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Abstract & Commentary
Synopsis: The most common life-threatening manifestation of cancer is disease involving the liver. Barring surgery, there is no single predominant technique that offers durable local control in patients with unresectable malignant lesions in the liver. This study from Europe has reported the results of a Phase II trial evaluating CT-guided intralesional injections of chemotherapy. They found that achieving local control is possible in both cohorts studied, including primary hepatocellular carcinoma patients and metastatic colorectal carcinoma patients.Source: Vogl TJ, et al. Br J Cancer. 2002;86:524-529.
Vogl and colleagues at the university of frankfurt reported on results of their Phase II trial of percutaneous injections of cisplatin gel into primary hepatocellular carcinomas (HCC) and metastases from colorectal cancer (CRC). Seventeen patients participated in the study, all of whom had biopsy-proven progression of their liver disease following other treatment, including systemic chemotherapy, chemoembolization, and liver resection. No patient had evidence of extrahepatic disease, and no patient had > 3 liver lesions. There were 9 patients with 13 unresectable lesions from primary hepatocellular carcinoma, and 8 patients with 17 unresectable colorectal metastases. The average age was 67 years (range, 39-79), and there were 13 males and 4 females.
The injected agent consisted of cisplatin in a biodegradable bovine collagen carrier gel matrix, along with epinephrine used as a vasoconstrictor to keep the cisplatin from dispersing away from the injection site through local blood vessels. Each patient was hydrated prior to being injected. The number of injections per patient depended on the size of the lesions and the patient’s overall condition. Up to 4 weekly administrations were used per injection cycle, with a maximum of 40 mg of cisplatin in 10 cc of gel per session. The HCC patients averaged 3.1 injections (range, 1-4) and the CRC patients averaged 5.1 injections per patient (range, 1-8). A 19.5 gauge CT-guided needle with 6 side holes was used for injecting, and the various localizations per lesion were manipulated through a CT guidance system. Either 1 or 2 injection cycles were carried out, at the discretion of the physician. Responses were assessed by CT imaging at 2 weeks, 8 weeks, and 6 months, and by examination or phone interview every 3 months thereafter.
Initial median tumor volume in the HCC patients was 16 cc (range, 1-113 cc), and 107 cc in the CRC patients (range, 2-125 cc). Tumor volumes were further broken down into viable and necrotic components by CT volumetric evaluation.
Local control, defined as complete inactivity of the treated lesion at 3 and 6 months, was established in 70% of HCC lesions treated, and 38% of CRC lesions. Despite this, the volume of viable tumor in the liver did not drop significantly in either group. There were no reported cisplatin toxicities, and the treatment was well tolerated. Some patients exhibited transient subclinical elevations in their liver enzymes. Median survival for the entire group was 10.1 months. All except 2 patients died of overall disease progression by the conclusion of the study.
Available modalities for palliation of malignant disease in the liver include systemic chemotherapy, chemoembolization, ethanol injections, radiofrequency ablation, and laser thermotherapy. Cryotherapy has also been used, as has intrahepatic arterial and intralesional administration of radioactive microspheres. Vogl et al took an approach previously reported by them for palliation of head and neck lesions,1 and applied it to palliation of liver tumors. The advantages of this type of local chemotherapy administration are: 20-30 times higher cisplatin concentrations than that achievable with systemic administration, direct injection of every segment of a lesion regardless of its perfusion by vessels, and slow dispersion of cisplatin from the injection site. The latter is due to reduced blood flow as a result of the epinephrine in the gel, as well as tumor vessel compression by the gel bolus, and tumor vessel occlusion by the gel itself.
Vogl et al reported that this therapy was safe and effective, without major toxicity. Suggestions for future improvements are the establishment of optimum tumor size criteria, and better visualization of the gel. There were too few patients in the study to draw meaningful conclusions other than to say that this technique warrants additional investigation.
To my knowledge, there is only one similar chemotherapy product which has been FDA approved for implantation into tumors, and that is the Gliadelâ wafer used for applying carmustine directly onto the resection bed of recurrent high-grade gliomas. There is a small body of literature exploring the integration of external beam radiotherapy used in conjunction with implanted chemotherapy, and this remains an intriguing, albeit esoteric, area of investigation. Attawia et al described an in vitro system of Ewing’s sarcoma cells cultured with taxol-loaded microspheres, and demonstrated that taxol can be effectively released from a biodegradable system to serve as a radiosensitizer with much larger reductions in tumor cell counts than in control cultures.2 Similarly, Yapp and colleagues have shown synergistic effects between implanted cisplatin-impregnated polymer and radiation administered in mouse tumor models.3
Implantable chemotherapy is a relatively new area of oncology that holds interesting prospects for the future. The paper by Vogl et al is likely to be one of the first of many in this young field.
Dr. Kaplan is Acting Chairman, Department of Radiation Oncology, Cleveland Clinic Florida, Ft. Lauderdale, FL; Medical Director, Boca Raton Radiation Therapy Regional Center, Deerfield Beach, FL.