Modalities of Cancer Therapy

Cancer is treated in several ways, depending on each person’s medical condition and type of cancer.
Cancer treatment is a process that is designed to meet their needs. Physicians plan treatments based on several key factors, such as the type and stage of the cancer, as well as the person’s age, health and lifestyle.
If you have been diagnosed with cancer, it is important for you to know that you play an important role in the treatment process. Offering input, asking questions and expressing your concerns about treatment can help make treatment a better experience.

 Cancer treatment terms you should know

• Combined modality therapy – a term used to describe when physicians choose more than one therapy in treating a patient, such as a combination of radiation therapy and chemotherapy.
• Adjuvant therapy – a term used to describe when physicians choose more than one therapy in treating a patient. However, the term adjuvant therapy is more specifically used to describe treatment given after the primary cancer treatment is completed to improve the chance of a cure. For example, if the physician wants to treat cancer cells that may be present, he or she may prescribe one or more additional treatments.
• Neoadjuvant therapy – a term used to describe when physicians choose to use more than one therapy in treating a patient. However, the term neoadjuvant therapy is more specifically used to describe cancer treatment given before the primary therapy — both to kill any cancer cells and contribute to the effectiveness of the primary therapy.

Treatment of cancer can involve any of several modalities: Surgery Radiation therapy Chemotherapy Hormonal therapy Immunotherapy

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

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 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 .

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. 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 .

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 .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.

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.