Principles of Cancer Drug Therapy

Jeffrey W. Clark

Drug therapy for cancer includes cytotoxic, hormonal, targeted, and biologic response-modifying agents. The important goals of prolonging and improving quality of life (and in rare instances, effecting a cure) while minimizing the adverse effects of treatment are often achievable but require considerable skill, judgment, and much patient and family education. Many agents are unselective in their effects; targeted agents that hold promise may offer greater specificity. Oncologists strive to design well-constructed programs that strike an effective balance between beneficial and adverse effects. Such programs are usually based on results of clinical trials, with the strongest evidence coming from phase III studies. This type of information is usually available for initial treatment regimens of most common cancers. However, it is not always available for subsequent therapy decisions or for uncommon malignancies. As in all aspects of medicine and especially with regard to chemotherapy due to the significant risk of adverse effects and patients’ often unrealistic expectation, a careful evaluation of the potential benefits versus risks of the proposed therapeutic plan and a discussion of these openly and honestly with the patient are critical for a truly informed approach to treatment of the cancer.

The primary care physician has an important supportive role, which is increasing as more cancer chemotherapy is conducted on an outpatient basis and away from cancer centers and as the number of long-term cancer survivors who will need follow-up and treatment for all of their health concerns increases. While maintaining a close working relationship with the oncologist,
the primary physician may be called on to monitor the effects of therapy closely and provide initial care for the wide range of medical and emotional problems that may arise (see Chapter 87). These responsibilities necessitate a knowledge of the general indications for chemotherapy, including cytotoxic, hormonal, targeted and immunomodulatory agents, and an awareness of the major toxic and adverse side effects of commonly employed agents. The primary care physician must also know how to evaluate the response to treatment and alleviate side effects. Most importantly, there needs to be excellent communication between the primary care physician and the oncology team taking care of the patient to ensure that patients receive the best possible care at all times. This chapter is a brief, broad overview.

PRINCIPLES OF THERAPY (1, 2, 3, 4, 5, 6, 7 and 8)

Types of Regimens and Their Indications

Chemotherapy may be given as preoperative (neoadjuvant) therapy, as postoperative (adjuvant) therapy for cancers that can be resected, or as either curative (for a small subset of cancers such as germ-cell tumors, lymphomas, or Hodgkin disease) or palliative therapy for advanced disease. For each of these indications, it may be delivered alone or with radiation therapy depending on the nature of the tumor and the exact setting.

Neoadjuvant (Preoperative) Chemotherapy

Neoadjuvant chemotherapy (often in combination with radiation therapy) is used for the preoperative treatment of local or regional disease (including involved regional lymph nodes) to improve survival by reducing the risk for systemic disease via micrometastases. It may also decrease tumor bulk and make possible a more conservative surgical approach. For patients being considered for neoadjuvant therapy, an early consultation with the medical oncologist may be helpful and often occurs in the setting of a multimodality (e.g., surgery, medical oncology, and radiation oncology) review to define the best initial approach to the disease. Examples of proven efficacy include use in stage III non-small cell lung cancer, stage III breast cancer, stage III rectal cancer, esophageal cancer, and gastric cancer.

Postoperative Adjuvant Chemotherapy

Postoperative adjuvant chemotherapy is an established, standard form of treatment given to patients who have undergone what appears to be curative surgery in order to improve survival by countering relatively high frequencies of local recurrence and distant micrometastases. Prolongation of survival is best achieved when treatment is given as soon as feasible after surgery, allowing just enough time for the patient to recover sufficiently to tolerate the chemotherapy. A common example of such therapy is in most stages of breast cancer.

Chemotherapy of Advanced Disease

The goals of chemotherapy in advanced disease range from providing palliation and improving short-term survival (measured in months to a few years) to achieving cure in selected instances (e.g., lymphoma, germ cell tumors). There continues to be development of increasingly effective chemotherapeutic agents and multiple-drug regimens that have increased not only rates of response and remission but also duration of response and, in a small subset of patients, cure.

It is important to keep in mind and share with the patient that despite the few examples of cure, most chemotherapy for advanced disease remains palliative, designed to reduce discomfort and modestly prolong survival without placing too heavy a burden on the patient. Even the latter goal is not always possible. Survey study of patients with advanced disease undergoing chemotherapy finds that the majority harbor unrealistic expectations. It takes skill, time, and good judgment to communicate realistic expectations to patients and families, to decide what and when to offer, and when to explain that chemotherapy therapy is unlikely to be of further benefit, necessitating consideration of other measures. When patients fail to demonstrate a clinically meaningful response, their chemotherapy regimen should be changed to an alternative program or possibly stopped, depending on the circumstances.

Basic Chemotherapy Strategies

Combination Chemotherapy

The use of regimens comprising agents with different mechanisms of action within the cancer cell has the potential for increasing the effectiveness of therapy. Ideally, these combinations utilize drugs with side effects that do not significantly overlap so that each can be given as close to its optimal dose as a single agent as feasible. Synergistic or additional therapeutic effects can be achieved, while adverse effects can be minimized. Chemotherapy may provide benefit even when disease stability is the best response. Therefore, ongoing evaluation needs to include not only scans and tumor markers for objective evaluation but also a careful assessment of clinical benefit for the patient.

Dose Intensification and Density

For most cytotoxic agents, using the highest safe doses without causing intolerable toxicities over a defined time period is essential to ensuring effectiveness of therapy, especially when treating with curative intent. The use of too small a dose produces inferior outcomes. When cure is being attempted, it is best to try to maintain maximal doses and treat drug side effects by means other than dose reduction as long as this is feasible. Reductions in dose are among the most common causes of drug failure. For certain disease settings (primarily hematologic malignancies, especially specific settings of a variety of leukemias), dose intensity and consequent long-term survival can be increased substantially by complementing chemotherapy with marrowsupportive efforts that include bone marrow transplantation and the use of hematopoietic growth factors.

Bone Marrow Transplantation/Stem Cell Infusions

Efficacy for bone marrow transplantation is best established for use in hematologic malignancies (e.g., lymphomas, myelomas, and leukemias). High-dose chemotherapy with bone marrow transplantation (or more commonly stem cell infusion) also has a potential role in certain solid tumors, especially those arising in childhood or of the germ-cell variety in adults, but not for the common solid malignancies, except in the investigational setting.

For persons at high risk for recurrence, the allogeneic transplantation of HLA-matched donor marrow cells has produced the best outcomes once cancerous marrow cells are eliminated by dose-intensified chemotherapy. In some instances, autologous transplantation and the use of peripheral stem cells have also produced meaningful results, especially in patients with lymphomas or myeloma, extending the use of high-dose chemotherapy and reducing the costs and risks of marrow reconstitution.

Risks are substantial. The most serious in the short term are life-threatening infection and acute graft versus host reactions; subsequently, lymphomas and hematopoietic disorders may arise within the first several years, a consequence of compromised immune function and viral infections (e.g., Epstein-Barr virus).
Late risks include development of solid tumors, especially in patients also receiving radiation. Chronic graft versus host disease may also compromise outcomes.

Such risks underscore the importance of careful patient selection, follow-up, and attending to cancer risk factors such as smoking. Although risk-reward ratios often favor proceeding to transplantation, the decision to proceed should be informed whenever possible by data from well-designed randomized, controlled trials with long-term follow-up.

Nonmyeloablative allogeneic stem cell transplantation is being explored as a less toxic approach while still establishing a graft-versus-tumor effect, primarily for hematologic malignancies; specific indications for use are being developed.

Growth Factors to Support the Optimal Delivery of Chemotherapy

Granulocyte Colony-Stimulating Factor (G-CSF).

Either short-acting (Neupogen) or longer-lasting form (Neulasta), or granulocyte-macrophage colony-stimulating factor (GM-CSF), can provide support to the neutrophilic cell line and lessen the risks for infection associated with intensive chemotherapy. These agents are expensive, but cost-effective when used prophylactically in situations with a significant likelihood (e.g., >20%) of febrile neutropenia. They are not used routinely to treat episodes of neutropenia but should be considered for serious infections (e.g., pneumonia, progressive bacterial or fungal infections). They also have a role in supporting high-dose chemotherapy in appropriate settings (such as allogeneic and autologous bone marrow transplantation or peripheral stem cell transplants).

Erythropoietin.

Erythropoietin, delivered weekly or every other week, can be useful for treating the anemia associated with chemotherapy but only in restricted settings. It should not be used in potentially curative settings because of studies showing worse outcomes. Otherwise, recommendations for use include the following:

Threshold: Hgb <10 g/dL for patients receiving chemotherapy without curative intent
Target level: ≥10 g/dL (discontinued at lowest Hgb level above that appropriate for the individual patient—not given when Hgb >12 g/dL because of an increased risk of venous thromboembolic events occurring)

For Thrombocytopenia.

Treatments for thrombocytopenia remain a work in progress. Although recombinant interleukin-11 (rHuIL-11) is approved for this indication, its potential for benefit is small and rarely used.

Follow-Up

Follow-up assessment for response and determination of further chemotherapy is usually conducted every 2 to 3 months of the treatment program, although the exact evaluation period varies based on the exact setting. Only rarely does continuing the same treatment in the presence of disease progression result in subsequent response. However, when cure is unlikely, a patient with a persistent best response or stable disease can continue to receive benefit from chemotherapy in the absence of progression or unacceptable toxicity. In patients where cure is the objective, the rate and degree of response are important to follow closely so that any required changes in therapy can be made expeditiously.

Cytotoxic Chemotherapeutic Agents (1,5)

Cytotoxic drugs can be grouped into categories based on their mechanism of action or chemical derivation (Table 88-1). Most currently utilized cytotoxic agents work by inhibiting the replication of cells, primarily by interfering with DNA synthesis or function or by inhibiting mitosis.

Alkylating Agents

In general, the alkylating agents interact directly with DNA and have a broad spectrum of antitumor activity. Their most common major side effects (e.g., marrow suppression, GI toxicity, hair loss, infertility) occur in rapidly dividing normal cells such as those of the bone marrow, gastrointestinal mucosa, hair follicles, and gonads. Subsequent development of secondary malignancy (most commonly myelodysplastic syndromes and acute leukemias) is a concern. Some of the more commonly used drugs in this class are cyclophosphamide, bendamustine, chlorambucil, melphalan, ifosfamide, and the nitrosoureas (e.g., carmustine, lomustine, streptozocin). Common tumor types treated with these agents include non-Hodgkin lymphoma (including CLL), Hodgkin disease, multiple myeloma, small cell lung cancer, glioblastomas, and germ-cell tumors.

Antitumor Antibiotics and Related Compounds

This class of drugs includes the anthracycline and closely related antibiotics (doxorubicin, epirubicin, daunorubicin, mitoxantrone), bleomycin, and mitomycin C. Mechanisms of action include direct inhibition of DNA and RNA synthesis by intercalating or cross-linking DNA, inhibition of topoisomerase II while it is involved in DNA synthesis, and generation of free oxygen radicals.

Antimetabolites

These drugs interfere with the synthesis of DNA (and sometimes RNA) by blocking the action of important metabolic precursors and cofactors or by incorporation into DNA or RNA and preventing further synthesis. Because their primary effect leads to decreased DNA synthesis, their greatest benefits as well as toxicities regard effect on rapidly growing cells. GI toxicities are somewhat more common and bone marrow suppression somewhat less severe than with alkylating agents. The most commonly used of these agents belong to one of three groups, antifolates (e.g., methotrexate, pemetrexed), pyrimidine analogs (e.g., fluorouracil), or purine analogs (e.g., gemcitabine) (see Table 88-1).

In general, the antimetabolites are rapidly metabolized and excreted in the urine. Methotrexate and pemetrexed are distributed throughout total body water; pleural effusions and ascitic fluid are potential reservoirs of these drugs, significantly enhancing risk of toxicity—they should be avoided or used with great care in the setting of such fluid accumulations.

Topoisomerase Inhibitors

Etoposide forms a complex with DNA and the DNA topoisomerase II enzyme needed for DNA replication thus inhibiting its function. As discussed under Antitumor Antibodies, the anthracyclines also mediate part of their antitumor activity via topoisomerase II inhibition. Two inhibitors of topoisomerase I (also required for DNA replication) are approved for use in treating cancers: irinotecan (most commonly used for colorectal cancer but active against other malignancies as well) and topotecan (most commonly used for ovarian and small cell lung cancers).

Major adverse side effects are bone marrow suppression and GI toxicity (including diarrhea, which can be especially severe for irinotecan and requires aggressive treatment with Imodium, hydration, and careful monitoring if it occurs).

Mitotic Spindle Modulators (Including Plant Alkaloids)

These agents interfere with mitosis. Paclitaxel, nab-paclitaxel (paclitaxel bound to albumin), docetaxel, vincristine, vinblastine, and vinorelbine are the best-known examples. Paclitaxel and docetaxel are among the most commonly used of these agents, being active in a broad range of cancers.

TABLE 88-1 Cytotoxic Chemotherapeutic Agents

			Acute Toxicity
Class/Agents		Dose Frequency	Leukocyte	Platelet	Nausea/Vomiting	Other Toxicity	Elimination	Plasma Half-Life (h)
Plant Derivatives
	Paclitaxel	q3wk	Moderate	Moderate	Mild	Anaphylactoid response, sensory neuropathy, alopecia	M	6-8
	Vincristine	qwk	Mild	Mild	Mild	Distal neuropathy, inappropriate ADH	M	2.6
	Vinblastine	qwk	Marked	Marked	Mild	Mucositis	M	3.1
	VP-16 (etoposide)	qd × 3-5	Moderate	Mild	Mild	Distal neuropathy	M, R	6
Antibiotics
	Dactinomycin	qd × 5	Marked	Marked	Moderate	Alopecia, mucositis	M, R	36
	Doxorubicin	q3wk	Marked	Marked	Moderate	Alopecia, cardiomyopathy	M	20-48
	Daunorubicin	3 d, q3wk	Marked	Marked	Moderate	Alopecia, cardiomyopathy	M	18.5
	Mitomycin C	qd × 3, q3wk	Marked	Marked	Moderate	Renal, pulmonary	M	?
	Bleomycin	qwk	Rare	Rare	Mild	Skin, pulmonary, fibrosis, fever, allergic reactions	R	0.4-2
Antimetabolites
	Methotrexate (high dose with leucovorin)	q3wk q6hr × 7 doses	Mild	Mild	Moderate	Hepatic dysfunction, renal failure	R, M	2-8
	Methotrexate	Twice weekly	Moderate to marked	Moderate to marked	Mild	Stomatitis	R	2-8
	5-Fluorouracil	qwk or qd × 5, q4wk	Moderate to marked	Moderate to marked	Mild	Cerebellar, conjunctivitis	M	0.3
	5-Fluorouracil with leucovorin	qwk × 6, qd × 5, q4wk	Marked	Marked	Mild	Diarrhea, stomatitis	M	0.3
	6-Mercaptopurine	qd × 5	Moderate to marked	Moderate to marked	Mild	Cholestasis	M	0.3-0.6
	Cytarabine (cytosine arabinoside)	q12hr × 5-10 d	Marked	Marked	Moderate	Cholestasis, mucositis	R, M	0.15
	Hydroxyurea	qd × 5	Marked	Moderate	Moderate	None	R, M	1.7
	Fludarabine	qd × 5	Moderate	Mild	Mild	Pneumonitis, neurotoxicity	R, M	9.3
	Pemetrexed (Alimta)	q3 wk	Moderate	Mild	Moderate	Dyspnea	R	3.5
Alkylating Agents
	Cyclophosphamide	qd × 5	Marked	Mild	Moderate	Cystitis, water retention, alopecia	M	1-4
	Ifosfamide	qd × 5	Moderate	Moderate	Mild	Neurotoxicity, urothelial neurotoxicity	M	5-6
	Mesna	qd × 5.5	None	None	None	None	M	1
	Melphalan	qd	Moderate	Moderate	Mild	Leukemia	M	2
	Busulfan	qd	Marked	Marked	Mild	Pulmonary fibrosis	M	2.5
	CCNU (lomustine)	q6wk	Marked	Marked	Moderate	Leukemia, pulmonary fibrosis, renal failure	M	16-72
	BCNU (carmustine)	q6wk	Marked	Marked	Marked	Leukemia, pulmonary fibrosis, renal failure	M	1.0
	Streptozocin	qd × 5, q3-4wk	Mild	Mild	Moderate-marked	Renal failure, hyperglycemia, hepatic enzyme elevation	R	0.25
	Chlorambucil	qd	Moderate	Moderate	Mild	Leukemia	M	1.5
	cis-Diaminedichloroplatinum	q3-4wk	Moderate	Moderate	Severe	Renal failure, Mg²⁺ wasting, peripheral neuropathy, ototoxicity	R, M	0.3
	Carboplatin	q3-4wk	Marked	Marked	Mild		R
Topoisomerase I Inhibitors
	Irinotecan	q1-3wk	Moderate	Mild	Moderate	Diarrhea	M	10-20
	Topotecan	qd × 3-5	Moderate	Moderate	Moderate	None	M	2-3
Miscellaneous
	Dacarbazine	qd × 5	Mild	Mild	Marked	Flulike syndrome, venoocclusion	M	0.65
	Procarbazine	qd × 10-14 d	Moderate	Moderate	Mild	Sensitivity to amines	M	0.8
	Mitoxantrone	q3wk	Moderate	Moderate	Mild	Cholestasis, cardiac	M	0.25-37
ADH, antidiuretic hormone; M, metabolized in the liver; q, every; qd, daily; R, renally. Adapted from Chabner BA. Anticancer drugs. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 4th ed. Philadelphia, PA: Lippincott, 1993:325, with permission. Copyright © 1993. Lippincott Williams & Wilkins.