CHEMOTHERAPY DRUGS  FOR LUNG CANCER, 

6.6 PARTICULAR CHEMOTHERAPY DRUGS

6.61. Paclitaxel

6.611 Origin

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 Dr. 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).

6.612 Manufacturer

Taxol is manufactured by Bristol-Meyers Squibb. Www.BMS.com.

6.613 Taxol Side effects:

The degree and severity of the side effects depend on the amount and schedule of the administration of Taxol. Following are some of the most common and important ill effects: Low white blood counts, low platelet count, anemia, hair loss, soreness of the mouth, difficulty swallowing , diarrhea, nerve damage, allergic reactions, fluid retention. The occurrence of allergic reactions, skin reaction and fluid retention can be reduced by pretreatment of patients with steroids. It is imperative that patients relay any side effects or problems to their medical oncologist. Taxol is metabolized in the liver and excreted into bile. Dose of Taxol should be reduced in patients with liver dysfunction or massive liver metastasis.

2.Docetaxel

A recent press release touted the ability of Docetaxel to address non-small cell lung cancer, at least where prior chemotherapy had been unsuccessful:

"Aventis SA (NYSE: AVE), announced today that Taxotereź (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.

Each year an estimated 171,500 Americans will be diagnosed with lung cancer, and approximately 160,000 people will die of the disease. Deaths from lung cancer account for 28 percent of all cancer deaths.

Taxotere is the first chemotherapeutic agent to be approved by the FDA for the second-line treatment of  advanced non-small-cell lung cancer," said John Leone,Senior Vice President, US Commercial Operations, Aventis Pharmaceuticals. 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. 

This FDA approval is one of the first to be received by the newly created Aventis Pharmaceuticals, the recent merger between Hoechst Marion Roussel, Inc. and

Rhone-Poulenc Rorer Pharmaceuticals, Inc. The approval was based on the results of two landmark studies involving over 500 patients, and the first Phase III clinical trials ever conducted with advanced NSCLC patients.

We found that patients treated with Taxotere in the second-line setting had a significant improvement in their survival," said Frank V. Fossella, MD, Medical Director, Thoracic Medical Oncology Multidisciplinary

Care Center at The University of Texas, M. D. AndersonCancer Center in Houston, and primary investigator of one of the trials. Standard treatment regimens for this patient population have shown no evidence of survival improvement. With the one-year survival rates seen in both trials, Taxotere should be considered the standard of care for these patients with advanced non-small-cell lung cancer.  In a worldwide, multicenter Phase III trial, 204patients who had previously failed platinum-based chemotherapy received either 75 mg/m2 or 100 mg/m2 of Taxotere every three weeks plus best supportive care (BSC), or BSC alone. BSC refers to  measures aimed at maintaining patient comfort, including nutritional support and control of symptoms such as nausea, vomiting, pain and shortness of breath.

Patients treated with Taxotere, 75 mg/m2, had a median survival of 7.5 months versus 4.6 months in patients who received BSC. The time to disease progression  was 12.3 weeks and seven weeks in the Taxotere, 75 mg/m2, and BSC groups, respectively. The one-year survival rate was significantl/y higher in the Taxotere group (37 percent) versus the comparator group (12 percent).The clinical-benefit analysis showed that patients treated with Taxotere, 75 mg/m2, did not experience deterioration in performance status (daily life activities) or body weight compared to the other treatments.

In the other Phase III study, 373 patients with advanced NSCLC who were resistant to platinum-based chemotherapy received either treatment with Taxotere, 75 mg/m2 or 100 mg/m2, every three weeks, or treatment with either vinorelbine, 30 mg/m2 weekly, or ifosfamide, 2 gm/m2 daily for three days every three weeks. The study, which was carried out at 23 US cancer centers, found that the one-year survival rate in patients treated with 75 mg/m2 of Taxotere was 30 percent, compared to 20 percent in patients treated with either vinorelbine or ifosfamide.The major side effects of Taxotere, 75 mg/m2, in both studies were myelosuppression (low blood cell counts), fatigue, nausea and alopecia.

About Taxotere: Taxotere, a drug in the toxoid class of chemotherapeutic agents, inhibits cancer cell division by essentially "freezing" the cellĂs internal skeleton, which is comprised of microtubule. Microtubule assemble and disassemble during a cell cycle. Taxotere promotes their assembly and blocks their disassembly, thereby preventing cancer cells from dividing and resulting in cancer cell death. Recently, the Committee for Proprietary Medicinal Products (CPMP) recommended approval for Taxotere in the 15 Member States of the European Union for the treatment of patients with locally advanced or metastatic NSCLC after failure of prior chemotherapy. It is presently approved for the treatment of advanced NSCLC in more than 40 other countries, including Japan, Australia and Canada.

Taxotere was first approved in the US in 1996 for the treatment of advanced breast cancer after failure of anthracycline-based therapy. Taxotere is now approved

in more than 80 countries, including the US and the European Union, for the treatment of advanced breast cancer after failure of prior chemotherapy. In patients with normal liver function, side effects reported to date include neutropenia, thrombocytopenia (low platelet count), anemia, fluid retention, hypersensitivity, nausea and diarrhea. A premedication regimen with corticosteroid is recommended in order to prevent or reduce hypersensitivity and fluid retention.

Taxotere is generally not appropriate therapy for patients with liver impairment." About.Com Pharmaceutical Guide Quoting December 23, 1999 Press Release by Aventis 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.

6.64 Tamoxifen

6.641 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,

6.642 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)

6.643 Classification

Tamoxifen is classified as a hormonal/biological response modifier or an antineoplastic. (2)

6.644 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 and rarely severe enough to require discontinuation of treatment." (2)

6.644A Emotional Changes

Since Tamoxifen impacts a hormone which in turn interacts with mood, it can conceivably impact mood or create emotional changes

6.644B 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

3.Vinorelbine

It is active as single therapy in non pretreated NSCLC. It has been successfully combined with cisplatin. Vinorelbine has been investigated in 4 randomized trials. Administered alone, it has been shown to significantly improve survival in comparison to 5-fluorouracil (Crawford, J Clin Oncol 14:2774; 1996) and response rate (but not survival) in comparison to vindesine ( Furuse, Ann Oncol 7: 815; 1996). 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%). 

4.Gemcitabine

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. It has been successfully combined with cisplatin and ifosfamide in phase II studies. Results of phase III trials are waited. Some have suggested that the side effets from Gemcitabine, or Gemcar as it is sometimes called, are limited.

5.Topotecan

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.

6.Irinotecan

The drug has been shown active against unpretreated NSCLC. Confirmatory trials are required. In conclusion, new drugs have appeared with promising activity against NSCLC.

However, the data today available in the literature are too limited to define exactly their role and their indications in the management of this disease."

6.7 WHY CHEMOTHERAPY MAY NOT BE COMPLETELY SUCCESSFUL

Chemotherapy works best when there are (1) small numbers of cancer cells that are (2) actively dividing. Thus, chemotherapy is highly effective with small cell lung cancers promptly diagnosed, since this type of cancer rapidly divides. Chemotherapy works most effectively when the drugs target rapidly dividing cells. 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.

6.71 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 in subsequent is 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 100 fold.

6.72 Assessing Resistance to Chemotherapy

Twentyman comments on resistance to chemotherapy:

(One study found) that cell lines from patients with untreated small cell cancer were more sensitive to both drugs than lines from patients with small cell carcinoma who had received previous chemotherapy. Furthermore lines from patients with non-small cell tumors were less sensitive than either of these groups. Measurements of GSH showed the levels were on average 3-fold higher in non-small lines than in small cell lines. Twentyman, Mechanisms of Drug Resistance in Lung Cancer Cells, 214, in Carney, Lung Cancer (Arnold Pub. Co. 1995)

Another contributor to the same book states,

At least three different MDR (multi-drug resistance) phenotypes exist. two of which 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). See also, Bernal, Drug Resistance in Oncology (Date unknown)

6.72 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) 

One thing 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.

6.8 HOW DRUGS ARE SELECTED

The oncologist choice of drug selection depends on the type of cancer, location, stage, its impact on bodily functions, and the patient’s general health. Your doctor also may suggest that you join a clinical trial for chemotherapy, or you may want to bring up this option with your doctor. 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 only if they choose and they may make an important contribution to medical care. 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).

 6.8 CHEMOTHERAPY ADMINISTRATION

Where is Chemotherapy Administered

You may get chemotherapy at home, in your doctor's office, in a clinic, in your hospital's outpatient department, or in a hospital. The choice of where you get chemotherapy depends on which drug or drugs you are getting, your hospital's policies, and your doctor's preferences. When you first start chemotherapy, you may need to stay at the hospital for a short time so that your doctor can watch the medicine's effects closely and make any adjustments that are needed.

6.92 How Often Will I Get Chemotherapy, and How Long Will I Get It?

How often and how long you get chemotherapy depends on the kind of cancer you have, the goals of the treatment, the drugs that are used, and how your body responds to them. You may get chemotherapy every day, every week, or every month. Chemotherapy is often given in on-and-off cycles that include rest periods so that your body has a chance to build healthy new cells and regain its strength. Your doctor should be able to estimate how long you will be getting chemotherapy. It is very important to stick with whatever schedule your doctor prescribes. Otherwise, the anti cancer drugs might not have their desired effect. If you miss a treatment session or skip a dose of medication, contact your doctor for instructions about what to do.

Sometimes, your doctor may delay a treatment based on the results of certain blood tests. (See Fatigue/Anemia.) Your doctor will let you know what to do during this time and when it's okay to start your treatment sessions again.

6.93 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.

6.94 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.

6.95 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.

6.96 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.

6.97 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.

FOOTNOTES

1. Bruning, Coping with Chemotherapy (Ballantine Books 1993)

2. Devita, Principles and Practice of Oncology (1999)

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