Principles of chemotherapy

1

What is the single most important determinant when choosing a treatment using anticancer drugs (chemotherapy) and what is the concept of “risk stratification”?

Before embarking on a treatment plan that involves the use of anticancer drugs, every effort should be made to ascertain an accurate histologic and molecular diagnosis. This involves pathologic examination and molecular testing of tumor tissue after surgical excision or a well-planned biopsy. Empiric therapy, before pathologic diagnosis, is permissible only in the rare setting of a true oncologic emergency (see Chapter 17). Because chemotherapy is highly toxic, with both acute and long-term side effects, it is imperative that the choice of treatment be correct for the diagnosis and that the intensity and risk of the regimen be well-aligned with the prognosis of the disease. Most pediatric cancers can be divided into standard, intermediate, and high-risk categories, where the goals are to minimize risk and maintain excellent outcomes for lower risk patients and to augment therapy and improve survival for higher risk patients. Critical factors beyond pathologic diagnosis determining the appropriate risk stratification include:

• Patient age

• Disease stage: extent of disease

• Histologic subtype (e.g., favorable or unfavorable in Wilms tumor, T or B cell leukemia/lymphoma)

• Biological and molecular features (e.g., MYC-N amplification in neuroblastoma, BCR-ABL1 fusion, KMT2A rearrangement or additional adverse cytogenetics in acute lymphocytic leukemia [ALL], and molecular subtype in medulloblastoma)

2

What is meant by adjuvant and neoadjuvant chemotherapy , and what is the rationale behind them?

Adjuvant chemotherapy is given to patients without evidence of residual disease after local control of a malignant tumor has been achieved with surgery and/or radiation. Historically, patients treated with local measures alone had a high risk (60%–95%) for tumor recurrence with distant metastases. The goal of adjuvant chemotherapy is to eliminate microscopic spread of the tumor or micrometastasis, which is assumed to have already occurred by the time of diagnosis. This strategy has been successful in the treatment of most pediatric solid tumors including Wilms tumor, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, medulloblastoma, and anaplastic astrocytoma.

Neoadjuvant chemotherapy, or primary chemotherapy, is given to patients before surgical resection or radiation to the primary site. Neoadjuvant chemotherapy has been used to decrease tumor bulk, thereby making the primary more amenable to surgery. Other rationales include the early eradication of micrometastasis, preempting costly delays in systemic therapy from surgical or radiation-related morbidity, and the ability to assess tumor responsiveness to initial therapy, both clinically and histologically. The neoadjuvant strategy has been particularly important in the treatment of bone tumors. Orthopedic surgeons can offer a larger number of limb-sparing procedures, in part because of tumor shrinkage and the extra time available to plan and obtain individualized prosthetic devices. Additionally, the histologic tumor response to initial therapy (extent of necrosis) has proven to be a potent prognostic factor of relapse-free survival in osteosarcoma and is being studied in other diseases.

3

What does history tell us about the overall efficacy of single-drug regimens?

In the late 1940s and early 1950s, ALL was universally and rapidly fatal. The first single-agent trials were able to induce remarkable results with impressive complete remission rates of up to 60%. Nevertheless, remissions were short lived, lasting only 6 to 9 months, despite continued therapy with the agent. Today, outside of a few molecularly targeted agents like the ABL1 tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) or a TRK/ROS/ALK or RET inhibitor before surgery in a few low-grade malignancies like infantile fibrosarcoma, it is understood that curative therapy requires combination chemotherapy. In patients with refractory disease and no curative options, single agent trials are still used in early drug development to determine the safety profile, dose, and single agent anticancer activity across tumor types.

4

What is the rationale behind the use of combination chemotherapy?

The rationale behind combination chemotherapy is twofold.

First, combination chemotherapy may be used to overcome inherent tumor resistance to a particular single agent. Because it is neither feasible nor scientifically valid to test each individual tumor against a panel of cytotoxic agents, the concept is to treat with a combination of the most active agents for a given histologic diagnosis to increase the likelihood that any individual tumor will respond.

Second, combination chemotherapy may be used to prevent acquired resistance in an initially sensitive tumor. The assumption is that large, heterogeneous tumors harbor small populations of cells that are either naturally resistant or have undergone de novo mutation to acquire resistance. Single-agent therapy places selective positive pressure on these populations, whereas concurrent administration of other active drugs with different mechanisms of action may allow for independent cell killing.

5

What constitutes the ideal combination of agents for the treatment of a given neoplastic disease?

The ideal combination of agents includes the following:

• Drugs that are the most active in the disease

• Drugs that have different, nonantagonistic, and preferably additive or synergistic mechanisms of action

• Drugs that are non–cross-resistant (i.e., are subject to different mechanisms of resistance)

• Drugs that have nonoverlapping toxicities so that each can be delivered at the dose and schedule that optimizes efficacy

6

Define dose intensity

The concentration of a drug given over a specified time is dose intensity. Many chemotherapeutic agents have a very steep dose-response curve, and even small escalations in dose can have a profound effect on tumor cell kill. This is especially true of drugs that are not cell cycle dependent, particularly the alkylating agents, for which it has been shown that a twofold increase in the dose of cyclophosphamide can increase therapeutic efficacy up to 10-fold. Increased dose intensity can also be achieved by decreasing the time interval between cycles. Numerous clinical studies have demonstrated that patients who receive greater dose intensity have superior response rates and disease-free survival. Nevertheless, these gains must always be balanced against morbidity and mortality from drug toxicity.