Conventional approach to treat cancer is to cut it (surgery), burn it (radiotherapy) and poison it (chemotherapy). When a cancer is localised, it can be removed by surgery. But in most of the cases, it is practically impossible to detect cancer in such an early stage. The cancerous cells do get killed by chemotherapy and radiotherapy, but both of these therapies also destroy some vital cells in the body, leading to serious side effects. It is extremely difficult for the scientists to prepare a drug that could kill the cancerous cells selectively without harming normal cells of the body. Another major drawback of chemotherapy is the drug resistance. Moreover, recurrences are commonly seen after chemotherapy and radiotherapy. Other conventional techniques used in the treatment of cancer including bone marrow transplantation, peripheral stem cell transplantation, hormone therapy, photodynamic therapy, immunotherapy and gene therapy have their own limitations.
In radiotherapy, therapeutic doses of radiation (which are many times higher than the diagnostic doses) are used to kill the cancerous cells. A single large dose of radiation may kill the cancerous cells, but it will also burn the adjoining healthy tissues. Therefore, the required doses of radiation are usually fractionated into smaller doses, however damage to the healthy tissue still occurs. Radiotherapy has proved more effective in the treatment of tumours of the food pipe, testes and the brain.
The history of radiotherapy goes back to 1895, when Wilhelm Conrad Roentgen discovered X-rays for diagnostic purposes. Two years later, in 1897, it was disclosed in a meeting of the Vienna Medical Society that a mole has disappeared after repeated exposures to the X-rays. Since then, X-rays have been used to treat various tumours. Later, during 1950s, an artificial radioactive isotope of cobalt was developed that delivered radiation deeper into the body as compared to the X-rays. These were named gamma rays, which were similar to X-rays except that these have a shorter wavelength. The X-rays and gamma rays are almost outdated now and their place has been taken up by the high-energy electron beam generated by linear accelerators. In the past, the doses of radiation were used to be measured in rad (radiation absorbed dose), but this unit has recently been replaced by gray (1 Gy = 100 rad). Radiotherapy can be given internally or externally.
In internal radiotherapy, the radioactive implant (a sealed container of radioactive substance) is placed directly into the tumour or in one of the body cavities. The radioactive implant is usually kept in the body for 1 to 7 days but sometimes it is implanted permanently. In the after loading technique of internal radiotherapy, an empty container is first placed in the body and then the radioactive substance is inserted into it. In some patients, the radioactive substance (in the liquid form) is administered orally or by injection. There are three different techniques of giving internal radiotherapy. These are intracavitary radiotherapy, interstitial radiotherapy and brachytherapy.
In external radiotherapy, the X-rays and the gamma rays have been used extensively to treat cancer. The X-rays generate extranuclear radiation, whereas the gamma rays generate intranuclear radiation but both of these are ionising radiations, which form highly reactive ions in the exposed cells. The use of X-rays and gamma rays in radiotherapy is now replaced by the high-energy electron beam (generated by linear accelerators) that can be focused on a smaller area, thus minimising the damage to the adjoining tissues.
In the hyper fractionated technique of external radiotherapy, smaller doses of radiation are given throughout the day instead of a single large dose.
In the super fractionated technique of external radiotherapy, smaller doses of radiation are given many times in a day, but the total combined dose of radiotherapy is greater than that of the single daily dose.
The effect of radiotherapy can be enhanced by using the hyperbaric oxygen and the hyperthermia techniques.
Radioimmunotherapy is a new technique of radiotherapy that delivers radiation directly to the cancerous cells. In this technique, first of all, the specific antibodies produced in the patient’s body against some components of the cancerous cells are collected from the patient’s blood. Later, a radioactive isotope is attached to these antibodies in the laboratory. These antibodies carrying the radioactive isotope are then injected back to the patient, which travel through the blood stream to reach the cancerous cells and get attached to them. By this technique, the radioactive isotope is directly delivered to the cancerous cells that kill them selectively, thus sparing normal cells of the body from the damaging effect of radiotherapy.
The cancerous cells exist in the body in three different forms, i.e. dividing cells, dying cells and dormant cells. Radiotherapy can kill the dividing cancerous cells. The dormant cells do survive even after exposure to the radiotherapy. These dormant cancerous cells may get back into the cell cycle after some time and multiply to produce many more cancerous cells that may form the cancerous growth again. Such a cancerous growth, which reappears at the same site (or any other site in the body), from where the original cancerous growth apparently disappeared after administration of radiotherapy, is known as recurrence. There are various side effects of radiotherapy such as nausea, vomiting, dryness of mouth, difficulty in swallowing, change or loss of taste, earache, cough, frequency of urination, diarrhoea, change in texture of the skin, loss of hair, sterility and decreased blood cell counts.
In chemotherapy, the cytotoxic drugs are used to kill the cancerous cells. This therapy is preferred when surgery or radiotherapy is not possible. The history of chemotherapy is rather unusual. A toxic chemical compound known as Sulphur mustard (that causes burns in the skin, respiratory tract and eyes) was developed and used as a chemical weapon during the World War II. It was observed that Sulphur mustard also decreased the blood cell counts by destroying stem cells in the bone marrow. The research continued on Sulphur mustard and later its derivative known as Nitrogen mustard was developed, which was the first cytotoxic drug, ever used to treat cancer. Since then many cytotoxic drugs have been developed and used in the treatment of cancer including antimetabolites (such as Methotrexate), alkylating agents (such as Cyclo-phosphamide), antibiotics (such as Adriamycin), plant alkaloids (such as Vincristine), nitrosoureas and many other miscellaneous compounds.
Chemotherapy is usually given intravenously. It can be given by intramuscular, intra-arterial, intrathecal and oral administration. Sometimes the chemotherapeutic drugs are injected into the body cavities such as pleural cavity and peritoneal cavity. The doses of chemotherapeutic drugs are repeated at weekly, fortnightly, three-weekly or monthly intervals depending on combination of the drugs.
Regional chemotherapy is a technique of chemotherapy that delivers the chemotherapeutic drugs to a particular part of the body. This technique helps to increase anticancer effect of drugs at the site of cancer. It also minimises toxic side effects of the chemotherapy on other parts of the body.
Regional perfusion technique of chemotherapy, in which the chemotherapeutic drugs are delivered directly to the cancerous tissue, is usually preferred to treat the cancers located in the upper and lower extremities.
Chemoembolisation is another technique, which is proving successful, particularly in treatment of the liver cancer. In chemoembolisation, the cytotoxic drugs are delivered directly to the affected organ through a catheter along with another agent that slows down blood flow to the organ.
Chemotherapeutic drugs are capable to kill the cancerous cells during a particular phase of the cell division. At any given time, the cancerous cells are asynchronous, i.e. in different phases of the cell cycle. A specific chemotherapeutic drug that is capable to kill the cells in S phase may not harm the cells in G1, G2 and M phase. To overcome this problem, the multiple drug therapy is used, in which various chemotherapeutic drugs are added in the treatment plan.
Cancerous cells may become resistant to the drugs used in chemotherapy. The drug resistance may be intrinsic or acquired. In intrinsic drug resistance, the currently available drugs used in chemotherapy have no effect on the specific cancer as seen in the malignant melanoma and the renal cell carcinoma. The acquired drug resistance is developed in the cancerous cells due to gene amplification. Multi-drug resistance (MDR) is also seen in chemotherapy. MDR occurs due to excessive production of P-glycoprotein (also known as pump protein), which pumps out the chemotherapeutic drugs from the cancerous cells.
Chemotherapy leads to various side effects such as nausea, vomiting, loss of appetite, constipation, diarrhoea, ulcers in the mouth and loss of hair. Most of the cytotoxic drugs used in chemotherapy destroy the bone marrow cells leading to decreased blood cell counts. Such patients are highly susceptible to infections and need frequent blood transfusions. The administration of colony stimulating factors (CSF) restores the bone marrow functions in a shorter period by stimulating growth of the bone marrow cells. The colony stimulating factors are specific proteins that are normally produced in the human body.
Tumours originating in the hormonal dependent organs (such as the breast, prostate, endometrium and the thyroid) may retain the hormonal dependency. Hormone therapy is effectively used in the treatment and palliation of such cancers. Hormone therapy may be given by various modes including hormonal medication, surgical removal of the hormone producing glands (such as orchidectomy, oophorectomy and adrenalectomy) and by destroying the hormone producing glands with radiotherapy.
Some breast cancers need oestrogen for their growth. An antioestrogen compound known as Tamoxifen is used in the treatment and palliation of such cancers of the breast. Sometimes, oophorectomy is done to arrest the growth of hormone dependent breast cancers.
Megestrol acetate is a progestin hormone, which is used in treatment of the hormone dependent breast carcinoma.
Medroxyprogesterone is another progestin hormone, which is used in the treatment of endometrial carcinoma.
Fluoxymesterone is an androgen hormone, which is used in treatment of the hormone dependent breast carcinoma.
Oestrogen arrests growth of the prostate cancer. Diethyl stilbesterol (DES) is an oestrogen hormone, which is used in the treatment of disseminated cancer of the prostate.
Flutamide and Cyproteron are antiandrogens, which are used in the treatment and palliation of disseminated cancer of the prostate.
Leuprolide and Buserelin are GnRH agonists. These are used in the treatment of disseminated cancer of the prostate.
Orchidectomy (surgical removal of the testis) is done to arrest growth of the prostatic cancer. Orchidectomy helps by stopping production of testosterone.
Aminoglutethimide is an aromatase inhibitor hormone, which is used in the treatment and palliation of metastatic breast carcinoma and disseminated cancer of the prostate.
Octreotide is a somatostatin analogue, which is used in the treatment and palliation of metastatic carcinoid tumours & vasoactive intestinal polypeptide secreting tumours.
Thyroid hormone is used in the treatment and palliation of papillary carcinoma of the thyroid.
Adrenal steroids are used in the treatment of nonendocrine related tumours, for example prednisolone is used in the lymphatic leukaemia, methyl prednisolone in the lymphomas and dexamethasone in the breast carcinoma.
Hormone therapy is effective if the tumour contains cytoplasmic hormone receptors such as the oestrogen receptors and the progesterone receptors. The hormone receptors are assayed by the tissue biopsy and by the metastatic lymph node biopsy. The side effects of hormone therapy may be observed but these are usually less severe as compared to that of the chemotherapy.
Bone Marrow Transplantation
In the bone marrow transplantation (BMT), patient’s bone marrow is replaced by healthy bone marrow of the matching donor. BMT is usually recommended to the advanced cases of leukaemia, non-Hodgkin’s lymphoma and multiple myeloma. The technique of bone marrow transplant was first developed in 1950s. Bone marrow transplantation is of three types, i.e. syngeneic, allogeneic and autologous. In syngeneic bone marrow transplantation, donor is a perfect match to the patient, which is possible only in the identical twins. In allogeneic bone marrow transplantation, donor is the closest match to the patient. Six markers, known as human leucocyte antigens (HLA), which are found on surface of the white blood cells are considered while selecting a donor for the bone marrow transplantation. In autologous bone marrow transplantation, patient’s own bone marrow is harvested and then given back to the patient when required, for example after intensive chemotherapy. Autologous bone marrow transplantation is usually advised in those patients of acute leukaemia and the high-grade lymphoma, who have achieved good remissions. While performing BMT, bone marrow of the patient is first destroyed by giving high doses of chemotherapy or radiotherapy. Thereafter the bone marrow collected from the matching healthy donor (or harvested bone marrow of the patient) is injected to the patient intravenously, just like an ordinary blood transfusion. The injected bone marrow cells reach the bone marrow of the patient and get grafted there and start functioning within 2 to 4 weeks. This period of engraftment is very critical, during which the patient is kept in a germ free room till the grafted bone marrow cells start their normal functioning. The bone marrow transplantation has its own complications such as rejection and graft versus host disease.
Peripheral Stem Cell Transplantation
Peripheral stem cell transplantation, also known as haematopoietic progenitor cell transplantation (HPCT), is done in cancer patients to reconstitute the bone marrow. It is usually recommended to the patients of leukaemia, lymphoma and the multiple myeloma. Stem cells are primitive haematopoietic cells, which form mature cells of the blood. These are found in the bone marrow, umbilical cord blood and the peripheral blood. Stem cells are capable of self-renewal and differentiation. Peripheral stem cell transplantation is of three types, i.e. syngeneic, allogeneic and autologous. Autologous peripheral stem cell trans-plantation is the most popular technique, in which stem cells from the peripheral blood of the patient are separated by a technique called pheresis. The separated stem cells are then frozen and stored, to be reinfused to the same patient at a later stage, when the bone marrow of the patient gets destroyed with chemotherapy. Peripheral stem cell transplantation has a shorter recovery period as compared to bone marrow transplantation. Complications of the peripheral stem cell transplantation include graft versus host disease and veno-occlusive liver disease.
Immune system of the body executes its work by two different modes, known as antibody-mediated immunity (humoral immunity) and cell-mediated immunity. The antibody-mediated immunity works through B-lymphocytes, which produce specific antibodies in response to the bacteria, viruses and the toxic molecules that enter the human body. Cell-mediated immunity operates through the cytotoxic T lymphocytes (CTL), natural killer cells (NK cells), lymphokine activated killer cells (LAK cells) and the macrophages. Cell-mediated immunity empowers the immune cells to eliminate viruses, bacteria and other pathogens from the body, either physically (by engulfing) or by secreting specific chemicals. It is the cell-mediated immunity that protects human body from cancer.
Immune cells of the body produce certain biologically active substances known as cytokines (lymphokines and monokines), which include interleukins (IL-1 to IL-15), interferons (alpha, beta and gamma), tumour necrosis factors (TNF) and colony stimulating factors (CSF). Cytokines are capable to destroy cancerous cells by stimulating the effector cells, i.e. cytotoxic T lymphocytes (CTL), natural killer cells (NK cells) and lymphokine activated killer cells (LAK cells).
Researchers all over the world have been working on different techniques to enhance immune system of the body to fight cancer for more than 100 years. During this period, scientists have attempted specific and non-specific methods of immunotherapy in the treatment of cancer. Certain natural and synthetic substances have been used to restore or boost immune system of the body. A tremendous progress has been made in immunotherapy since the early 1970s, although there is still a long way to go. Alpha interferon was made by recombinant DNA technology in 1981 and has been used since then in the treatment of cancer. Monoclonal antibodies are under trial in the treatment of cancer since the 1980s.
Scientists are trying to replace the defective or missed genes by normal genes in the initiated, mutated and the cancerous cells in the prevention and treatment of cancer. Immune cells of the body can be altered genetically to arm them with cancer fighting genes. Another approach in the gene therapy is to alter the cancerous cells genetically and use them as cancer vaccine to enhance immune response of the body against cancer.
Dr. Steven Rosenberg of the National Institute of Health, USA, was the first to carry out gene therapy. He collected tumour-infiltrating lymphocytes (TILs) from cancerous growth of the patient and inserted the gene of tumour necrosis factor (TNF) in these TILs. He then multiplied the tumour-infiltrating lymphocytes (containing tumour necrosis factor) in culture and injected them back to the patient. By this procedure, Dr. Steven Rosenberg was successful in delivering the genes of tumour necrosis factor directly to the cancerous cells, thus killing them selectively without harming normal cells of the body.
Cancerous cells can be nipped in the bud with a new gene therapy, developed by scientists at Jefferson Medical College in Philadelphia, Pennsylvania, who focused on a gene called FHIT, which is located on the human chromosome 3. Disappearance of the FHIT gene is regarded as the earliest genetic signal indicating that the cell is about to become cancerous. Modified viruses carrying spare copies of FHIT gene are used to prevent onset of cancer.
Photodynamic therapy or Phototherapy was previously known as Photoradiation therapy. The photodynamic process was first reported in 1900 by a German scientist, who discovered that micro-organisms could be inactivated by certain dyes in presence of light. Photodynamic therapy was first tried on cancer patients in the 1960s. In photodynamic therapy, a photosensitiser called Photofrin is injected to the patient that gets concentrated in the cancerous cells. The tumour is then exposed to a laser beam, using fibre-optic probe. The laser beam activates the Photofrin leading to a toxic reaction that kills cancerous cells. Photodynamic therapy kills the cancerous cells selectively without harming normal cells of the body. Photodynamic therapy is used in the treatment of superficial tumours and those tumours that can be approached by an endoscope including cancers of the lung, oesophagus, bladder and the female pelvis. Photodynamic therapy has its limitations because the laser beam does not penetrate more than one centimetre of a tissue. The side effects of photodynamic therapy include skin sensitivity reaction (leading to severe sunburns on exposure to the sunlight), sensitivity of the eyes to light, local pain, nausea, vomiting, metallic taste and liver toxicity.
Dr. S.P. Kaushal
Sino Vedic Cancer Clinic