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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 41Regional Chemotherapy

, MD.

The regional delivery of anticancer agents is not a new concept. Following the recognition that cytotoxic alkylating drugs could cause shrinkage of tumors and a reduction in the quantity of malignant ascites in individuals with advanced ovarian cancer, researchers in the 1950s instilled the agents directly into the peritoneal cavity in an effort to treat the malignancy.1 The intrathecal administration of methotrexate in the treatment and prevention of meningeal leukemia,2 intravesical treatment of superficial bladder cancer,3 and direct administration of drugs into blood vessels feeding a localized cancer4 have been evaluated for more than a decade as therapeutic strategies in the management of malignant disease.

Pharmacokinetic Rationale for Regional Chemotherapy

The fundamental aim of regional anticancer drug administration is to deliver a higher concentration of the agent to the tumor present within a particular region of the body, and to expose the tumor to active drug for longer periods of time than safely possible with systemic (generally intravenous) administration.5–9 A favorable pharmacokinetic advantage for exposure of the particular body compartment (e.g., peritoneal cavity, liver, bladder) compared with that of the systemic compartment is measured by demonstrated increases in the peak concentration of drug, a greater AUC (area under concentration versus time curve), or both features (Table 41.1)

Table 41.2. Pharmacokinetic Advantage Associated with Regional Anticancer Drug Administration.

Table 41.2

Pharmacokinetic Advantage Associated with Regional Anticancer Drug Administration.

Table 41.1. Rationale for Regional Anticancer Drug Administration.

Table 41.1

Rationale for Regional Anticancer Drug Administration.

The entire pharmacokinetic advantage observed with regional drug administration occurs during the first passage of the agent through the infused or perfused area. Even if the drug subsequently reaches the cancer through the normal capillary flow into the region, there will be no additional pharmacokinetic benefit associated with this delivery compared with that accomplished through standard systemic administration of the agent.

Mathematical Model (Describing Regional Anticancer Drug Delivery)

The pharmacokinetic advantage resulting from regional drug delivery can be defined by comparing the amount of the agent entering the region following this technique of delivery with that observed with systemic treatment (Table 41.2, Equation 1). Similarly, the relative reduction in systemic exposure resulting from regional drug delivery can be calculated by comparing the concentration of drug found in the systemic compartment after regional and systemic administrations (see Table 41.2, Equation 2).

By combining these two calculations, it is possible to obtain a reasonable estimate of the overall relative pharmacokinetic advantage, which results following the regional delivery of a particular agent or agents (see Table 41.2, Equation 3).

Clinical Implications

Examination of Equation 3 (see Table 41.2) leads to a number of relevant conclusions regarding the clinical utility of regional anticancer drug administration (Table 41.3).

Table 41.3. Opportunities to Improve the Pharmacokinetic Advantage Observed with Regional Anticancer Drug Administration.

Table 41.3

Opportunities to Improve the Pharmacokinetic Advantage Observed with Regional Anticancer Drug Administration.

First, the relative pharmacokinetic advantage associated with regional drug delivery will be enhanced by strategies which either successfully reduce the clearance of the drug from the region and/or enhance the clearance from the systemic circulation. Several examples of approaches which have been examined clinically to increase the pharmacokinetic advantage of regional anticancer drug administration are outlined in Table 41.3.

Second, antineoplastic agents which are unable to be rapidly removed from the systemic compartment after infusion or perfusion through a region (by first-pass metabolism or artificial removal) will be found to possess a relatively less favorable pharmacokinetic advantage, in contrast to agents which do exhibit this important characteristic. However, it is important to emphasize that even under these circumstances, there may still be a valuable contribution associated with regional administration, depending on other clinical variables. For example, there may be inherently slow bloodflow through the region or the cytotoxic agent may be particularly active in the tumor type being treated (e.g., cisplatin in ovarian cancer).

Third, whether the pharmacokinetic advantage observed following the regional delivery of a particular agent is substantial (e.g., > 100-fold) or relatively limited (e.g., 10-fold), this feature of therapy will be only one factor in determining if regional anticancer drug administration is a rational option in a particular clinical setting.

A critical issue is the actual antineoplastic effectiveness of the cytotoxic agent against the particular tumor type to be treated. For example, the regional delivery of a drug with a > 1,000-fold pharmacokinetic advantage (either in peak concentrations or AUC) will not significantly change an essentially inactive agent against a specific malignancy into a useful therapeutic drug.

It is possible, however, that the often substantial increases in tumor-drug interactions, theoretically achievable with regional anticancer drug delivery, will result in enhanced cytotoxicity for cytotoxic agents whose activity is known to be either concentration dependent or cycle specific.10–11 Specifically, in certain clinical circumstances, regional therapy can increase both the peak levels and duration of exposure far beyond what realistically can be accomplished with systemic administration.8

Clinically relevant examples of rational uses of regional anticancer drug therapy include the intraperitoneal delivery of cisplatin in patients with ovarian cancer (20-fold increased exposure to the peritoneal cavity compared with the systemic compartment),12,13 and the hepatic artery infusion of 5-fluorouracil deoxyribonucleside (FUDR) (15-fold higher tumor drug levels compared with portal vein infusion of the drug).14

It is well recognized that there are significant limitations of preclinical models in predicting activity of antineoplastic drugs in patients. However, data demonstrating the relative importance of concentration and duration of exposure in model systems may be helpful in the selection of a drug or drugs for inclusion in human trials of regional anticancer therapy.15

For example, if an in vitro model demonstrates that the administration of 100 times higher concentrations of drug “A” than are achievable with systemic delivery will not lead to a significantly greater degree of tumor cell kill, and the regional pharmacokinetic advantage associated with this drug delivered by a specific technique (e.g., intraperitoneal) is only 10 to 50-fold, drug “A” would not be a very attractive candidate for this method of delivery.

Conversely, if the cytotoxic potential of another agent, drug “B”, is shown to be highly concentration dependent and (at least in theory) the concentration of the agent capable of producing major tumor cell kill can only be attained following regional administration (e.g., hepatic arterial infusion for colon cancer metastatic to the liver), drug “B” might be an ideal agent to consider for regional therapy.

Theoretical Concerns

Despite the attraction of regional anticancer drug delivery in the treatment of malignant conditions principally confined to a particular body region, a number of theoretical objections can be raised regarding the clinical relevance of this therapeutic concept.

First, even accepting the theoretical argument that the enhanced tumor-drug interactions (higher peak levels and AUC) which result from regional anticancer therapy will result in enhanced cytotoxicity, there is appropriate concern that the delivery of the agent to malignant tissue which is not in direct contact with the perfused/infused area will not benefit from this approach.

In addition, except for regional treatments employing the vascular compartment (e.g., intra-arterial chemotherapy), it might be suggested that delivery of drug to the tumor by capillary flow following regional therapy actually will be reduced, resulting in a negative impact on therapeutic efficacy. In fact, consideration of this issue leads to the conclusion that it is critically important in early trials of a particular strategy to measure drug levels in the systemic compartment following regional delivery. If insufficient drug concentrations are discovered in the systemic compartment after regional administration, it may be necessary to treat patients both regionally and by the systemic route to achieve optimal therapeutic results.

Second, it is now well recognized that despite the extremely high concentrations of cytotoxic agents achievable at the surface of a solid tumor following regional administration, the depth of penetration of these drugs directly into solid tumor tissue is actually quite limited (several cell layers 1 to2 millimeters from the surface).16–21

Therefore, it should not be surprising that the enhancement in tissue concentrations of cytotoxic anticancer agents following regional administration, compared with standard systemic drug treatment, is modest, despite the often dramatic increases in drug concentration measurable in the plasma or body compartment containing the tumor.

This issue is particularly relevant for regional strategies which do not employ the vascular compartment. In this setting, any therapeutic advantage associated with regional drug delivery must rely exclusively on the direct uptake of the agent from the body compartment.

The foregoing discussion leads to the logical conclusion that regional anticancer drug therapy should have its greatest theoretical potential to favorably influence clinical outcome in individuals with very small tumor nodules or microscopic disease only in the body compartment perfused or infused. Under these circumstances, the largest possible tumor volume will be exposed to the higher cytotoxic drug levels achievable with regional drug delivery. Support for this therapeutic concept is provided by clinical data examining the influence of tumor volume in determining the activity of intraperitoneal chemotherapy in the management of ovarian cancer.22

A third theoretical concern for regional anticancer drug delivery relates to the unique characteristics of specific techniques. For example, data from preclinical systems have demonstrated rather convincingly that when a drug is instilled into a rapidly flowing blood vessel, the agent will not mix completely in the plasma. This process (“streaming effect”) may result in nonuniform distribution of the agent in the perfused tissue.23,24 The impact of this laboratory observation at the clinical level is unknown. However, it is possible that regions of the cancer within the organ being perfused will be exposed to significantly lower concentrations of the antineoplastic agent than are necessary to achieve the desired cytotoxic effect.

A second example of a concern related to specific regional anticancer delivery strategies is that of the potential for inadequate distribution of an agent instilled directly into a body cavity.25–27 As the bloodflow through the region is not employed to deliver the drug to the tumor, there is legitimate concern that portions of the compartment (e.g., pleura, peritoneum) will not be exposed to the high concentrations of the cytotoxic agent. This may be secondary to interference with uniform distribution by the presence of tumor, adhesions, or even normal organs (e.g., bowel).

Practical Issues

Several important practical concerns must also be addressed when designing an experimental regional drug delivery approach or when employing a standard regional treatment strategy in the management of malignant disease (Table 41.4).

Table 41.4. Practical Considerations in Regional Anticancer Drug Administration.

Table 41.4

Practical Considerations in Regional Anticancer Drug Administration.

The establishment of a safe, convenient, and cost-effective technique for regional drug delivery is an important issue in the development of effective therapy for routine clinical use. For example, while it is certainly possible to insert a peritoneal dialysis catheter with each intraperitoneal treatment, this technique of drug delivery will likely seriously restrict the general application of this regional treatment strategy. First, only a limited number of physicians will feel comfortable placing these catheters in individuals who have previously undergone one or more abdominal surgeries and who do not currently have ascites. Second, the resources and time required for this method of drug delivery can be considerable. Finally, even if catheter placement is employed by well-trained physicians, there is a finite risk that insertion without direct visualization of the peritoneal cavity can result in bowel puncture and associated complications.28,29

In achieving access for intra-arterial therapy, the time, effort, and potential complications can pose even more serious concerns.30,31 For patients being considered for more than one or two courses of intra-arterial therapy, the surgical placement of a semipermanent delivery system would appear to be a more satisfactory technique for regional drug delivery than catheter insertion with each treatment.31–33 This strategy would also be relevant for individuals who are scheduled to receive weekly or more frequent intrathecal drug delivery for either the treatment or prevention of meningeal leukemia.34,35

It is also important to consider the unique potential toxicities associated with regional anticancer drug delivery. The side-effect profile of a particular agent may be well defined with systemic delivery at a standard dose level. However, the toxicity to normal tissues perfused or infused with the often extremely high concentrations attainable following regional administration potentially may be excessive. For example, the intrahepatic artery delivery of FUDR has been shown to be associated with development of biliary cirrhosis and sclerosing cholangitis.36,37 The intraperitoneal administration of a number of cytotoxic antineoplastic agents (e.g., doxorubicin, mitoxantrone) may result in severe abdominal pain, chemical peritonitis, extensive adhesion formation, and subsequent bowel obstruction.8,38,39

In addition, several proposed regional anticancer drug delivery techniques require extensive surgery (e.g., isolation-perfusion of mesenteric arterial vessels, hyperthermic intraperitoneal chemotherapy). Others have been demonstrated to be associated with considerable risk for the development of serious morbidity or even death.40–42 Such approaches will require extensive evaluation and a demonstrated impact on survival through the conduct of well-designed and conducted randomized trials. Until such results are available, these therapeutic strategies must continue to be considered highly experimental treatment programs and not accepted as routine or standard clinical practice.

It is important to note that even regional anticancer drug delivery approaches which do not require such intensity of treatment, or are not associated with excessive toxicity, will require the conduct of randomized trials to be certain the theoretical advantages of the novel therapeutic technique can be translated into actual clinical benefit.

Clinical Examples

Intrathecal Therapy for the Prevention and Treatment of Meningeal Leukemia

One of the most established regional anticancer drug delivery strategies is that employed to either prevent or treat established leukemia in the central nervous system.2,43–45 In well-defined clinical settings, the risk of developing meningeal leukemia has been shown to be significantly reduced following the prophylactic intrathecal or intraventricular administration of cytotoxic chemotherapy. In addition, established meningeal leukemia (documented by cerebral spinal fluid cytology) can also be treated effectively in many circumstances with a number of regional antineoplastic drug programs.

Intraperitoneal Chemotherapy in the Management of Ovarian Cancer

While intraperitoneal drug delivery has been evaluated in phase II clinical trials for more than a decade,46 the true clinical potential of this unique therapeutic strategy has more recently been examined in two large randomized phase III trials.47,48 In a landmark study conducted by the Southwest Oncology Group and the Gynecologic Oncology Group, involving more than 600 newly diagnosed women with small-volume residual advanced ovarian cancer (stage III) following surgical cytoreduction, the intraperitoneal delivery of cisplatin (in combination with intravenous cyclophosphamide) was documented to result in a statistically significant improvement in overall survival (20% decrease in risk of death), compared with a control treatment program of intravenous cisplatin plus intravenous cyclophosphamide.47

A second randomized trial comparing a standard intravenous cisplatin/paclitaxel program with a regimen of intravenous paclitaxel and intraperitoneal cisplatin has reached similar conclusions.48 This study, also involving newly diagnosed advanced ovarian cancer patients with small-volume residual disease, revealed that the use of the regional cisplatin strategy was associated with a statistically significant improvement in progression-free survival, and borderline improvement in overall survival. Of importance to the overall validity of the conclusions reached in the two intraperitoneal trials, the second study also revealed a 20% reduction in the risk of death associated with regional cisplatin administration. It should be noted that this second study employed two courses of moderately dose-intensive intravenous carboplatin (AUC 9) prior to the administration of the regional program, designed to “chemically debulk” any residual tumor nodules before the use of the regional drug delivery strategy.

Intrahepatic Arterial Therapy for Colon Cancer Metastatic to the Liver

Several randomized phase III trials have demonstrated a higher objective response rate associated with the direct intrahepatic arterial administration of FUDR, compared with systemic delivery of the agent, in the treatment of colon cancer metastatic to the liver.49–55 There has been criticism of a number of these studies due to the fact a “cross-over design” was utilized, whereby the individuals randomized to systemic treatment were allowed to be treated with the regional strategy at the time of disease progression. The impact of this cross-over on the ultimate outcome has been debated extensively in the medical literature.

Questions have also been raised regarding the overall benefits of this strategy, in view of the morbidity and costs of the regional treatment approach. However, data available though the conduct of these trials do support the clinical utility of the therapeutic strategy in carefully selected individuals with colon cancer metastatic to the liver. These clinical features include the presence of an adequate performance status, absence of serious comorbid medical conditions which may increase the potential for serious toxicity associated with the program, and the demonstration that the metastatic process is confined to the liver.

Further support for the clinical utility of hepatic arterial therapy comes from the preliminary report of a randomized trial examining this regional strategy in patients who had undergone surgical resection of hepatic metastatic disease from colon cancer.56 Individuals treated in this study received adjuvant chemotherapy following surgery either with hepatic arterial FUDR plus systemic fluorouracil and leucovorin, or systemic chemotherapy alone. In the more than 150 patients entered into this trial, both 2-year overall survival (p = .023) and progression-free survival in the liver (p = .000012) were significantly improved in the patient population receiving the combined regional and systemic treatment approach.

Intravesical Therapy of Localized Bladder Cancer

The intravesical delivery of both cytotoxic (e.g., mitomycin, thiotepa, doxorubicin) and biologic (BCG [Bacillus Calmette-Guérin]) agents has been demonstrated to be effective treatment of superficial bladder cancer and carcinoma in situ of the bladder.57–58

The ease of administering high concentrations of antineoplastic drugs directly into the bladder and the simplicity of measuring the effects of treatment through the performance of urinary cytology and/or bladder wall biopsy make the bladder an ideal organ to employ regional therapy.

Intravesical antineoplastic therapy has been shown to prevent the progression of superficial cancer to invasive disease and reduce the requirement for more radical surgical interventions, including the performance of a cystectomy.

Conclusion

Over the past decade the regional administration of antineoplastic drugs has evolved from a theoretical concept to a rational treatment strategy in a number of clinical settings.

The often profound pharmacokinetic advantage associated with regional drug delivery is appealing, but a number of theoretical and practical issues limit the patient populations where this therapeutic approach is a reasonable option in both clinical trials and standard oncologic practice.

In a number of clinical settings, randomized controlled trials continue to be required to demonstrate if the potential for enhanced tumor cell kill associated with increased drug concentrations and more prolonged exposure can be translated into improved outcomes for patients with malignant disease.

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