Cancer chemotherapy and radiation therapy.
- Radiation oncology
- Further reading
The last two decades have brought significant improvements in cancer therapy: patients with previously fatal diseases, including acute leukaemia, non-Hodgkin’s lymphoma, Hodgkin’s disease, and germ cell tumours, now have a reasonable expectation of cure. For patients with the more common solid tumours, including lung, colon, and breast cancer, new chemotherapeutic and hormonal agents and monoclonal antibodies have improved treatment of both early and late stage disease and have extended survival. Nevertheless, cancer remains the second leading cause of death in the Western world, and nearly 40% of patients diagnosed with cancer will die of their disease.
Surgery, chemotherapy, and radiation therapy are the major modalities of cancer therapy, and are employed together in various sequences and combinations in most cancer patients.
Mechanism of action—most chemotherapy drugs block steps in the synthesis of DNA or its precursor nucleotides (purines and pyrimidines), or attack the integrity of DNA. These drugs are maximally effective if tumour cells are exposed during the S phase of the cell cycle, although some drugs (e.g. vinca alkaloids and taxanes) directly block cells during mitosis, and others (e.g. alkylating agents) act throughout the cell cycle.
Clinical use—chemotherapy can be applied as (1) combination chemotherapy with multiple drugs to cure some sensitive diseases, e.g. some types of leukaemia, or diminish tumour-related symptoms, improve the quality of life, and extend survival in less sensitive cancers, e.g. lung, colon; (2) palliative therapy for the treatment of advanced-stage or metastatic cancer; (3) adjuvant therapy, administered after the completion of definitive local surgery and/or radiation therapy to decrease the risk of recurrence of disease locally and at distant sites.
Complications—most of the commonly used chemotherapy agents cause acute myelosuppression; nausea and vomiting are frequent, but can often be helped by corticosteroids and serotonin uptake inhibitors (e.g. odansetron). Other problems specific to particular agents or classes of agent include (1) alopecia—doxorubicin and alkylating agents, (2) peripheral neuropathy—vinca alkaloids and platinum analogues, (3) left ventricular failure—doxorubicin, (4) pneumonitis—bleomycin, (5) infertility—alkylating agents. A very significant, delayed side effect of chemotherapy is the development of secondary leukaemias.
Mechanism of action—radiation therapy generates free radicals that damage DNA, producing breaks that must be repaired if the cell is to survive. Many tumours are less able than normal tissues to repair these breaks, providing a therapeutic window for successful treatment. Irradiation also inflicts potent damaging effects on tumour vasculature.
Clinical use—radiation doses are usually delivered as an external beam from a source outside the body in a number of daily fractions, the total fractionated dose being determined by tumour sensitivity and normal tissue tolerance. Other methods of delivery include (1) brachytherapy—when the radiation source is implanted within the substance of the tumour, e.g. cervical cancer; (2) intraoperative radiation therapy—delivering a single, large fraction of radiation directly to the tumour bed; (3) radioisotopes—e.g. iodine-131 taken up by local and metastatic thyroid tissue; monoclonal antibodies coupled with radioisotopes to localize at tumour sites. For palliative irradiation of metastatic tumours, single large doses (radiosurgery) or abbreviated courses of irradiation (hypofractionated radiotherapy) may be administered to relieve symptoms.
Complications—toxicity to normal tissues within the field of radiation therapy or at its margins can be significant. Effects can be (1) acute—during the treatment course—particularly including damage to skin (erythema, desquamation, oedema), mucosal linings (diarrhoea, nausea, vomiting) and bone marrow (cytopenias); (2) subacute—after treatment but within a few months of therapy—e.g. radiation pneumonitis; and (3) late—permanent—including local tissue damage (e.g. transverse myelitis, bowel strictures, renal failure) and secondary tumours within radiation fields.
The rationale for cancer chemotherapy is based on principles of tumour biology. Cancer results from mutations in critical genes that control cell proliferation, DNA repair, and cell death. Tumours are usually clonal in origin, beginning with a single transformed cell that grows in an uncontrolled fashion, and invades and destroys normal neighbouring tissues. Tumour cells acquire the ability to secrete factors that promote the local growth of new blood vessels. This so-called ‘angiogenic switch’ represents a critical transition in their life history. Tumour cells may also acquire the capacity to migrate through the lymphatics and bloodstream to distant sites. Each of these important steps in the natural history of tumours requires the expression of specific proteins and pathways that have become the targets for new therapies.
The life cycle of a cancer cell is characterized by several phases: resting (G0), pre-DNA synthesis (G1), DNA synthesis (S), post-DNA synthesis (G2), and mitosis (M). Most chemotherapy drugs block steps in the synthesis of DNA or its precursor nucleotides (purines and pyrimidines), or attack the integrity of DNA. These drugs are maximally effective if tumour cells are exposed during the S phase of the cell cycle, although some drugs, such as the vinca alkaloids and taxanes, directly block cells during mitosis and others, such as the alkylating agents, act throughout the cell cycle.
Chemotherapy can be used in several different settings (Table 1). Foremost, chemotherapy is applied as primary therapy for the treatment of advanced-stage or metastatic cancer, when surgery or radiation therapy can no longer offer cure. Some diseases, including leukemias, lymphomas, and advanced-stage germ cell tumours are sensitive to multiple chemotherapy agents and can be cured with combination chemotherapy. In the less sensitive epithelial cancers, such as colon and lung cancer, combinations of agents are used to diminish tumour-related symptoms, improve the quality of life, and extend survival. For example, randomized clinical trials of chemotherapy vs best supportive care have demonstrated a survival advantage and quality of life improvement when patients with advanced-stage lung cancer receive multidrug chemotherapy.
|Table 1 The role of chemotherapy in cancer management|
|Primary therapy (curative)|
|Acute lymphoblastic leukaemia, acute myeloblastic leukaemia|
|Germ cell tumours|
|Small cell lung cancer (with radiation therapy)|
|Oesophageal cancer (with radiation)|
|Stage III non-small cell lung cancer|
|Head and neck cancer|
Secondly, chemotherapy is effective when given prior to radiation or surgery to cause shrinkage or disappearance of locally advanced disease. In this ‘neoadjuvant’ setting, the drugs, if effective, allow less extensive and less morbid surgery or irradiation, and make it possible to preserve organ function. Neoadjuvant chemotherapy is routinely given to patients with osteosarcoma, and to those with locally advanced lung, head and neck, breast, or oesophageal cancers, prior to surgery or radiation therapy. In the case of osteosarcomas, the response to neoadjuvant therapy can provide important information about tumour sensitivity, thereby permitting a more tailored approach to further management after surgery.
Finally, the drugs can be used as adjuvant therapy, administered after the completion of definitive local surgery and/or radiation therapy in order to decrease the risk of recurrence of disease locally and at distant sites. Adjuvant chemotherapy reduces the risk of tumour recurrence and improves survival in node-positive colon cancer, lung cancer, and breast cancer following surgical resection of the primary tumour. In the adjuvant setting and, more commonly, in the neoadjuvant setting, chemotherapy may be administered in sequence with, or simultaneously with, radiation therapy to optimize local effects of treatment.
Only in rare circumstances, such as methotrexate therapy for choriocarcinoma, can single agents cure advanced-stage cancer. Single agents tend to select for drug-resistant cells. Most often, therapy with multiple drugs has been required to effect cure. In combining drugs, it is imperative to employ agents that have independent activity and non-overlapping toxicities so that the individual drugs can be used at their optimal dose and in their optimal schedule. Chemotherapy schedules are designed to permit marrow recovery before the next dose administration. Typically, peripheral blood counts will reach a nadir 5 to 10 days after therapy, with recovery by day 21. Hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) speed the recovery of neutrophils and allow regimens to be repeated every 2 weeks. Such ‘dose dense’ regimens may be more effective than the standard 3-week cycle in the adjuvant treatment of breast cancer.
Combinations of drugs circumvent tumour cell resistance, so treatments have been designed in which non-cross-resistant drugs are administered either together or in sequence. One of the earliest combination therapy programmes to cure a cancer was MOPP (mechlorethamine, vincristine, prednisone, and procarbazine), used for the treatment of Hodgkin’s disease. Combination chemotherapy is now the mainstay for treating most acute leukemias, non-Hodgkin’s lymphoma, testicular cancer, choriocarcinoma, and for most adjuvant and neoadjuvant regimens for epithelial cancers. Acute lymphoblastic leukaemia can now be cured in 90% of children using multidrug chemotherapy administered at frequent dosing intervals to avoid the development of resistant cells. Alternatively, extremely high doses of therapy can be used to overcome tumour resistance in patients with lymphoma who relapse after standard dose chemotherapy, but this may obligate the use of autologous haematopoietic stem cells harvested from peripheral blood or bone marrow to overcome the resulting profound bone marrow toxicity.
Chemotherapeutic drugs have both acute and late toxicities, and may affect virtually every organ system. The late toxicity may diminish organ function, causing congestive heart failure (after anthracyclines), pulmonary fibrosis (after alkylating agents or bleomycin), or kidney failure (after platinum-based therapies), or may damage reproductive tissues, brain, and other organs. In addition many drugs, particularly the alkylating agents, are leukaemogenic. Both the medical oncologist who manages the patient through the phase of active treatment, and the internist involved in later stages of follow-up must be alert to these toxicities and informed about their management.
Because of the serious toxicities of chemotherapy, physicians should administer regimens that have been carefully studied and reported in the peer-reviewed medical literature. New regimens tested in the context of well-designed clinical trials may offer the best alternatives to standard therapy. Clinicians should not routinely administer new drug combinations on the basis of anecdotal evidence.
Classes of chemotherapeutic agents
There are several distinct classes of chemotherapy agents (Table 2). In order to reduce inter-patient variability in exposure to drugs, doses of most chemotherapy agents are calculated on the basis of body surface area, as determined by the patient’s height and weight. In addition, doses of chemotherapy may need to be reduced in treating patients with renal dysfunction (methotrexate, bleomycin, hydroxyurea, fludarabine) or hepatic dysfunction (anthracyclines, vinca alkaloids, taxanes), depending on the primary route of drug clearance.
Adequate intravenous access, through an implanted central venous line, must be secured since many of the drugs are vesicants and extravasation can lead to tissue necrosis. Similarly, patients must be adequately hydrated before the administration of drugs such as high-dose methotrexate or routine doses of cisplatin, ifosfamide and cyclophosphamide, to prevent renal and/or bladder toxicity. Careful attention must be given to fluid and electrolyte balance with the administration of many agents. Cisplatin renal toxicity can cause profound hypomagnesaemia.
|Table 2 Cancer therapy agents|
|Alkylating agents and platinating drugs|
These exert their cytotoxicity by serving as inhibitors of pathways vital to cellular function and replication. Some are analogues of physiologic purines and pyrimidines, and are incorporated into DNA or RNA or alternatively inhibit enzymes involved in the synthesis of nucleic acids. Methotrexate inhibits the enzyme dihydrofolate reductase, which maintains intracellular pools of reduced tetrahydrofolates required for the synthesis of purine nucleotides and thymidylate. 5-Fluorouracil and the closely related prodrug capecitabine generate an active metabolite, fluorodeoxyuridine monophosphate, which inhibits thymidylate synthase, an enzyme required for the synthesis of deoxythymidine triphosphate, one of the precursors of DNA.
A third important antimetabolite is cytarabine (ara-C), which is converted to cytarabine triphosphate (ara-CTP) in the cell. Cytarabine triphosphate is incorporated into DNA and serves as a DNA chain terminator. A closely related deoxycytidine analogue, gemcitabine, is incorporated into DNA, but has the additional action of inhibiting the conversion of ribonucleotides to deoxyribonucleotides, which are DNA precursors. Prolonged exposure of tumour cells to some of the antimetabolites, such as 5-fluorouracil and cytosine arabinoside, through continuous intravenous infusion of drug, may be more effective than bolus injections alone. High dose ara-C is effective in remission consolidation for acute myelogenous leukaemia.
Purine analogues also have important roles as antimetabolites in the treatment of leukaemias and lymphomas; 6-mercaptopurinre (6-MP) is converted in the cell to a monophosphate, which inhibits the first step of purine synthesis. Moreover, the triphosphate nucleotides of 6-mercaptopurine and 6-thioguanine are incorporated into DNA resulting in an increase in strand breaks. Fludarabine, another purine analogue, serves as an adenosine mimic. Fludarabine is converted to 2-fluoro-ara-A in plasma and is then phosphorylated intracellularly. The resulting triphosphate inhibits DNA polymerase and ribonucleotide reductase. A closely related adenosine analogue, cladribine, has a similar mechanism of action and is highly effective in treating hairy cell leukemia.
As a group, the antimetabolites cause acute toxicity to bone marrow and are potent suppressors of the immune system. Methotrexate and azathioprine, a prodrug of 6-MP, have found important roles for suppressing graft rejection in organ transplantation and in treating autoimmune diseases.
These exert their cytotoxicity by binding to DNA and forming covalent bonds with electron-rich sites on DNA, blocking DNA replication and transcription. These drugs act throughout the cell cycle, but have their greatest effect on rapidly proliferating cells. Cyclophosphamide, melphalan, busulfan, and chlorambucil were among the first chemotherapy drugs and remain important agents in cancer therapy, with particular activity in haematological malignancies and breast cancer. Because there is a linear relationship between dose and cell kill, alkylating agents are commonly used in high dose regimens with bone marrow rescue. In a manner similar to alkylating agents, the platinum derivatives bind to, and cross-link DNA, leading to DNA breaks and apoptosis. Carboplatin is frequently included in high dose regimens.
A variety of natural compounds, isolated as products of fungal fermentation, or from plants or marine organisms, possess antitumour activity. The anthracyclines, represented by doxorubicin and its analogues, bind to topoisomerase II, and thereby trigger double strand breaks in DNA. Etoposide, a semisynthetic compound derived from a plant source, also inhibits topoisomerase II. In a similar way, the camptothecins (irinotecan and topotecan) interfere with topoisomerase I, inducing single strand breaks in DNA. The anthracyclines are distinguished by their potent antileukaemic activity, as well as their activity against breast cancers, childhood sarcomas, and other solid tumours. Their primary disadvantage is their tendency to cause free radical damage to myocardial cells, with late-onset congestive heart failure.
Antimitotic compounds derived from plants have become increasingly important in the treatment of leukaemia and epithelial cancers. Vinca alkaloids (vincristine, vinorelbine, and vinblastine) interfere with microtubule formation and disrupt cell division. In contrast, the taxanes stabilize microtubule assembly, but they also arrest cells in mitosis. The taxanes are particularly valuable for breast and lung cancer treatment. As a group these drugs are hampered by neurotoxicity and myelosuppression.
Along with the traditional cytotoxic agents, hormone-directed therapy can be critical in the treatment of breast and prostate cancers. Most breast cancers express receptors for oestrogen and progesterone, and most prostate cancers have androgen receptors. Depriving these tumours of the hormonal stimulus can exert cytostatic effects on the cell and induce apoptosis. Thus, more than 50% of breast cancers expressing the oestrogen receptor will respond to treatment with tamoxifen, an antioestrogen, or to aromatase inhibitors, which block the synthesis of oestrogen from adrenal androgens, an important source of oestrogen in postmenopausal women. The hormone antagonistics are included in regimens for adjuvant therapy of hormone-receptor positive breast cancer. Similarly, luteinizing hormone releasing hormone (LHRH) agonists (which reduce testosterone synthesis) and androgen receptor antagonists have inhibitory effects on most patients with metastatic prostate cancer, and are useful for decreasing tumour burden in locally advanced disease before radiation therapy. Side effects of hormonal agents result from deprivation of oestrogen or testosterone action, and include decreased libido, bone loss in both men and women, and profound metabolic effects such as an increased risk of endometrial cancer and thrombotic events in women on tamoxifen, and decreased muscle mass and an increased risk of myocardial infarction in men on anti-androgen treatment.
Tumours may become resistant to the effects of cytotoxic chemotherapy by a number of different mechanisms (Table 3). Decreased accumulation of drug in the cell through loss of active membrane transport mediates resistance to methotrexate. Drug exporters, such as the MDR gene, may be over expressed by drug resistant tumours, mediating resistance to natural products such as the anthracyclines, taxanes, and vinca alkaloids. Alternatively, the intracellular drug target may amplify in resistant cells, overwhelming the inhibitor and restoring pathway activity. Amplification of dihydrofolate reductase confers resistance to methotrexate. The target enzyme for 5-fluorouracil, thymidylate synthase, may be amplified and lead to resistance. Increased intratumoral drug metabolism, as occurs with ring reduction of 5-fluorouracil (by dihydropyrimidine dehydrogenase), also conveys drug resistance. In tumours resistant to alkylating agent and platinum analogues, the drugs may be inactivated through chemical reactions with thiol-containing compounds; resistance to DNA alkylators and platinum compounds is also mediated by up-regulation of DNA repair. It is now clear that even before therapy tumours harbour drug-resistant cells generated through spontaneous mutation, and these cells are selected for survival by exposure to chemotherapy. Thus, combinations of non-cross-resistant drugs are required for long-term effective treatment of most tumours.
|Table 3 Mechanisms of chemotherapy resistance|
|Drug||Mechanism of resistance||Biological change|
|Methotrexate||Decreased drug uptake||Increased expression of folate transporter|
|Decreased drug activation||Decreased folylpolyglutamyl synthetase|
|Altered drug target||Altered dihydrofolate reductase|
|Doxorubicin||Altered drug target||Altered topoisomerase II|
|Increased drug efflux||Increased MDR expression or MDR gene amplification|
|Alkylating agents||Increased detoxification||Increased glutathione or glutathione transferase|
|Enhanced DNA repair||Increased nucleotide excision repair|
|Cisplatin||Defective recognition of DNA adducts||Mismatch repair defect|
|Enhanced DNA repair||Increased nucleotide excision repair|
|Etoposide||Increased drug efflux||Increased MDR expression or gene amplification|
|Altered drug target||Altered topoisomerase II|
|Most anticancer drugs||Defective checkpoint function and apoptosis||P53 mutations|
|5-Fluorouracil||Increased drug target||Amplified thymidylate synthase|
MDR, multidrug resistance.
Side effects of chemotherapy
Most of the commonly used chemotherapy agents (Table 4) cause acute myelosuppression, although the timing of its onset and its duration differs with different groups of drugs. Most antitumour drugs cause an acute, 5- to 7-day depression in counts, affecting the white blood count more than platelets, allowing retreatment on 14- to 21-day cycles. By contrast, the nitrosoureas lead to delayed-onset reductions in both neutrophils and platelet with nadir counts typically reached 4 to 6 weeks after therapy.
|Table 4 Side-effects of chemotherapy|
|Adverse effect||Representative agents|
|Alopecia||Cisplatin, adriamycin, taxol|
|Renal toxicity||Cisplatin, methotrexate|
|Pulmonary toxicity||Bleomycin, BCNU, methotrexate|
|Bladder toxicity||Cyclophosphamide, ifosfamide|
|Mucositis||5-FU, Methotrexate, doxorubicin|
|Nail changes||Bleomycin, cyclophosphamide, 5-FU|
Nausea and vomiting remain significant side effects of chemotherapy, though corticosteroids and serotonin uptake inhibitors such as odansetron have diminished the incidence and severity of vomiting even with the most emetogenic agents, including cisplatin. Alopecia occurs in most patients receiving doxorubicin and the alkylating agents, but less commonly in patients treated with antimetabolites or antimitotic drugs. A peripheral neuropathy frequently results from treatment with vinca alkaloids and platinum analogues.
Many agents have unique side effects that are of concern to the practising internist. Doxorubicin causes a cumulative, dose-dependent decline in left ventricular ejection fraction, with a 7–20% incidence of congestive heart failure in patients receiving a cumulative dose of more than 550 mg/m2. Bleomycin produces lung toxicity, including pneumonitis, which can progress to interstitial fibrosis. The carbon monoxide diffusing capacity of the lung diminishes with increasing cumulative bleomycin doses. Exposure to high concentrations of inhaled oxygen during surgery can precipitate acute respiratory failure in patients previously treated with bleomycin. Methotrexate in high doses can cause acute renal failure due to drug precipitation in the renal tubules, a complication that can prevented by intense hydration and urine alkalinization before and during drug infusion. The administration of paclitaxel can cause anaphylaxis due to Cremophor EL, the vehicle in which it is delivered. Hence, premedication with dexamethasone and antihistamines is required to reduce the risk of adverse reactions to paclitaxel. Cytarabine administered in high single doses (3 mg/m2 or more) can cause irreversible cerebellar dysfunction. A careful neurological examination should be performed daily on patients receiving high-dose cytosine arabinoside so that it can be discontinued at the earliest sign of such toxicity.
Many of the chemotherapeutic drugs, particularly the alkylating agents, have profound effects on reproductive tissues. Men become azoospermic after receiving these drugs for lymphoma treatment, and the same drugs, with doxorubicin, may produce early menopause in women receiving adjuvant chemotherapy for breast cancer. These issues need to be discussed with young adults of childbearing age, as sperm banking is possible for men prior to lymphoma treatment, while egg harvesting and in vitro fertilization before treatment may allow conception after completion of adjuvant therapy in premenopausal women. Hormonal therapies, such as aromatase inhibitors and LHRH agonists, also have profound effects on oestrogen and testosterone levels, and thus can lead to changes in sexual function in patients with breast or prostate cancer, respectively.
A major, delayed side effect of cancer chemotherapy is the development of secondary leukaemias due to therapy. Leukaemia is most commonly seen in patients 2 to 4 years after receiving therapy with alkylating agents, as was the case for the treatment of Hodgkin’s disease with MOPP chemotherapy. Newer regimens such as ABVD (adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine) for Hodgkin’s disease treatment avoid this devastating complication. More recently, topoisomerase II therapy (etoposide, anthracyclines) in high total doses has been associated with a risk of secondary leukaemias. High-dose therapy with alkylating agents such as cyclophosphamide, busulfan, or melphalan, followed by autologous stem cell infusion, confers a 10% risk of secondary myelodysplasia and leukaemia. As survival rates improve with intensive combination chemotherapy regimens, the long-term complications of cancer chemotherapy become more evident.
With advances in our understanding of cancer biology and the discovery of specific genetic changes that cause cancer, it has become possible to design therapies to block the master controls responsible for the proliferation, survival, and metastasis of tumour cells. These targeted drugs differ from cytotoxic chemotherapy, which block the synthesis of DNA or interfere with its function. Classic chemotherapy drugs have limited specificity for malignancy, and thus exert profound toxic effects on normal tissues. By contrast, the new targeted therapies attack features unique to the cancer cell or pathways upon which the cancer cell depends for survival. Examples of such pathways are activated growth factor receptors and their ligands, highly expressed signal transduction pathways, and tumour-induced angiogenesis. The first of these tumour-specific targets to be exploited was the bcr-abl1 kinase, created by the 9:22 translocation in chronic myelogenous leukaemia. Imatinib, an inhibitor of the ATP catalytic site of this enzyme, produces both haematological and cytogenetic remission in most patients with this disease. However, resistance to imatinib arises through the emergence of cells that carry mutations in the bcr-abl1 kinase. Dasatinib, an analogue of imatinib that binds to a slightly altered configuration of the enzyme, is highly effective in most patients who develop resistance to imatinib through kinase mutation.
Other targeted compounds block key growth factor receptors, such as the epidermal growth factor receptor (EGFR). Erlotinib and gefitinib proved highly effective in causing tumour regression in a subset of patients with non-small cell lung cancer whose tumours carry a constitutively activated mutant form of EGFR. Further mutations in EGFR lead to resistance to these drugs.
Tumours require new blood vessels to keep pace with their demands for oxygen and nutrients. They secrete potent angiogenic factors, including vascular endothelial growth factor (VEGF), which cause a proliferation of leaky vessels in the immediate environment of the tumour. Low molecular weight inhibitors of the VEGF receptor have proved effective in causing regression of renal cell cancers. The particular sensitivity of renal cell cancer to antiangiogenic agents is explained by their unique biology. These tumours are driven by loss of function of the Von Hippel–Lindau gene (VHL), which normally acts as an oxygen sensor for a highly angiogenic pathway. Loss of the VHL gene leads to high levels of expression of VEGF, cell transformation, and prominent angiogenesis. Sorafenib and sunitinib, both inhibitors of VEGFR, block angiogenesis and inhibit the growth of renal cell cancers, as does bevacizumab, a monoclonal antibody to VEGF. Bevacizumab partners effectively with chemotherapy in the treatment of many epithelial cancers, including tumours of the breast, lung, and colon.
Monoclonal antibodies have certain advantages over small molecules. They have long half-lives in plasma, and may, in addition to their own biological effect, recruit participation of the immune system in complement or cell-dependent cytotoxicity. Monoclonal antibodies that target receptors on the tumour cell membrane have become important components of regimens for treating lymphomas, breast and colorectal cancer. Rituximab binds to the CD20 antigen expressed on the surface of both normal and malignant B lymphocytes. Nearly 50% of patients with low-grade B-cell lymphoma respond to this targeted therapy. The most common side effects of Rituxan and other antibodies are infusion-related fevers, chills, and hypotension. Another biologically active antibody, herceptin, binds to the Her-2 receptor that is overexpressed in 25% of breast cancer cases. Herceptin is used exclusively for patients with breast tumours that have amplification of the Her-2 receptor. When given in conjunction with paclitaxel, herceptin prolongs survival for patients with metastatic breast cancer, and dramatically improves the effectiveness of adjuvant chemotherapy for the same disease. Antibodies to the EGFR receptor (cetuximab and panitumumab), and as mentioned previously, to VEGF (bevacizumab), are effective in a variety of epithelial tumours.
Naturally occurring cytokines, produced by the immune system, have found limited usefulness in cancer treatment. The interferons are a class of proteins produced by macrophages and lymphocytes in response to viral infections. α-Interferon has relatively modest antitumour activity, inducing responses in a minority of patients with melanoma and renal cancer. More consistent responses are seen in chronic myelogenous leukaemia and hairy cell leukemia. Except for its use in melanoma, it has been replaced by other, more effective drugs. Toxicities include fevers, chills, liver function test abnormalities, cytopenias, and depression. Activated T cells produce interleukin 2. It triggers proliferation of T-cells and produces long-term complete responses in a small fraction of patients with renal cell carcinoma and melanoma. However, its toxicities include fevers, renal dysfunction, and a capillary leak syndrome, with occasional severe pulmonary dysfunction.
Targeted therapies offer great promise for further contribution to cancer treatment. As the molecular pathways and specific mutations responsible for malignancy are elucidated by basic science, new targets will be exploited. The transition from laboratory to clinic is a complex process, in which information travels back and forth from clinician to scientist, informing the drug discovery and development process. Thus, it is becoming clear that current pathological classifications of disease inadequately describe the underlying heterogeneity of human tumours. This heterogeneity is most obvious in gene expression profiles of leukaemias, lymphomas, and many solid tumours, and in the variable expression of signalling pathways and receptor mutations. Further, there is a growing confidence that, with appropriate molecular and immunohistochemical tests, it will be possible to assign therapies to individual patients with a high chance of predicting response, as is now standard practice in hormonal therapy of oestrogen receptor-positive breast cancer and in the use of herceptin in Her-2 positive tumour treatment. An important study of EGFR receptor mutations has identified a subset of patients with non-small cell lung cancer who are uniquely responsible to EGFR inhibitors. Other molecular tests will likely be useful in identifying patients at risk for toxicity because of polymorphisms in enzymes responsible for drug metabolism or DNA repair. Most cancer researchers agree that cancer therapy will become increasingly individualized as molecular medicine helps identify the determinants of response and toxicity.
Since the earliest demonstration of the cytotoxic effects of high energy radioisotopes by Marie Curie more than 100 years ago, the use of ionizing radiation has become a critical component of the curative and palliative treatment options for patients with cancer. The field of radiation oncology has enjoyed a technical revolution that has provided more conformal and reproducible delivery capabilities. These improvements in radiation delivery have resulted because of the significant evolution of computer science, biomedical engineering, imaging, and robotics. High-energy (>4 MV) photons produced from linear accelerators coupled with three-dimensional image manipulation have allowed for intensity modulated radiation therapy (IMRT), robotic image-guided delivery (e.g. CyberKnife), and direct CT-guided radiation therapy (tomotherapy). High-energy electron beams carry no appreciable mass and are used to treat superficial structures such as skin cancer and tumours of the anterior eye. In the last 5 years (2004–09), the number of proton therapy centres has more than doubled around the world. Protons, unlike photons, have no exit dose beyond the treatment target and can reduce the integral dose by 50% or more. This is particularly important in the treatment of developing children with radiation as well as targeting tissues that are close to critical structures (e.g. spinal cord). Heavier charged particles (e.g. carbon, helium) have the same physical characteristics as protons, but have a greater biological effect. Two heavy-particle facilities are currently treating patients with resistant tumours.
The new technologies outlined above all provide much more conformal treatment delivery than was available a decade or so ago. A greater degree of conformality results in an improved therapeutic ratio. Highly conformal treatments can allow for dose escalation for resistant tumours while maintaining a fixed level of normal tissue complications and a resultant improvement in local tumour control. Improved treatment field planning is now possible with the help of advanced radiological techniques (MRI, functional MRI, PET). Treatment planning platforms can fuse or correlate images from a wide variety of radiographic studies to guide the selection of treatment volume and dose.
The principle mechanism for radiation-induced cytotoxicity appears to be damage to tumour DNA. Radiation therapy generates free radicals that damage DNA, producing breaks that must be repaired if the cell is to survive. Many tumours lack an effective capacity to repair DNA strand breaks, as compared to normal tissues. The difference in DNA repair between tumour and normal tissue provides a therapeutic window for successful treatment. Irradiation also inflicts potent damaging effects on tumour vasculature.
The dose of irradiation is defined as the unit of energy absorbed by each kilogram of tissue. The unit now used is the gray (Gy): 1 Gy (= 100 rad) is the absorption of 1 joule of energy by 1 kg of matter. Each normal tissue and each tumour type has a characteristic threshold of radiation dose above which the capacity to repair DNA damage is exceeded, and cell death occurs. As the dose of radiation is increased beyond the threshold, the percentage of cells killed increases. Simply stated, the higher the dose of radiation, the higher the probability of tumour control. Also, the higher the dose of radiation received by surrounding normal structures, the higher the probability of normal tissue injury.
Radiation doses are usually delivered in a number of daily fractions, the total fractionated dose being determined by tumour sensitivity and normal tissue tolerance. Seminoma is an exquisitely radiation controllable tumour and requires a low relative dose (30 Gy) for cure, while epithelial tumours such as lung cancer and melanoma, are relatively resistant to conventional doses (e.g. 60 Gy) of radiation.
Within 4–8 h after exposure to ionizing radiation, cells begin to recover from the effects of therapy. Thus, fractions administered too close together can offer increased toxicity to normal tissues, but those too far apart can permit repair of lethal or sublethal damage. Conventional therapy is usually given in daily radiation fractions of 1.8 to 2 Gy over 4–7 weeks, to total doses of 50 Gy or higher, but alternative schemes have been investigated. Hyperfractionated therapy, in which a smaller fraction sizes (<2 Gy) are used more than once daily, takes advantage of the more rapid repair of DNA by normal tissues as compared to tumour cells within the radiation treatment volume. This approach permits a higher total radiation dose to be administered over a shorter time interval, with tolerable late toxicity and slightly increased acute effects. This has been shown to be particularly helpful in the treatment of advanced epithelial tumours of the head and neck region.
The presence of oxygen is important in the generation of free radicals after exposure to ionizing radiation. Relatively hypoxic tissues are less sensitive to the toxic effects of radiation than those tissues that are well oxygenated. Attempts to overcome tumour hypoxia with biochemical manipulation or hyperbaric oxygen have failed. However, concurrent or neoadjuvant chemotherapy appears to improve the chances of curing a locally advanced head and neck cancer by reducing tumour bulk and restoring oxygenation prior to irradiation. Antiangiogenic drugs, such as bevacizumab may improve response to both chemotherapy and irradiation by reducing the tangled mass of leaky tumour vessels and partially re-establishing normal flow, thereby reducing intramural oncotic pressure and improving drug delivery and oxygenation.
Radiation used for the treatment of patients is generally delivered as an external beam from a source outside the body. In selected cases brachytherapy, in which the radiation source is implanted within the substance of the tumour, is effective in the treatment of cervical cancer and endometrial cancer, delivering high local doses and obviating the requirement for daily outpatient visits. For palliative irradiation of metastatic tumours, single large doses (radiosurgery) or abbreviated courses of irradiation (hypofractionated radiotherapy) may be administered to relieve symptoms, but this type of treatment offers limited expectation of long-term control except in the treatment of benign brain tumours (e.g. acoustic neuroma). At some centres, intraoperative radiation therapy can be used to deliver a single large fraction of radiation directly to the tumour bed. In some circumstances, radioisotopes themselves can be used for systemic treatment. For example, iodine-131 is taken up by thyroid tissue both locally and at sites of metastatic disease. Monoclonal antibodies such as tositumomab and ibritumomab tiuxetan, coupled with radioisotopes, may be administered intravenously, and localize at the tumour site. The radioisotope carried by the antibody emits β or γ particles that destroy malignant lymphomas.
Complications of radiation oncology
Radiation is highly effective in killing tumour cells, but toxicity to normal tissues within the field or at its margins can be significant. Effects of radiation can be acute (during the treatment course), subacute (after treatment but within a few months of therapy), and late (permanent). Tissues that proliferate rapidly, such as skin, mucosal linings, and bone marrow, are most susceptible to acute radiation injury. Thus, cutaneous erythema, desquamation, and oedema are important local effects of therapy. Oral and intestinal mucosae are particular susceptible to irradiation. Diarrhoea, nausea, and vomiting are common in patients receiving abdominal irradiation. If a significant radiation dose is delivered to the bone marrow, particularly the pelvis and spine, patients may develop cytopenias. In the case of whole-body irradiation, the lymphocyte count also falls and significant immune suppression may result. On occasion, these acute side effects are severe enough to require delays in treatment in order to allow recovery of the normal tissues and blood counts. When patients receive irradiation to a mass in the chest cavity, e.g. a lymphoma, the resultant radiation pneumonitis may cause fever, cough, dyspnoea, and pulmonary infiltrates. Relief from these pulmonary symptoms may require treatment with corticosteroids.
Long-term sequelae are tissue specific and occur most commonly if normal tissue tolerance is exceeded. Thus, careful radiation field planning and treatment delivery must be carried out to ensure that tissues do not receive treatment beyond their maximum predicted tolerated dose. For example radiation doses to the spinal cord in excess of 60 Gy can cause transverse myelitis, with paresthesias and neuropathies. Doses to large volumes of small bowel in excess of 45 Gy can cause strictures, and doses to an entire kidney above 25 Gy can cause irreversible renal damage. The whole liver tolerates radiation therapy up to doses of 40 Gy, above which hepatic necrosis and fibrosis result. However, partial liver irradiation to very high doses can be done safely as long as the volume of irradiation is restricted. Accelerated coronary artery disease was seen in patients with Hodgkin’s disease years after they received mediastinal irradiation with the more primitive treatment techniques than are currently employed. Early results suggest that modern conformal radiation techniques can reduce both acute and late effects of treatment.
Perhaps the most distressing late effect of radiation therapy is the development of secondary tumours within radiation fields. Such radiation associated secondary neoplasms can occur 5 to 50 or more years after treatment. Ordinarily, this is not an issue for patients with metastatic cancer receiving radiation therapy for palliation of disease-related symptoms since the patients’ survival will be limited. However, in treating paediatric tumours, and in patients with lymphomas, who will also be cured with radiation therapy, the development of solid tumours in the radiation field, including sarcomas and lung and breast cancers, represents a devastating complication. These secondary tumours can occur within the full-dose region as well as in the lower-dose regions of beam entrance and exit. Again, treatment techniques such as IMRT and proton therapy reduce the irradiated volume by 50% or more and will likely be associated with a reduced risk of secondary tumour formation.
Role of radiation therapy in cancer treatment
In the clinical management of patients, radiation therapy is used as the sole therapy for many localized tumours and as a component of primary therapy for many patients, either as an adjuvant after surgery to prevent local recurrence, or as neoadjuvant therapy to decrease tumour mass and thereby allow a less morbid procedure. It may be used alone or in conjunction with chemotherapy (which often acts as a radiation sensitizer). It is also valuable as palliative therapy for advanced stage treatment (Table 5).
Radiation therapy has a role in the management of several acute complications of cancer. Radiation can be valuable in the treatment of bone metastases, both to decrease painful lesions and to diminish the risk of pathological fractures. Radiation therapy can be delivered as an emergency procedure in patients with spinal cord compression to reduce the risk of permanent neurological toxicity. Likewise, radiation therapy has an important role in the management of brain metastases, either as primary therapy for patients with multiple lesions or as an adjuvant therapy for patients after excision of a solitary brain metastasis. In lung cancer, radiation can be used to palliate obstructive symptoms. In bleeding oesophageal or gastric tumours, radiation therapy can often assist in local control of haemorrhage.
In the management of many tumours, radiation therapy can serve as the sole modality or a component of definitive treatment. In early-stage Hodgkin’s’s disease, patients can be cured with either mantle radiation therapy alone or with mantle and para-aortic radiation. Similarly, 35 to 50-Gy doses of radiation therapy can cure 50 to 60% of patients with stage I/II non-Hodgkin’s’s lymphoma. Seminoma is exquisitely sensitive to irradiation and most patients with early stage disease can be cured with radiation therapy alone. Radiation therapy cures patients with early stage prostate cancer and laryngeal cancer, and causes less local morbidity than surgery. Finally, in early-stage breast cancer, lumpectomy and radiation therapy provides an equivalent survival outcome to a modified radical mastectomy.
|Table 5 Role of radiation therapy in cancer treatment|
|Curative therapy alone|
|Non-Hodgkin’s lymphoma (early stage, indolent histology)|
|Central nervous system tumours (e.g. medulloblastoma)|
|Breast cancer (postsurgery)|
|Curative in conjunction with chemotherapy|
|Small cell lung cancer (limited stage)|
|Non-Hodgkin’s lymphoma (early stage aggressive histology)|
|Rectal cancer (with 5-FU)|
|Gastric cancer (with 5-FU)|
|Lung cancer (stage III)|
In other diseases, combinations of radiotherapy and chemotherapy are highly effective. For example, in patients with squamous cell carcinoma of the anus, combined modality therapy using radiation therapy in conjunction with 5-fluorouracil and mitomycin C chemotherapy yields a high cure rate without surgery. Similarly, in patients with limited stage small-cell lung cancer, combined modality therapy using cisplatin-based chemotherapy and radiation therapy eradicates the primary tumour, and improves survival. Likewise, in cervical cancer, a combination of cisplatin and radiation after resection reduces tumour recurrence. It has been recently shown that radiation combined with concurrent and adjuvant temodar prolongs survival and disease-free progression in adults with malignant gliomas.
Radiation therapy also has an important role in adjuvant therapy. Prior to surgical resection of rectal cancer, radiation therapy administered in conjunction with 5-fluorouracil chemotherapy can reduce local, regional, and systemic recurrence and can improve both disease free and overall survival. In node-positive gastric cancer, a postoperative combination of 5- fluorouracil-based chemotherapy, with irradiation of the tumour bed, can reduce the risk of recurrence and improve survival. Recent studies have demonstrated that the administration of prophylactic cranial irradiation to patients with small-cell lung cancer who achieve a complete remission can reduce the risk of tumour recurrence in the central nervous system. In the neoadjuvant setting, radiation in combination with cisplatin-based chemotherapy improves survival and decreases recurrence in patients with stage IIIA lung cancer.
Advances in radiation therapy, chemotherapy, and biological therapy have revolutionized the care of cancer patients. Significant improvements in supportive care and the development of new, active anticancer agents have improved the prospects for long-term survival even for patients with metastatic disease. The internist has a pivotal role in coordinating care for such patients, recognizing the early and late consequences of treatment, and coordinating the long-term follow-up of such patients with the cancer specialists.
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