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ABSTRACT & COMMENTARY
Synopsis: The treatment of advanced pancreatic cancer remains generally unsatisfactory, inasmuch as demonstrable responses to chemotherapy or radiation are uncommon and survival is measured in months. In this report, a novel approach to chemotherapy is presented. Fourteen patients received microencapsulated enzymes into the pancreatic tumor bed prior to systemic chemotherapy. The enzymes were selected because of their activation of the chosen chemotherapy. The procedure was well tolerated and definite anti-tumor responses were observed. Although, larger, confirmatory studies need to be performed, the presented approach may represent an advance in the treatment of this disease.
Source: Lohr M, et al. Lancet. 2001;357:1591-1592.
Lohr and colleagues from the university of Rostock (Germany) and other European sites did a phase I/II trial in 14 patients with inoperable pancreatic cancer to assess the safety and efficacy of local activation of low-dose ifosfamide. Prior to chemotherapy, patients received cellulose-encapsulated allogeneic cells by intra-arterial infusion of the tumor bed. The cells expressed cytochrome P450 2B1, as well as other liver enzymes known to activate ifosfamide. The rationale was to present higher levels of the active chemotherapy metabolites within the tumor microenvironment than would be feasible with systemically administered drugs. Prior work in experimental animals with human tumor xenografts had demonstrated complete tumor regression in about 20% of animals and significant tumor regression in the remainder.1-4
Over a 10-month period, Lohr et al enrolled 14 (of a total of 51 evaluated) patients with histologically proven, measurable (by CT scan), but unresectable pancreatic adenocarcinoma (stage III/IV). Patients with prior chemotherapy (n = 8), prior pancreatic surgery (n = 13), or considered in "poor health" (n = 18) were excluded from study. Five eligible patients declined study participation. A historic control group of 36 patients with unresectable pancreatic cancer treated at the same institution was used for survival comparison.
Treatment involved intra-arterial infusion of cells followed by chemotherapy. On day 0, 300 cellulose sulfate capsules (average diameter 0.8 mm, with 104 cells in each) were infused into a suitable artery feeding a primary tumor. Technically, the procedure was successful in 14 of 15 patients in which it was attempted. Temporary spasm of the blood vessel was observed in most cases, but complete occlusion in none. Chemotherapy (ifosfamide, 1 g/m2) was administered intravenously on days 1, 2, and 3 as was a 60% dose of the uroprotective agent, mesna.
Although 12 serious adverse events were recorded in this group of patients, none were attributable to treatment, and there was no evidence for pancreatitis or allergic reaction. With regard to the chemotherapy specifically, no toxicity beyond grade II was observed.
Of the 12 patients who were evaluable, 2 had a greater than 50% reduction in tumor mass (by CT) and 2 had a 25-50% reduction. The remaining 8 patients were shown to have stable disease (tumors 75-125% of the initial size). Treated patients had longer median survival times than controls (10 months [range, 1.5-12] and 5 months [2.5-12], respectively; P = 0.008).
Thus, Lohr et al suggest that this novel approach may be an advance in the treatment of pancreatic cancer and they suggest that additional research is warranted.
COMMENT by William B. Ershler, MD
The treatment of pancreatic cancer remains a challenge. Most frequently, patients present with unresectable tumors and chemotherapy and radiation therapy have done little to extend survival. Thus, novel, experimental approaches are warranted.
The findings reported by Lohr et al appear promising. The concept is intriguing and the approach appears feasible. However, for one reason or another, only 14 of the 51 patients presenting to their research unit with advanced pancreatic disease were evaluable. Several patients were excluded from study because of prior pancreatic surgery or chemotherapy, but over 50% were considered either too ill or unwilling to participate. Thus, generalized applicability remains a question. Yet, for those selected, the vascular procedure was successful in all but one, and was well tolerated by all.
Pancreatic cancer is only one of several malignancies characterized by relentless growth and resistance to chemotherapy and radiation. To the extent that the vascular supply to those tumors can be accessed, using microencapsulated enzymes localized to the tumor microenvironment may be explored. Certainly, tumors in the head and neck region, as well as sarcomas of the trunk or extremities would be reasonable targets for such an approach.
1. Lohr JM, et al. J Mol Med. 1999;77:393-398.