Clinical Pharmacology of Anti-Caner Drugs

Thursday October 10, 2002 1:00 p.m. - 2:00 p.m. John D Roberts, MD Email Address: jdrobert@vcu.edu Post a question to the bulletin board PowerPoint Presentation

Lecture Outline:
| Objectives | Introduction | Two Important Biological Concepts |Classification of Anticancer Drugs | |Combination Chemotherapy | Hormonal Therapy | Biological Agents | | Drug Treatment in the Context of Cancer Treatment | Cancer Staging | Adjuvant Therapy | High Dose Therapy | | Chemoprevention of Cancer |

OBJECTIVES Learners should focus upon: 1. 2. 3. 4. 5. 6. Concepts of tumor hetereogeneity and micrometastasis Major classes of drugs used in cancer treatment Mechanisms of hormonally active and biological agents Major types/time frames of cytotoxic agent toxicity Principles of combination (cytotoxic) chemotherapy Rationale for surgical adjuvant therapy in terms of micrometastases, tumor heterogeneity, and drug resistance 7. Rationales and problems associated with high dose therapy and hematopoietic stem cell transplantation (Specific drug names contained in this lecture are not test items.)

I.

Introduction Although most physicians do not prescribe anticancer agents, most physicians encounter patients who are receiving or have received anticancer agents. These agents cause many side effects or toxicities that affect most organ systems, and these side effects may appear months or years later. Thus, it is important that physicians are aware of anticancer agent side effects. Attempts to treat cancer largely preceded identification of biochemical differences

between cancer cells and normal cells. As a result, and in contrast with other areas of therapeutics, medical (or drug) therapy of cancer largely has been empiric. Most anticancer agents or their prototypes were discovered simply by screening large numbers of chemical compounds for their ability to inhibit the growth of cancer cells in tissue culture or in animal tumor models. The mechanism of action of these agents is poorly understood. It also has been difficult to identify general principles that underlie their successful clinical use. Perhaps it is not surprising, then, that medical therapy of cancer is not especially effective. II. Two Important Biological Concepts Two biological concepts that are used to understand the clinical results of anticancer therapy are tumor heterogeneity and micrometasis. Tumor (the term tumor is used here interchangeably with cancer) heterogeneity refers to the genetic and phenotypic diversity found among the cells that comprise a cancer. Diversity is derived at least in part from genetic changes. Most cancers represent the accumulation of multiple genetic alterations. In many cases the changes intrinsic to the development of a cancer also facilitate the development of further genetic change. An early genetic change common to most colon cancers, for example, disrupts DNA mismatch repair; this facilitates the accumulation of further genetic change. Thus, a cancer is composed of cells that share the genetic changes that conferred malignancy; but, within this population, there are subpopulations that differ in terms of subsequent genetic events. These subpopulations may include cells that are resistant to otherwise effective anticancer agents. Thus, the larger a cancer, the less likely it is to be eradicated by drug therapy. Metastases are tumor cell deposits remote from the site of a primary tumor. Metastases may arise from local spread (for example, from one site to another within the peritoneal cavity), lymphatic invasion and spread to lymph nodes, and hematogenous spread. Metastases to the immediate tumor-draining lymph nodes are regional; other lymph node metastases are distant. Micrometastasis refers to microscopic (or sub-microscopic) deposits of tumor cells. Patients with micrometasis have no clinical, laboratory, or imaging evidence of metastatic cancer. By definition, then, in an individual patient the presence of micrometastasis can be known only in retrospect, as tumor deposits grow to a sufficient size to become clinically apparent. Nevertheless, the concept is an important one as many or most cancer deaths are due to metastases (that at some point were only microscopic). Patients at high risk for micrometastases can be identified on the basis of clinical and laboratory features that correlate with the subsequent development of metastastic disease in similar patients studied previously.

The concepts of tumor heterogeneity and micrometastasis are invoked to explain many of the various clinical scenarios that are devastating to patients and frustrating to clinicians:
o

A surgeon removes all of the apparent lung cancer lung and regional lymph nodes, but months later the patient experiences a recurrence of lung cancer metastatic to the liver and dies (effect of micrometastases). A tumor initially shrinks in response to chemotherapy, but as treatment continues tumor growth resumes (tumor heterogeneity with drug resistance). Chemotherapy induces complete regression of all apparent lymphoma, but months later the lymphoma recurs and is resistant to chemotherapy.

III.

Classification of Anticancer Drugs Although there is no generally satisfactory classification of anticancer agents, the following classification is used here: cytotoxics, hormonally active agents, and biologics. Most drug treated patients are treated with cytotoxic agents, either alone or in combination with agents of other classes. Although chemotherapy means treatment with chemicals, for many years almost all anticancer agents were cytotoxic, and oncologists tend to use the term exclusively in reference to cytotoxic treatment. Cytotoxic agents cause direct injury to cancer cells, and usually considerable injury to normal tissues as well. Many cytotoxic agents, for example, inhibit DNA synthesis and thus are toxic primarily to rapidly proliferating tissues, including both rapidly proliferating cancers and normal tissues with rapid turnover such as the bone marrow and digestive tract mucosa. For cytotoxic agents for which an aspect of the mechanism of action is understood, drug resistance sometimes has been characterized. The anticancer agent methotrexate, for example, is a competitive inhibitor of dihyrofolate reductase, an enzyme of importance in the synthesis of thymidine, a DNA precursor. Amplification of the dihydrofolate reductase gene (the presence of multiple gene copies) may lead to increased gene expression, an increase in enzyme activity, and resistance to methotrexate. The concept of tumor heterogeneity suggests that the larger the tumor, the more likely that it will harbor a subpopulation of cells with an amplified dihydrofolate reductase gene and methotrexate resistance. Under the selective pressure of methotrexate treatment, this subpopulation will tend to grow out and become the dominant population within the remaining tumor mass.

The anticancer effects of cytotoxic agents generally increase with increasing dose. Cytoxics have a narrow therapeutic index: an unacceptably toxic dose is only slightly greater than the dose that causes cancer regression. As most cancers requiring medical therapy are life-threatening, cytotoxics usually are used at their maximum tolerated dose, and this use is associated with significant toxicity. Toxicities of cytotoxics can be classified by time of onset. Early onset toxicities frequently are transient, whereas late onset toxicities frequently persist. Not all agents cause all of the listed toxicities, and not all patients experience all the toxicities associated with an individual agent. Time of onset Toxicity minutes allergic/anaphylactoid reactions hours/days nausea and vomiting days/weeks myelosuppression (anemia, leukopenia, thrombocytopenia) digestive tract mucosal injury hair loss kidney injury weeks/months peripheral neuropathy ototoxicity lung injury cardiac injury gonadal injury Years carcinogenesis IV. Combination Chemotherapy Comment

Infections, bleeding mouth ulcers, esophagitis, diarrhea cisplatin

glove-stocking sensory change bleomycin doxorubicin infertility (temporary or permanent; men and women) new cancers

Cytotoxic agents often are used in combination with other cytotoxics or agents of other classes (combination chemotherapy). This practice is empirically based, but is understood in terms of the following principles:
o

An individual agent commonly is active against only certain types of cancer. As single agent therapy rarely is curative, agents active against a specific tumor are combined. To the extent possible, agents with non-overlapping toxicities are combined so that each agent can be administered in maximum tolerated doses.

The combination is repeated in cycles. The duration of a cycle is determined by the typical duration of transient side effects in order to allow for recovery between cycles. Chemotherapy is continued for some number of cycles beyond regression of all clinically apparent disease in order to treat persistent micrometastases.

BEP combination chemotherapy for germ cell tumors (usually testicular in origin). Repeat every three weeks for three or four cycles. Drug Schedule Toxicities Comments Bleomycinweekly fever, rash, increased skin Weekly administration allows administration pigmentation, pulmonary of higher cumulative doses than every three fibrosis week administration Etoposide daily for 5 only myelosuppression Myelosuppression resolves in about three days the first second malignancy weeks. divided dose administration is more week effective than administration of the same total dose in animal tumor models and possibly in the clinic. Cisplatin daily for 5 nausea and vomiting, historically, division of a dose into 5 daily days the first fatigue, anorexia, doses resulted in less renal toxicity week only peripheral neuropathy, renal injury Cytotoxics also may be administered with palliative (temporary disease control, not curative) intent, in which case it may be appropriate to administer only one or two agents at a time in a manner associated with less toxicity. The year 2001 was an important year in the history of chemotherapy with the advent of imatinib (Gleevec) for chronic myelogenous leukemia (CML). The characteristic genetic abnormality of CML is a (9:22) translocation that approximates the abl proto-oncogene with the bcr (breakpoint chromosome region) proto-oncogene, creating the oncogene bcr/abl. The bcr/abl gene product is a novel, intrinsically active protein tyrosine kinase that functions as an autonomous growth signal in myeloid progenitor cells. Imatinib was designed with molecular modeling techniques to specifically inhibit this oncogene product. Although imatinib has been used in the clinic for only a few years, results to date, especially as compared with past chemotherapy efforts, are astonishing: Imatinib is both much more effective and much less toxic than all previous agents used in the treatment of CML. This successful development of a specific therapeutic based upon insights into fundamental biological differences between malignant and normal cells raises the prospect that similar, new

antineoplastic agents targeted to more common cancers can be developed that will be similarly effective and well tolerated. V. Hormonal Therapy Normal prostate and breast tissues require sex hormones for normal maturation and health. Most prostate and breast cancers retain partial sex hormone dependence. Therapies designed to deprive these cancers of sex hormones may be of considerable palliative benefit; that is, they may lead to cancer regression or stasis for months or years, but they generally do not lead to eradication of the cancer and cure of the patient. This is understood in terms of the concept of tumor heterogeneity. These cancers are conceptualized as having a cell population that is dependent upon sex hormones for survival and growth and another cell population that is capable of survival and growth independent of sex hormones. The initial response to a hormonal manipulation presumably reflects regression of the hormone dependent cell population. The subsequent clinical progression of cancer that almost inevitably occurs presumably reflects the outgrowth of the cell population that is sex hormone independent. In order to deprive these cancers of the growth stimulating effects of sex hormones, the organs that give rise to these hormones may be removed surgically, or drugs may be used. Drug therapy generally either inhibits production of sex hormones or inhibits the utilization of sex hormones by cancer (and susceptible normal) cells. Gonadotropin releasing hormone analogs (leuprolide, goserelin) inhibit pituitary release of LH and FSH and thereby inhibit testicular production of testosterone or ovarian production of estrogen and progesterone. Aromatase inhibitors (letrozole, femarazole) competitively inhibit enzymatic reactions related to estrogen biosynthesis. Receptor antagonists occupy but do not activate membrane bound sex hormone receptors: tamoxifen and others for breast cancer; biclutamide and others for prostate cancer. VI. Biological Agents Biological agents refers to two sub-classes. Some biological agents mimic natural human substances and are therapeutic when administered in supra-natural (pharmacological doses). Others are agents that are understood, and generally were developed, to have a specific, cancer-biology based mechanism of action. (Of course, by the later definition, both imatinib and the general class of hormonal agents might be considered to be biological agents). Another largely correct generalization is that whereas cytotoxics generally are small molecules (molecular weight less than 1000), biological agents are proteins or have protein constituents

and are large molecules (molecular weight greater than 10,000). Biologicals are be used to treat cancer or to ameliorate the side effects of other anticancer agents. Interleukin-2 is a cytokine that amplifies endogenous immune, especially T cell, responses to cancer and is used in the treatment of renal cell cancer and melanoma (a skin cancer that arises from melanocytes). Hematopoietic growth factors are cytokines that promote the growth of myeloid stem cells. They are used to ameliorate the myelosuppression of cytotoxic agents: erythropoietin for red blood cells, and G-CSF (filgrastim) (or GM-CSF (sargamostrim) for granulocytes (and macrophages). Monoclonal antibodies offer the potential to specifically target tumor tissues when antigens unique or greatly overexpressed on tumor cells have been identified. Rituximab is a humanized anti-CD20 antibody used alone or in combination with cytotoxic agents in the treatment of CD20+ lymphoid malignancies (B cell chronic lymphocytic leukemia and B cell lymphomas). Monoclonal antibodies also can be chemically linked with cytotoxic agents in order to deliver the cytoxic agent preferentially to tumor cells. Alemtuzumab is an yttrium-radiolabeled version of rituximab that targets cytotoxic doses of radiation to CD20+ tumor cells. Gemtuzumab ozogamicin is a conjugate of a humanized anti-CD33 antibody and an extremely potent cellular toxin, It is used in the treatment of acute myelogenous leukemia. Denileukin difitox is a fusion protein of diptheria toxin and fragments of interleukin-2 that targets the toxin to interleukin-2 receptor expressing cells including certain T cell lymphomas. An alternate therapeutic strategy to killing cancer cells through chemical or immune-mediated mechanisms is to coax cancer cells to differentiate to a nonreplicating state. Trans-retinoic acid binds a mutated retinoic acid receptor found on acute promyeloid leukemia cells and promotes so-terminal differentiation. Bisphosphonates (pamidronate, zoledronate) are bioinorganic compounds that are incorporated into bone matrix and inhibit osteoclasts. This apparently alters the seed-soil relationship between tumor cells and bone in a manner that prevents growth of bone micrometastases and promotes shrinkage of established metastases and bone healing. Toxicities of biological agents are unlike those of cytotoxics and are agent specific. Interleukin-2 in moderate doses, for example, causes a flu-like syndrome characterized by fever, malaise, anorexia, and muscle and joint pain and in high doses causes potentially life-threatening hypotension, capillary leak, and renal dysfunction.

VII.

Drug Treatment in the Context of Cancer Treatment Cancer is treated with three modalities: surgery, radiation, and drug therapy. Surgery and radiation therapy are similar in that both largely are limited to cancers that are local or regional in spread and both are highly effective. Surgery and radiation usually cannot address distant metastatic disease, however, as metastases commonly are numerous and widespread; further, clinically apparent metastases typically represent the tip of the iceberg in the sense that they herald even greater numbers of micrometastases. This usually, but not always, renders surgery not feasible, at least as a curative modality, for obvious reasons. It usually renders radiation not feasible, at least as a curative modality, as delivery of tumoricidal doses of radiation to a significant fraction of the body would be associated with unacceptable toxicity. Drug therapies, because the agents usually are distributed in the circulation, offer the potential for treatment of widespread metastatic disease; unfortunately, drug therapies are only occasionally effective.

Treatment of advanced cancer with drug therapy:

Potentially curable with drug therapy alone Potentially curable with drug therapy and and surgery acute lymphocytic leukemia (with a possible assist from radiation) acute myelogenous leukemia Hodgkins disease breast carcinoma lymphoma (certain subtypes) colorectal carcinoma germ cell tumors osteogenic carcinoma gestational trophoblastic neoplasia soft tissue sarcoma Wilms tumor embryonal rhabdomyosarcoma Ewings sarcoma Neuroblastoma small cell lung cancer ?chronic myelogenous leukemia Potentially curable with radiation therapy (with a Potentially curable with high dose therapy possible assist from drug therapy) squamous cell carcinoma of the head and necks leukemias quamous cell carcinoma of the anus lymphomas uterine carcinoma Hodgkins disease non-small cell lung carcinoma (stage III) Myeloma Potentially palliated, but not cured, with drug therapy bladder cancer chronic myelogenous leukemia lymphoma chronic lymphocytic leukemia myeloma gastric cancer cervix cancer endometrial cancer soft tissue sarcoma melanoma

breast cancer lung cancer colon cancer prostate cancer

Two or three modalities often are combined to increase effectiveness or to reduce side effects. Drug therapy after local/regional treatment generally is intended to eradicate micrometastases presumed to be present on the basis of clinical, laboratory, or imaging features of the primary tumor and/or regional lymph nodes. This is sometimes referred to as surgical adjuvant therapy (see below). Drug therapy before local/regional treatment may be intended to eradicate micrometastases, or to facilitate subsequent surgical or radiation treatment through tumor size reduction, or both. Drug therapy also may be administered concurrently with radiation in order to enhance the cytotoxic effects of radiation upon tumor cells. VIII. Cancer Staging Oncologic practice is based in clinical epidemiology; that is, it is largely based upon the study of groups of patients with similar cancers. Tumor staging is used to categorize patients into meaningful groups in terms of prognosis and response to therapy. Solid tumors (carcinomas and sarcomas) commonly are staged according to a TNM -- Tumor, Node (regional lymph node), Metastasis classification specific to each tumor type. In a TNM classification, a subscript notation is used to categorize each aspect of the tumor. For example, N0 generally indicates that regional lymphatics are not involved, whereas N1 through N4 indicate increasing degrees of regional lymphatic involvement. As this approach may generate a large number of categories, combinations of TxNyMz, these categories usually are grouped into Stages numbered from I to III or I to IV. In general, prognosis becomes less favorable as Stage assignment increases. IX. Adjuvant Therapy Drug therapy after a local/regional treatment often is referred to as adjuvant therapy. Adjuvant therapy is a standard approach for a number of solid tumors including breast and colon cancer. In principle, adjuvant therapy may be appropriate when the following conditions prevail:
o

Patients at high risk for recurrent disease (micrometastasis) can be identified by tumor stage or other clinical or pathological parameters. Available drug therapy is moderately effective, that is, often causes tumor regression but rarely cures metastatic disease.

The underlying clinical hypothesis is that moderately effective drug therapy may eradicate minimal (microscopic metastatic) disease even though it is not capable of eradicating clinically apparent metastatic disease. The related mechanistic

hypothesis is that large (clinically apparent) tumors are more heterogeneous and more likely to harbor drug resistant cell populations. Adjuvant therapy may not be inappropriate for a disease in which highly effective drug therapy for metastatic disease is available. In such cases, a wait and watch approach allows one to administer toxic drug therapy only to those patients who need it.

Abbreviated TNM Staging of Breast Cancer TNM definitions AJCC stage groupings

Primary tumor (T): Stage 0 T0: No evidence of primary tumor Tis N0 M0 Tis: Carcinoma in situ T1: Tumor 2.0 cm or less in greatest dimension Stage I T2: Tumor more than 2.0 cm but not more than 5.0 cm in greatest dimension T1 N0 M0 T3: Tumor more than 5.0 cm in greatest dimension T4: Tumor of any size with direct extension to (a) chest wall or (b) inflammatory Stage IIA carcinoma T0-1 N1 M0 T2 N0 M0 Regional lymph nodes (N): N0: No regional lymph node metastasis Stage IIB N1: Metastasis to movable ipsilateral axillary lymph node(s) T2 N1 M0 N2: Metastasis to ipsilateral axillary lymph node(s) fixed to each other or to other T3 N0 M0 structures N3: Metastasis to ipsilateral internal mammary lymph node(s) Stage IIIA T0-2 N2 M0 Distant metastasis (M): T3 N1-2 M0 M0: No distant metastasis M1: Distant metastasis present (includes metastasis to ipsilateral supraclavicular Stage IIIB lymph nodes) T4 N0-3 M0 T0-4 N3 M0 Stage IV T0-4 N0-3 M1

There are at least three problems with the adjuvant therapy strategy:

It requires administration of toxic therapy to some patients already cured by surgery and/or radiation. Assessment of the adjuvant therapy hypothesis requires clinical trials in which large numbers of patients are assigned at random to adjuvant treatment or observation. Results to date have been positive in some tumor types, but generally success has been less striking than originally hoped.

X.

High Dose Therapy High dose therapy refers to treatment approaches in which high, otherwise lethal, doses of chemotherapy and/or radiation are followed by the infusion of hematopoietic stem cells. The original source of stem cells was bone marrow; hence, this approach often is referred to as bone marrow transplantation. Currently, the peripheral blood is enriched with stem cells through hematopoietic growth factor stimulation and stem cells are harvested with centrifugal elutriation (leukopheresis) devices temporarily connected to the venous circulation. The original rationale for high dose therapy was found in the limitations of cytotoxics: although these agents commonly show an increasing dose-response relationship, bone marrow toxicity generally limits tolerated doses to non-curative doses. Hematopoietic stem cell infusion following high dose therapy allows the administration of otherwise supra-lethal doses as hematopoietic function is reestablished by infused hematopoietic stem cells. Regeneration of adequate bone marrow function, however, takes weeks. During this time patients experience infections due to leukopenia and require transfusions of platelets and red blood cells. Therapeutic dose limiting toxicities become the toxicities to other organs, especially the digestive tract, lung, liver, and heart. High dose therapy is potentially curative for some cancers not cured by standard dose chemotherapy (see table) and may be curative for individual patients with cancers that have not been cured by potentially curative standard dose chemotherapy. Hematopoietic stem cells are used from various sources. Patients may serve as their own donor (autologous transplant) by having stem cells harvested and frozen prior to administration of the high dose therapy. This approach avoids problems seen with stem cells from other sources (see below), but is involves the risk that the harvested stem cells may be contaminated by tumor cells that allow the cancer to be re-established following the high dose therapy upon infusion of the rescuing stem cells. Stem cells also may be harvested from others (allogeneic transplant): relatives, unrelated individuals, and fetal cord blood. (This form of high dose therapy also has had limited application in the treatment of non-malignant myeloid or immune diseases (sickle cell anemia, thalessemia, rheumatoid arthritis, systemic lupus erythematosis).) A major problem is that the engrafted hematopoietic system, including the immune system, may recognize the patient, or host, as foreign, resulting in graft versus host disease. This potentially life-threatening condition is characterized by immune-mediated destruction of skin, digestive tract, liver, and lung tissues. In order to reduce the frequency and severity of graft versus host disease, an effort is made to match the stem cell donor to the patient in terms of tissue histocompatibility antigens (HLA system). Matched relatives are preferred to matched unrelated individuals as relatives are more likely to share other poorly or uncharacterized antigens that contribute to graft versus host disease. Fetal cord blood is under investigation as a general source of

hematopoietic stem cells as it appears that fetal grafts may develop host tolerance. Graft versus host disease is managed with immunosuppressive medications. Although the original rationale for stem cell support was purely to permit high dose therapy, it became apparent that part of the therapeutic effect of allogeneic transplantation was due to graft recognition and destruction of the tumor: graft versus disease effect. This has lead to a new line of investigation, called minitransplantation, in which patients receive lower dose, immunosuppressive but not myeloablative cytotoxic therapy followed by allogeneic stem cell infusion in order to establish an allogeneic hematopoietic and immune system that controls the cancer through a graft versus disease effect. XI. Chemoprevention of Cancer Tamoxifen, an estrogen antagonist, prevents or delays the development of breast cancer in women at greater than average risk. Unfortunately, this effect is associated with a (lesser) increase in uterine cancer and thromboembolic events. Similar to adjuvant therapy, implementation of an effective chemoprevention strategy generally requires:
o

Preventive agents of very low toxicity, as they will be administered to healthy people potentially for prolonged periods of time A target population at increased risk Clinical trials involving large numbers of subjects assigned at random to treatment or observation.

o o