Clinical Applications of Continuous Infusion Chemotherapy and Concomitant Radiation Therapy

Most anti-cancer drugs produce toxic side-effects at the doses used for treatment. This low therapeutic index, or ratio between therapeutic and toxic doses, has prompted various approaches towards increasing the selectivity of cancer chemotherapy. Perhaps the most successful of these has been the use of combination chemotherapy, which increased the therapeutic ratio by combining drugs with non-overlapping side-effects and in some cases lowering individual doses. This approach over the last twenty years has resulted in the cure of several types of cancer (leukemias, Hodgkin’s and non-Hodgkin’s lymphomas, germ cell cancers). The use of drugs in combination is not curative for most human solid tumors, however, and in fact may increase toxicity without increasing therapeutic efficacy for tumors which are refractory to the drugs employed.

Bleomycin was isolated by Umezawa¹. It has been in clinical use for more than 15 years. The initial clinical studies performed by Ichikawa, et al² demonstrated useful activity in the squamous carcinomas. Subsequent studies have demonstrated useful therapeutic activity in lymphomas and germ cell tumors^3–5.

The use of adriamycin is frequently limited by the development of a cumulative-dose-dependent cardiomyopathy, which increases substantially in incidence at doses ≥550 mg/m². To avoid the potential development of fatal refractory congestive heart failure (CHF), dose limitation to 450–550 mg/m²has been recommended by a variety of authors.^1–3Since an oncologist may not wish to stop treatment of an individual patient at an arbitrary level, a considerable investment of time and resources has been made in an effort to extend the use of adriamycin or develop analogs with diminished cardiotoxicity to accomplish the same aim.

5-Fluorouracil (FUra) has been the drug of choice in the treatment of colorectal cancers (1,2), and it is widely utilized in a variety of other malignancies (3). FUra exerts its antiproliferative effect following metabolic activation to various nucleotides (Chart 1). 5-Fluorouridine triphosphate (FUTP), due to its resemblance with uridine triphosphate (UTP), is incorporated into RNA (4–7); the consequence of this incorporation is the production of fraudulent mRNA, rRNA and tRNA which can ultimately cause cell death. The other proposed mechanism for FUra cytotoxicity is the inhibition of thymidylate synthetase (dTMP-S) by 5-fluorodeoxyuridine monophosphate (FdUMP) (8–11), leading to decreased thymidine triphosphate (dTTP) pools and to inhibition of DNA synthesis. The biochemical mechanism by which FdUMP binds to the dTMP-S involves a cofactor, N^5,10methylene tetrahydrofolic acid (N^5,10CH₂FH₄). Santi et al. have calculated that the dissociation constant (Kd) of the ternary complex FdUMP-dTMP-SN^5,10CH₂FH₄, is of the order of 5×10^-11M. In absence of the reduced folate cofactor, FdUMP binding to dTMP-S is relatively weak, with a Kd of about 10^-5M (9). An additional proposed mechanism of cytotoxicity of FUra is its incorporation into DNA (12–15). To date, little is known about the biological significance of this finding.

The Epipodophyllotoxins, VP16-213 and VM26, and the heavy metal cytotoxic agents, Cisplatin and its analogs, Spirogermanium and Gallium, represent two classes of agents which in clinical trials are traditionally delivered on an intermittent bolus schedule. Extensive clinical reviews of the clinical trials employing these agents have not emphasized the continuous infusion schedule (1–3). In fact, the thrust has been directed toward maximizing the dose of delivery on an intermittent bolus schedule to increase therapeutic effects (4,5). Such has been the traditional approach to cancer chemotherapy in general based upon the concept of the dose-response relationship developed in experimental tumor systems and upon practical issues involving patient convenience and outpatient delivery. Such precepts have been the basic tenets for the day one and eight schedule for such programs as MOPP chemotherapy for Hodgkin’s disease and the CMF program for breast cancer.

Spherex is a medical device which produces controlled occlusion of arterial vessels for a half life of 15′, governed by serum amylase digestion. The purposes of this study were to determine the feasibility and toxicity of the use of Spherex with standard chemotherapeutic agents for the treatment of unresectable cancers of the liver.

Twenty two patients with advanced cancer involving the liver were treated with hepatic arterial (HA) chemotherapy mixed with 900mg of 45µ biodegradable starch microspheres (Spherex-Pharmacia) in a phase II study of Spherex combined with standard chemotherapy. Thirteen patients were treated repeatedly via permanent HA catheters placed operatively using subcutaneous ports whereas 9 patients received their treatments through percutaneously femoral placed HA catheters.

Seven patients of 22 treated clearly showed regression of liver metastases with 4 showing improvement in quality of life. All but one patient studied had >50% tumor liver replacement. Twelve colorectal patients received 5FU 600mg/m² day 1 and mitomycin, 10mg/m² day 3 in 28 day cycles. Adriamycin, 30mg/m², was used to treat one breast cancer patient; and 2 hepatoma patients with a significant partial remission of 9 months in the patient with breast cancer. Five patients received BCNU 100–200mg; 3 with melanoma with one dramatic response that lasted 7 months; one epidermoid carcinoma responded to 2 courses of BCNU and one of thiotepa with dramatic regression and clinical improvement and is still alive at 10 months. One patient, a systemic FAM failure, has responded to 5FU/mito and 5FU alone x 3 courses. Eight patients had one course, 3:2, 3:3, 4:5, 1:5, 1:7, 1:8, 1:14 of Spherex/chemotherapy.

Mild hematologic toxicity was present in only one patient and only 1 of 22 patients had a complication with duodenitis from improper catheter placement. Transient pain in liver and nausea and vomiting were the major toxicities seen.

From our Phase II study, we feel that Spherex chemotherapy can be repeatedly administered via the HA as a convenient palliative approach to liver metastatic or primary disease. The advantages of Spherex HA occlusion combined with chemotherapy relate to the fact that 85–95% of the blood supply to metastatic carcinoma of the liver is of HA origin and Spherex achieves a tumor ischemia combined with an increase in chemotherapy concentration to the HA bed with minimal systemic toxicity.

This study demonstrates the safety and convenience of Spherex/chemotherapy combinations, but the therapeutic advantages of Spherex over other forms of hepatic arterial occlusion or chemotherapy can only be inferred unless a larger controlled or comparative study is undertaken.

Spherex occlusion has also been used experimentally in Sweden to produce transient ischemia of bowel and peripheral limbs to protect target organs from radiation injury during the occlusive period. Hyperthermia to liver metastasis can be regionally enhanced during Spherex administration and this approach deserves study.

Regional chemotherapy is based on the premise that many chemotherapeutic agents display a steep dose response for toxicity and for therapeutic effect. Regional chemotherapy administration represents a means to generate increased drug exposure in the region where the tumor resides, while maintaining a lower drug exposure at the level of dose-limiting normal host tissues elsewhere in the body. Thus, even in circumstances where systemically administered chemotherapy is relatively ineffective, regional chemotherapy may improve the likelihood of response by the generation of much greater drug exposure. With sufficient regional selectivity, dose-limiting toxicity should be manifested by the normal tissues of the region infused and not by tissues elsewhere in the body. In this regard, regional chemotherapy has similarities to radiation therapy, but may be more selective in those situations where tumor and normal tissue in the treated region differ significantly in intrinsic drug sensitivity and blood supply.

Development of a totally implantable infusion pump produced a renewed interest in hepatic infusional therapy. An initial study employing this pump and continuous hepatic infusion of FUDR produced an 83% response rate¹. However, further work with this method brought the mean response rate down to 59%²which, however, is still higher than the mean response rate obtained with systemic chemotherapy.

Early in 1977, a new combination chemotherapy program was initiated at the New York Hospital-Cornell Medical Center for large cell lymphoma (LCL). This program, known as COPBLAM: {cyclophosphamide, Oncovin, (vincristine), prednisone, bleomycin, Adriamycin, Matulane (procarbazine)} was an intensive multidrug regimen designed to maximize tumor cell kill¹. Unique to this treatment for LCL was the incorporation of then novel concepts and features which were as follows:

The beneficial effect of adjuvant chemotherapy to surgery in children with resectable hepatoblastoma and hepatocellular carcinoma has been documented. However, the same chemotherapy regimens have failed to improve survival for patients with unresectable disease.

The combination of adriamycin and vincristine administered as bolus injections have antitumoral activity in pediatric cases; however there are no published reports of concomitant constant infusion vincristine and adriamycin. Due to their short serum half-life, it seems reasonable that an improvement in their therapeutic index might occur if these drugs were given as a continuous infusion. In support of this, there is published evidence of reduced cardiotoxic effects in adults for adriamycin when it was administered as a constant effusion (1). We considered it reasonable to evaluate the clinical effects of the combination administered as a constant infusion in patients who were considered refractory to these same drugs given as bolus injections.

Thirteen patients with acute non-lymphocytic leukemia (ANLL) or myelodysplastic syndrome (MDS) were treated with low-dose cytosine arabinoside (Ara-C) 20 mg/m²/day by continuous intravenous infusion for 21 days. Seven patients attained complete remissions (CR) and two patients had partial remissions (PR). Two patients required two courses of treatment before attaining CR. Two of four patients with abnormal cytogenetics also achieved complete response with reversion of cytogenetic abnormalities to normal. All patients who responded showed profound pancytopenia with marked hypoplasia of bone marrow. The universal occurrence of pancytopenia and reversion of cytogenetic abnormalities to normal suggests that low-dose Ara-C is cytotoxic and may not act as a differentiating agent.

Cis-Diamminodichloroplatinum (II), or DDP, has been shown to be an effective agent in the treament of various neoplastic diseases. The drug has been usually administered in high intravenous (IV) bolus dose, or rapid infusion. By these schedules, the toxicity of DDP included severe nausea and vomiting, nephrotoxicity, mild to moderate myelosuppression, and hearing loss¹. Renal and gastrointestinal toxicities were dose-limiting and constituted major obstacles to prlonged therapy. Although nephrotoxicity was partially ameliorated by fluid and mannitol diuresis², it remains a major impediment of long-term treatment. Also, in several studies, nausea and vomiting were so severe that many patients refused to continue treatment.

One of the most difficult problems in the clinical judgement of cancer patients is the determination of the effectiveness of any treatment modality. This is particularly apparent in the evaluation of solid malignancies of the gastrointestinal tract. In 1966, Drs. Lemon and Foley proposed the slow infusion of one gram of 5FU for periods of eight hours daily for 14 days followed by weekly bolus I-V injections of .5 grams 5FU in l0cc of dilutent. They felt that this method was not only effective but also avoided the frequent severe iatrogenic complications of current anti-neoplastic chemotherapy.