This Article Discusses About:
- Chemotherapy as a Standalone or Adjuvant Treatment For Cancer
- The Goals of Chemotherapy in Cancer
- The Effect of Chemotherapy on Cancer Cells
- Different Types of Chemotherapy Drugs
- Choice of Chemotherapy Drugs
- Dosing is Dependent on Side Effects of Chemotherapy Drugs
- Drug Interactions
- Side Effects of Chemotherapy
- Route of Administration of Chemotherapy
- New Advances in Chemotherapy
- Clinical Impact of Chemotherapy on Cancer
- Why Does Hair Grow Back Crinkly or Curly After Chemotherapy?
What Is Chemotherapy?
Chemotherapy is a term widely used today with reference to the treatment of cancer. The original meaning of chemotherapy is to treat a disease with a chemical (drug).There are two kinds of cancer chemotherapies depending on mode of action of the drug. The anti-neoplastic therapy inhibits cancer while the cytotoxic chemotherapy kills cells.( http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapyprinciplesanin-depthdiscussionofthetechniquesanditsroleintreatment/index ref )
History Of Chemotherapy
During world war I nitrogen mustard gas was used in chemical warfare. Nitrogen mustard is extremely toxic by inhalation. During world war II, troops were exposed to spills of mustard accidentally on a bombed ship in Bari Harbor, Italy (A History of Cancer Chemotherapy. Vincent T. DeVita, Jr. and Edward Chu. Cancer Research 2008; 68: (21). November 1, 2008 ref ). After world war II, it was found that these individuals had very low white blood cell counts in their bone marrow and lymph nodes. Milton Winternitz at Yale University launched a study into this phenomenon, with the help of Goodman and Gilman, two renowned pharmacologists, at Yale. It was reasoned that depletion of white blood cells may be therapeutic in case of lymphomas. Lymphomas are cancers of the white blood cells that result in un-controlled multiplication of white blood cells with concentrations several-fold magnitude higher than normal white blood cell counts. In 1943 Goodman and Gilman administered nitrogen mustard intravenously to lymphoma patients. Regression of lymphoma was observed in these patients. Gustaf Lindskog, a thoracic surgeon and a colleague of Gilman and Goodman, treated a non- Hodgkins’s lymphoma patient with mustard gas by intravenous administration. Again, a marked regression of the cancer was observed. Other patients were subsequently treated with successful regression of their lymphomas.
Now, there are in excess of 100 chemotherapeutic drugs available for cancer treatment. Further treatment modalities are even more numerous, as drugs can be administered as monotherapy (only one drug), or in combination as two or more drugs. The drugs available today have different chemical compositions, structures, mechanisms of action, and hence differ in their therapeutic effects on different cancer forms, are useful in different drug combinations for treating different cancers. The side-effects of the drugs are also distinct due to the difference in mode of action. Both therapeutic effect and bystander or side effect differ depending on chemical nature of the drug. In lay terms the side effect represents collateral damage, during treatment of cancer. Efforts are constantly on for novel and better therapeutics with more effective modes of action, and stronger tumor regression, or even eradication of cancer, which are difficult goals to achieve.
Several drugs are in preclinical and even clinical trial stages. Successful drugs today include not only small chemical entities, but large molecules such as proteins and antibodies- jointly called biotherapeutics. A further class of compounds- a combination of small chemical molecules conjugated to antibodies or antibody-drug conjugates, has also been found effective in cancer therapy.
Chemotherapy As A Standalone Or Adjuvant Treatment For Cancer
Chemotherapy alone can be administered to treat cancer, or it is used in combination with other forms of cancer therapy such as radiotherapy and/or resection (excision of tumor by surgery). When chemotherapy is used along with other treatment modalities it is referred to as adjuvant therapy. Chemotherapy is given prior to surgical removal of tumor or radiotherapy as chemotherapy shrinks the tumor, making it easier to remove. This is called neoadjuvant chemotherapy. In other cases chemotherapy is given after a tumor is removed either by surgical excision or by radiotherapy, in order to kill any stray tumor cells and prevent them from establishing new tumors, i.e. to prevent tumor metastasis. Chemotherapy when used before or after other tumor eradication procedures, is particularly useful in getting rid of any cancer cells that escape detection by conventional methods such as X-rays or CT scans as chemotherapy is generalized - unlike radiotherapy and of course, surgical resection, which target only the specific tumor harboring area in the body, chemotherapy affects the entire body. Generally chemotherapy is administered systemically (whole body). However, chemotherapy can also be localized by using specific administration methods.
The Goals Of Chemotherapy In Cancer Treatment
There are 3 possible goals for chemotherapy treatment:
Cure: Since cancer cannot be guaranteed to never “come back” or relapse, cancer treatment including chemotherapy is considered of curative intent, if complete irreversible eradication is a possibility. The relapse can occur many years after the treatment period is over. However complete cures do occur.
Prolonged Survival/Control: Often chemotherapy alleviates the cancer to a significant extent, sending the cancer into regression or a dormant phase by shrinking the tumor and inhibiting tumor metastasis (spreading). Thus the tumor is held in check, allowing the patient to live longer. Eventual progression occurs but it is slow, and hence the acute phase is delayed, and the devastation caused by cancer is delayed. Here cure is not possible but the patient gets a “lease on life’, allowing a longer lifetime with higher quality of life. Survival is prolonged.
Palliation: When the cancer is incurable and in an advanced stage, chemotherapy is used to relieve the debilitating effects of cancer to the extent of improving the quality of life of the patient. However it is not possible to decrease tumor progression rate. Survival is not improved.
Render Radiosensitivity to Cancer Cells:
Phytochemicals in combination with ionizing gamma radiation induce cytotoxic effects on cancer cells by initiating oxidative damage to cell membranes and generation of intracellular reactive oxygen species that cause damage to cellular proteins, and nucleic acids- DNA and RNA, thus resulting in killing of cancer cells. Researchers measured reactive oxygen species generation and membrane peroxidation by DCF-FDA and DPH fluorescence in cancer cell lines like Human cervical (HeLa) and breast (MCF-7), Ehrlich Ascites (EAC). Examples of phytochemicals that render tumor radiosensitive include Arachidonic acid , Tocopherol Succinate (TOS), Eugenol, (EU), Triphala (TPL), and Eugenol (EU).
The use of chemotherapy along with radiotherapy may be considered both as a treatment goal of chemotherapy to sensitize tumor to radiation, and also as a new treatment approach to cancer (Potential of radiosensitizing agents in cancer chemo-radiotherapy. S Girdhani, SM Bhosle, SA Thulsidas, A Kumar, KP Mishra. Journal of Cancer Research and Therapeutics. 2005,Volume : 1, Issue : 3, Page : 129-131 ref )
The Effect of Chemotherapy on Cancer Cells
During a cell’s life cycle five stages occur. The cell replicates its genome and divides to produce two identical daughter cells that carry identical genetic material. The cell cycle keeps repeating- this is called cell multiplication or replication. Like all cells, tumor cells also go through cell replication. To inhibit and to eliminate the tumor, it is basic to prevent or inhibit replication of cancer cells. Chemotherapeutics inhibit the cell cycle and thus prevent the cell’s replication.
The five stages of a cell’s life cycle are:
- G0 Phase: The cell is in the resting stage. The cell proceeds to the next phase G1 when it receives a signal which induces it to do so. Most of the time cells spend in the resting stage. G0 can be a few hours or a few years depending on the cell type
- G1 Phase: The cell prepares for DNA synthesis. During this phase the size of the cell increases, it increases protein synthesis as it needs enough cellular machinery to distribute between two daughter cells, and it needs proteins and factors needed for DNA replication as well as transcription and translation factors. This phase covers 18-30 hours.
- S Phase: In this phase the cell undergoes DNA replication to make duplicate copies of its entire genome- two sets of identical chromosomes are made ready to distribute to the two daughter cells. The phase covers 18-20 hours.
- G2 Phase: The cell undergoes rapid growth and protein synthesis and starts preparing for mitosis i.e. splitting of the cell into two cells. At the G2 phase there is a DNA damage checkpoint- any cell with damage to its DNA is arrested, and prevented from continuing to the next phase which is the M phase. The G2 phase takes 2-10 hours
- M Phase: Here the cell undergoes mitosis and splits into two daughter cells, undergoes condensation of DNA and chromosomal segregation into the two daughter cells. This phase lasts 0.5-1 hour
At any stage of the cell’s life cycle chemotherapeutics disrupt cellular processes or molecules required for cell replication, thus inhibiting the cell cycle and cell growth. There are two kinds of chemotherapeutic drugs: those that target all stages of the cell cycle and those that target only a specific stage of the cell’s life cycle. Knowing the exact mechanism of the action of each drug helps decide the best drug combination to use for treating a particular cancer. For e.g. a drug that attacks the G1 phase and a drug that attacks the M phase can be used effectively, while combining two drugs that attack the G1 phase will provide no additional benefit or purpose due to the redundant action of the two drugs.
In addition, certain drug activities can have synergistic effects. Another very important consideration is the side-effects of chemotherapy. The safest combination to give the greatest benefit with the least damage to normal tissue due to side-effects is the sought-after treatment choice. The physician strikes a balance between efficacy in control of the cancer cells and negative drug effects in order to deliver the best therapeutic benefit to the patient. Drugs that have similar or augmentative side-effects should not be used together. Depending on the specificity of the chemotherapeutic drug towards a cell cycle stage, the clinician determines the dosing schedule which depends on the timing of the cell cycle phase. If a combination of drugs is used, the sequence in the cell cycle and timing of the phase targeted by each drug helps decide the sequence in which the drugs must be administered.
The Drugs That Do Not Target A Specific Stage Of The Cellular Life Cycle Include:
- Alkylating agents (mechlorethamine, melphalam, busulfan, chlorambucil, cycophosphamide, ifosfamide)
- Anthracyclines darubicin(doxorubicin, daunorubicin, idarubicin
- Rifampicin and derivatives
- Mitomycin C
- Dacarbazine, cisplatin, carboplatin
G1 phase interference by:
S phase interference by:
- Antimetabolites (antifolates e.g. methotrexate;antipyrimidines e.g. cytarabine, capecitabine, 5-fluorouracil, gemcitabine; antipurine e.g.mercaptopurine, thiguanine, fludarabine, chlorodeoxyadenosine; hydroxyurea; procarbazine; steroids
G2 phase interference by:
- Podophyllotoxins e.g. etoposide (VP-16), teniposide (VM-26)
M phase interference by:
- Vinca alkaloids (vincristine, vinblastine, vinorelbine)
- Taxanes (paclitaxel, docetaxel)
Different Types Of Chemotherapy Drugs
Chemotherapeutic drugs can be classified on the basis of chemical structure, mode of action and relationship to other drugs. Following is a classification based on their mode of action. Often chemicals with similar structure act in a similar manner as they possess related chemical properties.(http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapyprinciplesanin-depthdiscussionofthetechniquesanditsroleintreatment/chemotherapy-principles-types-of-chemo-drugs ref )
Alkylating agents are chemicals that damage DNA by alkylating the guanine base within DNA. Alkylating agents damage DNA in rapidly dividing tissue. Bone marrow and lymph nodes where white blood cells are generated are major organs to be adversely affected resulting often in development of secondary leukemia five to ten years after cessation of chemotherapy. The risk of developing leukemia increases with increase in dose strength of the alkylating agent. Alkylating agents are used to treat both hematologic and solid tumors such as leukemia, lymphoma, Hodgkins disease, sarcoma, multiple myeloma, breast cancer, lung cancer and ovarian cancer.
Nitrogen mustards, nitrosoureas, alkyl sulfonates, triazines, ethylenimines and platinum drugs are all alkylating agents. However the platinum drugs are safer as the induction of leukemia is significantly lower with these drugs than other alkylating agents. This is because platinum drugs act differently as they do not have an alkyl group, but they do attach to DNA and cause DNA damage.
The subclasses of alkylating agents and examples are listed below as per American cancer society and www.cancer.org:
- Nitrogen mustards include mechlorethamine (nitrogen mustard), chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan.
- Nitrosoureas include streptozocin, carmustine (BCNU), and lomustine
- Alkyl sulfonates include busulfan
- Triazines include dacarbazine (DTIC) and temozolomide (Temodar®)
- Ethylenimines include thiotepa and altretamine (hexamethylmelamine)
- Platinum drugs include cisplatin, carboplatin and oxalaplatin
Antimetabolites are analogs of purine and pyrimidine bases that inhibit DNA and RNA synthesis during the S phase of the cell cycle. Antimetabolites are used for treating many types of cancer including leukemias, cancers of the breast, ovary, and the intestinal tract. As an example, 5-fluorouracil (5-FU) is an irreversible inhibitor of the enzyme thymidylate synthase. It is used to treat various cancers such as anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers, head and neck cancers. It was designed by Charles Heidelberger in 1957, who demonstrated its anti-tumor activity in mouse models. It is a suicide inhibitor that prevents the synthesis of the pyrimidine base thymidine which is an essential nucleotide of the DNA molecule, and hence required for DNA synthesis and replication. 5- fluorouracil is converted in the body to 5-fluoro-2-deoxyuridine. This nucleotide contains a very strong carbon-fluorine bond which prevents the addition of a methyl group at position 5 preventing its conversion to 2-deoxythymidine. Thus 5-FU acts as an anti-metabolite that blocks thymidine synthesis, and ultimately halts DNA synthesis.
The subclasses of antimetabolites are:
- 5-fluorouracil (5-FU)
- 6-mercaptopurine (6-MP)
- Capecitabine (Xeloda®)
- Cytarabine (Ara-C®)
- Gemcitabine (Gemzar®)
- Pemetrexed (Alimta®)
Anthracyclines inhibit enzymes involved in DNA replication. They are used to treat many different cancers. Anthracycline treatment is dose-limiting because higher doses of these antibiotics cause damage to the heart. Anthracyclines include:
- Doxorubicin (Adriamycin®)
Other Anti-Tumor Antibiotics
Anti-tumor antibiotics that are not anthracyclines include:
Mitoxantrone is an antibiotic similar to doxorubicin which can cause damage to the heart, and can also cause leukemia. It is a topoisomerase II inhibitor. Mitoxantrone is used in treatment of prostate cancer, breast cancer, lymphoma, and leukemia.
Rapamycin (sirolimus) is an antibiotic with anti-fungal activities which also acts as anti-cancer agent due to its mTOR inhibiting action, interfering with mTOR signaling pathway which is involved in controlling cell cycle progression. Sirolimus and higher activity derivatives e.g. everolimus, temsirolimus are in use for treatment of various cancers such as renal, breast cancer, neuroendocrine tumors and B-cell lymphomas.
Topoisomerases are enzymes that mediate unwinding and relaxation of DNA required for DNA synthesis and replication. Drugs that inhibit these enzymes are therefore potent inhibitors of DNA synthesis and hence of the cell cycle. These drugs are used to treat leukemias, lung, ovarian, and gastrointestinal cancer among others. There are two classes of topoisomerases: topoisimerase I and topoisomerase II.
Topotecan and irinotecan(CPT-11) inhibit topoisomerase I, while etoposide (VP-16), teniposide and mitoxantrone inhibit topoisomerase II. Patients treated with topoisomerase II inhibitors are at increased risk of developing secondary post-treatment leukemia called acute myelogenous leukemia (AML) within two to three years following treatment.
Phytochemicals such as plant alkaloids and other plant derived compounds block mitosis or inhibit protein synthesis enzymes involved in cell division. Mitotic inhibitors block the M phase of the cell cycle and are used in treating various cancers such as breast, lung, myelomas, lymphomas, and leukemias. These drugs also cause damage to cells which is not phase dependent. Vinca alkaloids depolymerize microtubules, while taxanes stabilize microtubules, both activities perturb the microtubule dynamics. Mitotic inhibitors can damage the peripheral nervous system, and hence are dose-limiting.
Mitotic inhibitors include:
- Taxanes: paclitaxel (Taxol®) and docetaxel (Taxotere®)
- Epothilones: ixabepilone (Ixempra®)
- Vinca alkaloids: vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®)
- Estramustine (Emcyt®)
Steroids are used to treat lymphoma, leukemias, and multiple myeloma. Steroids are hormones and their derivatives. Steroids slow growth of cancer cells, and also act as immunosuppressants. Corticosteroids prevent adverse effects of chemotherapy such as nausea and vomiting. Prior to chemotherapy corticosteroids are used to prevent hypersensitivity. When steroids are used to slow and control cancer they are considered chemotherapy drugs, not when they are used to relieve the adverse effects of chemotherapy.
Prednisone, methylprednisolone (Solumedrol®), and dexamethasone (Decadron®) are steroids used in chemotherapy.
Miscellaneous Chemotherapy Drugs
Chemotherapy drugs whose action does not conform to any particular category of drugs are grouped here e.g. the enzyme L-asparaginase, an enzyme that breaks down asparagine. In the 1950s it was discovered that asparagine is synthesized by normal cells, but leukemic cells cannot synthesize asparagines(http://chemwiki.ucdavis.edu/Biological_Chemistry/Drug_Activity/Anti-Cancer_Drugs_I ref ), hence leukemic cells die if deprived of asparagines. In an independent discovery, serum from guinea pigs and South American rodents was found to be active against leukemia. The active factor was isolated and identified as L-asparaginase, and now is used as a chemotherapy drug in the clinical setting.
The proteosome inhibitor bortezomib (Velcade®) induces G2–M cell cycle arrest and apoptosis by causing phosphorylation of Bcl-2 and its cleavage thus inactivating Bcl-2 (Ling Y-H, Liebes L, Perez-Soler R, et al.vPS-341, a novel proteosome inhibitor, induces bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther 2002;1:841–9.). Bcl-2 family of proteins controls and suppresses apoptosis. Bortezomib is used to treat multiple myeloma and mantle cell non-Hodgkin's lymphoma (NHL).
Other Types of Cancer Drugs
There are chemical and biological drugs whose mode of action on cancer cells is distinct from chemotherapy drugs. These drugs specifically target cancer cells by engaging unique properties of cancer cells and directing inhibitory or cell killing action against only cancer cells. These drugs are highly desirable for their selectivity towards cancer cells, and therefore less or negligible toxicity towards normal cells, with less side-effects. These drugs are used often in conjunction with conventional chemotherapy or radiotherapy.
Cancer cells result from the transformation of normal cells. Transformation is a process where mutations of certain genes induce uncontrolled cell growth or cancer. The distinct mutant proteins specific to cancer cells are targeted by constructing specific chemical compounds that interfere with or inhibit the cancer-specific mutant proteins. Another mechanism involved in cell transformation is polyploidy and multiple copies of individual genes with resultant overload of the coded protein product. Controlling such proteins by drugs inhibits growth of cancer cells. These drugs are used as monotherapy in cancer treatment- as first or secondline. They may also be used as maintenance therapy to keep the tumor in remission and prevent tumor relapse.
Targeted therapy drugs include imatinib (Gleevec®), gefitinib (Iressa®), sunitinib (Sutent®) and bortezomib (Velcade®). The first targeted therapeutic developed was imatinib which is used to treat chronic myelocytic leukemia. Imatinib is a chemical that inhibits the tyrosine kinase Bcr-Abl found only in chronic myelocytic leukemia. Specific to the cells of this cancer a gene translocation called the Philadelphia chromosome was first discovered in 1961 by Nowel and Hungerford. The product of this translocation is the Bcr-Abl tyrosine kinase which is highly active in these cancer cells and solely responsible for the malignancy. Inhibition of the Bcr-Abl tyrosine kinase activity occurs when imatinib binds the ATP-binding site of this kinase, with consequent control of chronic myelocytic leukemia.
Genomic data on various types of cancers strongly reveals that many malfunctional protein kinases arising from abnormal mutations are associated with cancer cells. Hence efforts are on for generating chemical drugs that specifically target these protein kinases. Many new kinase inhibitors are being approved by the U.S. Food and Drug Administration on a regular basis since the advent of imatinib. Such protein kinase inhibitors are in use for treating cancer of renal, hepatic and gastrointestinal stoma tumor origin. Thus these agents are used as chemotherapy for cancers of both solid tumor type and hematologic cancers, where the cancer cells are resistant to conventional chemotherapy drugs.
Retinoids, tretinoin (ATRA or Atralin®), bexarotene (Targretin®), and arsenic trioxide (Arsenox®) are differentiating agents that induce cancer cells to differentiate into normal cells. The differentiating agents also induce apoptosis i.e. cell death in cancer cells. Thus tumor growth is decreased (Tumor Suppressor Genes Methods in Molecular Biology™ Volume 223, 2003, pp 505-522 . Hormonal and Differentiation Agents in Cancer Growth Suppression. Mikhail V. Blagosklonny ref )
Hormones are chemical messengers that control the functions of tissues and organs and maintain the body’s homeostasis. Hormone therapy uses sex hormones, and hormone-like drugs, that modulate the production and action of sex hormones are used to control breast, prostate, and endometrial (uterine) cancers. These cancers are dependent on particular sex hormones. Depriving the cancer cells of the hormone by stopping its synthesis in the body, by blocking uptake of the hormone by cancer cells, or by blocking the action of the hormone, induces apoptosis in cancer cells (Tumor Suppressor Genes Methods in Molecular Biology™ Volume 223, 2003, pp 505-522 . Hormonal and Differentiation Agents in Cancer Growth Suppression. Mikhail V. Blagosklonny ref ) and prevents growth of the cancer cells. As an example estrogen-sensitive breast cancer can be treated with drugs that inhibit the enzyme aromatase which is involved in estrogen production.
- The anti-estrogens: fulvestrant (Faslodex®), tamoxifen, and toremifene (Fareston®)
- Aromatase inhibitors: anastrozole (Arimidex®), exemestane (Aromasin®), and letrozole (Femara®)
- Progestins:megestrol acetate (Megace®)
- Anti-androgens: bicalutamide (Casodex®), flutamide (Eulexin®), and nilutamide (Nilandron®)
- Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH) agonists or analogs: leuprolide (Lupron®) and goserelin (Zoladex®)
Immunotherapy To Treat Cancer
Immunotherapy is distinct from other cancer treatments like chemotherapy, radiotherapy and surgical removal. These drugs tend to be biotechnology products i.e. proteins and polypeptides such as growth factors, cytokines, proteins such as receptors, ligands or their analogs, and antibodies, involved in the immune system. There are two approaches to immunotherapy. Active immunotherapy where immunomodulators, or immune boosters are used to bolster the immune system of the patient to attack and control the cancer. On the other hand passive immunotherapy involves use of drugs such as antibodies, antibody-cytotoxic drug conjugates, and vaccines, that specifically target the cancer cells. Immunotherapy is less toxic in general compared to other treatment modalities. Immunotherapy drugs are used to treat both hematologic and solid tumors of various different cancer types.
The mechanism of action of bevacizumab is interesting as it specifically targets cancer cells, but many different types of cancer cells due to its angiogenesis inhibitory action. Fast growing tumors need constant blood supply. Therefore these tumors develop extensive vasculature to enable high blood flow to the tumor. Depriving the blood flow will kill the tumor. This is achieved by bevacizumab which cuts the vasculature of the tumor by blocking the growth factor required for growth of blood vessels, namely the vascular endothelial growth factor, from binding its receptor on blood vessels by binding free vascular endothelial growth factor and making it unavailable for receptor binding. Bevacizumab is approved for treatment of lung cancers, renal cancers, ovarian cancers, and glioblastoma multiforme of the brain.
Other antibodies target receptors specific to cancer cells, or over-expressed in cancer cells. For example, trastuzumab is an anti-HER2/neu antibody which interferes with the function of the HER2 receptor. HER-2/neu receptor is over -expressed on breast cancer cells, and required for their proliferation and uncontrolled growth resulting in tumors. The antibody blocks the HER-2/neu receptor by binding to it, thus preventing the receptor from activation by the epidermal growth factor ligand and hence preventing the downstream signaling cascade which induces cell proliferation.
Examples Of Immunotherapy Include:
- Monoclonal antibody therapy (passive immunotherapies), such as rituximab (Rituxan®), alemtuzumab (Campath®), bevacizumab (Avastin), and trastuzumab (Herceptin)
- Non-specific immunotherapies and adjuvants (agents or cells that boost the immune response), such as BCG vaccine, cytokines interleukin-2 (IL-2), and interferon-alfa
- Immunomodulatory drugs, like thalidomide and lenalidomide (Revlimid®)
- Cancer vaccines (active specific immunotherapies). In 2010, the U.S. FDA approved the Provenge® vaccine for treatment of advanced prostate cancer. Provenge is the first cancer vaccine approved for use.
Choice of Chemotherapy Drugs
Physicians consider many factors when choosing chemotherapy drugs depending on the particular type of cancer and the drugs that have a record of clinical success in treating those cancers, whether the cancer is at an early or advanced stage, whether the cancer is aggressive i.e. fast growing or indolent, whether the cancer is metastatic, the patient’s health, patient’s age, any health complications that patient has such as other disorders e.g. diabetes, heart condition, liver, kidney problems; medications the patient is being treated with for any condition. As discussed earlier, usually a combination of different chemotherapeutcis with distinct modes of action are used so as to more effectively destroy cancer cells. The side-effects of the drugs as well as drug-drug interactions are taken into account as well.
Dosing is Dependent on Side Effects of Chemotherapy Drugs
In order to achieve the maximal benefit with minimum side –effects, a drug is administered at the lowest dose which shows optimal efficacy in eliminating the cancer cells, with minimum adverse effects. Some drugs in combination at lower dose achieve the same or greater therapeutic benefit with lesser side-effects than higher dose of each drug given individually.
Besides considering the best combination of chemotherapy drugs to avoid drug-drug interactions and achieve maximal therapeutic benefit for the patient, if a patient is under treatment for other ailments, their interaction with the chemotherapy drug must be considered. Certain drugs can interfere with or negate the action of the chemotherapy drug while other drugs may aggravate side-effects of chemotherapy, or cause combined adverse effects. These drugs include not only prescription drugs but vitamins, and herbal or dietary supplements. E.g. platelets are important in mediating blood clotting. Aspirin and other blood thinners weaken platelets. Chemotherapy lowers platelet counts. Hence a combination of aspirin and chemotherapy in cancer patients can be dangerous, as it will deplete platelets further, and prevent blood clotting as well. Another example: Vitamins A, E and C are scavengers of reactive oxygen radicals, and are thought to prevent cancer, as reactive oxygen radicals damage DNA, giving rise to mutations that are carcinogenic . On the other hand, reactive oxygen intermediates are generated in the cell by various chemotherapy drugs and by ionizing radiation, both of which are pivotal cancer therapies. These reactive oxygen radicals cause cellular damage to cell membranes and DNA, RNA, lipids and proteins and kill the cell. Therefore it is also considered that ingesting these vitamins while on chemo or radio therapy could be detrimental as the vitamins can negate the anti-cancer action of these therapies.
Side Effects of Chemotherapy
Because chemotherapy drugs interfere with the cell cycle, they do not attack the resting stage G0. Cells undergoing the remaining cell cycle stages are actively dividing cells. Chemotherapy does not discriminate between dividing cells of normal and cancer origin. Rapidly dividing cells in any G1-M phase of the cell cycle are inhibited or killed by chemotherapy, therefore cancer cells are susceptible to chemotherapy. In fact chemotherapy is not effective on indolent cancers. However other normal tissues that have rapidly dividing cells are also targeted by chemotherapy resulting in “collateral damage”. Cells of bone marrow, blood cells, hair follicles, reproductive system and the gastrointestinal tract are among rapidly dividing cells and therefore undergo heavy damage. The toxic side-effects of chemotherapy drugs are neutropenia, anemia, and thrombocytopenia (collectively called myelosuppression or bone marrow suppression), mucositis, diarrhea (GI toxicity), nausea and vomiting, alopecia (hair loss) and sterility/infertility (especially sterility in males).
A question that comes frequently to mind is ‘Why does hair grow back curly after hair loss due to chemotherapy ?” This is discussed in the last section of this article.
A serious side-effect of chemotherapy is secondary leukemia which has poor prognosis ( Introduction to conventional chemotherapy. Karen Sweiss. http://chicago.medicine.uic.edu ref ). Secondary leukemia is seen following chemotherapy with alkylating agents and topoisomerase inhibitors because these agents cause irreversible permanent alterations in the DNA which encode genetic material, resulting in chromosomal aberrations and carcinogenic mutations that lead to leukemia. Secondary leukemia occurs 5 – 7 years following treatment with alkylating agents, and 2-3 years following treatment with topoisomerase inhibitors. Alkylating agents induce intra- and interstrand cross-links between DNA molecules. Alterations of chromosomes 5 and/or 7 are seen in 60% – 90% cases. Topoisomerase I and II inhibitors cause frequent translocation of chromosome 11 (11q23) t(11;19)(q23;p13).
Route Of Administration Of Chemotherapy
The standard route of chemotherapy administration is via systemic mode i.e. total body administration which include oral, intravenous, intramuscular and subcutaneous routes of administration. The most popular route of administration is intravenous. Chemotherapy drugs are usually administered via a central venous catheter, a catheter in a large vein in the chest, or neck.
Chemotherapy can be administered to the region where the tumor occurs to prevent side-effects on rest of the body so that rest of the tissues and organs remain largely unaffected. It also helps concentrate the chemotherapy drug to the tumor environment, thus providing higher local concentrations of the drug, and better efficacy at tumor control.
The regional administration routes of Chemotherapy include:
- Intra-arterial — injected into an artery that goes to a certain area of the body.
- Intravesical — infused into the bladder
- Intrapleural — infused into the chest cavity between the lung and chest wall
- Intraperitoneal — infused into the abdomen around the intestines and other organs
- Intrathecal — infused into the central nervous system via spinal fluid
- Intralesional/intratumoral — injected directly into the tumor
- Topical — applied to the skin as a cream or lotion.
New Advances in Chemotherapy
Monoclonal antibodies and vaccines for active and passive immunotherapy of cancer are already discussed. Today a wide range of antibodies are available to specifically treat different types of cancer. In addition liposomal therapy and exosomal therapy are being developed, where chemotherapy drugs are packaged inside these vesicle particles and carried inside the body to the site of the cancer with greater efficacy and lesser drug loss than by administration of the naked drug. Also due to their selective delivery and attack on the cancer cells, side-effects are decreased, as normal tissue are spared. E.g. Doxil (the encapsulated form of doxorubicin) and DaunoXome (the encapsulated form of daunorubicin).
Protective agents that protect against undesirable side- effects of chemotherapy drugs have also been made. For example, dexrazoxane (Zinecard) helps prevent heart damage, amifostine (Ethyol) helps protect the kidneys, and mesna protects the bladder.
Cancer cells acquire resistance to chemotherapy drugs by pumping out the drugs or by preventing their cellular uptake. Agents have been developed to overcome resistance of cancers against chemotherapy drugs with chemotherapy to help overcome drug resistance by inactivating the pumps, so the chemotherapy drug cannot be expelled by the cell.
Clinical Impact Of Chemotherapy On Cancer
In the U.S since 1990, the incidence and mortality of cancer have declined, with a doubling of the rate of decline in 2007, half of which is attributed to enhanced application of more effective cancer treatment methods, largely chemotherapy modalities ( A History of Cancer Chemotherapy. Vincent T. DeVita, Jr. and Edward Chu. Cancer Research 2008; 68: (21). November 1, 2008 ref ).
Why Does Hair Grow Back Crinkly or Curly After Chemotherapy?
Changes in texture, color and shape of hair regrowth after alopecia due to chemotherapy is well known, but the basis is not. It is generally understood that damage to the hair shaft is responsible. Researchers studies hair shaft alterations using optical coherence tomography in chemotherapy-induced alopecia and patients on tamoxifen for breast cancer treatment (Br J Dermatol. 2012 Dec;167(6):1272-8. Hair shaft abnormalities after chemotherapy and tamoxifen therapy in patients with breast cancer evaluated by optical coherence tomography. (Lindner J, Hillmann K, Blume-Peytavi U, Lademann J, Lux A, Stroux A, Schneider A, Garcia Bartels N ref ).
Hair from women in the age range of 29-68 years, either on tamoxifen (n = 17) or chemotherapy (n = 17) were analyzed before and after treatment. At each time, 20 hairs from frontal, and occipital regions of the scalp were measured by optical coherence tomography for hair cross section and form factor. The ratio of maximal to minimal hair diameters defined the form factor. Following chemotherapy, the hair cross section was decreased significantly compared with corresponding hair former to therapy, while the form changed for only the occipital area and not the frontal area.
In tamoxifen- treated patients no changes were observed in cross section of form factor after treatment. The authors concluded that changes in hair structure e.g. curly hair texture after chemotherapy could result from the reduced hair shaft calibre and increased form factor in the new hair.