CHEMOTHERAPY, excerpted from the upcoming book, A COMPLETE GUIDE TO LUNG CANCER
Our website lungcancerclaims.com contains over 14 sites and 200 pages of detailed information about the medical and legal aspects of lung tumors, including excerpts from the upcoming book, A Complete Guide to Lung Cancer The attached is intended to provide general information, For medical advice, please consult with your physician.
5.0 WHAT IS CHEMOTHERAPY
5.01 "Chemo" or Chemical Therapy
The term "Chemo" means chemical and chemotherapy is the use of particular drugs alone or in combination to treat cancer. The term anti-cancer drugs is simpler. However, anti-cancer drug is a broad term covering a number of different types of drugs which affect cancer. Chemotherapy is generally used to identify anti-cancer drugs whose primary goal is to kill cancer cells.
The mechanisms by which chemotherapy drugs attempt to attack cancer are varied. Since the drugs perform different functions, it should make sense to use a number of different drugs simultaneously to attack cancer (so long as normal organs are not significantly impaired ) and that is what is being done today.
Most patients are given more than one drug. The best mix of drugs or even the optimum dose is not known for lung cancer, and clinical trials continue to investigate the success of different combinations, with these trials yielding varying and sometimes contradictory results. Clinical trials generally divide patients by stage and category and it is possible that the particular type of tumor, squamous, adeno or large cell, might play a role, or the degree of differentiation in the cell, poorly differentiated to well-differentiated. Medical abstracts summarizing the results of clinical trials are available on Medline, www.healthgate.com (Medline is the world medical literuature database).
Generally, chemotherapy targets any area where cancer cells are located, in comparison to surgery and radiation which target defined areas. Chemotherapy may be used to reduce tumors, or in some cases, prevent the development of cancer in particular areas. These drugs generally destroy cancer cells by stopping them from growing or multiplying at one or more points in their life cycle. Most oncologists will recommend multi-modal chemotherapy (more than one drug), though the best mix of drugs is not known with clinical trials yielding varying results. The task is to provide a large enough dose to successfully attack the cancer while not unduly affecting the normal cells.
5.02 History of Chemotherapy
An accident in World War 2 paved the way for modern chemotherapy. A U.S. navy vessel sank in Naples, Italy. When the mustard gases it was carrying exploded, the casualties who had been exposed to the poisonous gases were examined and it was found that large number of cells in their bone marrow had disappeared and their lymphatic system had atrophied. An Army biologist began testing on animals with similar substances and found he was able to inhibit lymphoid tumors in animals. These drugs were tested on humans with Hodgkin's disease and found to temporarily inhibit tumors.
5.1 THE FDA APPROVAL PROCESS
The Food and Drug Administration (FDA) regulates prescription drugs. Prescription drugs must be given with a doctors supervision and have FDA approval for use in the United States. FDA approval comes after review of clinical trials and other data to determine the safety and effectiveness of a particular drug. For example, in a shining moment, the FDA refused to approve Thalidomide in the early 1960's believing that adequate information about its safety had not been provided. Subsequently it was found that the drug caused serious birth defects.
5.11 FDA approval is Organ and Treatment Specific.
Cancer or chemotherapy drugs are not approved for all purposes. Instead the FDA limits their use to certain organs and sometimes in certain doses. For example, look at this FDA approval:
"FDA today approved Taxotere for treating non-small cell lung cancer that does not respond to cisplatin-based chemotherapy....
Taxotere was approved for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior cisplatin-based chemotherapy. Most patients with non-small cell lung cancer are found to have metastatic disease (cancer which has spread to other organs) when diagnosed, and curative treatment is not possible. Two randomized controlled clinical trials demonstrated that patients treated with Taxotere had increased survival compared to patients receiving supportive care or cancer therapy consisting of either vinorelbine or ifosfamide."
Note, that the approval denotes the type of cancer covered, the status of the patient, and the circumstances of use.
5.21 Chemotherapy Generally Targets Rapidly Growing Cells
Chemotherapy attacks all body cells to some extent, but targets rapidly dividing cells such as cancer cells. Its effect on other rapidly dividing cells such as hair follicles, cells lining the stomach, and red blood cells, accounts for at least some of its side effects. Chemotherapy affects the course of cancer by taking advantage of the cancer cell's penchant for constant reproduction. Almost all of the drugs used in chemotherapy suppress cancer by somehow altering the cells' DNA and thus their ability to reproduce. See Bruning, Coping with Chemotherapy (Ballantine Books 1993) (an excellent book written by a woman with breast cancer) .
5.22 What Does Cell_Cycle Specific Chemotherapy Mean
Almost all the drugs used in chemotherapy suppress cancer by altering the cells' DNA and thus their ability to replicate or reproduce. Since DNA is most vulnerable to drug interference during the reproductive phases of the life cycle, cancer cells are more likely to be affected than are the bulk of the body's normal cells, which reproduce at a much more relaxed pace. Thus, the very characteristic that makes cancer so dangerous has in some cases helped to contribute to its undoing. Indeed, some rapidly growing cancer such as small cell cancer are particularly susceptible to chemotherapy.
Chemotherapy drugs are either cell_cycle_specific (lethal to cells only during a specific reproductive phase) or "cell_cycle_nonspecific" (able to sabotage the cells no matter what phase they are in). In a sense, the inner workings of cells (cancerous and otherwise) are like gearboxes; what chemotherapy does is to throw a biochemical monkey wrench into the gearbox causing the machine to grind to a half_causing the cells to stop working, to die.
5.23 Adjuvant Therapy, Combining Chemotherapy with Other Therapy
Sometimes chemotherapy is the only therapy a patient receives. One advantage of primary chemotherapy is that because the cancer cells have not yet been exposed to anticancer drugs, they may be more vulnerable. A case of primary chemotherapy could be a patient with a severe heart problem who could not tolerate surgery and chemotherapy would be the exclusive form of treatment. The disadvantage of such chemotherapy is that the drugs must destroy a larger target, since none of the cells were removed by surgery or diminished by radiation.
Chemotherapy used in addition to surgery or radiation is called adjuvant therapy (adjuvant or in addition to). Chemotherapy is sometimes used after surgery and/or radiation therapy to help destroy any cancer cells that may remain.
5.25 Considerations Before Treatment Begins
Because chemotherapy can be harmful to certain organs, preliminary tests are conducted. For example, cells in the bone marrow frequently divide and therefore like other rapidly dividing cells are susceptible to the effects of chemotherapy. Thus, a blood test would be conducted to determine that the patient has a healthy number of red and white blood cells and platelet. Liver, kidney, and heart would normally also be checked.
5.3 CHEMOTHERAPY TERMINOLOGY
The first question that must be asked is whether the drug has some favorable impact upon a particular type of cancer. If it does, the drug is "active." That a drug is active does not mean it will always or usually be used. Its level of activity may be less than other drugs, or its side effects could be significant. Let use assume that we have drugs A, B, C, and D.
5.32 Partial and Complete Response
There are some objective ways of categorizing activity. Most scientists call a partial response, a 50% decrease in the size of the tumor. Thus, if we have an 8 centimeter tumor, and with a particular drug, the tumor is reduced to 4 centimeters, the drug is active and the patient had a partial response.
If the tumor is completely eliminated, for example, it cannot be seen on an x-ray, that is called a complete response. A complete response must unfortunately be distinuished from a cure. Chemotherapy might temporarily eliminate a tumor, only to have it later return, or it might leave microscopic traces undiscernible by x-ray or perhaps even Ct Scan.
There are five basic types of chemotherapy drugs:
5.41 Alkylating Agents
Alkylating agents bind with DNA, preventing the cell from dividing. Cisplatin, a widely used drug is considered an alkylating agent, though it inhibits DNA by a mechanism that is different from most drugs in this category. It is cell cycle nonspecific, meaning it is not designed for any specific cycle in the cell.
Antimetabolite mimic nutrients the cells needs, tricking the cell into consuming them, so it eventually starves to death.
5.43 Plant Alkaloids
Plant alkaloids, also called vinca alkaloids are cell cycle specific. They interfere with those parts of chromosomes necessary for cell division. "Vinorelbine is now the major vinca alkaloid worth consideration. Vinorelbine is a classic antitubulin agent that arrests cell mitosis in metaphase and prevents tubulin polymerization to form microtubules. It is a cell cycle-dependent antimitotic agent." Pritchard, Other Chemotherapeutic Agents: Do We Need Them," The 2nd International Breast Cancer International Research Group Conference, medscape.com
Taxol, a popular drug, is a plant alkaloid and destroys a cancer cells ability to function and divide by preventing the cell from dissembling its fibrous skeleton of micro tubules. When the natural process is inhibited, the cell becomes choked with fibrous structures
5.44 Antitumor Antibiotics
These are not the same drugs used to treat bacterial infections. Rather, these drugs cause the strands of genetic material that make up DNA to uncoil, thereby preventing the cell from reproducing. An example is doxorubicin, though this type of chemotherapy has had limited use with lung cancer.
Hormones occur naturally in the body and are involved with the normal growth process. Since some tumors may require certain hormones to grow, when the hormone is blocked, the tumor may not grow. Tamoxifen is an example of a hormone. Cuneo-Lung Cancer Study Group, M. Tonato, From Nitrogen-Mustards to cis-platinum and Beyond, www.culcase.org. The Cuneo lung cancer study group is one of the few organizations devoted solely to lung cancer and it holds an important conference on lung cancer each year.
5.5 PARTICULAR DRUGS
Taxol has been used to treat cancer for some years. It is an extract from the bark and needles of the yew tree, Taxus brevi folia. Taxol is a white powder and when prepared for use becomes a clear, colorless liquid which is given by intravenous route only. It has been used to treat the following cancers: Ovarian, Testis Metastatic breast cancer Head and neck cancer, melanoma, and lung cancer.
Taxol is most commonly used in combination with other chemotherapy drugs such as: 5_FU, Adriamycin, Vinorelbine, Cytoxan and Cisplatinum .The type and extent of a cancer will determine the method and schedule of administration of this drug. This decision is made by the medical oncologist. At present, Taxol is normally given once every three weeks.
The history of Taxol is supplied on a webpage entitled The Taxol Molecule:
Taxol was discovered at Research Triangle Institute in 1967 when Dr. Monroe E. Wall and Mansukh C. Wani isolated the compound from the Pacific Yew Tree, taxus brevi folia and noted its antitumor activity in a broad range of rodent tumors. Interest in Taxol waned for nearly a decade. ... In 1980, scientists at Albert Einstein Medical College reported that Taxol has a unique mechanisms of action, making it the prototype for a new class of chemotherapeutic drugs. Taxol bind tubulin, thereby inhibiting cell division... RTI.org. (Research Triangle Institute)
It is active as single agent therapy in non pretreated NSCLC and probably also after prior chemotherapy. Combinations with cisplatin or carboplatin have been the object of multiple phase II studies.(7). Taxol is manufactured by Bristol-Meyers Squibb. www.BMS.com.
5.511 Taxol Side effects:
While its consistent effectiveness throughout many clinical trials has made it a stable of lung cancer chemotherapy, there are side effects effects associated with Taxol. Some patiients will experience nausea or loss. I discuss some ways to deal with nausea in the next chapter. Other side effects have included: Low white blood counts, low platelet count, anemia, hair loss, soreness of the mouth, difficulty swallowing , diarrhea, nerve damage, allergic reactions, fluid retention.. Taxol is metabolized in the liver and excreted into bile and dosage may be reduced for patients with liver dysfunction or liver metastasis. Some patients have considered Gemcitabine instead of Taxol to reduce these side effects, though Gemcitabine has fewer clinical trials to confirm its efficacy. Patients should relay any side effects or problems to their oncologist.
A recent press release touted the ability of Docetaxel to address non-small cell lung cancer, at least where prior chemotherapy had been unsuccessful:
"Events SA (NYSE: AVE), announced today that Taxotere« (docetaxel) for Injection Concentrate, 75 mg/m2, was cleared for marketing by the US Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic non_small_cell lung cancer (NSCLC) after failure of prior platinum_based chemotherapy.
Taxotere is the first chemotherapeutic agent to be approved by the FDA for the second_line treatment of advanced non_small_cell lung cancer.... We hope this new approval for Taxotere will enable physicians to extend the lives of non_small_cell lung cancer patients who previously had limited options once their disease had progressed.....
About.Com Pharmaceutical Guide Quoting December 23, 1999 Press Release by Events Co. Note that the above is a quotation from a press release, not an impartial analysis, and it is not clear whether the FDA has approved this drug for patients without prior unsuccessful chemotherapy. From the press release, it appear further clinical trials should directly compare Taxotere with other chemotherapy drugs in patients who have not undergone chemotherapy.
5.5541 Trade Name and Manufacturer
Tamoxifen is manufactured by Zeneca and has the trade name Nolvadex. It is also less commonly called Tamoxifen Citrate, Tamaxin, Tamofen,
5.5542 Mechanism of Action
Some cancer cells are estrogen sensitive, and estrogen binds to these cells and stimulates them to grow and divide. Tamoxifen is an anti-estrogen which inhibits the binding of estrogen and with it the division and growth of cancer cells. Not surprisingly, Tamoxifen has been used during the last twenty years for treatment of breast cancer. (1) Tamoxifen is also known to work through other growth factors and the immune system to provide some benefit to patients whose tumors are not estrogen sensitive. It appears to exert its anti-tumor effects by competing with estradiol for estrogen receptor protein. (2)
Tamoxifen is classified as a hormonal/biological response modifier or an antineoplastic. (2)
5.544 Potential Side Effects
Any form of chemotherapy drug should be carefully monitored by the oncologist for potential side effects. According to one source speaking about the use of Tamoxifen for breast cancer, "adverse reactions to Tamoxifen citrate are relatively mild andrarely severe enough to require discontinuation of treatment." (2)
5.644A Emotional Changes
Since Tamoxifen impacts a hormone which in turn interacts with mood, it can conceivably impact mood or create emotional changes
5.644B Liver Changes
Tamoxifen has been associated with changes in liver enzyme levels or other liver abnormalities. Thus, the existence of liver problems may be a contraindication
This drug is active or effective with non-small cell lung cancer and has been successfully combined with cisplatin. Vinorelbine has been investigated in 4 randomized trials and found to improve survival. The combination of vinorelbine to cisplatin has been compared in two randomized trials to vinorelbine alone with significant response rates improvement with survival increase in one (Le Chevalier, J Clin Oncol 12: 360; 1994) and not in the other (Depierre, Ann Oncol 5: 37; 1994). In the first one, the comparison was also performed with a third arm treatment made of cisplatin and vindesine, with a marginal effect on survival. It should be noted that both trials have obtained high quality score in our review (89 and 79,8%).
It is active as single therapy in non pretreated NSCLC and has been shown in phase II randomized trials to be better tolerated than the combination cisplatin_etoposide. That is, its side effects appear to be less and is generally not associated with nausea or vomiting. Gemciabine, sometimes called Gemcar has been successfully combined with cisplatin and ifosfamide in phase II studies. Results of phase III trials are pending.
Two studies assessing its effectiveness as single therapy in non pretreated NSCLC have shown contradictory results. Further data are required to specify the place of topotecan.
5.6 THE ERA OF MULTI-MODAL OR COMBINATION CHEMOTHERAPYFrom a search for the magic bullet or cure, has come a recognition that success is most likely to come from a combination of drugs, each of which has an incremental impact on cancer. While combining four drugs with 20% response rate will unfortunately not lead to an 80% response, it will yield success beyond that of any one drug. One article explains the considerations in multi-modal chemotherapy:
"Four principles underlie the design of chemotherapy combinations. First, each agent in a regimen should be independently active against the tumor. Unless there is unexpected synergy, adding an agent with the same mechanism of action or inhibiting the same enzyme is unlikely to enhance the response with an additive effect, but will add to the toxicity. Secondly, each drug in the regimen should have an independent mechanism of action, preferably with each drug in the combination targeting different steps along a biochemical pathway. Third, there should be no cross resistance among the drugs in the regimen, so that if one drug selects a resistant tumor subpopulation, it is unlikely to be cross-resistant to another drug in the combination that kills through a different mechanism. Fourth, each of the drugs should have a different dose-limiting toxicity. Two drugs with the same toxicity profile given at maximum tolerated dose can produce unacceptable toxicity." Chemotherapy //www.pitt.edu/~super1/lecture/lec0701/l24.htm
One of the presenters at the 1998 Cuneo Lung Cancer conference
summarized the status of chemotherapy for late stage lung cancer patients:
"During the two decades from 1970 to 1990. the results of chemotherapy for stage IV disease have been unimpressive. Cisplatin was demonstrated to have modest activity, and appeared to be synergistic with etoposide and vinca alkaloids. Numerous phase III studies compared different cisplatin combination chemotherapy regimens and failed to identify a "standard" program (2,3). Furthermore, phase III studies comparing chemotherapy to supportive care had mixed results, with others failing to demonstrate an advantage for chemotherapy in stage IV disease. Only from a recent meta_analysis a small advantage for the combinations containing cisplatin could be demonstrated (4).
During the past 5 years, several new agents have been evaluated in NSCLC (Non small cell lung cancer) and demonstrated improved results compared toolder regimens. The first of these, vinorelbine, was developed in France. Le Chevalier and colleagues conducted a phase III study in 612 evaluable patients with NSCLC (5). Patients were randomized to vinorelbine plus cisplatin, vinorelbine alone, or vinorelbine + cisplatin. Objective responses were seen in 30%, 14% and 19% of patients. Furthermore, there was statistically significant improved survival with cisplatin + vinorelbine, with 35% one year survival versus 27% for cisplatin + vindesine. The Southwest Oncology Group (SWOG) in the U.S. evaluated single agent cisplatin (100 mg/m) versus the same cisplatin + vinorelbine (25 mg/m) weekly in 432 patients with NSCLC. The response rates were 10% versus 26%, and there was a statistically significant survival advantage for the vinorelbine regimen, with 16.4% versus 35.4% 1 year survival (6).
The taxons (paclitaxel and docetaxel) have also demonstrated activity, with a 20_30% single agent response. In the U.S., paclitaxel achieved a 40% 1 year survival in studies by Eastern Co_operative Oncology Group (ECOG) and M.D. Anderson, ECOG subsequently performed a phase III study in 571 evaluable patients, randomizing patients to cisplatin (75 mg/m) + etoposide, versus cisplatin (75 mg/m) + paclitaxel, given as a 24 hour infusion at a dosage of 135 mg/m or 250 mg/m with G_CSF. Response rates were 12%, 27% and 32% and there was improved survival with the two paclitaxel arms (7).
Gemcitabine is one of the most extensively evaluated single agents in NSCLC, with response rates of 20_30% world_wide (8). Several phase II studies have evaluated cisplatin + Gemcitabine, with 30_50% response rates and 40% 1 year survival (9). Carboplatin + paclitaxel (3 hour or 24 hour infusions) are among the most popular regimens in the U.S., based entirely upon phase II studies (10)..... Other large randomized trials comparing the new combinations are being performed in Europe. It is reasonable to expect that one of these new regimens will achieve improved survival in advanced disease and more probably when used as adjuvant therapy or combined with radiotherapy in earlier stage disease."
Cuneo-LungCancer Study Group, M. Tonato, From Nitrogen-Mustards to cis-platinum and Beyond, www.culcase.org. The Cuneo lung cancer study group is one of the few organizations devoted solely to lung cancer and it holds an important conference on lung cancer each year.
In another article presented at the 1999 conference entitled, "Activity of Drugs Recently Introduced in the Market for the Treatment of Non-Small Cell Lung Cancer, Sculier, et., al write,
"During the last decade, chemotherapy has been shown to significantly improve survival in patients with non_small cell lung cancer (NSCLC), whatever the disease stage _ loco_regionally advanced or metastatic _ is. The most active "classical" cytotoxic drugs in that indication are cisplatin, mitomycin C, ifosfamide, vindesine and vinblastine , as reported in a meta_analysis that we performed in 1990 (Lung Cancer, 7: 243_252;1991). The level of evidence of survival benefit is based on multiple randomized trials testing a cisplatin_containing chemotherapy arm versus a control arm without chemotherapy.
There are very few data yet available about non_cisplatin based regimens. A series of new active drugs against NSCLC has been identified during the last ten years and most of them are today commercially available, at least in some countries. They are gemcitabine ( a pyrimidine analogous antimetabolite like cytarabine), the taxons paclitaxel and docetaxel (inhibitors of the depolymerisation of the tubulin molecules of the micro tubules, blocking the cell in phase M), the camptothecin derivatives irinotecan and topotecan (topoisomerase I inhibitors), vinorelbine (a vinca_alkaloid inhibiting tubulin polymerization).
5.7 MULTI-DRUG RESISTANCE
Chemotherapy works best when there are (1) small numbers of cancer cells that are (2) actively dividing. Chemotherapy is highly effective with small cell lung cancers promptly diagnosed, since this type of cancer rapidly divides. The effectiveness of chemotherapy with non-small cell lung cancer is less clear. One writer states,
Whereas radical surgery or radiotherapy are potentially curative treatments for disease which is localized, chemotherapy is the only major modality with the potential to eradicate disease which has disseminated. In some less common malignancies, chemotherapy is indeed curative in a large proportion of patients. Examples of such diseases are acute leukemias, lymphomas and testicular teratoma. For the more common solid tumors, however, long-term disease eradication by chemotherapy is rarely seen. The main reason for this is the relative lack of selectivity displayed by current anticancer drugs. Their differential toxicity towards malignant cells within the body is such that they cannot be administered at dose level which may eliminate the malignant population without killing the patient. Some progress has resulted from the development of combination regimens which combine several drugs with different modes of action and nonoverlapping toxicities. Twentyman, Mechanism of Drug Resistance in Lung Cancer Cells, excerpted in Carney, Lung Cancer (Arnold Publ. Co. Great Britain 1995).
In "cell kinetics" experiments it has been shown that drugs destroy a constant fraction or percentage of cells, not a constant number. So if there are 10 trillion cancer cells and 99 percent are killed, 100 billion are still left after the first treatment. After the second treatment, 1 billion cells are left, and after the third 10 million remain. The proportion of cells killed is the same, but each time a smaller number of cells is killed. The cells that are resting rather than actively reproducing escape the drugs' killing effects.
In between treatments, when it is safe, the resting cells resume production and replace the ones that have been killed. Chemotherapy under the best of conditions is a matter of taking two steps forward and one step back, and it is very difficult to make enough progress to kill off every single cell. Kinetic studies have also shown that as the cancer increases in size_the more cells it contains_the number of actively reproducing cells (the "growth fraction") decreases. The higher the number you start with, the harder and longer you have to work at getting the cell population down, because not only are there more cells to kill, there are more cells that are not vulnerable.
5.71 The Development of MDR, Multi-Drug Resistance
In addition to the fact that chemotherapy may not reach every cancer cell, unfortunately cancer cells develop resistance to certain drugs. Thus, while initially successful, chemotherapy is subsequently less effective at addressing recurrent cancer. One author suggests that PGP (P-glycoprotein) is produced which inhibits the ability of the drug to reach cancer cells, thus reducing "intracellular drug concentrations and hence reduced cytotoxicity." Twentyman, Mechanisms of Drug Resistance in Lung Cancer Cells, 214, in Carney, Lung Cancer (Arnold Pub. Co. 1995).
In a laboratory, Twentyman developed cancer cells which increased their resistance to doxorubicin, a chemotherapy drug.
5.72 Assessing Resistance to Chemotherapy
A contributor to the same book states,
At least three different MDR (multi-drug resistance) phenotypes exist, two of which are are relatively well defined. The best known is the so-called classical or P-glycoprotein- related MDR phenotypes, in which resistance is due to reduction of the intracellular drug accumulation via a 170 kDa protein pump (P-glycoprotein). Jensen, et. al., New Directions in Drug Therapy of Small Cell Carcinoma based on in vitro studies, 234, in Carney, Lung Cancer (Arnold Pub. Co. 1995).
5.73 Why Dosage and Scheduling Can Be Critical
Devita and Park in their book on cancer, discuss the reasons why dosage scheduling can be critical and is the subject of many clinical trials.
"Rapidly growing tumors tend to be most sensitive to chemotherapy. Also, damage to normal tissues at short intervals after chemotherapy or wide_field radiation is most often observed in organs such as the bone marrow or the intestine, which are renewal tissue known to contain rapidly proliferating cells. These observations suggest that rapidly proliferating cells may be more susceptible to therapy and have led to several studies of the relationship between cytotoxicity and proliferative rate.
When mammalian cells are cultured, they show a period of exponential growth when all cells are proliferating, followed by slowing of growth as cells become crowded and consume available nutrients.... Frequently this type of experiment leads to survival curves which show that rapidly proliferating cells are more sensitive to the drug. This technique and others have demonstrated that some drugs (e.g. methotrexate, cytarbine, and vinca alkaloids) exert lethal effects only against proliferating cells. Others, including anthracylines and most alkylating agents, have some activity against slowly proliferating cells but are considerably more toxic to proliferating cells. Only for alkylating drugs, including cisplatin, nitrosoureas, and bleomycin, is there little or no selectivity, and this may be cell_line dependent.
Most drugs and ionizing radiation vary in their lethal effects at different phases of the cell Because most drugs have varying toxicity for cells in different phases of the cell cycle, immediately after treatment a high proportion of surviving cells will be partially synchronized in a resistant phase. Several investigators have proposed that drug treatment might be scheduled at intervals that allow the surviving tumor cells to progress to a drug sensitive phase of the cell cycle, or, conversely, such that cells in critical normal tissues are again in a drug_resistant phase. In practice, the wide heterogeneity of cell cycle parameters makes this difficult to achieve. It has been demonstrated that therapeutic outcome is markedly dependent on scheduling interval for drug treatment of experimental tumors, but it has been difficult to predict the optimum scheduling interval from knowledge of cell kinetics. Institute. For updated information visit its website(s) at www.nci.org. Devita, et. al, Principles and Practice of Oncology (Lippincott 3d ed. 1989)
This tells us is that chemotherapy administrations should not be missed. Since the oncology staff has carefully constructed a regimen based upon its knowledge of the location of the cancer, its stage, and other dynamics, that schedule should not be disrupted. If an administration is missed, the doctor should be immediately informed.
5.8 HOW DRUGS ARE SELECTED
The oncologists choice of drug depends on the type of cancer, location, stage, its impact on bodily functions, the patients general health, and his assessment of clinical trials or studies. Clinical trials are research studies that test new cancer treatments or refine existing ones. While some increase in survival times may be seen, most clinical trials do not show tremendous breakthroughs. Patients participate in clinical trials to make an important contribution to medical care and because other treatment options may be limited. To learn more about clinical trials, call the National Cancer Institute's Cancer Information Service and ask for the booklet What Are Clinical Trials All About? You also may want to ask about the videotape "Patient to Patient: Cancer Clinical Trials and You." The Cancer Information Service can be reached by dialing 1_800_4_CANCER (1_800_422_6237).
5.9 CHEMOTHERAPY ADMINISTRATION
5.91 Where is Chemotherapy Administered : Chemotherapy for lung cancer is generally administered in a phsyicians office, a clinic or hospital's oncology department. When the patient first begins chemotherapy, a hospital stay might be needed to assess the medicine's effects.
5.92 How Often Will Chemotherapy be administrered.?
How often the therapy is administered will vary. Chemotherapy is sometimes given in on_and_off cycles that include rest periods so that the body has a chance to re-build new cells and the patient regain its strength.
5.93 Goals of Chemotherapy
Depending on the type of cancer and its stage of development, chemotherapy can be used:
* To cure cancer.
* To keep the cancer from spreading.
* To slow the cancer's growth.
* To kill cancer cells that may have spread to other parts of the body from the original tumor. To relieve symptoms that may be caused by the cancer.
* Chemotherapy also help people live more comfortably by eliminating cancer cells which cause pain, discomfort or other problems. This is called palliative care, where the goal is to help the patient better function, not cure.
5.94 Methods of Administration
One common way for the drug to be given is by mouth. This is more convenient and less costly than other methods. The disadvantage is that may be many instructions given with the drug, and the patients should follow these instructions explicitly and maintain careful records of when the drugs are taken.
Drugs may also be injected into a vein where the cancer cells appear to be circulating. Two kinds of pumps_external and internal_ may be used to control the rate of delivery of chemotherapy. External pumps remain outside the body. Some are portable and allow a person to move around while the pump is in use. Other external pumps are not portable and may restrict activity. Internal pumps are placed surgically inside the body, usually right under the skin. They contain a small reservoir (storage area) that delivers the drugs into the catheter. Internal pumps allow people to go about most of their daily activities.
5.95 Does Chemotherapy Hurt
Getting chemotherapy by mouth, on the skin, or by injection generally feels the same as taking other medications by these methods. Having an IV started usually feels like drawing blood for a blood test. Some people feel a coolness or other unusual sensation in the area of the injection when the IV is started. Report such feelings to your doctor or nurse. Be sure that you also report any pain, burning, or discomfort that occurs during or after an IV treatment.
Many people have little or no trouble having the IV needle in their hand or lower arm. However, if a person has a hard time for any reason, or if it be comes difficult to insert the needle into a vein for each treatment, it may be possible to use a central venous catheter or port. This avoids repeated insertion of the needle into the vein. Central venous catheters and ports cause no pain or discomfort if they are properly placed and cared for, although a person usually is aware that they are there. It is important to report any pain or discomfort with a catheter or port to your doctor or nurse.
5.96 Use of Other Medication During Chemotherapy
Some medicines may interfere with the effects of your chemotherapy. That is why you should take a list of all your medications to your doctor before you start chemotherapy. Your list should include the name of each drug, how often you take it, the reason you take it, and the dosage. Remember to include over_the_counter drugs such as laxatives, cold pills, pain relievers, and vitamins. Your doctor will tell you if you should stop taking any of these medications before you start chemotherapy. After your treatments begin, be sure to check with your doctor before taking any new medicines or stopping the ones you already are taking.
5.97 Working During Chemotherapy
Most people are able to continue working while they are being treated with anticancer drugs. It may be possible to schedule your treatments late in the day or right before the weekend, so they interfere with work as little as possible. If your chemotherapy makes you very tired, you might want to think about adjusting your work schedule for a while. Speak with your employer about your needs and wishes at this time. You may be able to agree on a part_time schedule, or perhaps you can do some of your work at home. Under Federal and state laws, some employers may be required to allow you to work a flexible schedule to meet your treatment needs. To find out about your on_the_job protections, check with your local American Cancer Society, a social worker, or your congressional or state representative. The National Cancer Institute's publication Facing Forward: A Guide for Cancer Survivors, also has information on work_related concerns. How Will I Know If My Chemotherapy Is Working? Your doctor and nurse will use several methods to measure how well your treatments are working. You will have frequent physical exams, blood tests, scans, and x_rays. Don't hesitate to ask the doctor about the test results and what they show about your progress. While tests and exams can tell a lot about how chemotherapy is working, side effects tell very little. (Side effects_such as nausea or hair loss_occur because chemotherapy harms some normal cells as well as cancer cells.) Sometimes people think that if they don't have side effects, the drugs aren't working, or that, if they do have side effects, the drugs are working well. But side effects vary so much from person to person, and from drug to drug, that having them or not having them usually isn't a sign of whether the treatment is effective. If you do have side effects, there is a lot you can do to help relieve them. The next section of this document describes some of the most common side effects of chemotherapy and gives you some hints for coping with them.
1. Bruning, Coping with Chemotherapy (Ballantine Books 1993)
2. Devita, et. al. Principles and Practice of Oncology (1999)
It is important to discuss, but not overemphasize, the significance of side effects from chemotherapy. With the emergence of new drugs, medication to reduce side effects, and refinements in dose, some of the traditional side effects have been reduced. I discuss side effects generally, but only your oncologist can give you a case-specific analysis based upon, the nature of your disease and the type of chemotherapy provided.
The American Cancer Society Guide, Informed Consent (172) describes the reason for side effects:
"All the tissues and organs of the body are subject to an anticancer drugs action, which is to destroy rapidly dividing cells or prevent them from reproducing. Cancer cells, which continuously and quickly replace themselves, are obviously targets. But some health cells that also divide rapidly, such as those in the hair follicles and lining the intestinal trace, are vulnerable to the drugs as well. Consequently, temporary hair loss and nausea are common side effects. The challenge, then, for the oncologist is to balance the cancer-destroying benefits of a particular drug or combination of drugs against their toxic effects. It is sometime quite a delicate balance, but with good emotional and physical care and support the side effects can be managed in most cases and, if not fully controlled, at least made tolerable." The American Cancer Society Guide, Informed Consent 172 (1997).
Chemotherapy causes side effects in some patients. However, it is incorrect to therefore conclude that the decision to use chemotherapy represents a tradeoff between length and quality of life. One recent study analyzes quality of life with the use of an increasingly popular chemotherapy drug for lung cancer, vinorelbine. Effects of Vinorelbine on Quality of Life and Survival of Elderly Patients with Advanced Non Small-Cell Lung Cancer, 91, No. 1 66-72 (Jan. 6, 1999)
First, the study found that vinorelbine extended life among the stage 3b and 4 patients with advanced lung cancer. Survival rates at 6 months and .12 months were 55% and 32% in the chemotherapy treated group versus 41% and 14% in the group receiving best available care without chemotherapy. Indeed, the trial had to be stopped because physicians were increasingly reluctant to assign patients to the control group whose mortality rate was demonstrably higher. There is increasingly little debate that chemotherapy extends life even among advanced lung cancer patients, at 3b and 4. In the vinorelbine chemotherapy group, there was one patient with a complete remission and 14 partial responses of 50% or more reduction in tumor volume (of approximately 76 in the group). There should be little question that chemotherapy has proven to be effective even with patients whose cancer has metastasized to lymph nodes or other organs. Chemotherapy will extend life in many cases, and in a few it had the capacity to serve as a cure. Based upon this study and some others, the only realistic question is what type of chemotherapy should be prescribed.
Equally important to cancer patients were the findings of quality of life. Quality of life or (Qol) can be statistically measured using a questionnaire given to patients in the clinical trial, and comparing results in the group receiving chemotherapy and the one given best supportive care. Vinorelbine-treated patients scored better on quality of life, and the study found a reduction in cancer-related symptoms such as pain and dyspnea, loss of breath. This would presumably correlate with the reduction in the size of the tumor in many cases. The study did find an increase in certain chemo-related side effects. Constipation was observed in three patients, heart arrhythmias in two, loss of hair- alopecia in three, and other side effects in approximately five. Thus there is a sad tradeoff between chemo-related side effects and those of the disease itself, but most would prefer the chemotherapy and the prospect of extending life with the drug. The study concludes, "we obtained a survival advantage that was not at the expense of a worse Qol (quality of life). It should be noted that while these results may be representative, they remain to be duplicated, since quality of life has generally not be the focus of studies of chemotherapy and lung cancer. Likewise, the results of other chemotherapy drugs such as cisplatin could be conceivably different.
Some anticancer drugs cause nausea and vomiting because they affect parts of the brain that control vomiting and/or irritate the stomach lining. The severity of these symptoms depends on several factors, including the chemotherapeutic agent(s) used, dose, schedule, and the patient's reaction. Management of nausea and vomiting caused by chemotherapy is an important part of care for cancer patients when it does occur. Although patients usually receive antiemetic drugs that help control nausea and vomiting, there is no single best approach to reducing these symptoms in all patients. Doctors must tailor antiemetic therapy to meet each individual's needs, taking into account the type of anticancer drugs being administered; the patient's general condition, age, and related factors; and, of course, the extent to which the antiemetic is helpful. Note, however, that our ability to combat nausea has improved, and do not assume that side effects encountered by a patients 10 years ago will occur with the same severity today.
5.21 Mainstream Anti_emetic Drugs
The informative book, A Guide to Chemotherapy states, "Sedative/hypnotics such as Valium and almane have been used to reduce nausea in patients. Many oncologists are prescribing Ativan, an antinausea medication that also acts as an antidepressant and sleeping pill."
5.22 Marijuana and Nausea
There has been some interest in the use of marijuana to treat a number of medical problems, including chemotherapy_induced nausea and vomiting in cancer patients. Two forms of marijuana have been used: compounds related to the active chemical constituent of marijuana taken by mouth and marijuana cigarettes. Dronabinol (Marinol), a synthetic form of the active marijuana constituent delta_9_tetrahydrocannabinol (THC), is available by prescription for use as an antiemetic. The U.S. Food and Drug Administration has approved its use for treatment of nausea and vomiting associated with cancer chemotherapy in patients who have not responded to the standard antiemetic drugs.
NCI scientists feel that antiemetic drugs or combinations of antiemetic drugs have been shown to be more useful than synthetic THC as "first_line therapy" for nausea and vomiting caused by anticancer drugs. Examples include drugs called serotonin antagonists, including ondansetron (Zofran) and granisetron (Kytril), used alone or combined with dexamethasone (a steroid hormone); metoclopramide (Reglan) combined with diphenhydramine and dexamethasone; high doses of methylprednisolone (a steroid hormone) combined with droperidol (Inapsine); and prochlorperazine (Compazine). Continued research with other agents and combinations of these agents is under way to determine their usefulness in controlling chemotherapy_induced nausea and vomiting. However, NCI scientists believe that synthetic THC may be useful for some cancer patients who have chemotherapy_induced nausea and vomiting that cannot be controlled by other antiemetic agents. The expected side effects of this compound must be weighed against the possible benefits. Dronabinol often causes a "high" (loss of control or sensation of unreality), which is associated with its effectiveness; however, this sensation may be unpleasant for some individuals. The informative book, A Guide to Chemotherapy deals specifically with the side effects of chemotherapy and discusses them generally, though not specifically with reference to chemotherapy drugs for lung cancer. "Sedative/hypnotics such as Valium and Dalmane have been used to reduce nausea in patients. Many oncologist are prescribing Ativan, an antinausea medication that also acts as an antidepressant and sleeping pill."
5.3A CHEMOTHERAPY AND INFECTION
Chemotherapy may increase the risk of infection:
Chemotherapy and extensive radiotherapy often interfere with t he formation and maturation of blood cells (hematopoeises)... According to a Gallup poll of chemotherapy patients,nearly half had their treatment postponed at least once because their white counts were alarmingly low. White cells safeguard us again infection, partiuclarly the neutrophils, which make up 60 percent of all white cells. Their job is to intercept and destroy bacteria. A person is said to be mildly neutropenic when her absolute neutrophil count (ANC) is between 2,000 and 1,000. The ANC is determined by multiplying the percentage of neutrophils by the total white-blood-cell count. Oncologists will generally continue chemotherapy so long as the number says in the 500-1000 range, which is considered moderate netrupenia....
Most chemo regimens suppress your immune system for perhaps a week to ten days, after which time the neutrophil count starts climbing back. The other key players in fighting off disease are the lymphocytes
Some general precautions against infection:
CWash your hands frequently. Be sure to clean under your nails and between your fingers. Take a warm bath or shower each day and wash between folds of skin. Germs may locate inside the groin, between a womans breasts- anywherte than skin touches skin and is not exposed to air.
CStay anyone from anyone with a cold or disease. Do not share drinking glasses, washclothes or other items which may carry germs.
CWhen you are done preparing food- particularly meat, poultry, and eggs, disinfect countertops and cutting boards.
CAvoid small groceries and check food expiration dates. Avoid food leftover for more than a day. Check that your refridgerator and freezer are working properly.
CCook fresh vegetables. Avoid raw foods like shellfish or sushi.
Any observer must express tremendous admiration for the typical patient. Chemotherapy can bring major changes to a person's life. It can affect overall health, threaten a sense of well_being, disrupt day_to_day schedules, and put a strain on personal relationships. No wonder, then, that many people feel tearful, anxious, angry, or depressed at some point during their chemotherapy. These emotions are perfectly normal and understandable, but they also can be disturbing. Fortunately, there are ways to cope with these emotional "side effects," just as there are ways to cope with the physical side effects of chemotherapy. (Some time after this was written, my wife contracted a form of cancer, not of the lung. However, I realized that is far easier to talk about calmness and relaxation as anoutlooker, than as a patient or family member).
5.5 SOURCES OF SUPPORT
There are many sources of support you can draw on. Here are some of the most important:
* Doctors and nurses. If you have questions or worries about your cancer treatment, talk with members of your health care team. Some doctors may be easily to speak with about side effects, while others may be more distant and clinical. Try to find a knowledgeable and sympathetic person at your hospital or phsyicians office so you can discuss issues of side effects or other questions.
* Counseling professionals. There are different kinds of counselors who can help you express, understand, and cope with the emotions cancer treatment can cause. Depending on your preferences and needs, you might want to talk with a psychiatrist, psychologist, or social worker.
* Religious Groups Your priest, minister, or rabbi is best qualified to talk about the difficult questions you may experience during treatment. It is perfectly appropriate to reach out to your clergyman even if you have not attended services.
* Friends and family members. Talking with friends or family members can help you feel a lot better. Often, they can comfort and reassure you in ways that no one else can. You may find, though, that you'll need to help them help you. At a time when you might expect that others will rush to your aid, you may have to make the first move.
Some people do not understand cancer, and may withdraw from you because they're afraid of your illness. Others may worry that they will upset you by saying "the wrong thing." You can help relieve these fears by being open in talking with others about your illness, your treatment, your needs, and your feelings. By talking openly, you can correct mistaken ideas about cancer. You can also let people know that there's no single "right" thing to say, so long as their caring comes through loud and clear. Once people know they can talk with you honestly, they may be more willing and able to open up and lend their support. The National Cancer Institute's booklet Taking Time offers useful advice to help cancer patients and their families and friends communicate with one another.
* Support groups. Support groups are made up of people who are going through the same kinds of experiences as you. Many people with cancer find they can share thoughts and feelings with group members that they don't feel comfortable sharing with anyone else. Support groups also can serve as an important source of practical information about living with cancer. Support can also be found in one_to_one programs that put you in touch with another person very similar to you in terms of age, sex, type of cancer, and so forth. In some programs, this person comes to visit you. In others, a "hotline" puts you in touch with someone you can talk with on the telephone. Sources for information about support programs include your hospital's social work department, the local office of your American Cancer Society, and the National Cancer Institute's Cancer Information Service. (See Resources.)
There are a variety of sources of assistance available on the Internet. One is a group which shares their experience by way of posting to a news group. For those unfamiliar with the Internet, these are groups devoted to specific subjects, on American Online, simply use the key word newsgroup. Individuals can post a question or comment on a prior posting with the posts divided by topic. For some, it is easier to talk about sensitive topics on computer in the anonymity of your own home. The occasional disadvantage is that misinformation could be communicated. However, by and large, people find these news groups to be a useful way of acquiring information and communicating your feelings.
Here are some tips to help yourself while you are getting chemotherapy from the National Cancer Institute:
* Try to keep your treatment goals in mind. This will help you keep a positive attitude on days when the going gets rough. Remember that eating well is very important. Your body needs food to rebuild tissues and regain strength.
* Keep a journal or diary while you're in treatment. A record of your activities and thoughts can help you understand the feelings you have as you go through treatment, and highlight questions you need to ask your doctor or nurse. You also can use your journal to record the steps you take to cope with side effects and how well those steps work. That way, you'll know which methods worked best for you in case you have the same side effects again.
* Set realistic goals and don't be too hard on yourself. You may not have as much energy as usual, so try to get as much rest as you can, let the "small stuff" slide, and only do the things that are most important to you.
* Ask your doctor or nurse about a safe and practical exercise program. Using your body can help you feel better about yourself, help you get rid of tension or anger, and build your appetite.
5.6 RELIEVING STRESS
You can use a number of methods to cope with the stresses of cancer and its treatment. Here are some techniques recommended by the National Cancer Institute.
" Muscle tension and release. Lie down in a quiet room. Take a slow, deep breath. As you breathe in, tense a particular muscle or group of muscles. For example, you can squeeze your eyes shut, frown, clench your teeth, make a fist, or stiffen your arms or legs. Hold your breath and keep your muscles tense for a second or two. Then breathe out, release the tension, and let your body relax completely. Repeat the process with another muscle or muscle group.
You also can try a variation of this method, called "progressive relaxation." Start with the toes of one foot and, working upward, progressively tense and relax all the muscles of one leg. Next, do the same with the other leg. Then tense and relax the rest of the muscle groups in your body, including those in your scalp. Remember to hold your breath while tensing your muscles and to breathe out when releasing the tension.
* Rhythmic breathing. Get into a comfortable position and relax all your muscles. If you keep your eyes open, focus on a distant object. If you close your eyes, imagine a peaceful scene or simply clear your mind and focus on your breathing. Breathe in and out slowly and comfortably through your nose. If you like, you can keep the rhythm steady by saying to yourself, "In, one two; Out, one two." Feel yourself relax and go limp each time you breathe out.
You can do this technique for just a few seconds or for up to 10 minutes. End your rhythmic breathing by counting slowly and silently to three.
* Biofeedback. With training in biofeedback, you can help control body functions such as heart rate, blood pressure, and muscle tension. A machine will sense when your body shows signs of tension and will let you know in some way such as making a sound or flashing a light. The machine will also give you feedback when you relax your body. Eventually, you will be able to control your relaxation responses without having to depend on feedback from the machine. Your doctor or nurse can refer you to some one trained in teaching biofeedback.
* Imagery. Imagery is a way of daydreaming that uses all your senses. It usually is done with your eyes closed. To begin, breathe slowly and feel yourself relax. Imagine a ball of healing energy_ perhaps a white light_forming somewhere in your body. When you can "see" the ball of energy, imagine that as you breathe in you can blow the ball to any part of the body where you feel pain, tension, or discomfort such as nausea. When you breathe out, picture the air moving the ball away from your body, taking with it any painful or uncomfortable feelings. (Be sure to breathe naturally; don't blow.) Continue to picture the ball moving toward you and away from you each time you breathe in and out. You may see the ball getting bigger and bigger as it takes away more and more tension and discomfort. To end the imagery, count slowly to three, breathe in deeply, open your eyes, and say to yourself, "I feel alert and relaxed." .
* Visualization. Visualization is a method that is similar to imagery. With visualization, you create an inner picture that represents your fight against cancer. Some people getting chemotherapy use images of rockets blasting away their cancer cells or of knights in armor battling their cancer cells. Others create an image of their white blood cells or their drugs attacking the cancer cells.
Visualization and imagery may help relieve stress and increase your sense of self_control. But it is very important to remember that they cannot take the place of the medical care your doctor prescribes to treat your cancer.
* Hypnosis. Hypnosis puts you in a trance_like state that can help reduce discomfort and anxiety. You can be hypnotized by a qualified person, or you can learn how to hypnotize yourself. If you are interested in learning more, ask your doctor or nurse to refer you to someone trained in the technique.
* Distraction. You use distraction any time an activity takes your mind off your worries or discomforts. Try watching TV, listening to the radio, reading, going to the movies, or working with your hands by doing needlework or puzzles, building models, or painting. You may be surprised how comfortably the time passes."
5.7A LOSS OF WEIGHT, ANOREXIA AND CACHEXIA
Anorexia, the loss of appetite or desire to eat, is the most common symptom in cancer patients that may occur early in the disease or later as the cancer grows and spreads. Cachexia is a wasting condition in which the patient has weakness and a marked and progressive loss of body weight, fat, and muscle. Anorexia and cachexia frequently occur together, but cachexia may occur in patients who are eating an adequate diet but have malabsorption of nutrients. "Tumor cells deprive normal cells of nutrients. Meanwhile the body is expending extra energy as it heals from the effects of cancer surgery, radiotherapy, or chemotherapy . In order to sustain vital functions, the body retrieves nutrients stored in fatty tissue. Once all available fat has been broken down for fuel, it sets to work on muscle. Of all nutrients, protein is the one most essential for building muscle, bone, skin, and bood cells. If the bodys cells consume more protein than you take in, muscle mass rapidly wastes away, causing the emaciated look often associated with cancer." Teelley & Bashe, The Complete Cancer Survival Guide (Doubleday 2000). Maintenance of body weight and adequate nutritional status can help patients feel and look better, and maintain or improve their performance status. Teely recommends the following:
COMPLETE PROTEINS canned tuman, skinless turkey, steak, whitemeat chicken, whole milk, hard-boiled effs, nuts, wheat germ.
NUTRIONAL SUPPLMENTS with your oncologists approval
LIGHT EXERCISE To stimulate your appetite,
The author of that book, a cancer patient himself, recommends foods dense in high-quality protein. such as meat, chicken, fish, egs, and dairy products. Some patients may not easily tolerate these foods, and you will need to structure a diet which provides the necessary nutrients without creating nausea.
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