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Treatment - Chemotherapy

SYSTEMIC THERAPY

Chemotherapy

The introduction of the polyfunctional alkylating agents in the early 1940's ushered in the modern era of chemotherapy. Now several classes of these agents are in common use and many more are under continual development. Chemotherapy is a systemic treatment and is the main one used for disseminated cancer. How effective is chemotherapy? As the tables below show, it can be given with curative intent with success in a few tumors, but often its role is only palliative, sometimes with improved survival. Unfortunately it has only minor activity with several of the common solid tumors. Its role in the adjuvant setting is still evolving.

How Tumors Respond to Chemotherapy

(Table adapted from WHO, 1995)

WHO has established a list of 14 drugs to constitute an essential drug list for treating the 10 most common cancers of adults (WHO 1995). They have been chosen based on their efficacy and cost-effectiveness. Another 6 drugs are used for pediatric tumors and 2 more are used for adult leukemia and lymphoma. This essential drug list is recommended to form the basis of national policies on chemotherapy. Most of them are available in generic form, but their quality and biological activity must be routinely monitored.

Essential Drugs for Oncology

*1 Drugs needed to treat curable pediatric tumors
*2 Drugs needed to treat the 10 most common tumors in the world
*3 Drugs used for palliative purposes to improve quality of life and/or extend survival
            (Table adapted from WHO,1995)

Chemotherapy is given in a course of multiple cycles of treatment. Tumor response is best ascertained by palpating superficial tumor masses or by imaging internal lesions. To permit comparisons, uniform definitions are used. The disappearance of all detectable tumor is a complete response (complete remission). In a partial response measurable lesions shrink by more than 50% in the sum of the products of the perpendicular diameters, and no lesion increases in size nor do any new lesions appear. No change in measurable tumor dimensions means stable disease, while progressive disease is indicated by an increase of at least 25% in the sum of the products of the perpendicular diameters of measurable lesions or the appearance of new ones.

Cytokinetics. Agents like antimetabolites or alkylating agents that are mainly effective during a partic-ular phase of the cell cycle are called cell-cycle-specific or active since they kill (are cytotoxic to) mainly actively cycling cells. Some of these cell-active drugs are also phase-specific, killing cells in a particular phase of the cell cycle. Drugs whose action is prolonged and independent of DNA synthesis are called cell-cycle nonspecific or phase-nonspecific and will be effective against tumors with relatively low prolifer-ative activity. They can kill cells at any phase of the cell cycle, including G0/G1. This distinction between specific and nonspecific agents is relative rather than absolute.

Skipper's log cell-kill model of drug effectiveness assumes that tumors grow exponentially with first order kinetics until a lethal tumor burden is reached. A given dose kills a constant percentage of tumor cells rather than a constant number regardless of the size of the tumor. But most human solid tumors grow with Gompertzian kinetics in which the growth slows and begins to plateau with a decreasing growth fraction as tumor size increases, so that large tumors become relatively insensitive to chemotherapy because of unfavorable cytokinetics. Thus chemotherapy is most effective when the tumor burden is small and the growth fraction maximal as in the adjuvant setting.

Pharmacology. Most agents work by affecting enzymes or sub-strates acted upon by enzyme systems. Most are inducers of programmed cell death (apoptosis). Usually these effects relate to DNA synthesis or function. Drugs interfering with DNA synthesis or mitosis are active against proliferating cells rather than resting cells. They are most effective during the S phase (DNA synthesis) of the cell cycle or when the mitotic spindle is forming. These drugs are most active against tumors with a high rate of cellular proliferation and relatively ineffective against tumors with a small growth fraction. Drugs like the purine/pyrimidine analogs, the alkylating agents and the topoisomerase inhibitors damage DNA. Cells respond to this toxic damage to the genome by arresting at two checkpoints: the G1/S and G2/M boundaries. The tumor suppressor p53 activates the expression of p21, a cyclin-independent kinase inhibitor, and this in part mediates the G1 arrest. With G1 arrest the cell can repair damage before DNA replication, while G2 arrest allows repair before mitosis. But if the cell cannot repair the DNA damage then it undergoes apoptosis via p53-dependent or -independent pathways.

When cytotoxic effect on cancer cells is compared to plasma chemotherapeutic drug concentration a dose-response effect is observed. There is no cytotoxicity at low concentrations, and then as the concentration increases the cell kill is proportional to drug concentration until it reaches a plateau at high concentrations. A similar effect is seen with normal cells, but the response curve is shifted to the right indicating that normal tissues are less sensitive to drug cytotoxicity than are malignant cells; it takes a much greater drug concentration to give the same cytotoxic effect for normal cells, say 50%, than for malignant cells. This difference represent the therapeutic index. Unfortunately that difference is narrow for most chemotherapeutic drugs, which limits their effectiveness. One cannot give doses above those that are toxic to normal tissues (dose-limiting toxicity). The maximum tolerated dose lies just below this limiting point. Normal proliferating tissues like gastrointestinal mucosa or the bone marrow or hair follicles are the most susceptible to toxicity form chemotherapy.

Dosing of most chemotherapeutic agents is based on body surface area (square meters) calculated from height and weight. The drugs should be administered by trained medical oncologists. There are several classes of drugs depending on their mechanisms of action:

• 
  Antimetabolites are cell-cycle-active, mainly for S phase. The nucleoside analogs act as false substrates in biochemical pathways and inhibit nucleic acid synthesis by being incorporated into DNA or RNA. Some inhibit enzymes involved in nucleotide biosynthesis. Pyrimidine analogues include fluorouracil, cytarabine and gemcitabine. Purine analogues include fludarabine, cladribine and pentostatin. 6-Mercaptopurine and 6-thioguanine are thiopurine analogues. Other antimetabolites include methotrexate and hydroxyurea.
• Plant alkaloids include the vinca alkaloids vincristine and vinblastine from the periwinkle plant, with vinorelbine a semisynthetic derivative. They bind to tubulin to inhibit the assembly of microtublues, and are cytotoxic during the M phase of the cell cycle. Paclitaxel and docetaxel are taxanes from the Pacific and European yew trees respectively. They prevent the disassembly of microtubules, thereby stabilizing them.
• Topoisomerase inhibitors interfere with the enzymatic process of adjusting conformational and topological changes in DNA during its transcription and replication. Topoisomerase I and II are the enzymes involved. Camptothecin and its analogues 9-aminoamptothecin, topotecan and irinotecan are topoiosomerase I inhibitors. The eipodophyllotoxins (etoposide and teniposide) and anthracyclines (doxorubicin, daunorubicin and idarubicin) inhibit topoisomerase II. Mitoxantrone and dactinomycin are related to the anthracyclines.
• Alkylating agents are mostly bifunctional and cross-link DNA to cause strand breakage leading to cell death. Examples include cyclophosphamide and ifosfamide, melphalan, busulfan, mechlorethamine, chlorambucil and thiotepa. Carmustine and lomustine are nitrosoureas with high lipid solubility and excellent penetration into the nervous system. The platinum compounds, cisplatin and carboplatin, are not true alkylating agents but kill by covalent cross-linking of DNA.
• Antitumor antibiotics are isolted from soil microorganisms. They include bleomycin and mitomycin C, which respectively cause single and double-strand breaks in DNA with cytotoxicity in the G2 and M phases of the cell cycle, or cross-link DNA
• Other agents dacarbazine and procarbazine, which damage DNA like alkylating agents. L-Asparaginase is an enzyme that depletes extracellular pools of asparagine.

An undesirable consequence of these drug ac-tions is that normal tissues that have a high rate of cellular proliferation suffer toxic side effects. These include normal bone marrow elements (myelosuppression with anemia, leu-kopenia with infection, thrombocytopenia with bleed-ing), the gastrointestinal tract (stomatitis, anorexia, nausea, vomiting, diarrhea, surface ulceration), and the hair follicles (alopecia).

The major toxicities for individual drugs can be significant. Because of the seriousness of potential side effects, the narrow therapeutic range separating toxicity from therapeutic efficacy, and the necessity to use maximum tolerated doses for effec-tive tumor cell kill, it is essential that cancer chemo-therapy be given in consultation with an experienced oncologist. Specific written protocols for particular disease regimens should be consulted and carefully followed for details of drug dose and scheduling as well as indications and contraindications defining patient eligibility. Drug doses are frequently modified for specific toxicities as well as for concomitant he-patic or renal dysfunction.

In addition to the development of sensitive meth-ods to measure the active portion of both drugs and their cellular targets within the therapeutic range, the advent of infusion devices to provide continuous infusion chemotherapy has been a significant advance. This strategy can overcome pharmacokinetic prob-lems with drugs that have short half-lives by exposing tumor cells to effective drug levels for periods in excess of the cell cycle of the tumor. In the liver one can use drugs that are metabolically inactivated by normal liver to reduce systemic toxicity. Totally im-plantable access ports and infusion pumps allow out-patient therapy with flexible scheduling and greater convenience and comfort for the patient. Treatment of hepatic metastases from colon carcinoma by this approach is promising and can be combined with external radiation therapy with or without the use of vasoconstrictors or drugs trapped in starch granules which are subsequently dissolved by amylase. Exper-imental approaches to ovarian cancer uses intraperi-toneal therapy with dialysis. Intra-arterial infusion therapy is used for gliomas, hepatic metastasis, and malignant melanoma in extremities combined with hyperthermia by warming the infusate.

Combination Chemotherapy. Drug combinations are used principally to try to circumvent the devel-opment of drug resistance, and most tumors are treated with multiagent chemotherapy. Various mechanisms have been proposed for the development of resistance, chiefly on the basis of experimental systems. Unlike animal tumors, human tumors have a very small percentage of cells in the proliferating pool so that single drugs used over a short time will not guarantee maximum tumor cell kill. Repeated therapy over long time periods not only increases the risk of toxicity but also leads to clinical resistance to the drugs. Tumor cells regrow between cycles of therapy (which must be separated by intervals long enough to let normal tissues re-cover), and few tumor cells are killed with each successive treatment cycle because of the evolution of resistant cell lines.

Human tumors are heteroge-neous, so resistance may relate to the preferential selection of a pre-existing population of neoplastic cells in the tumor inherently resistant to the drug used. Alternatively, drug resistance can result from a stepwise induction of resistance by analogy with bac-terial populations. Thus, additional effective drugs are needed to treat each resistant cell line. The success of drug treatment will thus depend both on the number of resistant lines in the tumor and on the number of available drugs for use in effective com-binations.

Four principles underlie the design of chemotherapy combinations. First, each agent in a regimen should be independently active against the tumor. Unless there is unexpected synergy, adding an agent with the same mechanism of action or inhibiting the same enzyme is unlikely to enhance the response with an additive effect, but will add to the toxicity. Secondly, each drug in the regimen should have an independent mechanism of action, preferably with each drug in the combination targeting different steps along a biochemical pathway. Third, there should be no cross resistance among the drugs in the regimen, so that if one drug selects a resistant tumor subpopulation, it is unlikely to be cross-resistant to another drug in the combination that kills through a different mechanism. Fourth, each of the drugs should have a different dose-limiting toxicity. Two drugs with the same toxicity profile given at maximum tolerated dose can produce unacceptable toxicity.

The biochemical approach to designing drug combinations selects agents that produce multiple, different biochemical lesions in biosynthetic pathways or inhibit several processes needed to maintain the function of essential macromolecules. Both of these strategies reduce the production and availability of a specific end product vital for tumor cell growth and replication. In sequential blockade different enzy-matic steps are inhibited in a biochemical pathway that produces an essential metabolite. In concurrent blockade there is simultaneous inhibition of parallel metabolic pathways that synthesize a common end product. Complementary inhibition occurs when one product. Complementary inhibition occurs when selects agents that-produce biochemical lesions at different sites in the synthesis of polymeric macro-molecules. Although intellectually satisfying, none of the successful drug combinations used today have been developed purely by this approach but may owe some of their effectiveness to such synergistic mech-anisms.

The second approach is empirical and uses drugs that are active as single agents in the specific tumor. Such tumors are usually "drug sensitive" so that several effective drugs having differing mechanisms of action are available. Drug selection is also guided by the type of dose-limiting toxicity likely to be produced by the other agents to be used in thecombination. This allows each agent to be given in full clinical dosage.

Successful combinations use intermittent treat-ment schedules in full doses rather than continuous daily administration. If the combination selectively kills tumor over bone marrow, an interval of 2 to 4 weeks between courses allows recovery of the marrow to pretreatment levels without significant regrowth of the tumor. Intermittent scheduling also may permit recovery of the patient's immune system, often with rebound and overshoot, between the cycles of che-motherapy.

Useful or disadvantageous pharmacologic inter-actions between drugs in a combination may also occur. The action of some antitumor drugs can be enhanced by other drugs with no antitumor effect by preventing the metabolic degradation of the active agent. For example, allopurinol enhances the activity of 6-mercaptopurine by preventing its conversion into the inactive thiouric acid. Tetrahydrouridine and 2-deoxycoformycin prevent deamination of cytarabine by the ubiquitous deaminases present in serum and tissue. Cyclophosphamide is activated to the 4-OH metabolite by oxidative microsomal enzymes. Thus drugs that induce or inhibit these enzymes will en-hance or depress cyclophosphamide activity.

Higher cure rates have come with improvements in supportive care, the availability of a new generation of antimicrobials to handle infectious complications of marrow suppression, the ability to treat marrow suppression with multicomponent blood products and hemopoietic growth factors, and the development of high-technology intensive care uits with specialized oncology nursing. Another important development has been bone marrow transplantation (BMT), which is used to support the myelosuppression that occurs after high dose chemotherapy or chemoradiotherapy. Alkylating agents like cyclophosphamide or busulfan can be used to ablate the marrow and get higher tumor cytotoxicity. In autologous transplantation the patient's own bone marrow or peripheral stem cells are collected and cryopreserved, and then reinfused to reconstitute the hempoietic system. Bone marrow from a suitable donor is used in allogeneic transplantation. In the latter case immune effector mechanisms also help control the cancer through a graft-versus-tumor effect. BMT is used to treat tumors that are initially chemoresponsive like testicular carcinoma, acute leukemia and Hodgkin's and non-Hodgkin's lymphoma. But thus far the procedure has been ineffective in treating common epithelial tumors, although it is being evaluated with breast cancer.

Resistance. Drug resistance is likely the single most important obstacle to getting higher cure rates with chemotherapy. Resistance can be de novo when tumor cells are resistant to drugs from the start, unfortunately a phenomenon shown by many of the most common solid tumors. In acquired drug resistance the tumors are initially responsive, but become resistant with continued treatment. This phenomenon accounts significantly for the fact that only a small percentage of the many tumors that are responsive to chemotherapy can be cured with drugs alone.

By analogy with studies in bacterial populations, tumors consist of a heterogeneous population of cells because of spontaneous mutations from inherent genomic instability. Some of these mutations give rise to a drug-resistant phenotype by chance. Chemotherapy will kill the most sensitive cells and leave the resistant clones to grow out. Clinically it appears that the patient has responded to treatment with a complete or partial remission, but relapse and progression occur later with a form of tumors that is refractory to drugs. Thus small tumors are the most responsive to chemotherapy before multiple resistant subclones have evolved. Indeed regimens that will not work for bulky tumors can be curative in the adjuvant setting. Effective regimens use combination chemotherapy with non-cross-resistant drugs, since the probability that a malignant cell will undergo two simultaneous mutations resulting in resistance to two different classes of drugs is low. Thus the larger the number of non-cross-resistant drugs given at full dose in the regimen, the more likely the treatment will eliminate the entire tumor cell population. There are limitations to these principles. Some agents like the anthracyclines, epipodophyllotoxins ands the alkylating agents are mutagenic and promote the appearance of drug-resistant clones. Also resistance to some agents can result in cross-resistance to others that are distinct mechanistically and structurally. This phenomenon of multiple drug resistance seen with the anthracyclines, vinca alkaloids, epipodophyllotoxins and taxanes, involves a common mechanism with overexpression of either P-glycoprotein (a 170kDa membrane glycoprotein) or of MRP (the multidrug resistance protein - a 190 kDa membrane protein)., both of which are members of the family of ATP-binding cassette proteins. In adult acute myeloid leukemia and neuroblastoma in children the presence of P-glycoprotein at disease presentation gives a worse prognosis. There are modulating agents that block the efflux of drugs caused by P-glycoprotein. Verapamil, quinine and cyclosporine are too toxic at the required doses, but nwer analogues like dexverapamil and the cyclosporine derivative PSC 833 are in clinical trials.

Resistance to anthracyclines and to epipodophyllotoxins can also be due to altered activity or expression of topoisomerase II. Resistance to nitrogen mustard derivatives, nitrosoureas and anthracyclines can also be associated with an enhanced reducing environment from increased detoxification of glutathione with elevated cellular pools of reduced glutathione. Buthione sulfoximine depletes cellular levels of glutathione, and is in clinical trials as a chemosensitizing agent. Failure to undergo apoptosis can also contribute to resistance to both chemo- and radiotherapy. The Bcl-2, BclX and Bax proteins are all involved in the regulation of apoptosis, and may be responsible.

Clinical Trials and New Drug Development. The National Cancer Institute of the USA has had a large drug screening program since the 1940s. The process can take up to10 years for a drug to move from initial screening to approval by the US Food and Drug Administration for use in practice. New substances are screened against a panel of about 60 human cancer cell lines from common solid tumors. If in vitro antitumor activity is found then the substances are tested against a panel of human tunir xenografts in nude mice. Promising substances then undergo toxicology screening and formulation testing, and then are placed into clinical trials. Using an initial dose from animal studies, phase I trials of a drug are done to determine human toxicity. A dose-limiting toxicity and maximum tolerated dose are defined using dose escalation protocols in small cohorts of previously treated patients with diverse tumor types. A series of phase II trials determine whether a drug is active against a particular tumor type using a dose schedule from the phase I study in small patient groups with various advanced but measurable tumors. Only compounds that induce responses in more than 20% of patients go on to phase III trials. These latter studies compare a drug to standard existing therapy for a particular tumor type using large numbers of patients, often in multi-institutional trials, in randomized, two-arm studies.

Differentiating Agents. Cells that have undergone malignant transformation show maturation arrest. Substances like retinoids, vitamin D, phorbol esters and polar/planar compounds like dimethyl sulfoxide can induce tumor cells to differentiate to a more mature and less malignant phenotype. In clinical trials all-trans-retinoic acid has induced short remissions (<6 months) in a high fraction of patients with acute promyelocytic leukemia.

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