Chemotherapy-Related Topics

[TomHsiung]

What is primary chemotherapy, me-adjuvant chemotherapy, and adjuvant chemotherapy?

Primary chemotherapy refers to chemotherapy administered as the primary treatment in patients who present with advanced cancer for which no alternative treatment exists. This has been the main approach in treating patients with advanced metastatic disease, and in most cases, the goals of therapy are to relieve tumor-related symptoms, improve overall quality of life, and prolong time to tumor progression.

Studies in a wide range of solid tumors have shown that chemotherapy in patients with advanced disease confers survival benefit when compared with supportive care, providing sound rationale for the early initiation of drug treatment. However, cancer chemotherapy can be curative in only a small subset of patients who present with advanced disease.

In adults, these curable cancers include Hodgkin's and non-Hodgkin's lymphoma, acute myelogenous leukemia, germ cell cancer, and choriocarcinoma.

Neoadjuvant chemotherapy refers to the use of chemotherapy in patients who present with localized cancer for which alternative local therapies, such as surgery, exist but which are less than completely effective. At present, me-adjuvant therapy is most often administered in the treatment of anal cancer, bladder cancer, breast cancer, esophageal cancer, laryngeal cancer, locally advanced non-small cell lung cancer (NSCLC), and osteogenic sarcoma. For some of these diseases, such as anal cancer, gastroesophageal cancer, laryngeal cancer, and NCSLC, optimal clinical benefit is derived when chemotherapy is administered with radiation therapy either concurrently or sequentially.

The goal of the neoadjuvant approach is to reduce the size of the primary tumor so that surgical resection can then be made easier. In addition, in some cases such as with rectal cancer and laryngeal cancer, the administration of combined modality therapy prior to surgery can result in sparing of vital organs such as the rectum or larynx. In most cases, additional chemotherapy is given after surgery has been performed.

One of the most important roles for cancer chemotherapy is as an adjuvant to local treatment modalities such as surgery, and this has been termed adjuvant chemotherapy. In this setting, chemotherapy is administered after surgery has been performed, and the goal of chemotherapy is to reduce the incidence of both local and systemic recurrence and to improve the overall survival of patients.

In general, chemotherapy regimens with clinical activity against advanced disease may have curative potential following surgical resection of the primary tumor, provided the appropriate dose and schedule are administered. Adjuvant chemotherapy is effective in prolonging both disease-free survival (DFS) and overall survival (OS) in patients with breast cancer, colon cancer, gastric cancer, NCSLC, Wilms' tumor, anapestic astrocytoma, and osteogenic sarcoma.

[TomHsiung]

Certain principles have guided the selection of drugs in the most effective drug combinations, and they provide a paradigm for the development of new drug therapeutic programs.

1) Efficacy: Only drugs known to be somewhat effective when used alone against a given tumor should be selected for use in combination. If available, drugs that produce complete remission in some fraction of patients are preferred to those that produce only partial responses.

2) Toxicity: When several drugs of a given class are available and are equally effective, a drug should be selected on the basis of toxicity that does not overlap with the toxicity of other drugs in the combination. Although such selection leads to a wider range of adverse effects, it minimizes the risk of a lethal effect caused by multiple insults to the same organ system by different drugs and allows dose intensity to be maximized.

3) Optimum scheduling: Drugs should be used in their optimal dose and schedule, and drug combinations should be given at consistent intervals. Because long intervals between cycles negatively affect dose intensity, the treatment-free interval between cycles should be the shortest time necessary for recovery of the most sensitive normal target tissue, which is usually the bone marrow.

4) Mechanism of interaction: There should be a clear understanding of the biochemical, molecular, and pharmacokinetic mechanisms of interaction between the individual drugs in a given combination, to allow for maximal effect. Omission of a drug from a combination may allow overgrowth by a tumor clone sensitive to that drug alone and resistant to other drugs in the combination.

5) Avoidance of arbitrary dose changes: An arbitrary reduction in the dose of an effective drug in order to add other less effective drugs may reduce the dose of the most effective agent below the threshold of effectiveness and destroy the ability of the combination to cure disease in a given patient.

Dosage Factor
Dose intensity is one of the main factors limiting the ability of chemotherapy or radiation therapy to achieve cure. As described in pharmacology, the dose-response curve in biologic systems is usually sigmoidal in shape, with a threshold, a linear phase, and a plateau phase. For chemotherapy, therapeutic selectivity is dependent on the difference between the dose-response curves of normal and tumor tissues.

In experimental animal models, the dose-response curve is usually steep in the linear phase, and a reduction in dose when the tumor is in the linear phase of the dose-response curve almost always results in a loss in the capacity to cure the tumor effectively before a reduction in the anti tumor activity is observed. Although complete remissions continue to be observed with dose reduction down to as low as 20% of the optimal dose, residual tumor cells may not be entirely eliminated, thereby allowing for eventual relapse.

Because anti-cancer drugs are associated with toxicity, it is often appealing for clinicians to avoid acute toxicity by simply reducing the dose or by increasing the time interval between each cycle or treatment. However, such empiric modifications in dose represent a major cause of treatment failure in patients with drug-sensitive tumors.

A positive relationship between dose intensity and clinical efficacy has been documented in several solid tumors, including advanced ovarian, breast, lung, and colon cancers, as well as in hematologic malignancies, such as the lymphomas. At present, there are three main approaches to dose-intense delivery of chemotherapy. The first approach, dose escalation, involves increasing the doses of the respective anti-cancer agents. The second strategy is administration of anti-cancer agents in a dose-intense manner by reducing the interval between treatment cycles, while the third approach involves sequential scheduling of either single agents or of combination regimens. Each of these strategies is presently being applied to a wide range of solid cancers, including breast, colorectal, and NSCLC, and in general, such dose-intense regimens have significantly improved clinical outcomes.

[TomHsiung]

Cancers have eight biologic capabilities including:
1) sustaining proliferative signaling
2) evading growth suppressors
3) resisting cell death
4) enabling replicative immortality
5) inducing angiogenesis
6) activating invasion and metastasis
7) reprogramming energy metabolism
8) evading immune destruction

Sustaining Proliferative Signaling
Arguably, the most fundamental trait of cancer cells involves their ability to sustain chronic proliferation. Normal tissues carefully control the production and release of growth-promoting signals that instruct entry of cells into and progression through the growth-and-division cycle, thereby ensuring proper control of cell number and thus maintenance of normal tissue architecture and function.

• Upstream mechanisms

Cancer cells, by deregulating these signals, become masters of their own destinies. The enabling signals are conveyed in large part by growth factors that bind cell-surface receptors, typically containing intracellular tyrosine kinase domains. The latter proceed to emit signals via branched intracellular signaling pathways that regulate progression through the cell cycle as well as cell growth. Cancer cells can acquire the capability to sustain proliferative signaling in a number of alternative ways: They may produce growth factor ligands themselves, to which they can then respond via the coexpression of cognate receptors, resulting in autocrine proliferative stimulation. Alternatively, cancer cells may send signals to stimulate normal cells within the supporting tumor-associated stroma; the stromal cells then reciprocate by supplying the cancer cells with various growth factors. Mitogenic signaling can also be deregulated by elevating the levels of receptor protein displayed at the cancer cell surface, rendering such cells hyper responsive to otherwise limiting amouts of growth factor ligands; the same outcome can result from structural alterations in the receptor molecules that facilitate ligand-independent firing.

• Downstream mechanisms

1) Somatic mutations activate additional downstream pathways
2) Disruptions of negative-feedback mechanisms that attenuate proliferative signaling
3) Excessive proliferative signaling can trigger cell senescence

Evading Growth Suppressors
Cancer cells must also circumvent powerful programs that negatively regulate cell proliferation; many of these programs depend on the actions of tumor suppressor genes.

Resisting Cell Death

Enabling Replicative Immortality

[TomHsiung]

A fundamental problem in cancer chemotherapy is the development of cellular drug resistance. Primary, or inherent resistant refers to drug resistance in the absence of prior exposure to available standard agents. The presence of inherent drug resistance was first proposed by Goldie and Coleman in the early 1980s and was thought to result from the genomic instability associated with the development of most cancers.

For example, mutations in the p53 tumor suppressor gene occur in up to 50% of all human tumors. Preclinical and clinical studies have shown that loss of p53 function leads to resistance to radiation therapy as well as resistance to a wide range of anti-cancer agents.

Defects in the mismatch repair enzyme family, which are tightly linked to the development of familial and sporadic colorectal cancer, are associated with resistance to several unrelated anti-cancer agents.

In contrast to primary resistance, acquired resistance develops in response to exposure to a given anti-cancer agent. Experimentally, drug resistance can be highly specific to a single drug and is usually based on a specific change in the genetic machinery of a given tumor cell with amplification or increased expression of one or more genes.

In other instances, a multi drug-resistant phenotype occurs, associated with increased expression of the MDR1 gene, which encodes a cell surface transporter glycoprotein. This form of drug resistance leads to enhanced drug efflux and reduced intracellular accumulation of a broad range of structurally unrelated anti-cancer agents.