A Brief History of Chemotherapy

In the history of medicine, cancer was initially regarded as a localized disease, engaging the primary attention of surgeons and radiation oncologists. Metastatic disease was regarded as untreatable. With the arrival of cancer chemotherapy in the form of alkylating agents in the post–World War II era, it became possible for the first time to entertain the use of drugs to improve local control of cancer, to prevent distant recurrence after surgery, and even to cure systemic disease, as in childhood acute leukemia and choriocarcinoma. With the introduction of adjuvant therapy of breast cancer in the late 1960s, the concept that even apparently localized cancer was a potentially systemic disease that requires a systemic therapy was integrated into the thinking of cancer management in its earliest stages. However, progress in drug discovery was slow. At the time of the publication of the first trials of melphalan for adjuvant therapy of breast cancer in 1971, only a handful of agents were available for treatment of cancer and were primarily drugs developed for the treatment of leukemia. Since that time, the addition of anthracylines, taxanes, and platinum analogs—and, most recently, targeted agents and effective immunotherapy—has vastly expanded the range of options for systemic treatment.

The history of cancer chemotherapy begins with the development of alkylating agents by Goodman and Gilman in the pharmacology department at Yale University, as first reported in 1946. The Yale experiments proved that a systemically administered agent could cause regression of murine leukemia and ultimately a human tumor—in this case, a mediastinal mass in a patient with Hodgkin disease. The conceptual basis for clinical studies of nitrogen mustard was the observation that mustard gases used in military campaigns produced lymph node depletion and bone marrow aplasia. Although it was known at the time that these compounds were highly reactive with proteins, nucleic acids, and other electron-rich molecules, the specific intracellular targets on nucleic acids were not identified until more than a decade later. We are only now beginning to understand the reasons for the somewhat selective action of DNA-damaging agents on tumor cells.

This early experience with alkylating agents led investigators to undertake an alternative approach and search for compounds (antimetabolites) that would act as fraudulent counterparts of natural metabolites known to stimulate cancer cell growth. Among these metabolic targets, folic acid and analogs of nucleic acid bases, all essential to DNA synthesis, proved most effective in retarding tumor growth ( Fig. 10.1 ). In the late 1940s, scientists from American Cyanamid synthesized analogs of folic acid, an essential donor of carbons in the synthesis of purines and pyrimidines. Folic acid was known to stimulate the proliferation of cancer cells in culture and in humans with leukemia. Sidney Farber, a pathologist, found striking but short-lived responses to the first antifolate, aminopterin, and its closely related analog, methotrexate, in children with acute lymphoblastic leukemia (ALL). Prospects for the treatment of leukemia with drugs escalated in the following decade, as new antimetabolites were discovered. Hitchings and Elion at Burroughs Wellcome successfully developed purine analogs, 6-thioguanine and 6-mercaptopurine. Soon afterward, corticosteroids, first used as antiinflammatory agents, were found to kill malignant lymphocytes in children with ALL and in adults and children with lymphoma. Combinations of cancer drugs, each with a unique mechanism of action, produced longer remissions in childhood ALL, setting the stage for combination therapy of lymphomas and, later, solid tumors. The need for more novel and effective drugs led to the establishment of large-scale screening systems for anticancer drugs at the National Cancer Institute in 1955. These initial attempts at drug discovery tested random chemical libraries and natural product extracts against transplantable murine leukemias and, later, murine solid tumors. This led to the isolation of new cytotoxic compounds. The newly discovered compounds fell into four primary classes: agents that formed adducts with DNA (alkylators), agents that blocked mitosis (vinca alkaloids and taxanes), agents that blocked the function of topoisomerases (DNA-unwinding drugs, such as anthracyclines and camptothecins), and antimetabolites (purine and pyrimidine analogs).

Fig. 10.1, Examples of chemotherapy drugs that are analogs of natural metabolites.

Combinations of these drugs successfully overcome resistance to single agents and were able to cure childhood ALL and lymphomas. Solid-tumor chemotherapy advanced more slowly. Through the discovery of 5-fluorouracil (5-FU), an analog of thymine and a highly potent inhibitor of thymidylate synthase, breast and colon cancer proved modestly responsive. Platinum analogs with potent DNA-damaging activity were discovered to have antitumor activity in the early 1970s and, in combination with vinblastine and bleomycin, led to the cure of testicular cancer. Platinum-based combination therapy provided substantial benefits in ovarian and colon cancers. In addition, 5-FU and the platinum drugs had radiosensitizing properties and improved local control in head and neck cancers and rectal and anal tumors.

Equally rewarding efforts in the field of natural product chemistry yielded valuable new anticancer drugs with unique mechanisms of action. In the 1950s, scientists at Eli Lilly discovered the antimitotic and antitumor properties of the vinca alkaloids. Analysis of fermentation broths led to the discovery of DNA-damaging drugs such as mitomycin C, a novel alkylating agent; bleomycin, a DNA-cleaving peptide; and inhibitors of topoisomerase (anthracyclines and camptothecins); and from natural product screening, even more potent antimitotic agents (paclitaxel and eribulin). Drug combinations have become standard therapies for most metastatic tumors and, when combined with radiation treatment and surgery as neoadjuvant or adjuvant therapy, improved the 5-year survival of patients with cancer from 30% in 1950 to more than 65% currently.

The 21st century has witnessed a major breakthrough for cancer treatment with the arrival of targeted therapies ( Table 10.1 ). The development of highly efficient technology for gene sequencing led to the identification of molecular alterations (genomic mutations, amplifications, or translocations) that cause malignancy and shifted the emphasis of drug discovery from cytotoxics to therapies that selectively target oncogenic driver alterations. These driver mutations produce gene products that transform otherwise normal cells and create a tumor dependent for its survival on the specific activated pathway, a condition termed oncogene addiction . Inhibitors that shut down the target and its pathway lead to death of the cancer cell.

TABLE 10.1
FDA-Approved Targeted Cancer Therapies
Disease Target (Oncogene, Cell Surface Marker, Receptor) Drug(s)
Basal cell cancer Smoothed Vismodegib
Breast cancer HER-2 Trastuzumab, TDM-1, pertuzumab, neratinib, lopatinib
CDK4/6 Palbociclib, ribociclib, abemaciclib
Colorectal cancer VEGF Bezacizumab, ziv-afibercept, ramucirumab
VEGFR Regorafenib
Gastrointestinal stromal tumor C-KIT Imatinib, sunitinib
Gastric cancer HER-2 Trastuzumab
VEGF Ramucirumab
Glioblastoma multiforme VEGF Bevacizumab
Hepatocellular cancer VEGFR Sorafenib, sunitinib
Head and neck cancer, squamous EGFR Cetuximab
PD-1 Nivolumab, pembrolizumab
Hodgkin disease PD-l Nivolumab
CD-30 Brentuximab vendotin
Leukemia, acute lymphocytic Binatumumab
BCR-ABL Ponatinib, dasatinib
Leukemia, acute myeloid FLT-3 Midasturin
CD-33 Gemtuzumab ologomycin
Leukemia, chronic myeloid BCR-ABL Imatinib, dasatinib, nilotinib, bosutinib, ponatinib
Leukemia, acute promyelocytic RARα-PML All trans-retinoic acid
Leukemia, chronic lymphocytic CD-20 Rituximab, obitumumab, ofatumumab
BTK Ibrutinib, alabrutinib
BCL-2 Venetoclax
PI3Kinaseδ Idelalisib, copanlisib
CD-52 Alemtuzumab
Lymphoma, B-cell BTK Ibrutinib
CD-20 Rituximab
Lymphoma T-cell HDAC Romidepsin, vorinostat, belinostat
Myeloma 26 S proteosome Bortezomib, carfilzomib, ixazomib
CD-38 Daratumumab, elotuzumab
Cereblon Thalidomide, lenalidomide, pomalidomide
HDAC Pabinostat
Lung cancer, non–small cell VEGF Becacizumab
EGFR Gefitinib, erlotinib, afatinib, osimertinib
EML4-ALK Crizotinib, ceritinib, alectinib
ROS-1 Crizotinib
PD-1 Nivolumab, pembrolizumab, atezolizumab
Melanoma B-RAF Vemurafenib, dabrafenib
MEK Trametinib, cobimetinib
CTLA-4 Ipilumumab
PD-1 Nivolumab, pembrolizumab
Merkel cell cancer PDL-1 Avelumab
Neuroendocrine tumor mTOR Everolimus
Neuroblastoma GD2
ALK
Dinutuximab
Critozinib
Ovarian cancer VEGF Bevacizumab
PARP Olaparib, niraparib, rucaparib
Renal cell cancer VEGF Bevacizumab
VEGFR Sunitinib, pazopanib, cabozantinib, sorafenib, axitinib, lenantinib
mTOR Everolimus, temsirolimus
PD-1 Nivolumab
CTLA-4 Ipilumumab
Thyroid cancer RET, C-MET, VEGFR Cabozantinib, sorafenib, landetinib
Vandetinib
Urothelial cancer PDL-1 Avelumab
Durvalumab
Polycythemia vera JAK-2 Ruxolitinib
Myelodysplasia Cereblon Lenalidomide
AML, Acute myelocytic leukemia; B-CLL, B-cell chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; FDA, US Food and Drug Administration; GIST, gastrointestinal stromal tumor; NSCLC, non–small cell lung cancer.

The goal of targeted therapy is not to induce DNA damage but is rather to inhibit specific signaling pathways that control proliferation, cell survival, invasion, metastases, or angiogenesis. A growing number of these agents, approved for clinical use, have remarkably improved treatment of subsets of human cancer. These targeted drugs are highly potent small molecules that inhibit specific targets with nanomolar potency. Their targets may be a receptor tyrosine kinase (RTK) in lung cancer or intracellular signaling pathways, such as BCR-ABL kinase in chronic myelogenous leukemia, or even key regulators of apoptosis, such as BCL-2. A second class of anticancer targeted drugs, monoclonal antibodies, produce responses by blocking cell surface receptors, initiating immune responses against tumor antigens, carrying cytotoxic payloads (brentuximab vendotin), or blocking tumor blood vessel formation (bezacizumab). Monoclonal antibodies such as trastuzumab, cetuximab, and bevacizumab also enhance the effectiveness of chemotherapy; cetuximab, an inhibitor of epidermal growth factor receptor (EGFR), synergizes with irradiation as well (see Chapter 4 for biological and drug interactions with radiation therapy). The role of targeted drugs in the overall management of cancers is continuously evolving. Targeted drugs are used in sequence with or in conjunction with irradiation and chemotherapy to improve treatment of solid tumors, lymphomas, and leukemia.

The Basis of Chemotherapy: Cancer Cell Biology

Every phase of chemotherapeutic research, from discovery to clinical application, is based on our improved understanding of cancer cell biology (see Chapter 2 ). Cancer cells have unique properties that distinguish them from their normal counterparts and that form the basis for treatment. Among these properties are continuous and excessive proliferation; defective repair of DNA, leading to high mutation rates and great population diversity; reduced rates of apoptosis (i.e., programmed cell death); altered metabolism to enhance lipids and nucleic acid synthesis; induction of nutrient vessels; ability to escape immunosurveillance; and ability to invade neighboring tissues and to metastasize. Many of these properties have been the starting point for successful drug discovery efforts.

Most cancer cells display defects in DNA repair that allow the rapid generation of a diversity of subclones, thus increasing their adaptation to adverse environments (low pH, hypoxia, poor nutrients), increasing their potential for invasion and metastasis, and increasing the probability of drug resistance. With a few notable exceptions, the successful cytotoxic drugs have attacked only the first of these properties, proliferation. The new generation of targeted agents is expanding the horizon for cancer treatment by addressing the full circle of biological changes in human tumors. For example, venetoclax, an inhibitor of BCL-2, removes a prominent barrier to apoptosis in lymphoid tumors and markedly synergizes with other inhibitors of lymphoid proliferation, such as the Bruton tyrosine kinase (BTK) inhibitor, ibrutinib. Olaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP) 1, a base excision repair enzyme, promotes single- and double-strand breaks and induces apoptosis in BRCA1 - and BRCA2 -deficient ovarian cancers, which have underlying defects in double-strand break repair.

Models for Chemotherapy

In parallel with the discoveries of new drugs from 1946 to 1970, Skipper and Perry at the Southern Research Institute and at the National Cancer Institute developed and characterized transplantable murine leukemias—notably, L1210 and P388—as well as murine solid tumors, such as sarcoma 180 and B16 melanoma. Their model systems allowed reproducible, quantitative experiments with chemotherapy and radiation therapy in mice. They established a rational basis for understanding the kinetics of cell kill, evaluating efficacy of drug combinations, and studying mechanisms of drug resistance. From their experiments emerged the theoretical basis for combination chemotherapy:

  • 1.

    Fractional cell kill. Each dose of chemotherapy kills a constant fraction of the tumor cell population. Pharmacokinetic parameters correlate with cell killing. For example, cell kill by alkylating agents increases linearly with dose and peak drug concentration, whereas for most other drugs, kill depends on the area under the curve describing drug concentration over time (or C × T ; Fig. 10.2 ). For other drugs, such as paclitaxel, and for most of the targeted therapies, the time of exposure above a threshold concentration determines the cytotoxicity for tumor and for normal target tissues. For drugs that depend on continuous inhibition of the target, such as the RTK inhibitors, it is important to maintain a drug concentration in plasma above the receptor inhibitory concentration throughout the day. The plasma half-life of oral medications should thus ideally lie in the range of 6 to 8 hours.

    Fig. 10.2, Pharmacokinetic illustrations of patterns of drug elimination from plasma. (A) The solid blue curve illustrates a semi-logarithmic plot of drug concentration versus time after a rapid intravenous injection. The dashed red line intercepting the y -axis at C 2 represents an extrapolation of the log-linear terminal phase, from which the terminal half-life ( ) is calculated. The dashed red line that intersects the y -axis at C 1 is obtained by subtracting the extrapolated values of the log-linear terminal phase from the observed drug concentrations. Maximum drug concentration in plasma (C max ) = C 1 + C 2 . The initial (α) phase half-life (t 1/2,α ) is the time for C 1 to decay to one-half C 1 . The terminal (β) phase half-life (t 1/2,β ) is the time for C 2 to decay to one-half C 2 . This biphasic behavior results from distribution of the drug among rapidly and slowly perfused regions of the body, as well as its elimination. (B) Drug concentration in plasma versus time is plotted on linear axes. The blue shaded area is the area under the curve (AUC); it represents the integral of drug concentration over time and represents a measure of drug exposure. (C) Linear plots of drug concentration versus time are illustrated for a rapid intravenous injection (X) and a 24-hour continuous infusion (Y) of the same total dose of drug (the AUCs are equivalent). Note that the duration of drug concentrations above the threshold for cytotoxicity (C T ), from point A to point B, is much longer with the continuous infusion than with the bolus administration. Conversely, the maximum plasma concentration achieved by bolus administration (C max ) is much greater than that of the continuous infusion (C SS ).

  • 2.

    Importance of dose intensity (dose per unit time or mg/m 2 /unit time). During the time between cycles of treatment, tumor cells resume proliferation. Shorter rest periods between treatment cycles and higher drug doses (the components of drug intensity measurement) produce the best results. The use of granulocyte-colony stimulating factor (G-CSF) posttreatment ensures earlier recovery of the neutrophil count and shortens the intervals between treatment.

  • 3.

    Drug resistance. Exposure of tumors to single-agent chemotherapy or targeted therapy rapidly results in outgrowth of drug-resistant cells. Biochemical studies of these drug-resistant cells disclosed a number of changes, including decreased drug uptake (methotrexate), increased drug export (anthracyclines and taxanes), enhanced DNA repair (alkylating agents and platinum analogs), mutations or amplification in the drug target (methotrexate and 5-FU), or loss of intracellular pathways required for drug activation (many nucleoside and base analogs, such as 5-FU and fludarabine, require phosphorylation). Loss of apoptotic capacity due to increased expression of BCLXL or MCL and activation of stress responses, such as nuclear factor kappa B (NFκB), also contribute to resistance. For targeted drugs, mutation or amplification of the target is a frequent finding in resistant tumors, along with activation of alterative driver pathways. To overcome resistance, combinations of drugs with different mechanisms of action and different mechanisms of resistance have cured lymphomas and leukemia, which readily become resistant to single agents.

  • 4.

    Cell cycle dependency of cell kill. Most anticancer drugs, particularly the antimetabolites, have their greatest effect on actively proliferating cells. Drugs that act on DNA synthesis damage cells during periods of DNA synthesis (S phase), whereas mitotic inhibitors produce cell kill through exposure of cells during mitosis (M phase; Fig. 10.3 ).

    Fig. 10.3, The cell cycle, its controls and checkpoints, and the site of action of cell cycle phase-specific drugs. The cell cycle phases are G 0 (nondividing cells), G 1 (resting phase), S (DNA synthesis), G 2 (gap between S and M), and M (mitosis). Transitions between phases are controlled by the appearance of specific cyclin proteins that complex with and activate cyclin-dependent kinases. The G 1 /S transition is also controlled at a checkpoint by proteins such as TP53, which monitors DNA integrity and arrests progression in response to DNA damage. The proteins that regulate cell cycle transitions and the response to DNA damage are presented in greater detail in Chapter 2 and in Fig. 2.2 .

    The rate of cell proliferation slows and the number of nonproliferating cells increases with expansion of the tumor mass. As tumors outgrow their blood supply, poor perfusion and increased oncotic pressure discourage delivery of nutrients, oxygen, and drug. In response to hypoxia, tumors secrete angiogenic factors; the resultant vessels lack appropriate organization and permeability (see Chapter 2 ). Chemotherapy (and radiation therapy!) is most effective when the tumor burden is lowest, cell proliferation is most active, and drug delivery is optimal, as in the adjuvant setting.

These principles, derived from studies in mouse models, profoundly influenced all aspects of clinical chemotherapy, including regimen design, the use of specific drugs in combination, adjuvant and neoadjuvant chemotherapy, and high-dose chemotherapy. Relying on these principles, the cure of ALL was accomplished through development of effective combination therapy. However, other measures were required to prevent relapse: the institution of intrathecal methotrexate and neuro-axis irradiation to eliminate tumor in sanctuary sites such as the central nervous system (CNS), refinement of drug dosage and schedule to maximize drug efficacy, the implementation of intensive consolidation therapy and maintenance therapy with methotrexate and 6-mercaptopurine, and supportive care with platelets and antibiotics. Each of these insights, further refined by the use of new antinausea medications and G-CSF, has become a basic component of modern chemotherapy.

Solid-Tumor Chemotherapy

These principles have been applied with greatest success to the treatment of aggressive and rapidly proliferating tumors, such as leukemias and lymphomas. The development of drug therapy for the more common solid tumors has taken a slower and more tortuous course. Drugs identified in mouse leukemia screening systems have been less effective against most solid tumors, notable exceptions being choriocarcinoma and testicular cancer, which can be cured with repeated cycles of intensive chemotherapy. However, a steady progression of new drugs has improved response rates and extended survival for many forms of metastatic cancer: 5-FU, the vincas, and methotrexate were followed by doxorubicin and cisplatin in the early 1970s, etoposide and paclitaxel in the late 1980s, the antimetabolites pemetrexed and gemcitabine in the 1990s, and, since 2000, a new antimitotic, eribulin ; a unique alkylator, bendamustine ; and an albumin-encased taxane, abraxane.

An important breakthrough in solid-tumor chemotherapy was the proposal to employ drugs in the adjuvant setting after removal of the primary tumor in patients at high risk for relapse. Drugs that produced only partial responses in advanced disease could prevent disease recurrence in a significant fraction of women with stage II (node-positive) localized breast cancer. The conceptual basis for this strategy derived from experimental chemotherapy models that revealed that tumors are most susceptible to chemotherapy when the tumor burden is small and cells are actively proliferating. Cytotoxic drugs now have a firmly established role in the adjuvant treatment of lung, breast, and colorectal cancers, and many other solid tumors, either before or after surgery (see Chapter 4 ).

Newer concepts aimed at improving local control of otherwise inoperable tumors have led to so-called neoadjuvant , or induction, therapy. In this strategy, drugs are used alone or in combination with radiation therapy, before surgery, in the initial treatment of locally advanced tumors of the breast, head and neck, bladder, rectum, and lung. Preoperative chemo- and radiotherapies are increasingly employed in aerodigestive tumors. Compared to postoperative therapy, they have the advantage of treating a host not debilitated by major surgery and, therefore, more tolerant of side effects. This preoperative therapy reduces the size of otherwise unresectable tumors to a point at which total surgical removal is feasible, less morbid, and organ preserving, or, in some cases, such as anal cancer, even unnecessary. A new paradigm for drug approval has been established with accelerated approval by the US Food and Drug Administration (FDA) of the monoclonal antibody pertuzumab, in combination with traztuzumab and docetaxel, for neoadjuvant therapy of HER2+ breast cancer, based on improvements in the pathological complete remission rate at the time of surgery.

Advances in hematopoietic stem cell harvesting from peripheral blood, their storage, and reinfusion after high-dose chemotherapy have allowed escalation of drug dosage. In this setting, high-dose chemotherapy followed by marrow stem cell infusion is remarkably safe and reliably cures a significant fraction of patients with relapsed lymphomas and relapsed or high-risk leukemia and a fraction of patients with relapsed testicular cancer. The value of this approach for most solid tumors is unproven.

Drug Interactions With Irradiation

Because most patients with cancer now require multimodality therapy, even for early-stage tumors, it is important to understand the potential benefits and risks of drug interaction with irradiation (see Chapters 4 and 5 ). To be effective, irradiation requires the presence of oxygen to produce toxic oxygen radicals that cause DNA strand breaks, an action that is countered by the cell's attempts to scavenge the radicals and repair DNA damage. Radiosensitizers can act by increasing oxygenation, adding DNA cross-links and breaks, depleting the scavengers of oxygen free radicals, or blocking repair of DNA breaks. Each of these properties has been the subject of intensive clinical investigation. The most favorable of these interactions identified thus far take advantage of the radiosensitizing properties of three drugs, often used in combination with irradiation: 5-FU, a drug that inhibits thymidylate synthase and thereby blocks DNA synthesis and repair; platinum analogs, which form adducts with DNA, create DNA breaks, and deplete free radical scavengers, such as sulfhydrils and glutathione; and mitomycin C, which forms free radicals and DNA adducts in hypoxic environments. Other drugs—particularly gemcitabine, doxorubicin, and bleomycin—are extremely potent radiation sensitizers, and generally are not to be used simultaneously with irradiation for fear of serious toxicity to the heart, lungs, and other normal tissues. The potential value of combining irradiation with antivascular endothelial growth factor (anti-VEGF) therapies, which normalize tumor blood vessels and improve oxygenation and drug delivery, is reviewed in Chapter 3 and is again intriguing, but unproven. Cetuximab, an anti-EGFR antibody, enhances the response to irradiation in head and neck cancers (see Chapter 5 ).

Most recently, inhibitors of DNA repair have entered clinical trials. As an example, olaparib blocks the function of PARP, a central component of base excision repair, in patients with breast cancer or serous ovarian cancer who have defects in homologous repair of double-strand breaks due to BRCA1 or BRCA2 mutations. It is particularly useful. This class of drugs has interesting, but unproven, potential for enhancing radiation damage to DNA, particularly in tumors with DNA repair defects, such as BRCA1 or BRCA2 mutations (see Chapter 4 ).

Drugs and irradiation may share common mechanisms of tumor cell resistance. Increased proficiency of repair of double-strand breaks or defective recognition of DNA breaks may impair the antitumor response to irradiation and to several classes of antitumor drugs, including alkylating agents, platinum analogs, and topoisomerase inhibitors. Cells with defects in apoptosis and checkpoint function ( TP53 mutation, MDM2 amplification) fail to stop DNA synthesis in the face of DNA damage, and fail to initiate apoptosis. Reversion of epithelial tumors to a mesenchymal (and stem cell) phenotype may lead to resistance as stem cells in normal tissues and in tumors are inherently resistant to reactive oxygen damage and overexpress the multidrug resistance (MDR) transporter. Tumor stem cells are quiescent regarding cell cycle progression and may reside in hypoxic niches within tumors only to reactivate months to years after treatment. New drugs designed to reactivate apoptotic pathways (BH3 inhibitors, such as venetoclax), activators of cell checkpoint function (HMD2 inhibitors), and inhibitors of the Notch and PI3 kinase pathways are of particular interest in reversing epithelial-to-mesenchymal transition (EMT) changes.

Although repair defects in general sensitize tumors to DNA-damaging therapies, they may have sensitizing effects to immunotherapy, as they create neoantigens. The mismatch repair (MMR) pathway, characterized by the biomarker of microsatellite instability, underlies the hereditary Lynch syndrome of inherited colorectal cancer but is associated with endometrial, pancreatic, lung, and other cancers, and creates an increased mutational burden. These tumors are extremely sensitive to checkpoint inhibitor immunotherapy. At the same time, MMR defects confer resistance to chemotherapies such as the platinum analogs, as they inhibit the apoptotic response to DNA lesions.

Cytotoxic Drugs: Targeting DNA Synthesis, DNA Integrity, and Mitosis

Because drugs have become an integral part of the initial multimodality therapy of many patients with cancer, it is essential that the medical oncologist, surgeon, and radiation oncologist understand the principles of chemotherapy and the specific features of the commonly used agents. Most cytotoxic drugs in current clinical use act directly on the synthesis or integrity of DNA. These drugs may inhibit synthesis of DNA or its precursors, block cell division, inhibit necessary changes in DNA topology, or covalently bind to DNA, causing strand breaks or miscoding. All such drugs affect the integrity of DNA, and in the presence of the normal machinery ( TP53 ) for monitoring DNA integrity, they induce apoptosis. Unfortunately, they are also cytotoxic toward normal cells. The reasons for their selective toxicity for malignant versus normal cells, as is apparent in the cure of lymphomas and leukemias, are poorly understood. The process of malignant transformation may enhance sensitivity to DNA damage by virtue of defects in DNA repair, although at the same time, these same defects expand tumor cell diversity and encourage drug resistance. Many of the defective genes responsible for inherited cancer syndromes—such as the BRCA1 and BRCA2 genes, MMR genes, and nucleotide excision repair defects—create sensitivity to irradiation and to agents that further inhibit DNA repair.

In designing clinical regimens, the relationship of drug action to the cell cycle is important because this knowledge serves as the basis for combining drugs and sequences in clinical practice and influences their use in combination with radiation therapy. The cell cycle and its primary controls are shown in Fig. 10.3 . Antimetabolites such as methotrexate, 5-FU, cytosine arabinoside, gemcitabine, and the purine antagonists kill cells that are actively synthesizing DNA; therefore, they are cell cycle dependent. Nucleoside analogs—including cytosine arabinoside, fludarabine phosphate, and cladribine—must be incorporated into newly synthesized DNA to be cytotoxic. Alternately, other agents, such as the camptothecins, etoposide, and doxorubicin, produce DNA strand breaks at any stage of the cell cycle. They are less dependent on cell cycle events for cytotoxicity, although the DNA breaks become lethal only as the cell crosses a TP53 checkpoint and enters DNA synthesis. Antimitotic agents (the vincas, taxanes, and eribulin) block the formation of the mitotic spindle and thereby prevent separation of chromosomes to the daughter cells. Drugs of this class are therefore most effective against cells during the mitotic phase of the cell cycle. Still others, such as alkylating agents and platinum compounds, bind covalently to DNA and produce strand cross-links and strand breaks. Their toxicity seems less dependent on the cell cycle stage.

Once it has been damaged through its encounter with a cytotoxic drug, the cancer cell has several options; its eventual viability depends on which pathway it takes. If the normal monitors for genomic integrity (including, most prominently, the product of the TP53 gene) are intact, the cell may halt further progression in the cell cycle while its DNA is repaired. If the damage is sufficiently extensive, TP53 initiates apoptosis. If, however, TP53 function is absent, cell cycle progression may continue past the G1-S checkpoint despite drug-induced DNA damage, and the cell may prove viable despite its lesions. In most experimental settings, lack of wild-type TP53 is associated with drug and irradiation resistance.

From a theoretical viewpoint, it is understandable that rapidly dividing tumor cells, such as those found in acute leukemia, high-grade lymphoma, and choriocarcinoma, may be exquisitely sensitive to antimetabolites and cell cycle–specific drugs. How do these drugs kill the more slowly dividing solid tumors? Many of these tumors have long cell cycles (4–5 days). Many cells are in the G0 phase (nondividing state) and, at any moment, only 1% to 3% of cells are in S phase. Cell kinetic factors diminish the effectiveness of chemotherapy, and the disordered vascularization of tumors may also contribute by limiting drug entry into areas of slow blood flow. Despite these disadvantages, solid-tumor chemotherapy produces meaningful responses. Several factors, including pharmacological, pharmacokinetic, and tumor cell–specific factors, likely contribute to solid-tumor killing by cycle-specific or cycle-sensitive drugs:

  • 1.

    Drugs such as paclitaxel and doxorubicin clear slowly from the bloodstream and the extracellular space. Alternative regimens, such as prolonged drug infusion, may increase the activity of 5-FU compared with the results of bolus administration.

  • 2.

    Other drugs—such as methotrexate, which forms an intracellular polyglutamated species, and gemcitabine, which forms a long-lived intracellular triphosphate—persist inside the cell long after their disappearance from plasma.

  • 3.

    As mentioned, tumor cells may be less able to repair DNA and more susceptible to cell death induced by DNA damage than their normal counterparts.

  • 4.

    Underlying the tumor proliferation rate is a significant death rate that results from hypoxia, nutrient deprivation, disordered DNA synthesis, and mitosis and, in general, a high-background rate of mutation that affects genes essential for cell integrity and survival. A small shift in the balance between cell proliferation and cell death, as produced by drugs or irradiation, may lead to regression of a tumor, despite its low growth fraction.

Drugs That Induce Differentiation

Although differentiation inducers have long attracted interest for cancer drug development, only a small number of compounds have reached clinical evaluation. 5-aza-cytidine and its close congener, 5-aza-2′-deoxycytidine, are both approved for treatment of myelodysplastic syndrome. They induce differentiation by irreversibly inhibiting DNA methyltransferase. They are modestly myelosuppressive but induce the production of both myeloid and erythroid lineages and reduce transfusion dependence in myodysplastic syndrome (MDS).

A more compelling example of differentiation induction is provided by all-trans retinoic acid (ATRA), which binds to the mutated retinoic acid receptor created by the retinoic acid receptor/promyelocytic leukemia (RAR-PML) translocation in acute promyelocytic leukemia (APL), thereby inducing differentiation and remission. Its primary toxicity is a syndrome of pulmonary failure resulting from clogging of small vessels by the mature leukemic granulocytes. Arsenic trioxide is a second agent capable of induction of differentiation in APL. It promotes degradation of the translocated fusion protein, produces free radicals, and has antiangiogenic properties as well. Its toxicities include the pulmonary failure syndrome seen with ATRA, prolongation of the PR interval, arrhythmias that are accentuated by potassium (K+) and magnesium (Mg+) depletion, and hyperglycemia.

Immunotherapy

Immunotherapies have been the object of much research attention, but only in the past 2 decades have drugs of this kind proven useful. Monoclonal antibodies have won a place in the standard regimens for treatment of lymphoma (brentuximab for Hodgkin disease and rituximab and other anti-CD20 antibodies for B-cell lymphomas), for breast cancer (traztuzumab, pertuzumab, and TDM1 for HER-2-positive tumors), and cetuximab and panitumumab for colorectal cancer, as well as anti-CD38 antibodies for multiple myeloma. Their mechanisms of action may simply be engagement and inhibition of a receptor necessary for survival, but auxiliary actions such as antibody-dependent cellular cytotoxicity may play a role. The newest additions to immunotherapy include anti-CTLA-4 and anti-PD1 and anti-PDL-1 antibodies, which release autoimmune antitumor responses. These have shown remarkable long-term responses in melanoma, kidney cancers, bladder cancer, Merkel cell cancers, and adenocarcinoma of the lung (either alone or with pemetrexed), and seem most effective in tumors with a high mutational burden. In melanoma treatment, combined anti-CTLA-4 and PD-1 antibodies produce long-term remissions in 50% of patients refractory to conventional therapies. Their toxicities, related to induction of autoimmunity, may affect virtually any organ system, at times with fatal outcome due to myocarditis, colitis, or pneumonitis. Attempts to enhance the effectiveness of checkpoint inhibitors are focused on developing tumor vaccines or metabolic enhancers of the immune response and understanding the defects in antigen presentation (HLA and beta-2 microglobulin loss) that underlie resistance.

Equally impressive are the complete remissions in drug-resistant lymphoid leukemias and in lymphomas produced by chimeric antigen receptor T-cells (CAR-T cells) in which T-cell receptors are engineered to recognize the CD-19 autoantigen antigen. The CAR-T cells destroy all B-lymphocytes, physiological and malignant, and produce massive cytokine release with attendant pulmonary and neurological toxicities. Ongoing research aims to apply these technologies to unique tumor antigens in solid tumors.

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