Principles of isolated regional perfusion of the extremity or liver

Rationale for regional treatment

There are theoretic advantages of regional perfusion strategies that include the following:

• 1.

  Minimizing systemic exposure and toxicity from the chemotherapeutic agent. By separating the blood flow to the organ or region of interest, chemotherapy can be intentionally delivered to the tumor-bearing area. Systemic exposure to the chemotherapeutic agent is limited to that amount that leaks into the systemic circulation. With no leak, the only toxicity is confined to the treated organ or region.

• 2.

  Chemotherapeutic agents are delivered to the tumor-bearing area at a more effective dose. The therapeutic index is the dose that causes toxicity in 50% of recipient patients divided by the dose that causes regression of tumor in 50% of those treated. For many chemotherapeutic agents, the latter dose is higher than the former so that the therapeutic index is <1. The dose can be escalated if exposure is limited to an organ or region that does not experience significant toxicity from the agent. This brings the therapeutic index to a level significantly greater than 1, resulting in increased efficacy.

• 3.

  The entire tumor-burdened organ or region is treated. This is in contrast to local resection, ablation, or selective embolization procedures. In some instances, a single lesion or oligometastatic disease may be effectively controlled with resection, ablation, or selective embolization. But regional perfusion can encompass a larger distribution and/or volume of tumor burden.

Candidate cancers for regional perfusion

Regional perfusions, theoretically, are most applicable for cancers in which the disease is isolated to an upper extremity, a lower extremity, or the liver. Eradication of the cancer in these cases may result in prolonged disease-free survival. This usually includes a very narrow spectrum of clinical scenarios. By definition, only disease that is in the region of interest is treated by high-dose chemotherapy. But cancers are rarely confined to a region. Most cancers are confined locally to the primary site, metastatic to the regional lymph nodes, or systemically disseminated through hematogenous spread.

There are examples, however, where a regional approach makes sense. In the limb, advanced primary tumors or tumors with lymphatic spread may be susceptible to this approach. In the liver, advanced primaries or metastatic disease isolated to the liver, but not amenable to resection, may be candidates for regional perfusion.

In practice, only melanoma (cutaneous for limb regional perfusion, ocular for hepatic regional perfusion) has been adequately clinically investigated for this approach using single agent melphalan or melphalan-based combination therapies. Regional therapy to the limb or liver for other types of cancer should be considered investigational and completed on a research protocol.

When considering the range of cancers that can be treated with a regional perfusion, it is important to recognize that regional perfusion is a method of chemotherapy delivery and therefore the range of response is similar to systemic chemotherapy. It is not equivalent to ablative therapies like alcohol injection, radiofrequency ablation, or high-frequency focused ultrasound. If systemic chemotherapy kills one type of cancer, it cannot be expected to be equally efficacious if used for a completely different type of cancer, whereas ablative therapies may be used interchangeably against differing histologies.

Responses are dependent on the specific tumor’s susceptibility to the chemotherapy used.

In-transit metastases from cutaneous melanoma

Melanoma often has its primary lesion in the upper or lower extremity and initially treated by wide excision and staging of the regional nodal basin. In a small subset of patients, melanoma will recur as metastases within the lymphatic channels of the limb, either in a dermal or subcutaneous location. These can occur with or without nodal involvement, and without evidence of hematogenous distant spread. This disease pattern is referred to as satellite or in-transit metastases depending on the distance from the primary site (satellite lesions occur within 5 cm of the excised primary). Metastatic lesions can occur between the primary and draining lymph node bed, or on the limb, distal to the primary lesion as so-called retrograde in-transit lesions.

In-transit disease is an infrequent yet clinically significant pattern of spread from a primary melanoma. Between 1991 and 2001, a total of 1395 patients at the M.D. Anderson Cancer Center had their primary lesion treated with wide local excision and sentinel lymph node biopsy to assess the regional lymph node basin. Ninety-one patients, or 6.9%, subsequently developed in-transit melanoma. Similar trials show an incidence of in-transit disease of 3.5%–8%. The development of in-transit metastases portends a poor survival. In-transit metastases without lymph node metastases assigns the patient to American Joint Committee on Cancer (AJCC) stage 3A with a median survival approximating 5.5 years, and with nodal disease places the patient in stage 3C with median survival approximating 2.0 years.

Although in-transit metastases can be excised, they often represent disseminated disease throughout the limb lymphatics. In rare instances, the limb can be surgically sterilized of disease through one or multiple operations leading to long-term cure. The most aggressive form of local control is amputation and can result in a 5- and 10-year survival rate of 40% and 20%, respectively. Because systemic therapy provides only a modest objective response rate, more effective strategies of delivering chemotherapy such as regional treatment of the upper or lower extremity are adopted in an attempt to render these patients free of disease without the need for amputation.

Ocular melanoma and cancers for percutaneous hepatic perfusion

Ocular melanoma represents an example of a cancer with a natural history favorable for regional treatment. Uveal melanomas develop in the vascular layer of the orbit, including the iris, ciliary body, and choroid. Although the primary lesion is in the eye, metastatic spread tends to be to the liver. In the collaborative ocular melanoma study, 361 of 1003 subjects with large uveal melanomas developed metastatic disease and of these 93% had hepatic metastasis. Many patients die of hepatic failure from hepatic replacement with metastasis, in the absence of other disease. Regional treatment, therefore, has the potential to halt the life-threatening component of the metastatic disease.

Cancers metastatic to the liver or advanced primary hepatic cancers are likely to be susceptible to isolated hepatic perfusion or chemosaturation; however, current studies for these cancers are inadequate for perfusion to be a standard approach.

Gastrointestinal cancers that spread through the portal system to the liver have a natural history that is unique compared to other metastases from hematogenous spread. Patients with limited colon cancer metastases in the liver exemplify this point. When the disease is isolated to the liver, with minimal and anatomically favorable location, resection is often used to eliminate the metastasis. In selected patients treated with resection, 41% remain alive at 5 years following resection. This suggests that colon cancer may spread hematogenously to the liver, but that hematogenous spread does not continue systemically in all cases.

Other cancers with portal spread may also be limited to hepatic metastases. Therefore liver-directed therapies are often used when metastatic disease exceeds the limits for resection. The role of regional perfusion therapy—either isolated hepatic perfusion or chemosaturation with percutaneous hepatic perfusion—for these histologies is yet to be defined and treatment of these cancers remains experimental.