Clinical Strategies for Cancer Treatment: The Role of Drugs



Clinical Strategies for Cancer Treatment: The Role of Drugs


Bruce A. Chabner



Cancer treatment requires the cooperative efforts of multiple medical specialties. Although surgeons are often the first specialists to treat the cancer patient, the radiotherapist and medical oncologist have become increasingly important in the initial management of cancer patients, and responsibility for care of patients with metastatic cancer is usually in their hands. The array of alternatives for the treatment of cancer is constantly expanding. As new drugs and new biologics demonstrate effectiveness in advanced disease, and with the evolution of strategies for integrated multimodality treatment, the development of an initial plan of treatment requires the combined input of specialists from pertinent disciplines. The plan must be based on a thorough understanding of the potential benefit and likely acute and delayed toxicities of each component of the treatment regimen, as well as their possible positive and negative interactions. Thus, the medical oncologist must have a thorough understanding of the clinical pharmacology of drugs that are part of the therapeutic plan.

As a general rule, the medical oncologist is urged to use standard regimens as described in the Physician Data Query (PDQ) system of the National Cancer Institute (NCI).* PDQ contains information on state-of-the-art treatments for each pathologic type of cancer, as well as a listing of experimental protocols for each disease. An important alternative to “standard” therapy is the clinical trial, which should be considered for every eligible patient. Such trials are listed in cancer center and cooperative group websites, and offer new and potentially more effective treatments. While response rates are less than 5% in Phase I trials, and somewhat higher in Phase II studies, the risk of significant toxicity is low (Roberts) and for the patient seeking a rational alternative to supportive care, worth taking. Phase III trials compare a standard regimen to an experimental therapy that is thought to be at least as effective as the standard drugs. With either choice, standard therapy or a clinical trial, the medical oncologist and the patient must understand the potential benefits and risks of new and established drugs or combinations of drugs, often integrated with surgery and irradiation. Steps in the decision-making process are discussed in this chapter to provide the reader with an understanding of the overall role of drugs in cancer treatment.


Determinants of Treatment Planning

The first and primary determinant of treatment is the histologic diagnosis. Malignant neoplasms occur in many different pathologic forms, each with a characteristic natural history, pattern of progression, and responsiveness to treatment. Thus, the histologic diagnosis, usually made by surgical biopsy or excision of a primary tumor, is of critical importance as a first step in treatment planning. The clinical oncologist must be alert to the possibility of atypical presentations of treatable and even curable tumors, such as germ cell tumors of the testis and breast cancer, and must ask for special immunohistologic or molecular tests to rule in or rule out a potentially curable tumor type. In cases lacking a precise histologic diagnosis, treatment is usually directed against the most responsive tumor type within the realm of possible diagnoses. For example, young adult males presenting with poorly differentiated carcinoma of uncertain origin and lacking definitive tumor markers are best treated with a regimen effective against germ cell tumors of the testis, a highly curable disease. Some (15% to 20%) patients will experience a durable complete response.1

In a growing number of cases—for example, lung carcinoma or the non-Hodgkin’s lymphomas—accurate pathological and molecular subtyping of tumors is important because the subtypes of these diseases have different patterns of clinical response to treatment. Molecular or genetic analysis may reveal important prognostic information for subtyping breast cancer, leukemias, lymphomas, colon, and lung cancers.2 Epidermal growth factor receptor (EGFR) mutations identify a unique subgroup of patients with non-small cell lung cancer highly responsive to the EGFR inhibitor (Iressa), while the absence of kras mutation implies a reasonable chance of response to the anti-EGFR receptor antibodies, cetuximab, and panitumomab.3 In premenopausal women with stage I breast cancer (<2 cm primary, node negative), adverse tumor features, such as a high S-phase (DNA synthetic phase) fraction, absence of estrogen or progesterone receptors, high expression of the c-erbB-2/HER-2-neu oncogene, or a gene array signature predicting a high risk of relapse, guide the decision to use adjuvant chemotherapy and may influence the selection of specific drugs or regimens.4

Additionally, gene array studies have provided significant insights into subgroups of cancer with favorable or unfavorable prognosis, or with a high risk for metastasis, and therefore in need of adjuvant therapy. Array studies do not as yet guide the choice of specific drugs. With the exception of the EGFR mutation in non-small cell
lung cancer, kRas mutation in colorectal cancer, her2/neu amplification in breast cancer, and hormone receptor expression in breast cancer, molecular tests for drug sensitivity/resistance are not commonly used in current practice. Molecular profiling of tumors will contribute more significantly in the future, as targeted molecules gain a greater foothold in cancer treatment.5, 6, 7 Molecular analysis of receptor tyrosine kinases, signaling pathways, and DNA repair enzymes will subclassify common tumors into therapeutically relevant groups.5


Staging

The next step in treatment planning is to determine the clinical extent of disease and specifically to determine whether the tumor is curable by local treatment measures. This staging process requires radiological studies and biopsies of suspicious lesions, and plays an important role in planning therapy, for example, the treatment of Hodgkin’s lymphomas significantly for patients with localized versus widespread disease. Patients with disease confined to a single lymph node site or area (Stage I) are curable with radiotherapy with limited chemotherapy, while more advanced stages (II to IV) must be treated with aggressive chemotherapy.


Individualizing Treatment Choice

The choice of specific therapies depends on the tumor’s histology, its relevant molecular and immunologic subtype, and its stage; an additional factor, the patient’s probable tolerance for the side effects of the various possible treatments must also be considered. Although chemotherapy cures a substantial fraction of patients with diffuse large cell lymphoma, not all patients with this diagnosis are suitable candidates for intensive treatment. Severely debilitated patients and those with underlying medical problems—for example, heart disease, renal failure, diabetes, or chronic obstructive pulmonary disease—might well suffer severely disabling or fatal complications from potentially curative regimens, as indicated in Table 1-1. In such cases, the physician and patient may choose a less toxic, palliative regimen. The ultimate decision must be based on a thorough understanding of the disease, the clinical pharmacology of the drugs in question, and the potential benefits and risks of alternative forms of treatment, such as radiation therapy, or surgery.








TABLE 1.1 Toxicity of CHOP regimen for treating diffuse large cell lymphoma

























Drugs


Toxicitya


Risk factors


Cyclophosphamide


Hair loss, myelosuppression, hemorrhagic cystitis, secondary leukemia


Underlying infection


Doxorubicin hydrochloride (adriamycin)


Cardiomyopathy, myelosuppression, hair loss


History of heart disease, prior chest irradiation


Vincristine sulfate (Oncovin)


Peripheral and autonomic neuropathy


Liver dysfunction, other neurotoxic drugs, inherited or acquired peripheral neuropathy


Prednisone


Glucose intolerance, immune suppression, bone and muscle loss


Diabetes, underlying infection


a In general, elderly patients are at increased risk of toxicity because of underlying medical problems and altered rates of drug elimination.


Pharmacogenomic differences are increasingly identified as influencing response and toxicity of cancer drugs. Polymorphisms of genes responsible for inactivating irinotecan (UDG1A1), 6-mercaptopurine (thiopurinemethyltransferase, TMPT), arabinosylcytosine (cytidine deaminase), and 5-fluorouracil (5-FU) (dihydropyrimidine dehydrogenase) may be associated with significantly delayed drug clearance and may lead to toxicity to both host and tumor (see relevant chapters). Mutations, polymorphisms, or gene methylation may affect the expression or activity of DNA repair enzymes such as methyl guanine O-6 methyl transferase, ERCC1, and enzymes of the mismatch repair complex, and thereby influence response to alkylating and platinating drugs (Chapters 14 and 15). Genetic tests for these changes are available in specialized laboratories (Table 1-2), but they are sporadically used in clinical practice.

Finally, in the context of information about tumor histology, stage, and molecular features, and with information about the patient’s age and baseline health, the oncologist must decide whether a realistic opportunity exists for cure. A decision to treat with curative intent demands a high degree of adherence to drug dosage and schedule, as specified in the standard or experimental regimen, and a willingness to accept treatment-related toxicity. When cure is not a realistic expectation, a decision to treat must be based on an expectation for prolonging life or improving the quality of life. In patients receiving purely palliative treatment, dosage adjustments or treatment delays help to minimize the impact of myelosuppression or mucositis, but at the cost of antitumor efficacy. When the probability for benefit is low, chemotherapy should be offered only after frank and thorough discussion of the likely outcome. In such cases, experimental drugs may be a more attractive alternative in the setting of a clinical trial.









TABLE 1.2 Pharmacogenomic tests for cancer chemotherapy































Genetic test


Disease


Clinical impact


Laboratory


Thiopurine methyl transferasea


Childhood ALL


Identifies patients at high risk of 6-MP toxicity


ARUP Laboratories (Salt Lake City)




Promethius Laboratories (San Diego)


UDP glucuronyltransferase 1A1a


Colorectal cancer


Identifies patients at high risk of irinotecan toxicity


ARUP Laboratories


Dihydropyrimidine dehydrogenasea


Any 5-FU containing regimen


Identifies patients at high risk for 5-FU toxicity


Molecular Diagnostics Laboratories (Cincinnati)


Appropriate Web sites for the Laboratories identified are online.


a Test of host DNA for polymorphism.



Drugs in Cancer Treatment

Although initially designed for treatment of patients with metastatic cancers, drugs are now used at some time point during the course of the illness of most cancer patients. Cytotoxic drugs cure some disseminated cancers (Table 1-3) and are effective in decreasing tumor volume, alleviating symptoms, and even prolonging life in many other types of metastatic cancer that are not curable. Adjuvant chemotherapy regimens are used in patients who have had primary tumors resected and who, although possibly cured by surgery, are at significant risk of recurrence. Adjuvant therapy decreases tumor recurrence rates and prolongs survival in selected patients with breast cancer, colorectal cancer, non-small cell lung cancer, osteosarcoma, and other tumors. Neoadjuvant chemotherapy effectively reduces the bulk of primary tumors prior to surgical resection or irradiation of tumors that would otherwise be difficult or impossible to resect. It is often used in patients with locally advanced head and neck carcinomas, esophageal cancer, non-small cell lung cancer, osteosarcoma and soft tissue sarcomas, bladder cancer, and breast cancer. This approach often allows a more limited surgical operation, or even surgery-sparing radiation therapy, and thereby preserves organ function and minimizes cosmetic changes. It also may decrease local recurrence and the initial clinical response of the tumor mass can serve as an indication of tumor sensitivity to the drugs used, and therefore a signal to continue chemotherapy after surgery.

The design of multi-drug treatment regimens is based on a number of considerations. These include (a) the kinetics of tumor growth, (b) responsiveness of the pathologic and molecular type of tumor to specific drugs, (c) the biochemical mechanisms of each drug’s cytotoxic activity as well as their mechanisms of resistance, and (d) the pharmacokinetic behavior of drugs in question and their patterns of toxicity to normal organs. Some chemotherapy regimens have been designed to minimize emergence of drug resistance, based on preclinical experiments or theoretical models of drug resistance. The molecular actions and pharmacokinetic features of individual drugs are considered in detail in succeeding chapters, but the impact of these factors on trial design is reviewed at this juncture to provide a framework for understanding regimen design.








TABLE 1.3 Curability of disseminated cancer with drugs

















































Disease


Therapy


Probable cure rate


Adults


Hodgkin’s disease (stage III or IV)


Combination chemotherapy


70% or higher


Testicular carcinoma (stage III)


Combination chemotherapy followed by surgery


90% or higher


Gestational choriocarcinoma


Methotrexate sodium ± actinomycin D (dactinomycin)


90%


Ovarian carcinoma


Platinum-containing combination chemotherapy


10%


Acute myelogenous leukemia


Combination chemotherapy


50%


Hairy cell leukemia


Cladribine


80%-90%


Acute lymphocytic leukemia


Combination chemotherapy plus cranial irradiation


50% or higher


Intermediate- and high-grade non-Hodgkin’s lymphomas


Combination chemotherapy


50% or higher


Wilms’ tumor and sarcomas


Surgery, chemotherapy, and irradiation


50%


Burkitt’s lymphoma


Combination chemotherapy


80%




Kinetic Basis of Drug Therapy

The objective of cancer treatment is to reduce the tumor cell population to zero. Chemotherapy experiments with rapidly growing transplanted tumors in mice have established the validity of the fractional cell kill hypothesis, as developed by Skipper et al.,8 which states that a given drug concentration applied for a defined time period will kill a constant fraction of the cell population, independent of the absolute number of cells. Regrowth of tumor occurs during the drug-free interval between cycles. Thus, each treatment cycle kills a specific fraction of the remaining cells. Assuming that drug-resistant cells do not outgrow, the results of treatment are a function of (a) the dose of drug administered and (b) the number and frequency of repetitions of treatment.

Based on these cytokinetic considerations, most chemotherapy regimens consist of cycles of intensive therapy repeated as frequently as allowed by the tolerance of dose-limiting tissues, such as bone marrow or gastrointestinal tract. The object of these cycles is to reduce the absolute number of remaining tumor cells to 0 (or <1) through the multiplicative effect of successive fractional cell kills (e.g., given 99% cell kill per cycle, a tumor burden of 1011 cells will be reduced to <1 cell with six cycles of treatment: [1011 cells] × [0.01]6 < 1).

The fractional cell kill hypothesis was derived from studies of the treatment of murine leukemias, and was applied successfully to the cure of human leukemia and lymphoma. For more slowly growing solid tumors in humans, a number of confounding factors distort the fundamental assumption of constant fractional cell kill per cycle with. Most solid tumors (such as lung and colon cancers) are recognized at a stage of decelerating growth, when tumor vascularity is not adequate to provide oxygen and nutrients to the bulk of the tumor. These large tumors contain a high fraction of slowly dividing or noncycling cells (termed “G0 cells”). Most antineoplastic agents, particularly the antimetabolites and antitumor antibiotics, are effective against rapidly dividing cells. Some selectively kill cells during specific phases of the cell cycle (S-phase, for cytosine arabinoside, and mitosis, for the vincas and taxanes). The initial kinetic features of a large, poorly vascularized, and slowly growing tumor are unfavorable for treatment with these drugs. However, alkylators and adduct-forming platinum derivatives attack DNA in all phases of the cell cycle, and retain activity against nondividing or slowly dividing cells. Thus, they are often used to reduce tumor bulk. An initial reduction in cell numbers produced by surgery, radiotherapy, or non-cell-cycle-specific drugs may indirectly improve blood flow and thereby push the slowly dividing cells into more rapid cell division. A reduction in tumor volume may recruit nondividing cells into the cell cycle, where they become increasingly susceptible to therapy with cell-cycle-specific agents. Thus, an initially slowly responding tumor may become more responsive to antimetabolites or antimitotic drugs after surgical debulking or after initial treatment with alkylators, and fractional cell kill may actually increase with sequential courses of treatment.

The biochemical and molecular heterogeneity of advanced human tumors introduces additional complexity to the simple hypothesis that multiple cycles of fractional cell kill translate into tumor cure. Isoenzyme typing, karyotypic analysis, and molecular studies have demonstrated that most human tumors evolve from a single malignant cell.9 This original homogeneity does not persist during later stages of tumor growth; in fact, studies of human tumors disclose that clinically evident malignancies are composed of cell types with differing molecular, biochemical, morphologic, and drug-response characteristics. This heterogeneity results from the genomic instability of malignant cells. Indeed, mutations in cell-cycle checkpoint control genes, such as p53, and in DNA repair genes, such as the MSH genes in familial colon cancer, may be the initial event in malignant transformation of many tumor types, establishing a fundamentally mutable clone from which diverse subclones evolve. Thus, spontaneous amplifications, deletions, or other alterations affect a broad expanse of genes in tumors, some of which affect the target proteins that control drug response and cell cycle.10 These mutations lead to heterogeneity and account for outgrowth of resistant tumor cells during or after treatment. This has been clearly demonstrated in the pretreatment isolation of imatinib (gleevec)-resistant cells from selected patients with chronic myelogenous leukemia.11 When a diverse population of tumor cells are subjected to the selective pressure of drug treatment, drug-sensitive tumor cells are destroyed, but subpopulations of resistant cells survive and proliferate. With some notable exceptions (treatment of chronic myelogenous leukemia with imatinib, gestational choriocarcinoma treated with methotrexate, cyclophosphamide treatment for African Burkitt’s lymphoma, and cladribine treatment for hairy cell leukemia), single-agent chemotherapy rarely produces long-term remission or cure of advanced malignancies. Of necessity, the most successful treatment regimens have combined multiple agents with different mechanisms of action.

A second possible reason for failure of chemotherapy is the existence of stem cell populations within the tumor; these cells possess a multidrug-resistant phenotype and the capacity of unlimited self-renewal.12 It is postulated, but still unproven, that failure of therapy may result from the persistence of tumor stem cells following eradication of the more drug-sensitive and more differentiated bulk of the tumor population.


Prediction of Drug Response to Individual Agents

The results of clinical trials set the standard for treatment of most types of cancer, but for most metastatic cancers, only a fraction of patients respond, and those responses are temporary. To avoid the needless toxicity of ineffective treatment, especially in diseases with only modest rates of response, it would be desirable to predict sensitivity for the specific tumor and patient at hand. Various systems have been established and some even commercialized for testing tumor cells in vitro to predict response to a panel of candidate drugs, but only fragmentary evidence, and no prospective controlled trial data, exist to justify their routine use.

Biochemical and molecular tests for drug sensitivity have proven predictive value in the practice of oncology; these include tests for hormone receptor protein expression and HER-2-neu amplification in breast cancer, the mutational status of k-Ras in colorectal cancer, and most recently the test for mutational activation of the EGFR receptor in non-small cell lung cancer (see relevant chapters). The results of each of these tests are highly correlated with clinical responsiveness to specific therapies. Other tests offer promise for clinical use. Expression of components of the DNA repair pathway correlates with patient survival after platinum-based treatment.13 Similarly, high concentrations of dihydrofolate reductase have
been associated with resistance to methotrexate,14 as is a failure to transport or polyglutamate the drug.15 High intratumoral levels of the DNA repair enzyme methylguanine methyl transferase predict resistance to nitrosoureas, dacarbazine, and temozolomide, all of which damage DNA by alkylating the O6 position of guanine.16 Mutations in mismatch DNA repair (the MSH6 gene) are associated with resistance to methylating agents, to 6-mercaptopurine, and to cisplatin and carboplatin.17 However, these molecular/biochemical tests have not been tested prospectively to prove their value in selecting treatment with cytotoxic drugs, and routine laboratory tests are not available.

Molecularly targeted discovery offers the hope of identifying new drugs tailored to specific receptors and intracellular enzymes critical for cell signaling and for maintaining viability and growth of tumors. Targeted drugs are effective against subsets of human malignancy. One such target, the bcr-abl tyrosine kinase, results from a translocation specific for chronic myelogenous leukemia (CML), and virtually all CML patients have this translocation at diagnosis. Imatinib, an inhibitor of the kinase, has striking activity in chronic and blastic phases of CML, and has limited toxicity for normal bone marrow cells.18 Because imatinib also inhibits the c-kit tyrosine kinase, it is effective against gastrointestinal stromal tumors (GIST). Most patients with GIST express a mutated and activated form of c-kit. Pretreatment sequencing of the c-kit gene provides important prognostic information and allows appropriate selection of patients for treatment with imatinib (exon 11 mutations), sunitinib (exon 9 mutations), or other experimental drugs.19

Genetic tests to select patients for specific targeted therapies may dramatically improve response rates to these drugs. Activating mutations in the EGFR gene identify non-small cell lung cancer (NSCLC) patients who have a 70% response rate to gefitinib as first line therapy. Tumors lacking such mutations do not show clinical tumor regression, although some may derive benefit from a slowing of their growth.20 The test for EGFR mutations should be performed in any nonsmoking patient with unresectable NSCLC.

The list of molecularly targeted agents, discussed further in various chapters of this book, is constantly growing. Effective agents targeting the EML4-ALK mutation in non-small cell lung cancer, the ret

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May 27, 2016 | Posted by in ONCOLOGY | Comments Off on Clinical Strategies for Cancer Treatment: The Role of Drugs

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