Show Summary Details
Page of

Cancer chemotherapy and radiation therapy 

Cancer chemotherapy and radiation therapy
Cancer chemotherapy and radiation therapy

Bruce A. Chabner

and Jay Loeffler



Thorough updates include discussion of

(1) drugs that target protein degradation pathways, including proteasome inhibitors and ubiquitin ligase inhibitors in treatment of myeloma;

(2) a growing array of targeted drugs to treat haematological malignancies;

(3) use of hypofractionated radiation therapy schemes (higher dose per day, less fractions).

Updated on 30 Jul 2015. The previous version of this content can be found here.
Page of

PRINTED FROM OXFORD MEDICINE ONLINE ( © Oxford University Press, 2015. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).

Subscriber: null; date: 11 December 2017


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 high expectation of cure. For patients with the more common solid tumours, including lung, colon, and breast cancer, new chemotherapeutic and hormonal agents, molecularly targeted drugs, 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 one third 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. In recent years, small molecules targeted for specific cancer mutations, vaccines, monoclonal antibodies, monoclonals coupled to toxic molecules, and monoclonals that induce antitumour immunity have expanded the repertoire of agents useful for cancer treatment.


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 leukaemias, lymphomas, and testicular cancer, or to diminish tumour-related symptoms, improve the quality of life, and extend survival in less sensitive epithelial cancers, such as those arising from lung, colon, and breast; (2) adjuvant therapy, administered before or after the completion of definitive local surgery and/or radiation therapy to decrease the risk of recurrence of disease locally and at distant sites. Adjuvant therapy improves survival in patients with breast and colon cancers.

Complications—most of the commonly used chemotherapy agents cause acute myelosuppression and epithelial damage; nausea and vomiting are frequent, but can often be helped by corticosteroids and serotonin uptake inhibitors (e.g. ondansetron). Other toxicities specific to particular agents or classes of agent include (1) alopecia—doxorubicin and alkylating agents, (2) peripheral neuropathy—vinca alkaloids, bortezomib, and platinum analogues, (3) heart failure—doxorubicin and trastuzumab, (4) pneumonitis—bleomycin, fludarabine, gemcitabine, methotrexate, (5) infertility—alkylating agents. Secondary leukaemias may develop as a late complication of therapy with alkylating agents, platinum analogues, and topoisomerase II inhibitors.

Targeted anti-cancer molecules constitute a new approach to cancer treatment. In the past decade, both small molecules and monoclonal antibodies have proven useful for treating tumors that express mutated intracellular proteins or cell surface receptors essential for tumour growth. These molecules, such as those that target the braf signalling molecule in melanoma, the epidermal growth factor receptor (EGFR) in lung cancers, and the brc-abl kinase of chronic myeloid leukemia, produce remissions with very limited toxicity to normal tissues. Antibodies to the her2 receptor in breast and gastric cancer, EGFR in colon and head and neck cancers, and anti-CD 20 and anti-CD30 in lymphomas, have become significant new treatments. Anti-CD 30 antibody coupled to a toxic mitotic inhibitor, orastatin A (brentuximab vedotin), is highly effective in relapsed/refractory Hodgkin disease.

Immunotherapies are becoming increasingly useful for cancer treatment. A dendritic cell vaccine, Sipuleucel-T, extends survival in men with angrogen insensitivity prostate cancer, and ipilimumab, an anti-CTLA4 antibody, enhances host auto-immunity directed against melanoma, lung cancer, and renal cell cancers. Anti-PD-1 (nivolumab and pembrolizumab) antibodies have similar action in enhancing immunity against melanoma.

Pomalidomide, lenalidomide, and thalidomide are all effective agents against multiple myeloma. Their mechanism of action is related to the inhibition of degradation of key proteins, including IkappaB kinase. They exert a broad array of actions on the immune system, inhibiting cytokine production, and display anti-angiogenic activity.

Radiation therapy

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 uncomplicated tumor control. 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 irradiated local 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. Radiosurgery is also used as curative therapy for small, benign brain tumours such as meningiomas, acoustic neuromas and pituitary adenomas.

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; cerebral oedema and (3) late—permanent—including local tissue damage (e.g. transverse myelitis, bowel strictures, renal failure) and secondary tumours that can develop within radiation fields years after therapy.


Mechanisms of action and clinical use

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 multiplies in an uncontrolled fashion, and invades and destroys normal neighbouring tissues (see Chapter 6.2). 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 invade adjacent normal tissues and 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 (motility factors and proteinases) and pathways for blood vessel growth (angiogenesis) that 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 6.6.1). 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. While leukemias, lymphomas, and advanced-stage germ cell tumours can be cured with combination chemotherapy, in the less sensitive epithelial cancers (colon, breast, and lung cancer) combinations of agents diminish tumour-related symptoms, improve the quality of life, and extend survival in patients with metastatic disease, but are not curative.

Table 6.6.1 The role of chemotherapy in cancer management

Primary therapy (curative)

Acute lymphoblastic leukaemia, acute myeloblastic leukaemia

Hairy cell leukaemia

Hodgkin’s disease

Non-Hodgkin’s lymphoma

Germ cell tumours

Paediatric sarcomas

Small-cell lung cancer (with radiation therapy)

Anal carcinoma (with radiation therapy)

Adjuvant therapy (decreases disease recurrence rates)

Breast cancer

Colon cancer

Non-small-cell lung cancer

Osteosarcoma (with neoadjuvant therapy)

Neoadjuvant therapy

Oesophageal cancer (with radiation therapy)

Stage III non-small cell lung cancer

Head and neck cancer

Breast cancer (locally advanced)

Osteosarcoma and other paediatric sarcomas

Palliative therapy for metastatic disease

Lung cancer

Breast cancer

Pancreatic cancer

Colorectal 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, anal, or oesophageal cancers, prior to or with radiation therapy or prior to surgery. 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 adjuvant chemotherapy after surgery.

Finally, the drugs can be used as adjuvant therapy, administered after the completion of definitive local treatment 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 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, as notably in locally advanced breast cancer, oesophageal cancer, and lung cancer.

Only in rare circumstances, such as methotrexate therapy for choriocarcinoma or cladribine for hairy cell leukaemia, 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 an advanced cancer was MOPP (mechlorethamine (chlormethine), vincristine, prednisone, and procarbazine), used for the treatment of Hodgkin’s disease. MOPP has been replaced by a less toxic and more effective combination, ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Combination chemotherapy is now the mainstay for treating most curative regimens and for palliative treatment of advanced epithelial cancers. High doses of chemotherapy followed by bone marrow reconstitution by infusion of marrow stem cells can be used to overcome tumour resistance in patients with lymphoma, myeloma, or leukaemia.

Chemotherapeutic drugs have both acute and late toxicities that may affect virtually every organ system. These include congestive heart failure (after anthracyclines), pulmonary fibrosis (after alkylating agents or bleomycin), or kidney failure (after platinum-based therapies) and damage to reproductive tissues, brain, and other organs. In addition, alkylating agents and topoisomase inhibitors 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 6.6.2). In order to reduce inter-patient variability in exposure to drugs, intravenous 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 should be reduced in treating patients with renal dysfunction (methotrexate, bleomycin, hydroxycarbamide, fludarabine, carboplatin, capecitabine) or hepatic dysfunction (anthracyclines, vinca alkaloids, taxanes); these modifications depend on decreased kidney or liver function, whichever is the primary route of drug clearance.

Table 6.6.2 Cancer therapy agents


Alkylating agents and platinating drugs


Topoisomerase inhibitors

Mitotic inhibitors

Hormone therapy

Biological therapy

Monoclonal antibodies (armed or unarmed)

Conjugates with toxins or radionuclides



Targeted therapies (small molecules and monoclonals)

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 renal toxins such as high-dose methotrexate or routine doses of cisplatin, ifosfamide, and cyclophosphamide. Careful attention must be given to fluid and electrolyte balance with the administration of many agents. Cisplatin and arsenic trioxide can cause profound calcium and magnesium depletion; monitoring of these electrolytes is mandatory.


These exert their cytotoxicity by inhibiting the synthesis of DNA or its precursor nucleotides (the deoxyribose triphosphates of thymidine, cytidine, adenosine, and guanosine). Some are analogues of physiological purines and pyrimidines, and are incorporated into DNA, where they block DNA synthesis. Methotrexate and the newer antifolate, pralatrexate, inhibit dihydrofolate reductase, which maintains the intracellular pool of reduced tetrahydrofolates required for the synthesis of purine nucleotides and thymidylate. A third antifolate pemetrexed directly blocks thymidylate synthase, an enzyme that synthesizes the DNA precursor deoxythymidine monophosphate. Each antifolate is useful in specific clinical settings. Fluorouracil and the closely related prodrug capecitabine generate an active metabolite fluorodeoxyuridine monophosphate (FdUMP), which inhibits the same enzyme thymidylate synthase, as does pemetrexed.

A second class of antimetabolites inhibit DNA replication through inhibition of extension of the nascent DNA strand. Cytarabine (ara-C), which is converted to cytarabine triphosphate (ara-CTP) in the cell, is incorporated into DNA and serves as a DNA chain terminator. A closely related deoxycytidine analogue, gemcitabine, also becomes incorporated into DNA, but in addition it is self-potentiating as it inhibits ribonucleotide reductase and thereby blocks the formation of the physiological deoxyribonucleotides required for DNA synthesis.

Purine analogues 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 again 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 leukaemia. Other purine analogues (nelarabine and clofarabine) are effective in subsets of adult and paediatric leukaemias, respectively.

Hydroxycarbamide inhibits ribonucleotide reductase and is useful in acutely reducing leukaemic cell blood counts, as the initial chemotherapy for acute myeloid leukaemias.

As a group, the antimetabolites cause acute toxicity to bone marrow and gastro-intestinal epithelium, 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. Fludarabine, by inhibiting T-regulatory cells, promotes autoimmune toxicities such as bone marrow cytopenias and autoimmune haemolytic anaemia.

Alkylating agents

These exert their cytotoxicity by binding to DNA and forming covalent bonds with electron-rich sites on DNA, cross-linking the opposing strands of DNA, and thereby 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 haematological malignancies and breast cancer. A newer alkylating agent, bendamustine, has unique activity in lymphomas and does not share cross-resistance with the traditional alkylating agents. 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. Oxaliplatin differs from cisplatin and carboplatin in that it produces a bulkier DNA adduct, does not require the presence of an intact mismatch repair apparatus to produce strand breaks, and does not share cross-resistance with the other platinum analogues. Carboplatin is frequently included in high-dose regimens. As mentioned previously, the alkylating agents and platinum analogues are acutely toxic to bone marrow and gastro-intestinal epithelium, and may cause pulmonary fibrosis, renal failure, neurotoxicity, and acute leukaemias, particularly when used in high doses. The bladder toxicity of cyclophosphamide and ifosfamide may be relieved by MESNA and sulfhydril co-administered during high-dose therapy.

Natural compounds

Compounds isolated as products of fungal fermentation, or from plants or marine organisms, often possess antitumour activity. The anthracyclines, represented by doxorubicin and its analogues, and etoposide, a semisynthetic, bind to and inhibit topoisomerase II (topo II), a DNA unwinding enzyme necessary for DNA repair and replication. Inhibition of topo II triggers double strand breaks in DNA. In a similar way, the camptothecins (irinotecan and topotecan), derived from a medicinal Chinese herbal source, interfere with topo I, a closely related DNA unwinding enzyme, inducing single strand breaks in DNA. The anthracyclines are distinguished by their potent antileukaemic activity, as well as their efficacy against breast cancers, childhood and adult 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. Yondelis, derived from a sea squirt, binds to the minor groove of DNA and is effective against sarcomas and ovarian cancer.

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.

Chemotherapy resistance

Tumours may become resistant to the effects of cytotoxic chemotherapy by a number of different mechanisms (Table 6.6.3). 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 overexpressed 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. Hydroxycarbamide, an inhibitor of ribonucleotide reductide, selects for cell resistant on the basis of amplification of its target gene. Increased intratumoral drug metabolism, as occurs with ring reduction of 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 6.6.3 Mechanisms of chemotherapy resistance


General mechanism of resistance

Specific pathway or genetic change


Decreased drug uptake

Decreased expression of folate transporter

Decreased drug activation

Decreased folylpolyglutamyl synthetase

Amplified drug target

Amplified dihydrofolate reductase gene


Altered drug target

Mutated or decreased 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


Defective recognition of DNA adducts

Mismatch repair defect

Enhanced DNA repair

Increased nucleotide excision repair


Increased drug target

Amplified or increased expression of thymidylate synthase

Most anticancer drugs

Defective checkpoint function and failure of apoptosis

P53 mutations

MDR, multidrug resistance.

Side effects of chemotherapy

Most of the commonly used chemotherapy agents (Table 6.6.4) cause acute effects, such as nausea and vomiting, myelosuppression, and mucositis, in the week following drug administration, and prolonged immunosuppression. Most antitumour drugs cause an acute 5- to 7-day depression in the neutrophil count and platelet count, with recovery in 10 to 14 days, allowing retreatment on 14- to 21-day cycles. By contrast, the nitrosoureas lead to delayed-onset reductions in both neutrophils and platelets, with nadir counts typically reached 4 to 6 weeks after therapy.

Table 6.6.4 Side-effects of chemotherapy

Adverse effect

Representative agents

Nausea/vomiting (severe)

Cisplatin, doxorubicin


Cisplatin, doxorubicin, taxol


Taxol, platinum analogues, vinca alkaloids

Hepatic toxicity

Methotrexate, cytosine arabinoside, purine analogues

Renal toxicity

Cisplatin, methotrexate

Pulmonary toxicity

Bleomycin, alkylating agents, methotrexate, gemcitabine, fludarabine


Doxorubicin, daunorubicin, arsenic trioxide

Bladder toxicity

Cyclophosphamide, ifosfamide

Mucositis and myelosuppression

Virtually all chemotherapy agents

Nausea and vomiting cause significant discomfort, but are well controlled by corticosteroids and serotonin uptake inhibitors such as ondansetron. These symptoms tend to increase with each cycle of treatment. Alopecia occurs in most patients receiving doxorubicin and the alkylating agents, but less completely in patients treated with antimetabolites or antimitotic drugs. A peripheral neuropathy frequently results from treatment with vinca alkaloids, taxanes, and platinum analogues.

Many agents have unique and delayed 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 to 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. Many other drugs, including methotrexate and high-dose alkylating agent therapy, fludarabine, and gemcitabine, cause an organizing pneumonitis of unclear aetiology.

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, for methotrexate, urine alkalinization before and during drug infusion. Gemcitabine causes a delayed haemolytic–uraemic syndrome that appears after many months of treatment. Cisplatin renal toxicity is prevented by infusion of saline to induce chloride diuresis.

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. Newer taxanes (protein-bound paclitaxel and cabazitaxel) are much less likely to cause hypersensitivity. Cytarabine administered in high single doses (3 mg/m2 or more) can cause irreversible cerebellar dysfunction, especially in elderly patients, while cisplatin, the taxanes, and vinca alkaloids cause a cumulative peripheral neuropathy.

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.

A major delayed side effect of cancer chemotherapy is the development of secondary leukaemias due to therapy. A period of myelodysplasia, followed by overt leukaemia, associated with losses in chromosome 5 or 7, may appear 2 to 4 years after receiving therapy with alkylating agents. Topoisomerase II therapy (etoposide, anthracyclines) in high total doses has been associated with secondary leukaemias due to translocations involving the MLL gene on chromosome 11, and less commonly acute promyelocytic leukaemia. 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.

Hormone-directed therapy

Along with the traditional cytotoxic agents, hormone-directed therapy can be of great value in the treatment of breast and prostate cancers. More than half of breast cancers express receptors for oestrogen and progesterone, and virtually all prostate cancers have androgen receptors. Depriving these tumours of the hormonal stimulus can exert cytostatic effects on the cell and induce programmed cell death (apoptosis). Thus, 60% of breast cancers expressing the oestrogen receptor will respond favourably to treatment with tamoxifen, an oestrogen receptor antagonist, or to aromatase inhibitors (etrozole, exemestane), which block the synthesis of oestrogen from adrenal androgens, an important source of oestrogen in postmenopausal women. The hormone antagonists are standard therapy for both metastatic disease and for adjuvant therapy of hormone-receptor positive breast cancer, and prevent the development of breast cancer in high-risk subjects. Addition of everolimus, an mTOR inhibitor and PI3K pathway blocker, to exemestane significantly enhances the progression free survival and over-all survival of women with metastatic breast cancer. Similarly, luteinizing hormone releasing hormone (LHRH) agonists reduce testosterone synthesis in the testes and have high response rates in men with metastatic prostate cancer. Direct androgen receptor (AR) antagonists (flutamide) also cause regression of metastatic prostate cancer and relief of bone pain. The androgen-depleting therapies decrease tumour burden in locally advanced disease prior to radiation therapy. A newer agent abiraterone blocks CYP17, a key step in adrenal synthesis of androgens, and lowers serum levels of androgens below detection in men who have progressive disease on LHRH agonists. Likewise enzalutamide, a more potent AR blocker, also degrades the AR, and benefits patients unresponsive to LHRH agonists. Both androgen depletion and oestrogen depletion decrease libido and lead to bone loss, which can be averted by bisphosphonates and by denosumab, a monoclonal antibody against the RANK ligand.

Hormonal therapies have important side effects. Tamoxifen induces menopause in premenstrual women. It increases the risk of endometrial cancer and thrombotic events. Aromatase inhibitors also have antiestrogen side effects, but in addition cause joint discomfort. Anti-androgens have profound metabolic effects (decreased muscle mass, glucose intolerance, and an increased risk of myocardial infarction). Aberaterone induces mineralcorticoid excess and glucocorticoid deficiency, and requires supplemental prednisone to control hypertension and hypokalemia.

Resistance to hormonal therapy arises through increased sensitivity of steroid receptor pathways to low hormone concentrations, through selection of hormone-independent splice variants of the ER, through activation of the PI3Kinase pathway, and through alternative splicing or amplification of the AR, creating hormone-independent activation. It is not known whether prostate and ER+ breast cancers ever truly become hormone-independent.

Differentiating agents

Drugs that promote differentiation of cancer cells or modify gene expression have become useful in cancer treatment. Azacytidine and deoxyazacytidine block the methylation of cytosine residues in DNA and promote differentiation. They are useful agents in treating myelodysplasia (reversing cytopenias and delaying onset of acute leukaemia). Arsenic trioxide and all-trans-retinoic acid restore differentiation in acute promyelocytic leukaemia, a disease characterized by mutation in the retinoic acid receptor. Inhibitors of histone deacetylase (romidepsin and vorinostat) promote differentiation in cutaneous T-cell lymphomas and peripheral T-cell lymphomas.

Targeted therapies, monoclonal antibodies, and cytokines

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 both tumour and 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 tumour-specific target thus exploited was the bcr-abl kinase, created by the 9:22 translocation in chronic myeloid 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 catalytic domain of bcr-abl kinase. Dasatinib and nilotinib, newer analogues of imatinib, are effective in most patients who develop resistance to imatinib through kinase mutation. The newest analogue, ponatinib, effectively overcomes most mutations, including T315I, which is not blocked by other CML drugs.

Cancer chemotherapy and radiation therapy Drugs that target protein degradation pathways are effective against multiple myeloma; these include the proteosome inhibitors bortezomib and carfilzomib, and the ubiquitin ligase inhibitors thalidomide, lenalidomide, and pomalidomide. Lenalidomide is also active against myelodysplasia characterized by the loss of a portion of the 5q chromosome (5 q–).

Other targeted compounds block key growth factor receptors on the cell membrane. These receptors, such as the epidermal growth factor receptor (EGFR), or CKIT, become constitutively activated by mutations and initiate a phosphorylation cascade that leads to cell proliferation, angiogenesis, and enhanced survival. Erlotinib and gefitinib proved highly effective in causing tumour regression in patients with non-small-cell lung cancers (NSCLC) that carry a constitutively activating mutation of EGFR. Additional mutations in EGFR, as well as activation of the C-MET-driven pathway, may lead to resistance to these drugs. The ALK kinase is another membrane tyrosine kinase activated by a translocation (EML4-ALK) in NSCLC, and this subset of lung cancer, as well as the closely related tumours driven by ROS-1 kinase mutations, respond to treatment with crizotinib. Ceritinib, which evades many drug resistance mutations, is highly effective against crizotinib-resistant EML4-ALK mutated tumours. Gastrointestinal stromal tumours contain activating mutations in CKIT, and respond dramatically to imatinib, and sunitinib, while 60% of melanomas contain an activating mutation in BRAF, and regress with treatment of vemurafenib. A combination of a BRAF and MEK inhibitors provides longer remissions and fewer side effects than vemurafenib. All of these new drugs are analogues of ATP and attack the catalytic domain of their target enzyme. Resistance in clinical use emerges due to mutations in gatekeeper residues that prevent access to the catalytic enzyme pocket, or through activation of alternative pathways that circumvent the blockade, or through acquired defects in apoptosis.

Cancer chemotherapy and radiation therapy Haematological malignancies may be treated with a growing array of targeted drugs, including (1) ibrutinib, an inhibitor of the B-cell receptor, (2) idelalisib, a PI3 kinase delta inhibitor, both of which are effective against chronic lymphocytic leukaemia and follicular lymphomas, and (3) ruxolitinib, a JAK 2 kinase inhibitor for myeloproliferative disorders and polycythaemia vera. New drugs against leukaemias driven by mutations in the isocitrate dehydrogenase genes IDH-1 and IDH-2 have shown significant remission-inducing activity in early trials.

The PI3Kinase pathway has become a focus of intense interest, as it plays a critical role in cell metabolism, survival, and growth Mutations in the PI3K and PTEN genes are found in many epithelial tumors. A key convergence point for PI3K signalling is mTOR, a kinase that controls protein translation, cellular metabolism, and survival. mTOR inhibitors (rapamycin analogues) block the PI-3 kinase pathway that promotes tumour cell survival, and have found a useful place in the treatment of renal cell cancers (temsirolimus and everolimus), mantle cell lymphoma (temsirolimus) and neuro-endocrine tumors (everolimus).

While such targeted drugs are in general well tolerated, they tend to cause diarrhoea, hepatic enzyme elevations, and idiosyncratic toxicities, such as oedema (imatinib), pneumonitis (gefitinib), and other rarer events.

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 (VEGFR) 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, as well as malignant gliomas. The antiangiogenic drugs as a class cause hypertension, proteinurea, intestinal perforation, haemorrhage, and congestive heart failure as their primary toxicities. The anti-angiogenic drugs are highly useful agents in chemotherapy resistant ovarian cancer, relapsed gliomas, and in metastatic colorectal and non-small cell lung cancer.

Monoclonal antibodies as drugs have advantages over small molecules. They have long half-lives in plasma, limited off target side effects, and 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, and it improves survival, in combination with chemotherapy, in patients with aggressive large cell lymphoma. The most common side effects of rituximab and other antibodies are infusion-related fevers, chills, and hypotension. Rituximab also causes immunosuppression, with a predisposition to opportunistic infection. Brentuximab vedotin, an anti-CD 30 antibody coupled to a mitotic inhibitor, produces high response rates in Hodgkin disease patients refractory to chemotherapy, and with modest toxicity (primarily infusion reactions, myelosuppression, and neuropathy). Another biologically active antibody, trastuzumab, binds to the extramembranous segment of the HER2 receptor, which is amplified in 25% of breast cancer cases. Trastuzumab (Herceptin) is used for patients with breast tumours and gastric cancers that have amplification of the HER2 receptor. When given in conjunction with paclitaxel, trastuzumab prolongs survival for patients with metastatic breast cancer, and dramatically improves the effectiveness of adjuvant chemotherapy for the same disease. It synergizes with a second antibody pertuzumab which blocks the dimerization of HER2 and HER3 receptors. Lapatinib, a small molecule that attacks the catalytic pocket of the HER2 receptor, displays antitumor activity against trastuzumab-resistant tumours, as does the antibody-drug conjugate, ado-trastuzumab-emtansine, which delivers a highly toxic maytansine derivative to the tumour.

Antibodies to the EGFR receptor (cetuximab and panitumumab) are effective when used with chemotherapy in some epithelial tumours, but not in colon cancers expressing mutant KRAS. Antibodies conjugated to radionuclides (britumomab tiuxetan) or toxic antimitotic drugs (brentuximab vedotin) have notable antitumor activity against relapsed lymphomas, and Hodgkin disease, respectively. The most innovative use of monoclonal antibodies has been the use of ipilimumab (anti-CTLA4) to activate an auto-immune response to epithelial tumours (melanoma, renal cell cancer, NSCLC). Antibodies (pembrolizumab and nivolumab) against the PD-1 receptor have promising antitumour activity against melanoma and NSCLC as well, but with less toxicity than ipilimumab.

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. A Interferon alfa 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 molecular profiles of leukaemias, lymphomas, and many solid tumours; these profiles reveal dramatic molecular heterogeneity in common classes of tumours such as lung, colon, and breast cancer. Further, there is a growing confidence that, with appropriate molecular and immunohistochemical tests, it will be possible to detect the driver mutations and assign therapies to individual patients with a high chance of predicting response, and with less toxicity than conventional chemotherapy. 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 ‘personalized’ as molecular medicine helps identify the determinants of response and toxicity.

Radiation oncology

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) and stereotactic body radiosurgery. 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 11 years (2004–2015), the number of proton therapy centres has grown 4-fold around the world, with two active heavy ion facilities operating in Japan and Germany. 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.

Cancer chemotherapy and radiation therapy 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, CT/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. These improvements have led to the use of hypofractionated schemes (higher dose per day, fewer fractions), which appear to be as safe and efficacious as more standard fractionation, while reducing the overall costs of treatment and reducing the burden for patients.

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. There is continuing controversy concerning what proportion of the cytotoxic death of tumour cells is direct DNA damage to tumour cells versus damage to the stroma and supporting 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 radiocurable tumour and requires a low relative dose (20 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. Hypofractionated regimes (discussed above) are becoming quite common in radiation oncology clinics throughout the world.

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 54 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 6.6.5).

Table 6.6.5 Role of radiation therapy in cancer treatment

Curative therapy alone

Hodgkin’s disease

Non-Hodgkin’s lymphoma (early stage, indolent histology)

Laryngeal carcinoma

Prostate cancer

Central nervous system tumours (e.g. medulloblastoma, ependymoma)

Cervical cancer

Breast cancer (postsurgery)

Curative in conjunction with chemotherapy

Small cell lung cancer (limited stage)

Non-Hodgkin’s lymphoma (early stage aggressive histology)

Anal carcinoma

Adjuvant therapy

Rectal cancer (with 5-FU)

Gastric cancer (with 5-FU)

Neoadjuvant therapy

Oesophageal carcinoma

Lung cancer (stage III)

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, low dose 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, 30 to 36-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.

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 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 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 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.

Further reading

Chabner BA, Roberts TG Jr (2005). Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer, 5, 65–72.Find this resource:

    Deng C, et al. (2013). Brentuximab vedotin. Clin Cancer Res, 19, 22–7.Find this resource:

      Durante M, Loeffler JS (2009). Charged particles in radiation oncology. Nat Rev Clin Oncol, 7, 37–41.Find this resource:

        Ferraldeschi R, et al. (2013). Abiraterone and novel antiandrogens: overcoming castration resistance in prostate cancer. Annu Rev Med, 64, 1–13.Find this resource:

          Ferrara N, Kerbel RS (2005). Angiogenesis as a therapeutic target. Nature, 438, 967–74.Find this resource:

            Flaherty KT, et al. (2010). Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med, 363, 809–19.Find this resource:

              Fuks Z, Kolesnick R (2005). Engaging the vascular component of the tumor response. Cancer Cell, 2, 89–91.Find this resource:

                Izar B, et al. (2013). Pharmacokinetics, clinical indications, and resistance mechanisms in molecular targeted therapies in cancer. Pharmacol Rev, 65, 1351–95.Find this resource:

                  Kwak EL, et al. (2010). Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med, 363, 1693–703. Erratum in N Engl J Med (2011), 364, 588.Find this resource:

                    Levin WP, et al. (2005). Proton beam therapy. Br J Cancer, 93, 849–54.Find this resource:

                      Lynch TJ, et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med, 350, 2129–39.Find this resource:

                        Izar B, et al. (2013). Pharmacokinetics, clinical indications, and resistance mechanisms in molecular targeted therapies in cancer. Pharmacol Rev, 65, 1351–95.Find this resource: