Principles of Cancer Therapy

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Chapter 37 Principles of Cancer Therapy

Neville F. Hacker

The standard modalities for the management of gynecologic cancer are surgery, chemotherapy, radiation therapy, and hormonal therapy. In this chapter, the principles of chemotherapy, radiation therapy, and hormonal manipulation are discussed, together with the principles of pain management and end-of-life issues. Targeted therapies and hyperthermia are at present experimental modalities and are not included.

image Cellular Biology

The characteristic feature of malignant tumor growth is its uncontrolled cellular proliferation, which requires replication of DNA. There are two distinct phases in the life cycle of all cells: mitosis (M phase), during which cellular division occurs; and interphase, the interval between successive mitoses.

Interphase is subdivided into three separate phases (Figure 37-1). Immediately following mitosis is the G1 phase, which is of variable duration and is characterized by a diploid content of DNA. DNA synthesis is absent, but RNA and protein synthesis occur. During the shorter S phase, the entire DNA content is duplicated. This is followed by the G2 phase, which is characterized by a tetraploid DNA content and by continuing RNA and protein synthesis in preparation for cell division. When mitosis occurs, a duplicate set of chromosomal DNA is inherited by each daughter cell, thus restoring the diploid DNA content. Following mitosis, some cells leave the cycle temporarily or permanently and enter the G0 or resting phase.

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FIGURE 37-1 Phases of the cell cycle and sites of action of cell cycle–specific drugs.

The growth fraction of the tumor is the proportion of actively dividing cells. The higher the growth fraction, the fewer the number of cells in the G0 phase and the faster the tumor-doubling time.

Chemotherapeutic agents and radiation kill cells by first-order kinetics, which means that a constant proportion of cells is killed for a given dosage, regardless of the number of cells present. Both therapeutic modalities are most effective against actively dividing cells because cells in the resting (G0) phase are better able to repair sublethal damage. Unfortunately, both therapeutic modalities also suppress rapidly dividing normal cells, such as those in the gastrointestinal mucosa, bone marrow, and hair follicles.

image Chemotherapy

One of the major advances in medicine since the 1950s has been the successful treatment of certain disseminated malignancies, including choriocarcinoma and germ cell ovarian tumors, with chemotherapy.

CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS

Chemotherapeutic agents act primarily by disrupting nuclear DNA, thus inhibiting cellular division. They may be subdivided into two categories according to their mode of action relative to the cell cycle:

1. Cell cycle–nonspecific agents, such as alkylating agents, cisplatin, and paclitaxel, exert their damage at any phase of the cell cycle. They may damage resting as well as cycling cells, but the latter are much more sensitive.
2. Cell cycle–specific agents exert their lethal effects exclusively or primarily during one phase of the cell cycle. Examples include hydroxyurea and methotrexate, which act primarily during the S phase; bleomycin, which acts in the G2 phase; and the vinca alkaloids, which act in the M phase.

PRINCIPLES OF CHEMOTHERAPY

Chemotherapeutic agents are selected on the basis of previous experience with particular agents for a given tumor. The drugs are usually given systemically so that the tumor can be treated regardless of its anatomic location. To increase the local concentration, certain drugs may occasionally be administered topically, by intraarterial infusion, or by intrathecal or intracavitary instillation (e.g., intraperitoneal therapy for ovarian cancer).

Chemotherapy is generally not administered if the neutrophil count is less than 1500 cells/mm3 or if the platelet count is less than 100,000 cells/mm3. Nadir blood counts are obtained 7 to 14 days after treatment, and subsequent doses may need to be reduced if there is significant myelosuppression or if the patient develops febrile neutropenia. Dosage reduction may also be necessary because of toxicity to other organs, such as the gastrointestinal tract, liver, or kidneys.

Resistance to chemotherapeutic agents may be temporary or permanent. Temporary resistance is mainly related to the poor vascularity of bulky tumors, which results in poor tissue concentrations of the drugs and an increasing proportion of cells in the relatively resistant G0 phase of the cell cycle. Permanent resistance mainly results from spontaneous mutation to phenotypic resistance and occurs most commonly in bulky tumors. Permanent resistance may also be acquired by frequent exposure to chemotherapeutic agents.

CHEMOTHERAPEUTIC AGENTS

The common agents used in the management of gynecologic malignancies may be classified as shown in Table 37-1. This table also contains a summary of the main indications for and side effects of these drugs.

TABLE 37-1 INDICATIONS, SIDE EFFECTS, AND PRECAUTIONS FOR COMMONLY USED CHEMOTHERAPEUTIC AGENTS

image image

Alkylating Agents

The cytotoxicity of alkylating agents results from their ability to cause alkylation to DNA, resulting in cross-linkage between DNA strands and prevention of DNA replication. There is cross-resistance among the various alkylating agents.

Antimetabolites

Antimetabolites are compounds that closely resemble normal intermediaries, for which they may substitute in biochemical reactions, and thereby produce a metabolic block; for example, methotrexate competitively inhibits the enzyme dihydrofolate reductase, thus preventing the conversion of dihydrofolate to tetrahydrofolate. The latter is required for the methylation reaction necessary for the synthesis of purine and pyrimidine subunits of nucleic acid.

Antibiotics

Antibiotics are naturally occurring antitumor agents elaborated by certain species of Streptomyces. They have no single, clearly defined mechanism of action, but many agents in this group intercalate between strands of the DNA double helix, thereby inhibiting both DNA and RNA synthesis and causing oxygen-dependent strand breaks.

Plant Alkaloids

The most common plant alkaloids are the vinca alkaloids, which are derived from the periwinkle plant. These include vincristine and vinblastine. They are spindle toxins that interfere with cellular microtubules and cause metaphase arrest.

Other plant alkaloids include the epipodophyllotoxins such as etoposide (VP16), which are extracts from the mandrake plant, and paclitaxel (Taxol), an extract from the bark of the Pacific yew tree. Docetaxel (Taxotere) is the first semisynthetic analogue of paclitaxel. Etoposide appears to act by causing single-strand DNA breaks. Paclitaxel binds preferentially to microtubules, which results in their polymerization and stabilization.

Other Drugs

Cisplatin, one of the more important drugs in gynecologic oncology, causes inhibition of DNA synthesis by forming interstrand and intrastrand linkages. Carboplatin is an analogue of cisplatin with a similar mechanism of action and efficacy, but with less gastrointestinal and renal toxicity.

image Radiation Therapy

Radiation may be defined as the propagation of energy through space or matter.

TYPES OF RADIATION

There are two main types of radiation: electromagnetic and particulate.

Electromagnetic Radiation

Examples of electromagnetic radiation include the following:

• Visible light
• Infrared light
• Ultraviolet light
• X-rays (photons)
• Gamma rays (photons)

X-rays and gamma rays are identical electromagnetic radiations, differing only in their mode of production. X-rays are produced by bombardment of an anode by a high-speed electron beam; gamma rays result from the decay of radioactive isotopes, such as cobalt-60 (60Co).

X-rays and gamma rays (photons) are differentiated from electromagnetic radiation of longer wavelength by their greater energy, which allows them to penetrate tissues and cause ionization.

Particulate Radiation

Particulate radiation consists of moving particles of matter. Their energy consists of the kinetic energy of the moving particles.

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The particles vary greatly in size and include the following:

• Neutrons (no charge)
• Protons (positive charge)
• Electrons (negative charge)

The most commonly used particles are electrons. They may be derived from a linear accelerator, the beam of electrons being directed into the patient without first striking a metal target and producing x-rays. Alternatively, high-energy electrons (called β particles) may be derived from the radiodecay of an unstable isotope, such as phosphorus-32 (32P). Particulate radiation penetrates tissues less than photons but also produces ionization.

UNIT OF RADIATION MEASUREMENT

The Gray (Gy) is equivalent to an absorbed energy of 1 joule per kilogram of absorbing material.

INVERSE SQUARE LAW

The intensity of electromagnetic radiation is inversely proportional to the square of the distance from the source. Thus, the dose of radiation 2 cm from a point source will be 25% of the dose at 1 cm.

BIOLOGIC CONSIDERATIONS

Ionization of Molecules

Radiation damage is caused by the ionization of molecules in the cell, with the production of free radicals. Because about 80% of a mammalian cell is water, most of the cellular radiation damage is mediated by ionization of water and the production of the free radicals H (hydrogen) and OH (hydroxide). Free radicals may cause irreversible damage to DNA, making it impossible for the cell to continue replication. Minor or sublethal damage to DNA, which the cell is capable of repairing, may also occur. RNA, protein, and other molecules in the cell are also damaged, but these molecules can be more readily repaired or replaced.

Oxygen Effect

In the absence of oxygen, cells show a twofold to threefold increase in their capacity to survive radiation exposure. This means that hypoxic cells are less radiosensitive than are fully oxygenated cells. The enhancement of the lethal effects of radiation by oxygen is presumed to occur because the oxygen will combine with the free radicals split from cell targets by the radiation. This prevents the recombination of the free radicals with the targets, which would restore the integrity of the targets.

The effect of oxygen has important clinical implications. First, anemic patients should undergo transfusion before radiation therapy. Second, bulky tumors are usually poorly vascularized and, therefore, are often hypoxic, particularly in the center. Such areas are likely to be relatively resistant to radiation so that viable tumor cells may remain despite marked shrinkage of the tumor.

Pharmacologic Modification of the Effects of Radiation

A variety of chemical compounds are capable of enhancing the lethal effects of radiation. A series of randomized clinical trials has demonstrated a significant survival advantage, particularly in terms of local disease control, when cisplatin-containing chemotherapy is given concurrently with radiation for locoregionally advanced cervical cancer. Some of the regimens tested have included 5-fluorouracil in combination with cisplatin. This is called chemoradiation.

Time-Dose Fractionation of Radiation

Successful radiation therapy requires a delicate balance between dosage to the tumor and that to the surrounding normal tissues. A dose of radiation that is too high sterilizes the tumor but results in an unacceptably high complication rate because of the destruction of normal tissues.

Most normal tissues, such as gastrointestinal mucosa and bone marrow, have a remarkable capacity to recover from radiation damage by the division of stem cells as well as by repair of sublethal radiation damage. Tumors, in general, have less ability to repair and repopulate. This difference can be exploited by administering the radiation in multiple fractions, thereby allowing some recovery, particularly of normal cells, between fractions.

If the interval between each fraction increases, the total dose must increase to produce the same biologic effect because of the amount of recovery that will occur in the interval. Cells that survive the acute effects of radiation usually repair sublethal damage within 24 hours; therefore, conventionally fractioned radiation is usually given in daily increments.

When treating the pelvis with external radiation, each fraction is usually 180 to 200 cGy. In treating the whole abdomen, fractions are decreased to 100 to 120 cGy because the tolerance of normal tissues decreases as the volume irradiated increases. The major factors influencing the outcome of radiation therapy are summarized in Box 37-1.

BOX 37-1 Major Factors Influencing the Outcome of Radiation Therapy

Normal tissue tolerance
Malignant cell type
Total volume irradiated
Total dose delivered
Total duration of therapy
Number of fractions
Type of equipment used
Tissue oxygen concentration

MODALITIES OF RADIATION THERAPY

The modalities used to deliver radiation therapy are listed in Box 37-2. In general, there are two radiation techniques: teletherapy and brachytherapy. In teletherapy, a device quite removed from the patient is used, as with external-beam techniques. Figure 37-2 is a linear accelerator used to deliver external-beam pelvic radiation. In brachytherapy, the radiation source is placed either within or close to the target tissue, as with intracavitary and interstitial techniques. In contrast to external-beam therapy, intracavitary and interstitial techniques allow a high dose of radiation to be delivered to the tumor, whereas dosages to surrounding normal tissues are considerably lower and are determined by the inverse square law.

BOX 37-2 Modalities of Radiation Therapy

External Beams

Kilovoltage (“orthovoltage”) (125-400 kV)
Cobalt-60 machine (1.25 MeV)
Linear accelerator (4-35 MeV)
Betatrons (20-42 MeV)
Particle accelerators (e.g., electrons, protons, neutrons)

Intracavitary (Cesium or Iridium)

Afterloading applicators
Low dose rate (137Cs)
High dose rate (192Ir)
Intraperitoneal (e.g., 32P)

Interstitial

Permanent
Seeds (e.g., 198Au, 125I)
Removable
Ribbons (e.g., 192Ir)
Needles (e.g., 226Ra, 137Cs)

image

FIGURE 37-2 Linear accelerator used to deliver external-beam pelvic radiation.

Teletherapy

EXTERNAL-BEAM THERAPY

As the energy of the electromagnetic radiation increases, the penetration of the tissues increases, resulting in a relative sparing of the skin and an increased dosage to deeper tissues. At megavoltage energies (1 million electron volts or greater), there is no differential absorption of energy by bone.

Orthovoltage machines are no longer used except to treat skin cancers. Cobalt machines, developed in the early 1950s, have also been largely replaced by linear accelerators, which have a higher range of energies. The advantages of megavoltage therapy over the earlier orthovoltage machines are listed in Box 37-3.

BOX 37-3 Advantages of Megavoltage Therapy

Skin sparing
Greater dose at deeper depth in tissues
Shorter treatment times
No differential bone absorption (therefore no bone necrosis)
Can treat larger fields easily (e.g., whole abdomen)

External radiation allows a uniform dose to be delivered to a given field. The tolerance of the normal tissues (e.g., bowel, bladder, liver, kidneys) limits the total dosage that can be delivered. External radiation is usually used to shrink a large tumor mass before brachytherapy. When used alone, it is generally useful only when there is small residual macroscopic or microscopic disease following surgery. With highly radiosensitive tumors (e.g., dysgerminoma), external radiation alone may sterilize even bulky disease.

INTENSITY-MODULATED RADIATION THERAPY

Intensity modulated radiation therapy delivers radiation from many small beams with nonuniform dose intensities, but the collective set of beams produces a more homogenous dose to the target volume. The multiple beams of variable intensity are achieved by the use of a multileaf collimator. The end result is a high dose delivered to the target volume and acceptably low dose to the surrounding normal tissues.

Brachytherapy

INTRACAVITARY RADIATION

Intracavitary therapy is used particularly in the treatment of cervical and vaginal cancer. All applicators now in use should be afterloaded, which means that they are placed in the patient and their position checked by radiography before the radioactive substance is loaded into the applicator. Traditionally, brachytherapy has been given at a low dose rate using radioactive substances such as cesium-137 (137Cs). Applicators for the management of cervical cancer are placed under general anesthesia. For low–dose-rate therapy, the applicators are left in situ for 48 to 72 hours. Remote afterloading devices, such as the Selectron, allow the radioactive sources to be removed from the applicators when medical or nursing personnel enter the room, thereby significantly limiting staff exposure to radiation. More recently, high–dose-rate brachytherapy has been given, using radioactive sources such as iridium (192Ir) (Figures 37-3 and 37-4). Treatment is given as an outpatient, which is much more acceptable for patients.

image

FIGURE 37-3 Intrauterine tandem and vaginal colpostats used for high–dose-rate intracavitary radiation in cervical cancer.

image

FIGURE 37-4 Posteroanterior view of brachytherapy applicator in situ, loaded with 192Ir, for the treatment of cervical cancer. Note the isodose contours showing how the dose of radiation decreases with distance from the applicator.

Radioactive colloids, such as chromic phosphate (32P), may be instilled directly into the peritoneal cavity to treat minimal residual disease, particularly in patients with ovarian cancer. To be effective, these agents must achieve a uniform distribution throughout the cavity, which is difficult to achieve, so such agents are rarely used at present. 32P is a pure β (electron) emitter.

INTERSTITIAL RADIATION

Interstitial therapy (in which the radioactive source is placed directly in the tumor) may be delivered by removable or permanent implants. Permanent implants are used for inaccessible tumors. They use radioisotopes such as radon-222 (222Rn) or iodine-125 (125I) seeds and are usually placed in an unresectable tumor nodule at the time of laparotomy.

Removable implants are placed in tumors that are accessible (e.g., cervical or vaginal tumors). Interstitial therapy has the theoretical advantage of better dose distribution within the tumor but the disadvantage that it is easier to overdose normal tissues, thereby increasing the complication rate. As with intracavitary devices, afterloading devices are now available for interstitial therapy. The radioisotope of choice for afterloading interstitial implants is iridium-192 (192Ir).

COMPLICATIONS ASSOCIATED WITH RADIATION

The success of radiation therapy depends on an exploitable gradient of susceptibility to injury in favor of normal tissue. Unfortunately, most malignant tumors are only marginally more sensitive to radiation than are normal tissues, so the total dose that can be delivered, and therefore the radiocurability, is limited by the associated complications.

Acute Complications

Acute reactions to radiation occur in the first 3 to 4 months and include the following pathologic changes: rapid cessation of mitotic activity, cellular swelling, tissue edema, and tissue necrosis.

In the management of gynecologic tumors, these acute reactions may produce the following effects: acute cystitis, manifested by hematuria, urgency, and frequency; proctosigmoiditis, manifested by tenesmus, diarrhea, and passage of blood and mucus in the stool; enteritis, manifested by nausea, vomiting, diarrhea, and colicky abdominal pain; and bone marrow suppression, which is uncommon with pelvic radiation, but common with whole-abdominal or extended-field (pelvic and para-aortic) radiation, particularly if the patient has had previous cytotoxic chemotherapy.

Chronic Complications

Chronic complications occur 6 months or more after completion of radiation and are characterized pathologically by the following changes: internal thickening and obliteration of small blood vessels (endarteritis), fibrosis, and permanent reduction in the epithelial and parenchymal cell populations.

Significant chronic complications occur in 5% to 10% of patients receiving 50 cGy or more of radiation, and they may be slowly progressive over several years.

Common chronic complications of radiation follow.

Radiation Enteropathy

Previous surgery, with resultant loops of small bowel adherent in the pelvis, predisposes the patient to radiation enteritis, particularly when intracavitary or interstitial radiation is used in addition to teletherapy.

Large bowel injuries, which are best diagnosed by sigmoidoscopy or colonoscopy, may include proctosigmoiditis, manifested by pelvic pain, tenesmus, diarrhea, and rectal bleeding; ulceration, manifested by rectal bleeding and tenesmus; rectal or sigmoid stenosis, manifested by progressive large bowel obstruction; and rectovaginal fistula, manifested by passage of stool through the vagina. Figure 37-5 shows a radiation-induced stricture of the sigmoid colon.

image

FIGURE 37-5 Radiation-induced stricture of the sigmoid colon. Note the tight fibrotic constriction, necessitating partial sigmoid colectomy for large bowel obstruction.

Small bowel injuries usually present with cramping abdominal pain and vomiting, or with alternating diarrhea and constipation.

Vaginal Vault Necrosis

This is associated with severe pain and tenderness of the vaginal vault and a profuse vaginal discharge.

Urologic Injuries

The following are included in this category: hemorrhagic cystitis, which may necessitate frequent blood transfusions, and occasionally, urinary diversion; ureteric stenosis, which is manifested by progressive hydronephrosis; vesicovaginal fistula, manifested by the constant leakage of urine and demonstrable by cystoscopy; and ureterovaginal fistula, which is also manifested by constant leakage of urine and is demonstrable with an intravenous pyelogram.

image Hormonal Therapy

The estrogen receptor (ER) status of primary and metastatic breast cancer has been shown to be of therapeutic and prognostic significance. The ER and progesterone receptor (PR) status of endometrial cancer also have prognostic and therapeutic significance.

MECHANISM OF ACTION OF HORMONAL RECEPTORS

Most steroid hormones influence their target tissues by the following series of steps: passive diffusion of the hormone through the cell membrane, specific binding in the cytoplasm with the hormone receptor, translocation of the receptor-hormone complex to the nucleus, binding of the receptor-hormone complex to an “acceptor” site on the chromatin, and transcription of DNA in a manner characteristic of the specific hormone–target cell interaction, eventually resulting in either an increase or a decrease in specific protein synthesis.

Tamoxifen binds with the ER and is translocated to the nucleus, where it binds to chromatin. It does not influence gene transcription, so functionally, tamoxifen acts as an antiestrogen.

Estrogen exposure increases the production of both ER and PR, whereas progesterone inhibits production of both ER and PR.

Aromatase inhibitors work by blocking aromatase, the enzyme that is responsible for the final step of estrogen synthesis. They prevent the production of estrogen, the substrate of the ER, in postmenopausal women.

Luteinizing hormone–releasing hormone agonists act by pituitary desensitization and receptor downregulation, suppressing gonadotropin release. They are as effective as surgical oophorectomy in premenopausal women with ER-positive advanced breast cancer.

CLINICAL APPLICATIONS

Because tumor growth in patients whose tumors contain ER and PR is likely to be stimulated by estrogen exposure, tumor regression should occur if endogenous estrogen production is abolished or if the patient is exposed to a progestin or antiestrogen. In breast cancer, patients whose tumors contain ER and PR have an 80% response rate to hormonal manipulation, whereas fewer than 10% of receptor-poor tumors respond.

An objective response to progestin therapy occurs in about one third of patients with recurrent or metastatic endometrial carcinoma. Progestin therapy is more likely to be effective in well-differentiated endometrial adenocarcinomas than in more poorly differentiated tumors because well-differentiated tumors are the ones that are most likely to contain ER and PR.

ER and PR have been demonstrated in some ovarian adenocarcinomas, particularly endometrioid carcinomas. Tamoxifen is effective in up to 30% of women with recurrent ovarian cancer, and early data suggest that aromatase inhibitors are also active agents.

image Pain Management

More than 70% of patients with cancer develop significant pain at some point in their disease. Proper pain management requires an understanding of pain physiology, pain mechanisms, and the pharmacology of analgesics.

Pain in gynecologic cancer may be the result of soft tissue infiltration, bone involvement, neural involvement, muscle spasm (e.g., psoas spasm), infection within or near tumor masses, or bowel colic.

Therapeutic approaches vary according to the pain mechanism involved. Consideration must be given to the specific therapeutic measure that may be appropriate in the individual case, such as radiation therapy, chemotherapy, antibiotics, regional nerve block, or surgery.

Peripherally acting drugs such as acetaminophen (paracetamol) should rarely be omitted from analgesic regimes, and rectal suppositories are useful if oral intake is not appropriate. When pain is caused by bone metastases, nonsteroidal antiinflammatory drugs or bisphosphonates are helpful. Muscle spasm requires muscle relaxants such as diazepam, whereas bowel colic requires anticholinergics such as busulfan.

Opioid use will be necessary for severe pain, although nerve pain and muscle spasm are not well relieved by opioids. A variety of opioids are available, and in general, a low-potency opioid such as codeine or a high-potency opioid such as morphine is combined with a peripherally acting drug such as acetaminophen or aspirin.

Immediate-release morphine, which is best given orally or subcutaneously, should be given at regular 4-hour intervals. Controlled-release morphine tablets are a significant advance in convenience of administration because they need to be given only every 12 to 24 hours, once the total 24-hour requirement has been determined from the use of an immediate-release preparation. Constipation is a real problem with opioids, and prophylactic laxatives should be prescribed.

Alternative opioids (with equivalency to morphine 5 mg) include oxycodone (5 mg), hydromorphone (1 mg), pentazocine (45 mg), and meperidine (75 mg).

When pain is neurogenic in origin, an opioid and a peripherally acting drug should usually be supplemented by a tricyclic antidepressant, an anticonvulsant, or a corticosteroid.

image End-of-Life Issues

When it becomes clear that the patient is dying, the goals are to control symptoms, maintain dignity, and allow time and privacy for communication with loved ones.

Medications should usually be given subcutaneously or rectally, any unnecessary tubes or equipment should be removed to facilitate contact with loved ones, and nursing care should particularly focus on pressure areas, mouth care, and “grooming.” Sedation, for example, with sublingual lorazepam, 0.5 to 2.5 mg every 4 to 6 hours, may be helpful if the patient is agitated.

Important issues from a patient’s perspective are receiving adequate pain and symptom management, avoiding inappropriate prolongation of dying, achieving a sense of control, relieving the burden on caregivers, and strengthening relationships with loved ones.

SUGGESTED READING

Eifel P.J. Radiation therapy. In: Berek J.S., Hacker N.F., editors. Practical Gynecologic Oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:119-162.

Hortobagyi G.N., Theriault R.L., Lipton A., et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol. 1998;16:2038-2044.

Lickiss J.N., Philip J.A.M. Palliative care and pain management. In: Berek J.S., Hacker N.F., editors. Practical Gynecologic Oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:835-862.

Markman M. Chemotherapy. In: Berek J.S., Hacker N.F., editors. Practical Gynecologic Oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:89-118.

Singer P.A., Martin D.K., Kelner M. Quality end-of-life care: Patient’s perspectives. JAMA. 1999;281:163-168.

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