Treatment of cancer can involve any of several modalities:

• Surgery
• Radiation therapy
• Chemotherapy

Often, modalities are combined to create a 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 Table 2: Principles of Cancer Therapy: 5-Yr Disease-Free Survival Rates by Cancer Therapy).

Table 2
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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 B1 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's 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's 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 B2, C 54 Endometrium II 62 Hypopharynx II, III 33 Lung (Pancoast's 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's 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. 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 B1 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's 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's 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 B2, C 54 Endometrium II 62 Hypopharynx II, III 33 Lung (Pancoast's 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's 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.

Surgery

Surgery is the oldest form of effective cancer therapy. It may be used alone or in combination with other modalities.

Factors that increase operative risk in cancer patients include

• Age
• Comorbid conditions
• Debilitation due to cancer
• Paraneoplastic syndromes (less common—see Overview of Cancer: 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 Care of the Surgical Patient: Preoperative Evaluation).

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 is critical for the success of primary tumor resection. Intraoperative examination of frozen tissue sections by a pathologist may be needed, with immediate resection of additional tissue if margins are positive for tumor cells. However, frozen tissue examination 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 Table 2: Principles of Cancer Therapy: 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

With regional lymph node metastases, 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 lung, 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. Cytoreduction has yielded favorable results in pediatric solid tumors and in ovarian cancer.

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 Table 2: Principles of Cancer Therapy: 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 with surgery (for head and neck, laryngeal, or uterine cancer) or 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
• 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, overall sensitivity to radiation)

In general, cancer cells are selectively damaged because of their high metabolic rate. 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 in 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 produces 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, can provide sharp margins and is 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. 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 irradiation.

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, tositumomab plus iodine-131 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; 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 and cancers of the thyroid or breast. Peak incidence occurs 5 to 10 yr after exposure and depends on the patient's age at the time of treatment. For example, chest irradiation 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 Table 3: Principles of Cancer Therapy: Commonly Used Antineoplastic Drugs).

Table 3
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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/m2 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 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 Iodine-131 tositumomab Tositumomab Bind to CD20 on lymphoid cells Lymphomas Myelosuppression Fever Rash 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 Inhibits 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 Paclitaxel Promotes 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) Inhibits 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/m2 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 Erlotinib Gefitinib Inhibit epidermal growth factor receptor Non–small cell lung cancer Acne Diarrhea Imatinib Inhibits BCR-ABL kinase and c-kit kinase Chronic myelocytic leukemia GI stromal tumors Leukopenia Hepatocellular toxicity Edema Lapatinib Inhibits Her2/neu activity Breast cancer Diarrhea Nausea Rash Vomiting Fatigue Sorafenib Inhibits intracellular and cell surface kinases (eg, vascular endothelial growth factor receptors) Hepatocellular cancer Renal cancer Hypertension Proteinuria Sunitinib Inhibits receptor tyrosine kinases GI stromal tumors Renal cancer Hypertension Proteinuria 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/m2 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 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 Iodine-131 tositumomab Tositumomab Bind to CD20 on lymphoid cells Lymphomas Myelosuppression Fever Rash 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 Inhibits 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 Paclitaxel Promotes 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) Inhibits 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/m2 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 Erlotinib Gefitinib Inhibit epidermal growth factor receptor Non–small cell lung cancer Acne Diarrhea Imatinib Inhibits BCR-ABL kinase and c-kit kinase Chronic myelocytic leukemia GI stromal tumors Leukopenia Hepatocellular toxicity Edema Lapatinib Inhibits Her2/neu activity Breast cancer Diarrhea Nausea Rash Vomiting Fatigue Sorafenib Inhibits intracellular and cell surface kinases (eg, vascular endothelial growth factor receptors) Hepatocellular cancer Renal cancer Hypertension Proteinuria Sunitinib Inhibits receptor tyrosine kinases GI stromal tumors Renal cancer Hypertension Proteinuria

The most common routes of administration are IV and oral. 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, drug inactivation by tumor cells, defective apoptosis in tumor cells, and loss of receptors for hormonal agents. 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 produce bone marrow aplasia, necessitating bone marrow 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.

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's 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.

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 are also affective in renal cancer, hepatocellular cancers, and GI stromal 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 Tumor Immunology: Passive Humoral Immunotherapy). Trastuzumab, an antibody directed against a protein called Her-2 or Erb-B2, plus chemotherapy has shown benefit in metastatic breast cancer. 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.

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 this 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 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 Transplantation: 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.

Last full review/revision July 2009 by Bruce A. Chabner, MD; Elizabeth Chabner Thompson, MD, MPH