14 of the 94 disease-free patients on the rectal protocol (15%) exhibited a rate of increase of CEA as high as 3% per month over the entire period of observation. Two thirds of the relapsed patients on both studies showed a rate of increase this high or higher. The patterns of CEA rise in individual patients were quite varied, however, and monthly rates of increase as established in our study are not to be used as guidelines in patient management.
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