Several new agents have recently been approved or are soon to be approved
by the FDA for the treatment of cancer.
 These agents are very interesting compounds, and further research is needed
to determine their precise role in the treatment of cancer. The basic
properties of these agents are outlined in Table 1.
Table 1. New Anticancer Agents*
Table 1. New Anticancer Agents
||Dose and Administration
Refractory anaplastic astrocytoma that has failed prior
2/day orally for 5 days. Cycle is to be repeated every 28 days depending
on count recovery. Medication should be taken on an empty stomach. Dose
should be adjusted to keep ANC = 1000-1500/mm
3 and platelets = 50,000-100,000/mm
||Myelosuppression (white blood cells and platelets) Nadir occurs at 28 days.
Cycle should not be repeated unless counts are adequate. Nausea and vomiting--may
be decreased if dose administered at bedtime. Headache, fatigue, constipation
UFT and Leucovorin
||UFT: Antimetabolite activityLeucovorin: Potentiates activity of 5-fluorouracil (5-FU)
||Metastatic colorectal cancer
UFT 300 mg/m
2/day orally X 28 days with 1-week rest period. Leucovorin: 75-90 mg/day
in 3 divided doses
||Myelosuppression, diarrhea, mucositis, fatigue, increased bilirubin. Does
NOT cause hand-foot syndrome seen with 5-FU and its analogues.
Adjuvant therapy in node-positive breast cancer in patients who have undergone
2 as a single IV infusion or in 2 divided doses on days 1 and 8 of each
cycle of therapy
Myelosuppression, nausea and vomiting, alopecia, mucositis, vesicant properties,
secondary malignancies. Maximum recommended cumulative dose = 900 mg/m
Bladder cancer (insitu) that is refractory to BCG therapy in patients who have contraindications
for immediate cystectomy
800 mg intravesicularly weekly; dose should be diluted to 75 ml and retained
for 2 hours. Valrubicin is in
Cremophor EL base, so non-DEHP containers and administration sets should be used.
||Urinary frequency, dysuria, urinary urgency. Systemic toxicities of anthracyclines
(myelosuppression, mucositis, nausea/vomiting) are seen in patients with
||Persistent or recurrent cutaneous T-cell lymphoma expressing the CD25 component
of the IL-2 receptor
||9-18 mcg/kg/day IV over 15 minutes daily X 5 days. Cycle is repeated every
3 weeks. Product must be stored in the freezer. Product must be diluted
with NS. Glass containers should be avoided and the product should not
be filtered. Must use prepared solution within 6 hours of preparation.
||Acute hypersensitivity reactions, capillary leak syndrome (hypotension,
hypoalbuminemia, edema), chills, fever, asthenia, headache, nausea/vomiting,
anorexia, diarrhea, infection, pain at tumor site, pruritus, increased
* Some of these agents have yet to be approved by the FDA.
Temozolamide is an oral alkylating agent that is similar to dacarbazine.
Temozolamide undergoes spontaneous hydrolysis to MTIC, which is further
metabolized to 5-aminoimidazole-4 carboxamide (AIC) -- the active cytotoxic
compound. Because of the spontaneous hydrolysis of the compound, temozolamide
has less variability in its conversion to MTIC than does dacarbazine,
and therefore there are differences in activity, spectrum, and potency
between the 2 agents. Temozolamide is almost 100% bioavailable. There
is decreased absorption with food, so it is recommended that the doses
be taken on an empty stomach. Temozolamide crosses the blood-brain barrier
- hence, its activity in primary brain tumors and brain metastasis. Delayed
myelosuppression is the dose-limiting toxicity. Nausea and vomiting may
be less severe if doses are taken on an empty stomach at bedtime. Potential
future uses for temozolamide include the treatment of glioblastomas, melanoma,
and sarcoma. The cost of 1 course of therapy is approximately $1560 (average
wholesale price [AWP]).
UFT is a combination product that contains uracil and ftorafur in a 4:1
ratio. Ftorafur is a 5-fluorouracil (5-FU) prodrug and is combined with
uracil, which inhibits the metabolism of 5-FU. Leucovorin is added to
the UFT therapy as a potentiation agent. Leucovorin increases the binding
of 5-FU to thymidalate synthase, thereby increasing the cytotoxicity of
5-FU. Ftorafur is well absorbed orally and slowly metabolized. Surprisingly,
UFT + leucovorin does not cause hand-foot syndrome, which is a dose-limiting
toxicity of 5-FU therapy and the other available 5-FU prodrugs (ie, capecitabine).
Future uses for this combination may be for the treatment of gastrointestinal
malignancies, breast cancer, and head and neck tumors. The relative cost
of UFT/leucovorin is unknown; however, when evaluating the cost of the
regimen, it is important to keep in mind that 5-FU therapy requires IV
administration involving pumps and preparation time. Also, the average
cost for a course of capecitabine is approximately $770 (AWP).
Epirubicin is an anthracycline analogue that has been used in Europe for
several years. It is believed that epirubicin may have a lower incidence
of cardiotoxicity; however, there is little evidence to support this.
Epirubicin has a large volume of distribution and undergoes extensive
hepatic and biliary excretion. Dose modifications are required for patients
with hepatic dysfunction. There is evidence that there is decreased clearance
of epirubicin in elderly females. Cimetidine increases the area under
the curve of epirubicin by 50% and decreases the clearance of the drug
by 30%. Future uses of epirubicin may include treatment of metastatic
breast cancer and treatment of other solid tumors sensitive to anthracycline therapy.
Valrubicin, a semisynthetic analogue of doxorubicin, is a highly lipophilic
compound solubilized in
Cremophor EL. It is hypothesized that because of decreased interaction with negatively
charged molecules, valrubicin may be less irritating to local tissue than
other agents used for intravesicular administration. Valrubicin penetrates
the bladder tissue with negligible absorption and metabolism in patients
with an intact bladder. If patients have perforated bladders or inflamed
bladders, there is risk of systemic toxicities from valrubicin.
Clinical trials showed that valrubicin therapy in patients who had failed bacillus Calmette-Guérin
(BCG) therapy le
ad to more durable responses; however, there was a high incidence of metastatic
disease in patients treated with valrubicin. This increase in metastatic
disease may be attributable to the fact that cystectomy was delayed in
patients receiving valrubicin. Therefore, it is recommended that therapy
be discontinued in patients not responding after 3 months of treatment.
The cost of therapy is substantial at $9360 for 6 weeks of treatment.
Future possibilities for valrubicin may be in the front-line treatment
insitu of the bladder.
Denileukin diftitox is a fusion protein that directs diphtheria toxin to
cells that express the CD25 component of the IL-2 receptor. It is interesting
that all patients who receive denileukin will develop antibodies against
the protein. There is also an increase in the clearance of the drug with
prolonged exposure. Oddly, the antibody production and increased clearance
of the drug do not decrease the response of the tumor to the treatment.
Denileukin is a highly toxic compound, and the more serious toxicities
decrease with continued exposure to the agent. The cost of therapy ranges
from $14,888-$24,813, depending on the dose regimen used. Also there are
additional costs associated with the management of the toxicities caused
by denileukin. Potential future uses include: earlier use in the treatment
of cutaneous T-cell lymphoma (CTCL), use in CD25-negative patients with
CTCL, and use in non-Hodgkins lymphoma.
New Supportive Care Therapies and Management Strategies
Pharmacists have traditionally been involved in the management of patients
receiving chemotherapy. Pharmacists are often consulted on the management
of chemotherapy-related toxicities such as nausea and vomiting and myelosuppression.
Pharmacists need to be involved in managing all issues related to the
patient's therapy, including
radiation and surgery-related issues. Traditional methods of approaching patient
care problems must continually be applied to managing issues for cancer
patients; however, it is important to address a problem while also trying
to understand the impact of the problem on the patient and the cause of
the problem. In evaluating patients one must take the following steps:
Evaluate the situation.
Develop a patient-specific plan.
Implement the plan for management of the problem.
Re-evaluate the success of the plan.
Modify the treatment based on the patient's response.
Cancer patients experience many treatment-related problems. Management
of the treatment-related problems is complex, as they coexist with numerous
Treatment-related problems include, but are not limited to:
- bowel obstruction
- nausea and vomiting
- sleep disturbances
Understanding the pathophysiology of cancer and treatment-related problems
has increased our ability to treat these
symptoms more effectively.
Managing Cancer Pain
New discoveries in the pathophysiology of cancer pain have led to the development
of therapies that may increase our success in treating this problem. Cancer
pain is persistent pain, but there are episodes of breakthrough. Standard
practice in determining analgesic doses is based on empiric daily analgesic
requirements. It has been found that there is a lack of correlation between
the dose required for breakthrough pain and the dose determined by evidence-based
guidelines. Common practice in the past was to increase the running dose
of analgesic to prevent episodes of breakthrough pain. These attempts
resulted in increased daily consumption of opiates and also increased
side effects from the pain medication.
The N-methyl-D-aspartate (NMDA) receptor plays an important role in the
mediation of pain in cancer patients. NMDA does not participate in all
pain pathways, but there is evidence that using agents that antagonize
NMDA receptors may actually lead to decreased opiate requirements. Dextromethorphan
is an NMDA antagonist that has been shown to decrease daily morphine requirements
when used in combination with morphine (in a 1:1 ratio) for cancer-related
pain. In a practical application, more hospice patients are being treated
with the combination of morphine and dextromethorphan in order to provide
more consistent pain relief as well as to decrease the potential side
effects that commonly arise from over-medication with breakthrough medications
for pain. Pharmacists should be aware that patients may require titration
of their opiates when they are used in conjunction with dextromethorphan.
Treatment of neuropathic pain has been a complicated issue for practitioners
managing cancer patients. Neuropathic pain is caused by peripheral sensitization.
Agents shown to have efficacy in the treatment of neuropathic pain include
anticonvulsants, capsaicin, and neurokinin-1 receptor antagonists. Opiates
are also active in the management of neuropathic pain, despite a common
misconception that they are ineffective in treating this type of pain.
The anticonvulsants vary in their mechanism of action, and therefore they
are not cross-sensitive in their activity. Patients may fail one class
of anticonvulsants and respond to another. Gabapentin has had the biggest
impact on the treatment of neuropathic pain. There are few clinical trials
supporting its use in this setting; however, gabapentin shows significant
activity in treating neuropathic pain. In considering the agent of choice
when using anticonvulsants for pain management, the pharmacist must keep
in mind the toxicities and drug interactions associated with the potential agents.
Bisphosphonates have traditionally been used for the management of hypercalcemia
related to certain malignancies. Bisphosphonates also are used in the
management and prevention of skeletal complications in patients with metastatic
breast cancer, multiple myeloma, and possibly prostate cancer. There is
also some evidence supporting the role of bisphosphonates in decreasing
bone disease associated with certain malignancies. Bisphosphonates are
used routinely in the outpatient setting, and there has been great controversy
over infusion rates. There is recent evidence to suggest that there is
no difference in efficacy or toxicity between a 1-hour infusion of pamidronate
and a 4-hour infusion of pamidronate in patients with multiple myeloma.
 The newer bisphosphonates under investigation are significantly more potent
than those currently on the market. The potency of the bisphosphonates
is listed in Table 2.
Table 2. Bisphosphonate Potency
Table 2. Bisphosphonate Potency
Alternative methods of drug administration should always be considered
for the management of pain in cancer patients. Transmucosal delivery systems
(ie, fentanyl lollipops) have an advantage because of the increased surface
area in the mouth as well as the controlled pH and temperature. On the
other hand, rectal administration of medications should only be considered
in those medications approved for that route of administration. Differences
in absorption and dissolution may lead to erratic drug delivery and may
complicate evaluation of the patient's opiate needs.
Management of Fatigue
Lack of energy is a significant problem in cancer patients. Many cancer
patients say that fatigue is the primary symptom that prevents them from
leading a normal life. Fatigue decreases productivity in those patients
still trying to work through their therapy. There is a definite correlation
between hemoglobin concentration and quality of life in cancer patients.
Erythropoietin (EPO) is the agent of choice in treating chemotherapy-related
anemia and the associated fatigue. Studies have shown that weekly dosing
of EPO is equal in efficacy and safety to the 3 times weekly injections
originally used in cancer patients.
Management of Insomnia
Lack of energy is a significant problem in cancer patients. Sleep disturbances are the most frequently overlooked problem in cancer
patients. Sleep disturbances may be due to depression, pain, anxiety,
cognitive impairment, and many other factors. It is important for pharmacists
and other health practitioners to evaluate a patient's sleep disorders.
It is important to remind the patient about sleep hygiene:
- Maintain regular sleep patterns
- Minimize disruptions
- Avoid taking naps in the afternoon
- Increase daytime activities
- Avoid lying in bed at night when alert
- Remove disruptive stimuli
Managing Cancer-related Weight Loss and Anorexia
There are several agents that are effective in managing anorexia and weight
loss in cancer patients. Corticosteroids have traditionally been used,
and while they are effective in increasing quality of life and stimulating
appetite, they are wrought with side effects that make them less than
desirable in some patients. Megestrol acetate has been shown to be equally
efficacious to dexamethasone in stimulating appetite and preventing weight
loss in cancer patients. Dexamethasone is associated with a high incidence
of steroid-related toxicities, while megestrol acetate is associated with
an increased risk for deep venous thrombosis in cancer patients.
Managing the Febrile Neutropenic Patient
With changes in antibiotic prophylaxis and the use of growth factors following
chemotherapy, there has been a shift in the bacterial organisms being
treated in cancer patients. In the past, emphasis was placed on preventing
gram-negative infections, while current practices are placing more emphasis
on the prevention of gram-positive organisms. There is also a trend toward
treating febrile neutropenia in the outpatient setting, which makes the
role of the pharmacist even more important. There is a great need to have
sound guidelines for evaluating patients who are considered low-risk and
therefore eligible to be followed in the outpatient setting. This places
a large amount of responsibility on the pharmacist to educate the patient
about the appropriate use of their antibiotics and proper monitoring for
infection. The success of outpatient management of febrile neutropenia
is largely dependent on patient selection (expected duration of neutropenia,
comorbid diseases, previous treatment with fluoroquinolones, clinical
indication for antibiotic therapy).
Patient Education vs Patient Information
Patients have many sources for retrieving information about their illnesses
and treatment-related toxicities. The Internet is the largest source of
information for the patient. The pharmacist must ensure that the patient
not only receives drug information but that the patient or care giver
is educated about medication use and expected toxicities. The pharmacist
must have some way of measuring comprehension, be able to follow patient
compliance, and assist in monitoring for toxicities of therapy. There
must be a continuum of care for the patient, and communication about changes
in therapy must be documented in order to ensure compliance with the treatment
plan. The treatment plan must be communicated clearly to the patient or
care giver so they can be involved in monitoring and documenting outcomes.
Cancer Drugs of the Future
Where are we going with cancer drug therapy? The original thought process
on designing chemotherapeutic agents focused on the belief that cancer
cells are multiplying too quickly, and therefore we should design drugs
that destroy rapidly dividing cells. We quickly saw that normal cells
were affected as well as the tumor cells. Therefore, cancer therapy is
becoming more targeted, and significant discoveries in cancer cell biology
have been made, which have led to the development of new theories for
attacking cancer cells.
Using Old Drugs Better
Newer agents are being developed to reverse multidrug resistance (MDR),
which will allow further development of older drugs in the treatment of
previously resistant disease.
New Molecular Targets
Agents are being developed that focus on specific pathways in the cell
cycle. These include:
- signal transduction inhibitors
- protein kinase inhibitors
- antimetastasis agents
- matrix metalloprotease inhibitors
- oncogene regulators
These newer targets allow for the development of specific therapies that
are more effective and less toxic to the patient.
Understanding Cancer Biology
Over the past 25 years there have been significant accomplishments in defining
the cell cycle. As newer pathways within the cell cycle have been defined,
it has led to the development of new targets for therapy and has also
explained certain biologic processes that have led to treatment failure.
There are several reasons why a cell may be resistant to chemotherapy:
- The drug cannot enter the tumor cells.
- The drug is deactivated at the tumor cell site.
- The tumor cell repairs itself.
- The tumor cell has altered receptors, making it resistant to the therapy.
- The drug is pumped out by MDR transporters. This prevents accumulation
of the agent, thus preventing cytotoxicity.
Drugs have been targeted to block the MDR transporter pumps. Early developments
used common drugs such as verapamil and cyclosporine A to block the efflux
pumps of resistant cells. Success of these agents was limited by toxicity.
A new agent, PSC-833 (Valspodar), is close to FDA approval for use in combination regimens for acute myelogenous
leukemia (AML). It has been shown that PSC-833 increases the retention
of daunorubicin in cells and also increases the cytotoxicity of daunorubicin
on the leukemic cells.
Many drugs are affected by the MDR efflux pumps. Many of them are natural
products, and they have different mechanisms of action. It is believed
that one of the mediators of MDR is p-glycoprotein. P-glycoprotein is
believed to mediate MDR for the following agents:
P-glycoprotein is also expressed in many normal tissues, such as brain,
small bowel, pancreas, liver, adrenal glands, colon, kidney, and testis.
Many of these organs are natural detoxifiers for the body. Blocking the
efflux pumps with agents such as PSC-833 may lead to specific toxicities
due to the presence of p-glycoprotein in these organs.
Pharmacists should be cautioned that the use of agents to block MDR should
be strictly monitored. Agents to block MDR will be approved for use with
specific regimens, and dose reductions of the chemotherapeutic agents
may be needed to avoid excessive toxicity. Consideration should be given
to whether the cytoxicity is due to increased drug activity or increased
exposure of the cells to the chemotherapeutic agent.
Signal transduction cascades are activated by mitogens, stress, and hormones.
The cell receives signals that tell it to continually divide when it should
have already gone through cell death. New agents have been designed to
block signal transduction. Some of the more promising agents include:
- TNP 840
Cyclin-dependent kinases interact with molecules and tell the cell to go
through the cell cycle process. The cyclin-dependent kinases work in all
aspects of the cell cycle. Newer agents under investigation to block the
cyclin-dependent kinases are:
Angiogenesis is a process by which a cell induces neovascularization. It
is believed that inhibiting angiogenesis may also prevent metastatic disease.
Anti-angiogenesis agents under investigation include:
- Bayer 12-9566
- SU 5416
Tumor Suppressor Genes
Tumor suppressor genes exist in many cell lines.
p-53 is a gene that has tumor suppressor activity. It has been demonstrated
that lack of
p-53 in cells is a poor prognostic factor for response to chemotherapy. Onyx-015
is an agent that has been designed to mimic
p-53 in cells that are
p-53 deficient or have defective
p-53. In the cell, Onyx-015 replicates through a viral vector and causes cell
death. The viral vector then can be transmitted to other cells.
Apoptosis is "programmed cell death." Many developments have
been made to determine the events leading up to the terminal event for a cell.
Cancer vaccines are a highly specific targeted approach to cancer therapy.
The biggest barrier to cancer vaccine therapy is trying to find a way
to present the antigen to the immune system to activate the immune system
against the tumor cells. Methods have been used to load the antigens onto
presenting cells (such as fibroblasts), which allow the immune system
to be activated. Adjuvant agents have been used (such as interferon-gamma)
to enhance T-cell response to the antigen and increase the retention of
the vaccine within the cell. So far, vaccine therapy has been used in
melanoma, colon cancer, and prostate cancer.
Targeted toxins are another specific method to deliver cytotoxic agents
to a cell. There are 2 components--the targeting domain (needs a specific
receptor site in the cell) and the toxic domain (a diphtheria, ricin,
or Pseudomonas component). The toxin is internalized and inhibits protein
synthesis at a ribosomal level. The limitation is that the cells must
express the target receptor, and development of these compounds is labor
intensive and expensive. One new cancer agent that was designed as a targeted
toxin is denileukin deftitox.
Gene therapy is the most patient-specific targeted approach to treating cancer. Strategies
such as using lymphocytes as the gene carrier and gene-based
immunotherapy have not proven to be effective methods of gene manipulation for cancer
treatment. More promising data in gene therapy have come from direct injection
of genes, which allows insertion of missing immune recognition antigens
as well as the introduction of sensitivity genes. There are also therapies
targeted at replacing missing or mutant tumor suppressor genes.
Manipulation of the gene must include methods that will increase the immune
stimulation in response to the gene. Incorporation into a liposome is
a practical approach to delivering a gene into the patient. Sensitivity
genes are virally directed and take advantage of the transcriptional differences
between normal cells and tumor cells. Insertion of the gene not only causes
a "suicide" effect to the cell, but also creates a bystander
effect that results in selective destruction of transduced cells. Through
gene therapy, you can replace a missing or mutant tumor suppressor gene
and force that cell into a normal phenotype.
Future Directions of Cancer Therapy
With the identification of gene sequencing and the progress made by the
Human Genome Project, the future of cancer therapy will be focused at
the chromosomal level. Therapies will be targeted at preventing disease,
identifying genetic abnormalities, and developing agents that will trick
tumor cells into self-destruction without causing any toxicity for the patient.