Localized Chemotherapy Delivery: A Brief Review

HAI Chemotherapy

The concept of treating malignancies using a regional approach originated in 1950, when Klopp and associates began to infuse nitrogen mustard into the arterial supply of various neoplasms.^1,2 HAI chemotherapy was developed by Watkins and Sullivan, who placed a Tefl on catheter into the common hepatic artery and administered 5-fl uorouracil (5-FU) or 2’-Deoxy-5-fl uorouridine (FUDR) with the aid of an external infusion pump.^3,4 While this and other early systems were relatively labor-intensive and subject to multiple complications, subsequent advances in techniques and technology now make this method of administering therapy a viable option for many patients who are eligible to receive it.

Nearly all chemotherapeutic agents have a low therapeutic index, and because of the limited efficacy of most chemotherapeutic agents against the majority of solid tumors, the primary goal of regional chemotherapy is to deliver a higher concentration and total dose of drug to the tumor bed than can be safely achieved by a systemic infusion. Many classic antineoplastic agents exhibit steep dose-response curves, particularly alkylating agents. The ability to deliver higher doses locally should increase their cytocidal efficacy while also minimizing toxicity to uninvolved tissues, which is possible because of the extensive hepatic extraction of the drugs currently used, such as fl uorinated pyrimidines; the level of fi rst-pass extraction is a significant factor in reducing systemic toxicity. Most agents used in HAI chemotherapy also have high total body clearance and short plasma half-lives. On the basis of their pharmacokinetic profiles, drugs such as cisplatin, mitomycin C, and BCNU (carmustine) are good agents, with a 4- to 8-fold increase in drug exposure to the tumor bed by using the hepatic arterial route of administration versus intravenous delivery. Although most alkylating agents have limited efficacy against the majority of common cancers, such as gastrointestinal malignancies, the agents most often used for HAI chemotherapy, 5-FU and FUDR, have a 10- and a 400-fold increase in drug exposure, respectively, when given as HAI chemotherapy. Because of the substantial amount of drug extraction, the concentration of drug within normal hepatocytes usually exceeds that which is found in tumor tissue, where uptake may be heterogeneous. For example, a study by Sigurdson and associates documented that the liver-to-tumor ratio of the concentration of FUDR in metastatic colorectal carcinoma cells was 2.35:1.⁵ Therefore, while the liver is capable of tolerating high doses of chemotherapeutic agents due to its tremendous functional reserve and high regenerative capacity, HAI chemotherapy is associated with an increased risk of hepatotoxicity.

Many studies of HAI chemotherapy have focused on the treatment of colorectal carcinoma because of its predilection for developing liver-predominant metastatic disease. Although there are sound pharmacokinetic reasons for employing HAI chemotherapy, a clear benefit has been difficult to prove in a randomized fashion. Two randomized trials have been reported, one by the Medical Research Council (MRC) and European Organization for the Research and Treatment of Cancer (EORTC) and a separate North American trial by the Cancer and Leukemia Group B (CALGB).^6,7 The MRC/EORTC trial compared HAI chemotherapy with systemic chemotherapy,6 and both arms received 5-FU and leucovorin; no crossover was allowed. HAI chemotherapy was found to have equivalent toxicity to systemic delivery of these agents, which had been demonstrated by a prior phase I trial^.8 Although the authors reported no difference in objective response rates or median overall or progression-free survival between the two arms, the median progression-free survival was numerically superior in the HAI chemotherapy arm at 7.7 months versus 6.7 months in the systemic therapy arm. The significance of the study’s overall results, however, is unclear because the trial was hampered by technical difficulties. Of the patients randomized to HAI chemotherapy, 37% (n = 50) did not receive this treatment because of technical factors, such as aberrant arterial supply or catheter malfunction, and another 29% received fewer than six cycles of treatment because of catheter malfunction. The trial also fell short of its planned accrual of 312 patients, enrolling only 290 patients.

In contrast, the CALGB trial, which compared an HAI chemotherapy regimen of FUDR, leucovorin, and dexamethasone with systemic administration of 5-FU and leucovorin, demonstrated a superior rate of response for infusional treatment at 47% versus 24% for systemic delivery.⁷ The HAI treatment arm also had a greater than 4-month overall survival benefit compared with the systemic treatment arm at 24.4 months versus 20 months, respectively. Additionally, quality-of-life assessments showed improved physical functioning for the HAI chemotherapy arm at 3- and 6-month follow-up. While these results are promising, a definitive answer on the potential magnitude of benefit of HAI chemotherapy in colorectal cancer remains to be answered because this trial missed its accrual goal by nearly half, enrolling only 135 of a planned 340 patients.

HAI chemotherapy using newer agents, such as irinotecan and oxaliplatin, are also being evaluated; however, it is likely that this chemotherapy delivery method will remain investigational because of the lack of evidence of a broad benefit, technical difficulties in administering this treatment, and the knowledge that colorectal cancer truly is a systemic disease for the vast majority of patients. Regardless, HAI chemotherapy could be beneficial for a highly selected group of patients, and further investigations are warranted.

Intraperitoneal Chemotherapy

Peritoneal carcinomatosis is a sign of an advanced tumor stage and is considered an unresectable disease, except in the case of ovarian cancer, where aggressive cytoreductive surgery has demonstrated a survival benefi t when combined with effective chemotherapy. Because surgery has yet to demonstrate a clear benefit for most peritoneal carcinomatosis cases, it is usually not performed outside of a clinical trial setting, and then only at select centers that specialize in this therapy.

Peritoneal carcinomatosis is generally associated with a poor prognosis, with a survival of less than 6 months for the majority of patients with malignancies of gut origin. Patients with ovarian cancer can survive considerably longer, with many living more than a year.⁹ Most patients with these malignancies are offered palliative care options, such as systemic chemotherapy, or surgery for the management of specific focal problems, such and bleeding, pain, obstruction, or perforation. Patients with ovarian cancer can also undergo aggressive cytoreductive surgery, which has been demonstrated to improve overall survival.¹⁰

Since the early 1990s, multiple centers in North America, Japan, and Europe have been evaluating a combination of surgical cytoreduction of peritoneal neoplasms in combination with hyperthermic intraperitoneal chemotherapy, most often using cisplatin or mitomycin C-based regimens. The goal of surgery is to completely resect all grossly visible disease before administration of intraperitoneal therapy because of the limited depth of penetration of most chemotherapeutic agents into tissues when directly applied. Intraperitoneal delivery, however, should allow for greater local concentrations of the agent, while reducing the systemic levels of the agent and its potential toxicities. The concomitant heating of the chemotherapeutic solution may augment the cytotoxic activity of the chemotherapy, and the heat itself can be directly cytotoxic.¹¹ An intraperitoneal temperature of 42°C is typically achieved and maintained for 30 to 120 minutes. Although the procedure is technically complex, mortality is often quite low (usually less than 5%) when administered by an experienced clinician; however, substantial perioperative morbidity may occur in up to 40% of patients, including ileus, infection, or hemostatic complications. Despite the potential for less chemotherapy-related adverse effects with lower systemic concentrations, chemotherapy-related toxicities still occur.

In selected patients, complete surgical cytoreduction with hyperthermic intraperitoneal chemotherapy may provide a survival benefi t. Most of the data demonstrating this have been derived from phase II trials and observational reports of a series of patients, with subsequent historical comparisons. One such trial included 105 patients with colorectal cancer who were randomized to receive intraperitoneal therapy followed by intravenous 5-FU and leucovorin or to systemic therapy alone with 5-FU and leucovorin.¹² The study noted a 10-month improvement in overall survival with the addition of local therapy, extending it to a median of 22.3 months compared with 12.6 months with systemic therapy alone.¹² A 5-FU and leucovorin regimen is no longer considered the standard of care for the palliative treatment of medically fi t patients with advanced colorectal cancer; only six patients in the trial subsequently received irinotecan and none were reported to have received oxaliplatin or bevacizumab. Patients with colorectal cancer who receive irinotecan, bevacizumab, and oxaliplatin can expect median survivals of 2 years; thus, it is unclear what impact intraperitoneal therapy may have in comparison with, or in addition to, standard optimal systemic chemotherapy in this patient population.

The localized administration of antineoplastic agents is relatively well tolerated, though technically more diffi cult to deliver than systemic administration. While the arterial or intraperitoneal administration of chemotherapy may not be readily performed in the community setting because of the technology required, most larger institutions have interventional radiologists and surgeons on staff who are capable of placing intra-arterial access catheters and devices; however, a multimodality approach to the maintenance of such access and the administration of therapy may not be immediately available. Intraperitoneal therapy is further limited to a handful of high-volume centers that maintain expertise in such procedures. Currently, the technical complexities, intense use of resources associated with the administration of localized cancer chemotherapy in an uncertain economic climate, lack of data supporting the broad use of such procedures in large unselected patient populations, and the development of more effective systemic therapies prohibit the widespread use of localized administration of chemotherapeutic agents. Clinicians must decide who will receive regional treatments on a case-by-case basis, and this is often best performed in the clinical research setting. Further study of regional techniques in well-designed clinical trials is important to identify those patients who may best benefi t from locally administered antineoplastic therapy.

M. Houman Fekrazad, MD, and Dennie V. Jones, Jr, MD, practice in the division of hematology/oncology at the University of New Mexico Cancer Center, Albuquerque, New Mexico.

REFERENCES

1. Klopp CT, Alford TC, Bateman J, et al. Fractionated intra-arterial cancer; chemotherapy with methyl bisamine hydrochloride; a preliminary report. Trans Meet Am Surg Assoc. 1950;68:490-511. No abstract available.

2. Barberio JR, Klopp CT, Ayres WW, Gross HA. Effects of intra-arterial administration of nitrogen mustard. Cancer. 1951;4(6):1341-1363. No abstract available.

3. Watkins E Jr, Sullivan RD. Cancer chemotherapy by prolonged arterial infusion. Surg Gynecol Obstet. 1964;118:3- 19. No abstract available.

4. Sullivan RD, Norcross JW, Watkins E Jr. Chemotherapy of metastatic liver cancer by prolonged hepatic-artery infusion. N Engl J Med. 1964;270:321-327. No abstract available.

5. Sigurdson ER, Ridge JA, Daly JM. Fluorodeoxyuridine uptake by human colorectal hepatic metastases after hepatic artery infusion. Surgery. 1986;100(2):285-291. Abstract available at: http://tinyurl.com/yjhycfn.

6. Kerr DJ, McArdle CS, Ledermann J, et al; Medical Research Council’s colorectal cancer study group; European Organisation for Research and Treatment of Cancer colorectal cancer study group. Intrahepatic arterial versus intravenous fl uorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomized trial. Lancet. 2003;361(9355):368-373. Abstract available at: http://tinyurl.com/yfues7p.

7. Kemeny NE, Niedzwiecki D, Hollis DR, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol. 2006;24(9):1395-1403. Abstract available at: http://tinyurl.com/ykhfmcy.

8. Kerr DJ, Ledermann JA, McArdle CS, et al. Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial fluorouracil. J Clin Oncol. 1995;13(12):2968-2972. Abstract available at: http://tinyurl.com/yhgg8o6.

9. Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer. 2000;88(2):358-363. Abstract available at: http://tinyurl.com/yfg9z3q.

10. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20(5):1248-1259. Abstract available at: http://tinyurl.com/yzsw3sa.

11. Sugarbaker PH. Laboratory and clinical basis for hyperthermia as a component of intracavitary chemotherapy. Int J Hyperthermia. 2007;23(5):431-442. Abstract available at: http://tinyurl.com/yj8g5kj.

12. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21(20):3737-3743. Abstract available at: http://tinyurl.com/yz3c6np.