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Modalities of Cancer Therapy

by Bruce A. Chabner, MD, Elizabeth Chabner Thompson, MD, MPH

Treatment of cancer can involve any of several modalities:

  • Surgery

  • Radiation therapy

  • Chemotherapy

  • Hormonal therapy

  • Immunotherapy

Often, modalities are combined to create a treatment program that is appropriate for the patient and is based on patient and tumor characteristics as well as patient preferences.

Survival rates with the different modalities, alone and in combination, are listed for selected cancers (see 5-Yr Disease-Free Survival Rates by Cancer Therapy).

Surgery

Surgery is the oldest form of effective cancer therapy. It may be used alone or in combination with other modalities. The size, type, and location of the primary tumor may determine operability and outcome. The presence of metastases may preclude an aggressive surgical approach to the primary tumor.

Factors that increase operative risk in cancer patients include

  • Age

  • Comorbid conditions

  • Debilitation due to cancer

  • Paraneoplastic syndromes (less common—see Paraneoplastic Syndromes)

Cancer patients often have poor nutrition due to anorexia and the catabolic influences of tumor growth, and these factors may inhibit or slow recovery from surgery. Patients may be neutropenic or thrombocytopenic or may have clotting disorders; these conditions increase the risk of sepsis and hemorrhage. Therefore, preoperative assessment is paramount (see Preoperative Evaluation).

5-Yr Disease-Free Survival Rates by Cancer Therapy

Site or Type

Stage

5-yr Disease-Free Survival Rate (%)

Surgery alone

Bladder

0, A

81

B 1

66

Cervix

I

94

Colon

I, II

81

Endometrium

I

74

Kidney

I, II

67

Larynx

I, II

76

Lung (non-small cell)

I

50–70

II

37

Oral cavity

I, II

67–76

Ovary

I, II

72

Prostate

I

80

Testis (nonseminoma)

I

65

Radiation therapy alone

Cervix

II, III

60

Esophagus

10

Hodgkin lymphoma

Pathologic stage IA

80

Larynx

I, II

76

Lung (non-small cell)

III M0 (excluding Pancoast tumor)

9

Nasal sinuses

I, II, III

35

Nasopharynx

I, II, III

35

Non-Hodgkin lymphoma

Pathologic stage I

60

Prostate

I, II

80

Testis (seminoma)

II, III

84

Chemotherapy (sometimes plus radiation)

Burkitt lymphoma

I, II, III

60

Choriocarcinoma (in women)

All stages

95

Hodgkin lymphoma

IIIB,IVA, B

74

Leukemia (in children, ALL)

I, II, III

85

Leukemia (in children, ANLL)

50

Leukemia (in people 45 yr, ANLL)

40–50

Leukemia (in people 45–65 yr, ANLL)

25

Leukemia (in people > 65 yr, ANLL)

5

Lung (small cell)

Limited

25

Lymphoma (diffuse large cell)

II, III, IV

60

Testis (nonseminoma)

III

88

Surgery plus radiation

Bladder

B 2 , C

54

Endometrium

II

62

Hypopharynx

II, III

33

Lung (Pancoast tumor)

III M0

32

Oral cavity

III

36

Testis (seminoma)

I

94

Surgery plus chemotherapy

Colon

III

70

Ovary (carcinoma)

III, IV

15

Radiation plus chemotherapy

Anus (squamous cell carcinoma)

70

CNS (medulloblastoma)

70–80

Ewing sarcoma

All stages

70

Lung (small cell)

Limited

25

Surgery, radiation, plus chemotherapy

Breast (with radiation therapy and/or hormonal therapy)

I, II

70–90

Embryonal rhabdomyosarcoma

All stages

80

Kidney (Wilms tumor)

All stages

80

Oral cavity or hypopharynx

III, IV

20–40

Rectum

II, III

50–70

ALL = acute lymphocytic leukemia; ANLL = acute nonlymphocytic leukemia.

Primary tumor resection

If a primary tumor has not metastasized, surgery may be curative. Establishing a complete margin of normal tissue around the primary tumor (as in breast cancer surgery) is critical for the success of primary tumor resection and prevention of recurrence. Intraoperative examination of frozen tissue sections by a pathologist may be needed. Immediate resection of additional tissue is done if margins are positive for tumor cells. However, examination of frozen tissue is inferior to examination of processed and stained tissue. Later review of margin tissue may prove the need for wider resection.

Surgical resection for primary tumor with local spread may also require removal of involved regional lymph nodes, resection of an involved adjacent organ, or en bloc resection. Survival rates with surgery alone are listed for selected cancers (see 5-Yr Disease-Free Survival Rates by Cancer Therapy).

When the primary tumor has spread into adjacent normal tissues extensively, surgery may be delayed so that other modalities (eg, chemotherapy, radiation therapy) can be used to reduce the size of the required resection.


Resection of metastases

When cancer has metastasized to regional lymph nodes, nonsurgical modalities may be the best initial treatments, as in locally advanced lung cancer or head and neck cancer. Single metastases, especially those in the lungs or liver, can sometimes be resected with a reasonable rate of cure.

Patients with a limited number of metastases, particularly to the liver, brain, or lungs, may benefit from surgical resection of both the primary and metastatic tumor. For example, in colon cancer with liver metastases, resection produces 5-yr survival rates of 30 to 40% if < 4 hepatic lesions exist and if adequate tumor margins can be obtained.


Cytoreduction

Cytoreduction (surgical resection to reduce tumor burden) is often an option when removal of all tumor tissue is impossible, as in most cases of ovarian cancer. Cytoreduction may increase the sensitivity of the remaining tissue to other treatment modalities through mechanisms that are not entirely clear. Primary renal cell carcinomas and ovarian cancers should be resected, if feasible, even in the presence of metastases. Cytoreduction also has yielded favorable results in pediatric solid tumors.


Palliative surgery

Surgery to relieve symptoms and preserve quality of life may be a reasonable alternative when cure is unlikely or when an attempt at cure produces adverse effects that are unacceptable to the patient. Tumor resection may be indicated to control pain, to reduce the risk of hemorrhage, or to relieve obstruction of a vital organ (eg, intestine, urinary tract). Nutritional supplementation with a feeding gastrostomy or jejunostomy tube may be necessary if proximal obstruction exists.


Reconstructive surgery

Reconstructive surgery may improve a patient’s comfort or quality of life after tumor resection (eg, breast reconstruction after mastectomy).


Radiation Therapy

Radiation therapy can cure many cancers (see 5-Yr Disease-Free Survival Rates by Cancer Therapy), particularly those that are localized or that can be completely encompassed within the radiation field. Radiation therapy plus surgery (for head and neck, laryngeal, or uterine cancer) or combined with chemotherapy and surgery (for sarcomas or breast, esophageal, lung, or rectal cancers) improves cure rates and allows for more limited surgery as compared with traditional surgical resection.

Radiation therapy can provide significant palliation when cure is not possible:

  • For brain tumors: Prolongs patient functioning and prevents neurologic complications

  • For cancers that compress the spinal cord: Prevents progression of neurologic deficits

  • For superior vena cava syndromes: Relieves venous obstruction

  • For painful bone lesions: Usually relieves symptoms

Radiation cannot destroy malignant cells without destroying some normal cells as well. Therefore, the risk to normal tissue must be weighed against the potential gain in treating the malignant cells. The final outcome of a dose of radiation depends on numerous factors, including

  • Nature of the delivered radiation (mode, timing, volume, dose)

  • Properties of the tumor (cell cycle phase, oxygenation, molecular properties, inherent sensitivity to radiation)

In general, cancer cells are selectively damaged because of their high metabolic and proliferative rates. Normal tissue repairs itself more effectively, resulting in greater net destruction of tumor.

Important considerations in the use of radiation therapy include the following:

  • Treatment timing (critical)

  • Dose fractionation (critical)

  • Normal tissue within or adjacent to the proposed radiation field

  • Target volume

  • Configuration of radiation beams

  • Dose distribution

  • Modality and energy most suited to the patient’s situation

Treatment is tailored to take advantage of the cellular kinetics of tumor growth, with the aim of maximizing damage to the tumor while minimizing damage to normal tissues.

Radiation therapy sessions begin with the precise positioning of the patient. Foam casts or plastic masks are often constructed to ensure exact repositioning for serial treatments. Laser-guided sensors are used. Typical courses consist of large daily doses given over 3 wk for palliative treatment or smaller doses given once/day 5 days/wk for 6 to 8 wk for curative treatment.

Types of radiation therapy

There are several different types of radiation therapy.

External beam radiation therapy can be done with photons (gamma radiation), electrons, or protons. Gamma radiation using a linear accelerator is the most common type of radiation therapy. The radiation dose to adjacent normal tissue can be limited by conformal technology, which reduces scatter at the field margins. Electron beam radiation therapy has little tissue penetration and is best for skin or superficial cancers. Different energies of electrons are used based on the desired depth of penetration and type of tumor. Proton therapy, although limited in availability, has advantages over gamma radiation therapy in that it deposits energy at a depth from the surface, whereas gamma radiation damages all tissues along the path of the beam. Proton beam therapy also can provide sharp margins that may result in less injury to immediately adjacent tissue and is thus particularly useful for tumors of the eye, the base of the brain, and the spine.

Stereotactic radiation therapy is radiosurgery with precise stereotactic localization of a tumor to deliver a single high dose or multiple fractionated doses to a small intracranial or other target. It is frequently used to treat metastatic tumors in the CNS. Advantages include complete tumor ablation where conventional surgery would not be possible and minimal adverse effects. Disadvantages include limitations involving the size of the area that can be treated and the potential danger to adjacent tissues because of the high dose of radiation. In addition, it cannot be used in all areas of the body. Patients must be immobilized and the area kept completely still.

Brachytherapy involves placement of radioactive seeds into the tumor bed itself (eg, in the prostate or cervix). Typically, placement is guided by CT or ultrasonography. Brachytherapy achieves higher effective radiation doses over a longer period than could be accomplished by use of fractionated, external beam radiation therapy.

Systemic radioactive isotopes can direct radiation to cancer in organs that have specific receptors for uptake of the isotope (ie, radioactive iodine for thyroid cancer) or when the radionuclide is attached to a monoclonal antibody (eg, iodine-131 plus tositumomab for non-Hodgkin lymphoma). Isotopes can also accomplish palliation of generalized bony metastases (ie, radiostrontium for prostate cancer).

Other agents or strategies, particularly chemotherapy, can sensitize tumor tissue to the delivered radiation and increase efficacy.


Adverse effects

Radiation can damage any intervening normal tissue.

Acute adverse effects depend on the area receiving radiation and may include

  • Lethargy

  • Fatigue

  • Mucositis

  • Dermatologic manifestations (erythema, pruritus, desquamation)

  • Esophagitis

  • Pneumonitis

  • Hepatitis

  • GI symptoms (nausea, vomiting, diarrhea, tenesmus)

  • GU symptoms (frequency, urgency, dysuria)

  • Cytopenias

Early detection and management of these adverse effects is important not only for the patient’s comfort and quality of life but also to ensure continuous treatment; prolonged interruption can allow for tumor regrowth.

Late complications can include cataracts, keratitis, and retinal damage if the eye is in the treatment field. Additional late complications include hypopituitarism, xerostomia, hypothyroidism, pneumonitis, pericarditis, esophageal stricture, hepatitis, ulcers, gastritis, nephritis, sterility, and muscular contractures. Radiation that reaches normal tissue can lead to poor healing of the tissues if further procedures or surgery is necessary. For example, radiation to the head and neck impairs recovery from dental procedures (eg, restoration, extraction) and thus should be administered only after all necessary dental work has been done.

Radiation therapy can increase the risk of developing other cancers, particularly leukemias, sarcomas in the radiation pathway, and carcinomas of the thyroid or breast. Peak incidence occurs 5 to 20 yr after exposure and depends on the patient’s age at the time of treatment. For example, chest radiation therapy for Hodgkin lymphoma in adolescent girls leads to a higher risk of breast cancer than does the same treatment for postadolescent women.


Chemotherapy

The ideal chemotherapeutic drug would target and destroy only cancer cells. Only a few such drugs exist. Common chemotherapeutic drugs and their adverse effects are described (see Commonly Used Antineoplastic Drugs).

Commonly Used Antineoplastic Drugs

Drug

Mechanism of Action

Commonly Responsive Tumors

Toxicity and Comments

Antimetabolites: Folate antagonists

Methotrexate

Binds to dihydrofolate reductase and interferes with thymidylate synthesis

Acute lymphocytic leukemia

Choriocarcinoma (women)

Head and neck cancer

Malignant lymphoma

Osteogenic sarcoma

Ovarian cancer

Mucosal ulceration

Bone marrow suppression

Increased toxicity with impaired renal function or ascitic fluid (with pooling of drug)

Reversal of toxicity with leucovorin rescue at 24 h (10–20 mg q 6 h for 10 doses)

Pemetrexed

Inhibits thymidylate synthase

Lung cancer

Mesothelioma

Ovarian cancer

Bone marrow suppression

Mucosal ulceration

Antimetabolites: Purine antagonists

Cladribine

Inhibits ribonucleotide reductase

Leukemia

Lymphoma

Myelosuppression

Immunosuppression

Clofarabine

Inhibits DNA synthesis

Acute lymphocytic leukemia refractory to at least 2 prior chemotherapy regimens

Myelosuppression

Immunosuppression

Nausea

Diarrhea

Fludarabine

Terminates DNA synthesis and inhibits ribonucleotide reductase

Leukemia

Lymphoma

Myelosuppression

Immunosuppression

Autoimmune reactions

6-Mercaptopurine

Blocks de novo purine synthesis

Acute leukemia

Myelosuppression

Immunosuppression

Nelarabine

Inhibits DNA synthesis

Leukemia

Lymphoma

Myelosuppression

Immunosuppression

Pentostatin

Inhibits DNA synthesis

Leukemia

Myelosuppression

Immunosuppression

Nausea

Vomiting

Antimetabolites: Pyrimidine antagonists

Capecitabine

Inhibits thymidylate synthase

Breast cancer

GI tumors

Mucositis

Alopecia

Myelosuppression

Diarrhea

Vomiting

Hand or foot tenderness

Ulceration

Cytarabine

Terminates chain when incorporated into DNA

Acute leukemia (especially nonlymphocytic)

Lymphoma

Myelosuppression

Nausea

Vomiting

Cerebellar toxicity (at high doses)

Conjunctival toxicity (at high doses)

Rash

5-Fluorouracil

Inhibits thymidylate synthase

Breast cancer

GI tumors

Mucositis

Alopecia

Myelosuppression

Diarrhea

Vomiting

Gemcitabine

Terminates chain when incorporated into DNA and inhibits ribonucleotide reductase

Bladder cancer

Lung cancer

Pancreatic cancer

Myelosuppression

Hemolytic-uremic syndrome

Hydroxyurea

Inhibits ribonucleotide reductase

Chronic myelocytic leukemia

Myelosuppression

Biologic response modifiers

Interferon alfa

Has antiproliferative effect

Chronic myelocytic leukemia

Hairy cell leukemia

Kaposi’s sarcoma

Lymphomas

Melanoma

Renal cell cancer

Fatigue

Fever

Myalgias

Arthralgias

Myelosuppression

Nephrotic syndrome (rare)

Bleomycins

Bleomycin

Causes DNA strands to break

Lymphoma

Squamous cell cancer

Testicular cancer

Anaphylaxis

Chills and fever

Rash

Pulmonary fibrosis at dosage > 200 mg/m 2

Requires renal excretion

DNA alkylating agents: Nitrosoureas

Carmustine

Alkylates DNA with restricted uncoiling and replication of strands

Brain tumors

Lymphoma

Myelosuppression

Pulmonary toxicity (fibrosis)

Renal toxicity

Lomustine

Alkylates DNA with restricted uncoiling and replication of strands

Brain tumors (astrocytoma, glioblastoma)

Myelosuppression

Pulmonary toxicity (delayed)

Renal toxicity

DNA cross-linking drugs and alkylating agents

Bendamustine

Chlorambucil

Cyclophosphamide

Ifosfamide

Mechlorethamine (nitrogen mustard)

Melphalan

Form adducts with DNA, causing DNA strands to break

Breast cancer

Chronic lymphocytic leukemia

Gliomas

Hodgkin lymphoma

Lymphoma

Multiple myeloma

Small cell lung cancer

Testicular cancer

Alopecia with high IV dosage

Nausea

Vomiting

Myelosuppression

Hemorrhagic cystitis (especially with cyclophosphamide and ifosfamide), which can be ameliorated with mesna

Mutagenesis

Secondary leukemias

Aspermia

Permanent sterility (possible)

Dacarbazine

Temozolomide

Form adducts with DNA

Melanoma

Malignant glioma

Neutropenia

Nausea

Vomiting

Secondary leukemias

Procarbazine

Unclear

Hodgkin lymphoma

Neutropenia

Nausea

Vomiting

Secondary leukemias

Enzymes

Asparaginase

Depletes asparagine, on which leukemic cells depend

Acute lymphocytic leukemia

Acute anaphylaxis

Hyperthermia

Pancreatitis

Hyperglycemia

Hypofibrinogenemia

Hormones

Bicalutamide

Flutamide

Bind to androgen receptor

Prostate cancer

Decreased libido

Hot flushes

Gynecomastia

Fulvestrant

Binds to estrogen receptor

Metastatic breast cancer

Nausea

Vomiting

Constipation

Diarrhea

Abdominal pain

Headache

Back pain

Hot flushes

Pharyngitis

Leuprolide acetate

Inhibits gonadotropin secretion

Prostate cancer

Hot flushes

Decreased libido

Irritation at injection site

Megestrol acetate

Progesterone agonist

Breast cancer

Endometrial cancer

Weight gain

Fluid retention

Tamoxifen

Binds to estrogen receptor

Breast cancer

Hot flushes

Hypercalcemia

Deep venous thrombosis

Hormones: Aromatase inhibitors

Anastrozole

Exemestane

Letrozole

Block conversion of androgen to estrogen

Breast cancer

Osteoporosis

Hot flushes

Monoclonal antibodies

Alemtuzumab

Binds to B and T cells

Lymphomas

Immunosuppression

Bevacizumab

Binds to vascular endothelial growth factor

Colon cancer

Renal cancer

Hypersensitivity

Bleeding

Hypertension

Brentuximab vedotin (linked to antimitotic agent auristatin E)

Binds to CD30 on lymphoma cells

Lymphomas

Progressive multifocal leukoencephalopathy

Combining with bleomycin is contraindicated due to pulmonary toxicity

Gemtuzumab

Binds to CD33 on leukemic cells

Acute myelocytic leukemia

Myelosuppression

Ibritumomab tiuxetan

Binds to CD20 on lymphoid cells

Lymphomas

Delivers radiation to cancer cells

Ipilimumab

Anti-CTLA-4

Inoperable or advanced metastatic melanoma

Colitis

Hepatitis

Toxic epidermal necrolysis

Iodine-131 tositumomab

Bind to CD20 on lymphoid cells

Lymphomas

Myelosuppression

Fever

Rash

Ofatumumab

Binds to CD20 on lymphoid cells

CLL refractory to fludarabine and alemtuzumab

Myelosuppression

Rituximab

Binds to CD20 on B cells

B-cell lymphoma

Hypersensitivity

Immunosuppression

Trastuzumab

Binds to HER2/neu receptor

Breast cancer

Hypersensitivity

Cardiac toxicity

Other antibiotics

Mitomycin

Inhibits DNA synthesis by acting as a bifunctional alkylator

Breast cancer

Colon cancer

Gastric adenocarcinoma

Lung cancer

Transitional cell cancer of the bladder

Local extravasation causing tissue necrosis

Myelosuppression, with leukopenia and thrombocytopenia 4 to 6 wk after treatment

Alopecia

Lethargy

Fever

Hemolytic-uremic syndrome

Platinum complexes

Carboplatin

Establishes cross-links within and between DNA strands

Breast cancer

Lung cancer

Ovarian cancer

Myelosuppression

Peripheral neuropathy

Cisplatin

Establishes cross-links within and between DNA strands

Bladder cancer

Breast cancer

Head and neck cancer

Gastric cancer

Lung cancer (especially small cell)

Testicular cancer

Anemia

Ototoxicity

Nausea

Vomiting

Peripheral neuropathy

Myelosuppression

Oxaliplatin

Establishes cross-links within and between DNA strands

Colon cancer

Myelosuppression

Neuropathic throat pain

Peripheral neuropathy

Proteosome inhibitors

Bortezomib

Carfilzomib

Inhibit proteosome functions

Multiple myeloma

Myelosuppression

Diarrhea

Nausea

Constipation

Peripheral neuropathy

Spindle poison (from plants): Taxanes

Docetaxel

Promotes assembly of microtubules

Breast cancer

Head and neck cancer

Lung cancer

Ovarian cancer

Myelosuppression

Alopecia

Rash

Fluid retention

Carbezitaxel

Paclitaxel (as solution or albumin-bound microspheres)

Promote assembly of microtubules

Bladder cancer

Breast cancer

Head and neck cancer

Lung cancer

Ovarian cancer

Myelosuppression

Alopecia

Myalgia

Arthralgia

Neuropathy

Spindle poison (from plants): Vincas

Vinblastine

Arrests mitosis by inhibiting polymerization of microtubules

Breast cancer

Ewing’s sarcoma

Leukemia

Lymphomas

Testicular cancer

Alopecia

Myelosuppression

Peripheral neuropathy

Vincristine

Arrests mitosis by inhibiting polymerization of microtubules

Acute leukemia

Lymphoma

Peripheral neuropathy

Ileus

Syndrome of inappropriate antidiuretic hormone secretion

Vinorelbine

Arrests mitosis by inhibiting polymerization of microtubules

Breast cancer

Lung cancer

Myelosuppression

Neuropathy

Topoisomerase inhibitors: Anthracyclines

Daunorubicin (daunomycin)

Idarubicin

Inhibit topoisomerase II and causes DNA strands to break

Leukemia

Myelosuppression

Cardiac toxicity at cumulative dosage > 1000 mg/m2

Doxorubicin

Inhibits topoisomerase II and causes DNA strands to break

Acute leukemia

Breast cancer

Lung cancer

Lymphoma

Nausea

Vomiting

Alopecia

Myelosuppression

Cardiac toxicity at cumulative dosage > 550 mg/m 2

Epirubicin

Inhibits topoisomerase II and causes DNA strands to break

Acute myelocytic leukemia

Breast cancer

Gastric cancer

Myelosuppression

Cardiac toxicity at cumulative dosage > 1000 mg/m2

Topoisomerase inhibitors: Camptothecins

Irinotecan

Inhibits topoisomerase I

Colon cancer

Lung cancer

Rectal cancer

Diarrhea

Myelosuppression

Alopecia

Topotecan

Inhibits topoisomerase I

Ovarian cancer

Small cell lung cancer

Myelosuppression

Topoisomerase inhibitors: Podophyllotoxins

Etoposide

Teniposide

Inhibit topoisomerase II and cause DNA strands to break

Acute leukemia

Hodgkin lymphoma

Lymphoma

Lung cancer (especially small cell)

Testicular cancer

Nausea

Vomiting

Myelosuppression

Peripheral neuropathy

Increased toxicity in renal failure

Neutropenia

Cleared by liver and kidneys

Mitoxantrone

Inhibits topoisomerase II and causes DNA strands to break

Acute leukemia

Lymphoma

Neutropenia

Nausea

Vomiting

Tyrosine kinase inhibitors

Bosutinib

Desatinib

Imatinib

Nilotinib

Ponantinib

Inhibit BCR-ABL kinase and C-kit kinase

Chronic myelocytic leukemia

GI stromal tumors

Leukopenia

Hepatocellular toxicity

Edema

Crizotinib

Inhibits the EML-4/ALK kinase

Non–small cell lung cancer

Diarrhea

Hepatocellular toxicity

Erlotinib

Gefitinib

Inhibit epidermal growth factor receptor

Non–small cell lung cancer

Acne

Diarrhea

Pneumonitis

Lapatinib

Inhibits Her2/neu activity

Blocks epidermal growth factor receptor

Breast cancer

Diarrhea

Nausea

Rash

Vomiting

Fatigue

Pazopanib

Inhibits vascular endothelial growth factor

Sarcomas

Hypertension

Proteinuria

Hepatocellular toxicity

QT prolongation

Sorafenib

Inhibits intracellular and cell surface kinases (eg, vascular endothelial growth factor receptor)

Hepatocellular cancer

Renal cancer

Hypertension

Proteinuria

Sunitinib

Inhibits receptor tyrosine kinases (C-kit)

Blocks vascular endothelial growth factor receptor

GI stromal tumors

Renal cancer

Hypertension

Proteinuria

Poor wound healing

Intestinal perforations

Vandetanib

Blocks vascular endothelial growth factor receptor

Epidermal growth factor receptor

Thyroid cancer

Torsades de pointes ventricular tachycardia

Vemurafenib

B-Raf tyrosine kinase

Melanoma

Diarrhea

Hepatotoxicity

The most common routes of administration are IV for cytotoxic drugs and oral for targeted drugs. Frequent dosing for extended periods may necessitate subcutaneously implanted venous access devices (central or peripheral), multilumen external catheters, or peripherally inserted central catheters.

Drug resistance can occur to chemotherapy. Identified mechanisms include overexpression of target genes, mutation of target genes, development of alternative pathways, drug inactivation by tumor cells, defective apoptosis in tumor cells, and loss of receptors for hormonal agents. For cytotoxic drugs, one of the best characterized mechanisms is overexpression of the MDR-1 gene, a cell membrane transporter that causes efflux of certain drugs (eg, vinca alkaloids, taxanes, anthracyclines). Attempts to alter MDR-1 function and thus prevent drug resistance have been unsuccessful.

Cytotoxic drugs

Traditional cytotoxic chemotherapy, which damages cell DNA, kills many normal cells in addition to cancer cells. Antimetabolites, such as 5-fluorouracil and methotrexate, are cell cycle–specific and have no linear dose-response relationship. In contrast, other chemotherapeutic drugs (eg, DNA cross-linkers, also known as alkylating agents) have a linear dose-response relationship, producing more tumor killing as well as more toxicity at higher doses. At their highest doses, DNA cross-linkers may cause bone marrow aplasia, necessitating bone marrow/stem cell transplantation to restore bone marrow function.

Single-drug chemotherapy may cure selected cancers (eg, choriocarcinoma, hairy cell leukemia). More commonly, multidrug regimens incorporating drugs with different mechanisms of action and different toxicities are used to increase the tumor cell kill, reduce dose-related toxicity, and decrease the probability of drug resistance. These regimens can provide significant cure rates (eg, in acute leukemia, testicular cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, and, less commonly, solid tumors such as small cell lung cancer and nasopharyngeal cancer). Multidrug regimens typically are given as repetitive cycles of a fixed combination of drugs. The interval between cycles should be the shortest one that allows for recovery of normal tissue. Continuous infusion may increase cell kill with some cell cycle–specific drugs (eg, 5-fluorouracil).

For each patient, the probability of significant toxicities should be weighed against the likelihood of benefit. End-organ function should be assessed before chemotherapeutic drugs with organ-specific toxicities are used (eg, echocardiography before doxorubicin use). Dose modification or exclusion of certain drugs may be necessary in patients with chronic lung disease (eg, bleomycin), renal failure (eg, methotrexate), or hepatic dysfunction (eg, taxanes).

Despite these precautions, adverse effects commonly result from cytotoxic chemotherapy. The normal tissues most commonly affected are those with the highest intrinsic turnover rate: bone marrow, hair follicles, and the GI epithelium.

Imaging (eg, CT, MRI, PET) is frequently done after 2 to 3 cycles of therapy to evaluate response to treatment. Therapy continues if there is a clear response. If the tumor progresses despite therapy, the regimen is often amended or stopped. If the disease remains stable with treatment and the patient can tolerate therapy, then a decision to continue is reasonable with the understanding that the disease will eventually progress.


Hormonal therapy

Hormonal therapy uses hormone agonists or antagonists to influence the course of cancer. It may be used alone or in combination with other treatment modalities.

Hormonal therapy is particularly useful in prostate cancer, which grows in response to androgens. Other cancers with hormone receptors on their cells (eg, breast, endometrium) can often be palliated by hormone antagonist therapy or hormone ablation. Hormonal agents may block the secretion of pituitary hormones (luteinizing hormone-releasing hormone agonists), block the androgen (bicalutamide, enzalutamide) or estrogen receptor (tamoxifen), suppress the conversion of androgens to estrogens by aromatase (letrozole), or inhibit the synthesis of adrenal androgens (abiraterone). All hormonal blockers cause symptoms related to hormone deficiency, such as hot flashes, and the androgen antagonists also induce a metabolic syndrome that increases the risk of diabetes and heart disease.

Use of prednisone, a glucocorticosteroid, is also considered hormonal therapy. It is frequently used to treat tumors derived from the immune system (lymphomas, lymphocytic leukemias, multiple myeloma).


Biologic response modifiers

Interferons are proteins synthesized by cells of the immune system as a physiologic immune protective response to foreign antigens (viruses, bacteria, other foreign cells). In pharmacologic amounts, they can palliate some cancers, including hairy cell leukemia, chronic myelocytic leukemia, locally advanced melanoma, metastatic renal cell cancer, and Kaposi sarcoma. Significant toxic effects of interferon include fatigue, depression, nausea, leukopenia, chills and fever, and myalgias.

Interleukins, primarily the lymphokine IL-2 produced by activated T cells, can be used in metastatic melanomas and can provide modest palliation in renal cell cancer.

Ipilimimab, which promotes autoimmune responses, activates the antitumor response to melanoma and other tumors.


Differentiating drugs

These drugs induce differentiation in cancer cells. All- trans -retinoic acid has been highly effective in treating acute promyelocytic leukemia. Other drugs in this class include arsenic compounds and the hypomethylating agents azacytidine and deoxyazacytidine. When used alone, these drugs have only transient effects, but their role in prevention and in combination with cytotoxic drugs is promising.


Antiangiogenesis drugs

Solid tumors produce growth factors that form new blood vessels necessary to support ongoing tumor growth. Several drugs that inhibit this process are available. Thalidomide is antiangiogenic, among its many effects. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), is effective against renal cancers and colon cancer. VEGF receptor inhibitors, such as sorafenib and sunitinib, are also effective in renal cancer, hepatocellular cancers, and other tumors.


Signal transduction inhibitors

Many epithelial tumors possess mutations that activate signaling pathways that cause their continuous proliferation and failure to differentiate. These mutated pathways include growth factor receptors and the downstream proteins that transmit messages to the cell nucleus from growth factor receptors on the cell surface. Three such drugs, imatinib (an inhibitor of the BCR-ABL tyrosine kinase in chronic myelocytic leukemia) and erlotinib and gefitinib (inhibitors of the epidermal growth factor receptor), are now in routine clinical use. Other inhibitors of these signaling pathways are under study.


Monoclonal antibodies

Monoclonal antibodies directed against unique tumor antigens have some efficacy against neoplastic tissue (see also Immunotherapy of Cancer : Passive Humoral Immunotherapy). Trastuzumab, an antibody directed against a protein called HER-2 or ErbB-2, plus chemotherapy has shown benefit in metastatic breast cancer that expressed HER-2. Antibodies against CD antigens expressed on neoplastic cells, such as CD20 and CD33, are used to treat patients with non-Hodgkin lymphoma (rituximab, anti-CD20 antibody) and acute myelocytic leukemia (gemtuzumab, an antibody linked to a potent toxin).

The effectiveness of monoclonal antibodies may be increased by linking them to radioactive nuclide. One such drug, ibritumomab, is used to treat non-Hodgkin lymphoma.


Vaccines

Vaccines designed to trigger or enhance immune system response to cancer cells have been extensively studied and have typically provided little benefit. However, recently, sipuleucel-T, an autologous dendritic cell–derived immunotherapy, has demonstrated modest prolongation of life in patients with metastatic prostate cancer.

A new modality being studied modifies a patient's T cells to recognize and target tumor-associated antigens (eg, CD19). Initial reports show improvement in patients with chronic lymphocytic leukemia and certain types of acute leukemia that have become resistant to chemotherapy.


Multimodality and Adjuvant Chemotherapy

In some tumors with a high likelihood of relapse despite optimal initial surgery or radiation therapy, relapse may be prevented by addition of adjuvant chemotherapy. Increasingly, combined-modality therapy (eg, radiation therapy, chemotherapy, surgery) is used. It may permit organ-sparing procedures and preserve organ function.

Adjuvant therapy

Adjuvant therapy is systemic chemotherapy or radiation therapy given to eradicate residual occult tumor after initial surgery. Patients who have a high risk of recurrence may benefit from its use. General criteria are based on degree of local extension of the primary tumor, presence of positive lymph nodes, and certain morphologic or biologic characteristics of individual cancer cells. Adjuvant therapy has increased disease-free survival and cure rate in breast and in colorectal cancer.


Neoadjuvant therapy

Neoadjuvant therapy is chemotherapy, radiation therapy, or both given before surgical resection. This treatment may enhance resectability and preserve local organ function. For example, when neoadjuvant therapy is used in head and neck, esophageal, or rectal cancer, a smaller subsequent resection may be possible. Another advantage of neoadjuvant therapy is in assessing response to treatment; if the primary tumor does not respond, micrometastases are unlikely to be eradicated, and an alternate regimen should be considered. Neoadjuvant therapy may obscure the true pathologic stage of the cancer by altering tumor size and margins and converting histologically positive nodes to negative, complicating clinical staging. The use of neoadjuvant therapy has improved survival in inflammatory and locally advanced breast, stage IIIA lung, nasopharyngeal, and bladder cancers.


Bone Marrow/Stem Cell Transplantation

Bone marrow or stem cell transplantation is an important component of the treatment of otherwise refractory lymphomas, leukemias, and multiple myeloma (for an in-depth discussion of this topic, see Hematopoietic Stem Cell Transplantation).

Gene Therapy

Genetic modulation is under intense investigation. Strategies include the use of antisense therapy, systemic viral vector transfection, DNA injection into tumors, genetic modulation of resected tumor cells to increase their immunogenicity, and alteration of immune cells to enhance their antitumor response.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • SUTENT
  • ALIMTA
  • GEMZAR
  • VUMON
  • CYTOXAN (LYOPHILIZED)
  • No US brand name
  • ELOXATIN
  • ARIMIDEX
  • TASIGNA
  • MEGACE
  • CASODEX
  • IFEX
  • TYKERB
  • NOLVADEX
  • CRINONE
  • PLATINOL
  • MARQIBO KIT
  • MITOSOL
  • ALKERAN
  • VELCADE
  • PURINETHOL
  • AVASTIN
  • ARRANON
  • TAXOL
  • ELSPAR
  • LEUKERAN
  • KYPROLIS
  • HYDREA
  • IDAMYCIN PFS
  • MUSTARGEN
  • AROMASIN
  • TREANDA
  • XELODA
  • LUPRON
  • TARCEVA
  • RITUXAN
  • ETOPOPHOS
  • HYCAMTIN
  • MATULANE
  • NIPENT
  • HERCEPTIN
  • CARAC
  • ELLENCE
  • ZELBORAF
  • MESNEX
  • GLEEVEC
  • BICNU, GLIADEL
  • XALKORI
  • FEMARA
  • CEENU
  • OTREXUP
  • TEMODAR
  • NAVELBINE
  • CAMPATH
  • FASLODEX
  • ZEVALIN
  • CAPRELSA
  • TAXOTERE
  • CAMPTOSAR
  • NEXAVAR
  • DTIC-DOME
  • XTANDI
  • RAYOS
  • THALOMID

* This is a professional Version *