Diagnosis and Management of Cancer Ashok Mehta, SC Bansal
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The Nature of Cancer and Principles of Diagnosisone

Rigveda, an ancient Indian scripture compiled five thousand years ago, records the Science of Healing. A fatal tumour in the throat is described in Atharvaveda.1 The Egyptians (c.1600 BC) were the first to realise that tumours arising in various parts of the body, differ in their behaviour and therefore, should be treated in different ways. Reference was also made to the treatment of such tumours by excision and with arsenical compounds.2 Hippocrates (Greece, c. 460–370 BC) divided tumours into two broad groups, according to their behaviour: a) the “innocuous” and b) the “dangerous”. He also coined the terms “Karkinos” for non-healing ulcerating tumours and “Karkinoma” for solid tumours. Both terms are derived from the Greek term “Karkinos” meaning a crab.2,6,7
It was Aurelius Celsus (C30 AD), who gave a much clearer description of cancer, separating inflammatory swellings from neoplasms. Galen (AD 131–201) considered a tumour to be an entity that existed contrary to the laws of nature, representing a true “new growth”. Galen was also apparently aware of the phenomenon of metastasis. The term “cancer” appeared in literature much later, derived from the Latin term “cancrum”, also meaning a “crab”. Recamier coined the term “metastasis” in 1829, when he demonstrated secondary tumours in the brain of a patient with breast cancer. However, the thoughts that metastasis spread by a liquid dominated during this period.58
Development of microscope in the 17th century, helped in establishing the specialty of histology, which culminated in the introduction of a revolutionary new concept by Virchow (1821–1902), that new cells were continuously being formed by division of the old: omnis cellula e cellula. This is also the main concept that forms the basis of classification of tumours today.910
Cancer was considered a contagious disease and the first hospital established in France, some three centuries ago, to attend to cancer patients was forced out by the community. Ironically, this question is asked even today and bears a social stigma. The observations of the eminent doctors during the entire eighteenth century remained occupied with the thought that cancer had infective (parasitic, bacteria etc.) aetiology, either in soil or defective environment. Only valid observation that remains is the association of bladder cancer and Bilharzia in Egypt. So much so that a Nobel Prize was awarded to Prof. JA Grib Fibiger for his experimental work of producing cancer by Nematode (Spiroptera neoplastic) in rats, a work unproved till date. No concept on the aetiology of cancer has sustained scientific scrutiny. It is hoped that current research will help in unfolding the myth of cancer. Until then the doctors must perform in caring for patients inflicted with this disease even with limited scientific facts.
 
THE NATURE OF CANCER
There is no universally accepted definition of cancer, but the one enunciated by Willis, the famed British tumour pathologist, has become universally popular. According to him, a tumour is an abnormal mass of tissue, the growth of that exceeds and is uncoordinated with that of the adjacent normal tissue and persists in the same excessive manner after cessation of the stimuli that evoked the change initially.1112 This definition brings out three cardinal features of cancer:
  1. That an abnormal mass of tissue is present and that the essential component of a malignant tumour is made up of actively growing cells and not of the supportive stroma or vascular network.
    2
  2. That the growth is in excess of and uncoordinated with normal tissue. These attributes distinguish cancer from other proliferative processes such as inflammation, repair and hyperplasia, which are orderly and coordinated. The growth of a fertilised ovum into a child and of a newborn child to an adult is totally regulated. During life, epithelial surfaces (e.g. the endometrium) and the haemopoietic cells are constantly being replenished, when they age and die, through balanced growth by division of other cells. In malignancy there is a loss of this normal phenomenon of apoptosis.
  3. That such excessive growth persists, even after cessation of the initial stimuli. This distinctive characteristic of cancer makes it such a formidable disease.
There are numerous instances of cancers appearing in subjects exposed to occupational hazards, several years and even decades after cessation of the hazardous stimulus responsible for its initiation. Tumours can be transferred by successive passages in laboratory animals and in tissue cultures, without loss of their progressive growth property. This property has been equated with “lawless growth without control”.13 In fact, the late Professor James Ewing, of the Memorial Hospital in New York, defined tumour as “an autonomous new growth of tissue”. Simply stated precancerous changes that lead to cancer begin long before the clinical appearance of invasive cancer. During the latency period, following the exposure to potential carcinogen, preneoplastic changes may progress to invasive neoplasm or get arrested or may even reverse to normal. One can perhaps predict the statistical probability of preneoplastic foci to develop into a locus of invasive cancer.
 
IS CANCER AUTONOMOUS?
If cancer is an autonomous growth, then no form of treatment should be capable of controlling or curing the patient. There is no doubt that this aspect of cancer has been overemphasised. The following illustrate the overemphasis:
  1. Patients with documented metastatic spread have undergone spontaneous regression and remained disease-free, without receiving any treatment. Some have survived for years following incomplete removal of their cancers or without receiving any treatment.14,15
  2. The 5 and 10 years survival rates of patients treated by surgery, radiotherapy or chemotherapy are much higher than those of untreated patients.
  3. Malignant cells have been demonstrated in over 60% of cases in venous blood draining a particular site of cancer during an operation, yet only a few such patients eventually develop metastases.
  4. The biological behaviour of certain cancers can be modified by hormonal manipulation.
  5. Patients, subjected to immunosuppression receiving renal transplantation are highly susceptible to cancer arising at various sites. Similarly, experimental animals treated with immunosuppressive drugs or subjected to neonatal thymectomy are known to have a high incidence of spontaneous cancers. Emergence of HIV infection known to cause suppression or destruction of cellular immunity, results in high incidence of malignancy, albeit of specific types. The foregoing facts indicate the existence of immunity or host defence against cancer.
  6. Finally, the dramatic response of seemingly fatal uterine choriocarcinoma and acute lymphoblastic leukaemia of children to chemotherapeutic agents is well documented.
 
Understanding on the Development of Cancer
The term “cancer” refers to more than 100 forms of disease processes involving almost any tissue type. Each cancer has unique features yet the basic process is common and that is it violates usual interdependent controls placed on some 30 trillion normal cell in a human body. The incidence of most significant forms of disease has increased. Cancers of the lung, colon, breast, prostate are all likely to increase in countries where cigarette smoking, unhealthy dietary habits, exposure to carcinogenic chemicals and failing environment are common. Mutated genes inherited from parents influence cancer development. However, more common are inherited physiological traits which make the person more susceptible to carcinogenic effects, such as fair skin is more likely to develop skin cancer on exposure to sun light. Smoking and dietary habits lead the list of carcinogenic potential. In diet it is not so much what you eat but it is what you do not eat.
The origin of cancer has long fascinated medical investigators. Epidemiological studies suggest that major contribution to cancer risk for most solid tumours lies in non-shared environmental or sporadic genetic mutations, 3and not in shared environmental or inherited factors.16 Therefore greatest gains in the understanding and prevention of cancer will come from understanding the non-shared factors. Potential hereditary component for several cancers is dramatic such as prostate cancer. For cancers such as breast and colon known familial syndromes exist.
Malignant transformation of a cell comes about through the accumulation of mutations in specific classes of the genes within it. The molecular understanding of these alterations is much clearer now and it can be expected that newer forms of therapy will control the development of cancer. For simple understanding two sets of genes choreograph the cell cycle; proto-oncogenes encourage cell growth and suppressor genes inhibit it. When mutated, these genes can either contribute to too much growth or do not apply the necessary brakes when desired. However, factors (both stimulator and inhibitory), cell receptors etc. involved in deregulation of growth of cells and their relationship to oncogene are more complex and are not fully understood at present. Our ability to deliver suppressor gene to a large proportion of cancer cells is highly attractive but unfulfilled proposition. The molecular apparatus controlling the stimulatory and inhibitory pathways named ‘cell cycle clock’ runs wild in almost all cancer types.
System present in human cells provokes the cell to undergo apoptosis (commit suicide) if some of its components are damaged or its mechanisms deregulated. For example damage to its chromosomal DNA can result in apoptosis. Removal of damaged cells is one mechanism if the repair process fails to avoid danger of carcinogenic mutations. The cancer cells, therefore, emerges by evading the circuitry of the apoptotic system. p53 protein helps in this apoptotic process whereas Bcl-2 wards of the process of apoptosis. The mechanism of radiation injury or chemotherapeutic drugs resulting in DNA damage take advantage of this phenomena of apoptosis to eliminate cells.
A second system that cancer cells evade is the programmed mechanism that counts and limits the number of times cells can reproduce themselves (senescence). Cancer cell seems to become immortal. Normal cells on an average have 50–60 doubling potential after which they die (if p53 and RB genes are intact). Telomeres, DNA segments at the end of the chromosomes do this counting. Cancer cells circumvent the ability of cells to have limited expansion, thus grow indefinitely. Each time a cell divides the telomere shrinks a little and after reaching a critical length it instructs the cell to commit suicide. An enzyme telomerase helps achieve this objective for the cancer cells and seems a target for newer form of therapy.
Sometimes the cancer arises earlier in age then expected. Perhaps inherited genetic abnormalities play crucial role in such situations. Typical examples are colon polyposis, premenopausal breast cancer and ovarian cancers. These genes are inherited from one or both parents or genes mutate in early developmental phase to station in many body cells.
It is sporadic cancers that constitute the bulk of newly formed epithelial or mesenchymal malignancies. What causes the cells to be disobedient and become immortal? Chemicals in environment; endogenous hormones or products; stress; intake of drugs and chemicals; diet including herbs taken for minor ailments; sheer aging or microbes are many factors.17,18 Several leads are now available and some more common causing agents are enlisted in Table 1.1.
Breach of normal tissue (invasion) and capability to emigrate and establish at distant sites (metastasis) are characteristics of malignancy. In normal tissue the cells adhere to each other and to mesh of proteins (matrix). Perhaps controlled by an address system that recognises surface molecules (area codes). Loosening of these adhesive properties is an important early step. For example cancer cells lose all or some of the adhesive molecule called E-cadherin. Attachment of normal cells to matrix is through specific integrins. The cancer cells acquire skill to evade these mechanisms by producing proteins, giving signals to fool this relationship of cohesiveness, and avoid the natural phenomena of apoptosis (self death). The deceptive surface codes on cancer cells may also explain why certain cancers have predilection of metastatic sites. Invasion and metastasis require the development of new vessels (angiogenesis).19 It seems that mutation once occurred in a cell also evolves to fulfill several requirements of mutated cell for it to escape normal restrains.16,17
 
PATHOLOGICAL ASPECTS OF CANCER
 
 
Classification
Tumours can be classified on an aetiological, anatomical, functional, histological or behavioural basis. Aetiological classification is impractical, as the causes of most tumours are yet poorly understood. Classification according to the function of a tumour cell is possible but only for a limited number of tumours particularly those of the endocrine organs, such as the insulinoma, gastrinoma, etc.4
Table 1.1   Carcinogens: Population at Risk and Cancer Types
Suspect Carcinogens
Population at Risk
Cancer Types
Chemicals agents
Smoking
Tobacco chewing*
Arsenic (Insecticides, Herbicides)
Asbestos
Benzene (Dyes and Chemicals)
Diesel exhaust
Man-made fibers
Hair dyes
Mineral oils
Nonarsenical pesticides
Soot
Widespread
Widespread (Geographical)
Rare (Sprayers, Tanners; Refinery workers)
Uncommon (Demolition and Insulation workers)
Common (Painters; Distillers; Furniture and Finishers; Rubber and Petrochemical workers)
Common (Garage workers, Truck operators; Traffic police)
Uncommon (Wall and Pipe insulation workers)
Uncommon (Hairdressers and Barbers)
Common (Machining workers)
Common (Agricultural workers)
Uncommon (Chimney cleaners; Bricklayers;
Fire fighters; Heating-unit service workers)
Lung, Bladder
Oral
Lung, Skin
Mesothelioma, Lung
Myelogenous leukemia
Lung
Lung
Bladder
Skin
Lung
Skin
Diet
High in animal fat (saturated fat)
Alcoholic beverages
Common
Common
Breast, Colon, Prostate
Upper aerodigestive
Physical agents (Ionizing radiation,
Radon Gas, Sun-Ultraviolet rays; Electromagnetic fields)
Common
Haematologic?
Endogenous factor
Obesity and endogenous hormones
Common
Breast, Uterus
Microbes
Papillomavirus 16 and 18
Hepatitis B and C viruses
Epstein-Barr virus
HIV
Helicobacter pylori
Common
Common (Geographical variation)
Common (Geographical variation)
(Increasing world wide)
(Common in less developed countries)
Genital cancers
Liver
Hodgkin's, Pharyngeal
Kaposi's sarcoma
Stomach
Anticancer drugs
Uncommon
Lymphomas, others?
Herbs (Aristolochia fangchi - Chinese herb - Aristolochic acids)18
Rare
Uroepithelial
*Enactment of Law in State of Maharashtra (India)
Classification according to the behaviour of a tumour is into benign, borderline and malignant; further a malignant lesion is classified into low grade, intermediate grade and anaplastic (Grades I, II, III). Such grading has therapeutic relevance and is incorporated into all modern schemes of classification.21 The most satisfactory one is based on the histogenesis of a tumour, e.g. fibrosarcoma (from fibroblasts), rhabdomyosarcoma (from skeletal muscle), dysgerminoma (from the germ cells), etc. This system of classification has now been universally adopted.
 
Why Classify Tumours
This exercise is of great value, because of the following reasons: a) the biological behaviour of a malignant tumour varies according to the individual cell type. For example, most fibrosarcomas and liposarcomas are slow growing and indolent, whereas rhabdomyosarcomas and lymphomas grow rapidly and tend to disseminate early; b) treatment is radically different for the various tumour types. For example, squamous cell carcinomas arising from the mucous membrane of the oral cavity and oropharynx are radiosensitive and radiocurable, while in adenocarcinomas arising in the alimentary tract, surgical removal is the satisfactory primary treatment; c) uniform adoption of a classification permits comparison of the end results of treatment and assists in the epidemiological characterisation of different cancers.205
 
Grading of Cancer
The grading of a malignant tumour is based on the degree of differentiation of its cells that can be established only on microscopic examination. Customarily, tumours are graded numerically into three grades. Lower numbers (grades I and II) indicate a lesser degree of malignant behaviour and better prognosis.
Evidence of differentiation is based on the resemblance of a cancer to the normal tissue from which it arises. For example, a grade I squamous cell carcinoma of the oral cavity will reveal a considerable amount of keratinisation, whereas grade III varieties will present little or no keratinisation. The high-grade tumours often present bizarre nuclei and a high mitotic rate. In many instances, the differentiation is so poor that the cell of origin cannot be determined and the tumour is then labeled as anaplastic. Some pathologists choose to describe the grades as, well differentiated, moderately differentiated, poorly differentiated and undifferentiated or anaplastic. Grading of a tumour is a subjective parameter, when used alone it is insufficient to determine the prognosis, because (a) different pathologists can differ in their assessment of grading and (b) it does not take into account such factors as the duration of the disease (size) and the presence or absence of metastases. For optimal treatment selection and evaluation of prognosis, it is the extent or stage of the disease that is of paramount importance.
Some tumours that were low grade at one stage become increasingly malignant with the passage of time. Consequently, the once slowly evolving cancer may suddenly start to grow rapidly, invade adjacent tissue and ultimately disseminate to distant parts. Differentiated papillary or follicular cancers of the thyroid gland are known to transform into the undifferentiated variety, after a phase of slow growth for years.
 
Staging of Cancer
The staging of a cancer is an evaluation of its extent, based on clinical findings, supplemented by radiological, surgical and other investigations. There are many systems currently in use for staging cancers. Some are primarily clinical and are undertaken before instituting treatment, as in the case of breast cancer. Others are arrived at after undertaking pathological examination of the resected specimen, as in the case of cancer of rectum. In Hodgkin's disease, CT scan of chest and abdomen, bone marrow biopsy and exploratory laparotomy (splenectomy), and multiple lymph node and liver biopsies, were often used to assess the stage of the disease.
The TNM (Tumour, Lymph nodes, Metastasis) system of classification and staging has gained wide acceptance. “T”1,2,3 describe the extent of the primary tumour, “N”1,2 the status of lymph node metastases and “M” the presence of distant metastases.21 The numbers represent different sizes of the tumour mass, higher the number larger the size. However, none of these systems seem to satisfy in grouping the disease into progressive tumour load and many organ-based systems are also being advocated.
There will be no need to stage the neoplastic disease if we had non-toxic therapy capable of eradicating the entire population of cancer cells, including the metastatic clones. Until better prognostic factors can be assessed, staging is perhaps needed in cancers where additional effective therapy is available. The advances in molecular biology to detect occult metastatic tumour cells in blood and marrow may alter our concept of surgical staging for certain tumours, in time to come. However, such techniques need more careful scrutiny.2225
 
GROWTH AND SPREAD OF CANCER
 
 
Local Growth
Malignant tumours characteristically invade, infiltrate and destroy adjacent normal tissue consequently their margins are usually irregular and vague. A few low grade, slow-growing cancers are however, known to be circumscribed and partially encapsulated. Such tumours are said to have ‘pushing’ rather than ‘infiltrating’ margins and are thus more amenable to surgical excision. It is the invasive capability of malignant tumours, which results in continuous spread of the disease. The extent of local infiltration by a cancer is of practical importance, since its inadequate or incomplete removal inevitably leads to locally recurrent disease.
The mechanisms responsible for enabling the malignant cells to invade and destroy normal cells are not fully understood. Cancer cells often have amoeboid movements, but even normal cells are known to show such motility. It is likely that cancer cells produce enzymes or chemicals, to aid them in encroaching on adjacent structures. Tissues such as cartilage, tendon, ligament, bone and arteries are however relatively impervious to such invasion and hence often act as natural barriers. On the other hand, soft tissues and muscles are easily invaded. At certain sites, the tumour cells grow contiguously, spreading via hollow structures such as the ureter, the bronchus, etc. In 6the case of brain tumours, cancer cells are often transported through the CSF to the spinal cord. In the abdominal cavity, cells from cancer of the stomach or ovary characteristically spread along the peritoneal surface to other organs, known as trans-celomic spread.
 
Regional Spread
The invasive property of a cancer not only accounts for contiguous local extension, but also promotes lymphatic embolisation and involvement of the regional lymph nodes. Epithelial cancers characteristically spread to the regional lymph nodes, a feature which has led to the “en bloc” technique of radical excision. Because of the vagaries of lymphatic flow and obstruction of some of the lymphatic channels, metastases to distant or unusual sites are usually seen and the presenting symptoms are then related to these deposits. Knowledge of the lymphatic drainage of various organs is hence necessary, for planning of “en bloc” resection of the cancer-bearing area and its primary regional lymphatic drainage. Selective lymph node dissection of first echelon nodes that are at high risk is replacing radical dissection of nodes to reduce morbidity of radical dissection especially in neck, axilla and groins.
 
Distant Spread
In the vast majority of cancers, death results from distant spread. Once cancer cells invade blood vessels, they may get detached as tumour emboli, either as single cells or as cellular aggregates. Cancers arising in organs that drain into the portal venous system (e.g. stomach, colon, etc.) tend to metastasise to the liver. Most other cancers and sarcomas metastasise through venous channels to the lungs, bones, brain, etc.26 Blood borne metastases are known to appear at unusual sites, due to either normal or aberrant venous communications. It is not uncommon for tumour emboli arising from a primary prostatic cancer, to be diverted into the vertebral veins via anastomotic channels of the paravertebral venous plexus and lodge into vertebral bodies. The mechanism of metastatic spread is as yet poorly understood and the predilection of cancers to metastasise to certain organs “chosen sites” cannot always be explained on the basis of anatomical logistics.
There are three steps in the establishment of distant metastases: a) invasion of a vascular channel either directly or by lymphovenous anastomosis, b) detachment and migration of the cells to distant sites and c) establishment and growth of the cancer cells at the new site, to form a secondary tumour mass. It is realised today that invasion of blood vessel by cancer cells is quite common and yet distant metastatic deposits do not often thrive and grow. It would thus appear that floating cancer cells are mostly destroyed within the circulatory system or at “hostile” sites. Metastatic tumours grow easily in the lungs and the liver. On the other hand, metastases to the spleen and skeletal muscles are rare, even in disseminated cancers. It is therefore obvious that a third step in the development of metastases is of great importance. The cells transported to an organ must be capable of growing in their new location, to form a self-propagating mass. Immune reaction of the body is possibly of great importance for the survival or destruction of such micrometastases.27,28
 
Is Cancer a Systemic Disease? (Micrometastasis)
With increasing knowledge of cell biology and cell kinetics, we know today that what a clinician believed to be an early cancer is in fact not so in terms of cell kinetics. If cancer originates in a single aberrant cell, 10 microns in diameter, some 30 doublings (generations) will be required for the tumour to grow to a diameter of 1 cm, generally accepted as the minimal size necessary for clinical recognition, such as in diagnosis of breast mass by palpation.
This intriguing concept of tumour growth is based on the “doubling time” of a tumour cell. After a cancer cell undergoes mitosis to divide into two, each daughter cell in turn gives rise progressively to 4, 8, 16, 32 cells and so on, with each successive division, eventually resulting in doubling the size of the tumour mass. If the growth rate remains constant, the time for each doubling will also remain constant. In a rapidly growing tumour (i.e. one with a high mitotic rate) such as Burkitt's lymphoma, the estimated doubling time is a mere 5 days. For the slower growing tumours, the estimated doubling time may extend to 200 days or more. Therefore, “early” cancer would be more than 2 years old if it has four week doubling time and 7.5 years, if its doubling time is three months.
To what extent does “an early” removal of the primary lesion prevent dissemination? The self-evident answer is that for each day that the primary lesion has been present, 24 hours are available for metastases to occur and with an ever increasing number of cancer cells, there is a greater likelihood that a sufficient number of cells will escape the local environment, to seed remote sites in the body. These tumour seedlings at distant sites, called micrometastases, cannot be recognised with currently available clinical or radiological means.7
The logical conclusion to be drawn from this fact is that cancer is a systemic and not a localised disease. But why is it then that each and every patient with cancer does not die of the disease ultimately? Could host defences destroy or control small numbers of shed viable cells? There is enough experimental evidence to believe that this is so and that host defences are indeed capable of mopping up tumour cells before they develop into clinically evident metastases.
 
BIOLOGICAL ASPECTS OF CANCER
The information that is passed from one generation of cells to the next is stored in the DNA molecule of the genes and expression and replication is central to the understanding of cancer. Genetic basis of the development of cancer has been recognised for more than a century, supported by familial and epidemiological data. However, over the past three decades, studies from various disciplines have given some insight into the genetic basis of cancer. Current view is that cancer arises from the accumulation of multiple mutations in a single cell.29 Changes occur in three classes of genes: oncogenes, tumour suppressor gene, DNA repair genes.30 The vast majority of mutations in cancer are believed to be somatic that is they are present only in tumour cells. However, some of the mutations may be present in the germline of the individuals and can be passed on to the future generation.31,32
Many of these cancer-causing genes have been cloned. The protein products of these genes have been partially characterised and their interactions with other proteins are being explained. These protein products seem to regulate cell behaviour and its response to external stimulus. Today it is possible to detect the over expression of certain genes causing cancer (oncogenes) and under expression of genes conferring protection against cancer (suppressor genes).
The genetic mutation and neoplasia link is now an accepted fact.33 Chemical carcinogens, hormones, ionising radiation, infectious agents all or any can cause mutation in genes (see Table 1.1). Other mechanisms such as faulty repair enzymes are being studied. Multiple pathways to neoplastic state are involved. From genetic and clinical point of view, cancer is a multitude of diseases.
When the diagnosis of cancer is established, the most fearful question is whether it is localised or has spread to regional and distant sites. Intrinsic tumour cell properties (invasion of thin walled lymphatics and venules; motility and invasiveness; loss of adhesion molecules; proliferation at new site and growth factors) and host-associated factors (immune cell functions) are mechanisms involved in this metastatic behaviour. Further, the cells from the primary tumour and those from its metastasis differ in many aspects (antigenicity; receptor profile; grade; etc.), indicating heterogenous nature of neoplasia.34
Mammalian cells have evolved complex mechanisms for regulating life span. The normal adult cells have limited growth potential and senescence after a defined number of cell divisions. It has been demonstrated that the ageing of mortal cells appears to be controlled by molecular clock consisting of telomeres—a chain of repeated DNA segments found at the ends of the chromosomes. Each time a mortal cell divides; a small segment of telomeric DNA is lost, unless the termini (ends) are extended by some mechanisms.35 When a critical amount of telomere shortening has occurred, the genetic program of cell senescence is triggered and the cell stops dividing.
The length of telomere can be studied and is species specific.36 Telomeres are important for maintaining chromosome structure by protecting from DNA degradation, end-to-end fusion, rearrangement and loss. In a test tube, human cells have been shown to divide about 50 times before this happens, this limit of cell proliferation is often called the “Hayflick Limit”. Cells, such as reproductive and cancer cells, express telomerase which synthesises telomeres, allowing replicative immortality. Similarly, cancer cell colonies in culture remain youthful and divide endlessly without eroding the telomere. The tumour cells exhibit increased proliferation potential and do not age, thus described “immortalised cells”. Telomerase was not found in any of 22 normal cell cultures or in any of 55 normal or benign biopsies studied. On the other hand telomerase was detectable in all of more than 20 malignant cancer types examined.37,38 In conclusion, telomerase is inactive in adult nondiseased somatic cells but the activity is present in cancer cells and its activity is measured on cell extract (oral rinses, PAP smears and tissue biopsies).39,40
The gene for the telomerase protein has been identified. This enzyme is actually a complex of at least two distinct molecules, one made of RNA component and is designated hTR (human telomerase RNA) and the second a protein component and is designated hTRT (for human telomerase reverse transcriptase).41 The combination of hTR and hTRT makes active telomerase that can lengthen telomeres, “rewind” the clock of cell ageing, and expand the replicative life span of cells. The expression of hTRT in normal human cells was sufficient to produce active telomerase and lead to the extension of telomeres. The cells so treated have divided up to 90 times, showing no signs of ill health or cancerous behaviour.418
Recent studies indicate that telomerase has the potential of an important cancer marker and telomerase assays should be useful in screening for cancer. Level of telomerase may also help the doctors in determining how aggressively to treat a patient.
 
CLINICAL PRESENTATION
The symptoms produced by malignant disease in early stage are minimal, except in those tumours originating in endocrine organs. The clinical presentations are organ specific and are dealt in respective chapters. The persistent sore (oral, skin); abnormal bleeding (per anus or vagina or in urine); discharge; cough; abnormal mass; fever or sudden change in a pre-existing lesion, malignancy is one of the differential diagnosis. Nearly half the patients with metastatic disease are either asymptomatic or present with minimal symptoms that get ignored. A careful history sometime is the only clue to suspect malignant disease.
The malignancy on occasion may present by its effect on distant organs (paraneoplastic syndromes). The paraneoplastic manifestations/dysfunctions may well be the first sign of underlying malignant process and identification of primary site may be critical. Such presentation should herald a search for underlying malignancy. It has been estimated that paraneoplastic symptoms/dysfunctions will be present in near 7–10% of the patients at initial diagnosis of malignancy.42 Almost half the patients will develop symptoms remote to the cancer site during the course of their disease.42 The potential of underlying malignancy is so high in certain paraneoplastic syndromes that a search for the occult malignancy is mandatory. Many such paraneoplastic symptoms/dysfunctions are given in Table 1.2 with possible association of malignancies. Certain proteins secreted by the malignant tissue can be used as tumour markers to follow the disease. In certain situations, the paraneoplastic symptoms should be treated even when the primary tumour cannot be identified.
Similarly certain signs and symptoms attributed to well defined syndromes should alert the physician of their association with higher incidence of neoplastic disease (Table 1.3). Family history constitutes the first step to identify hereditary cancers.31,32 The associations of certain hereditary cancer are given in Table 1.4.
The tumour sometimes presents with a palpable mass (neck, lymph nodes, skin, intrathoracic, intraabdominal) and on diagnosis proves to be malignant, though the primary site is not identified nor there are any symptoms related to the primary location. Efforts should be made to identify favourable type of malignancy of unknown origin and such cases should be appropriately treated.43,44
 
DIAGNOSTICS AND CANCER
Multidisciplinary approach for the care of the patient uses a combination of technological development and medical expertise and is the best way to put the collective base of knowledge and experience in practice. Currently, an accurate anatomic profile of a tumour is established by a combination of physical examination and imaging techniques. This information is used with biologic profile to make informed management decisions for better outcome, with respect to the preservation of vital functions and life.
 
Laboratory Medicine
The role of laboratory medicine is becoming increasingly complex. The variety of tumour associated markers, such as alfa-fetoprotein (hepatoma, dysgerminomas); beta-human chorionic gonadotrophin (dysgerminomas, trophoblastic tumours); carcinoembryonic antigen (GI tumours); CA 125 (ovarian tumours); prostate specific antigen (prostate carcinoma); estrogen/progesterone receptors (breast cancer), etc. are being utilised in diagnosis, staging, follow up and as prognostic predictor of therapy.
The value of identifying tumour cells in blood and bone marrow (staging and prognosis); study of genetic changes (identifying individuals at risk); estimation of telomerase; estimation of drug levels (high dose chemotherapy); rapid microbiological testing etc. are bound to play a significant role in management of cancer patients.
 
Imaging
Routine diagnostic radiology, mainstay of investigations till seventies, is rarely sufficient today for evaluation of patient with deep-seated cancers. The advent of ultrasonography (USG), computed tomography (CT), magnetic resonance imaging (MRI) and other sophistications in imaging techniques (such as MR angiography, 3D reconstruction, etc.) have been of great help in diagnosis and assessing the exact anatomic location and extent of the deep seated tumours in the brain, head-neck, thorax, abdomen, etc.9
Table 1.2   Selected Paraneoplastic Syndromes and Relationship to Tumour Types*
Groups
Manifestations/Dysfunction
Tumour Types
Mode / Mediators
1. Endocrine and metabolic paraneoplastic manifestations : A wide variety of paraneoplastic endocrine manifestations/dysfunctions have been described. The production of abnormal hormones or prohormones or their improper end utilisation has been shown in several solid rumours and haematological malignancies. The ectopic hormones are not truly ectopic but augmented production of these proteins. The neuroendocrine cells are scattered throughout the body and many of these hormones are produced which act locally. A few which have sufficient occurrence are described here.
Adrenocorticotropic
Myopathy, muscle wasting, hirsutism, hypertension hyperpigmentation, hypokalaemia, glucose tolerance
Lung (Small cell), Pancreas, Thymus, Thyroid (medullary), Pheochromocytoma, Paraganglionoma
ACTH, MSH, Endorphins, Enkephalins
ADH
Hyponatraemia, hyposmolarity, water intoxication, urine hyperosmolarity
Lung (Small cell; 3–15% of patients), Head and Neck
Ectopic inappropriate hormone
Hypocalcaemia
Neuromuscular dysfunction, tetany. Signs of hypocalcaemia - Chvostek's, Trousseau's signs
Thyroid (medullary), Breast, Carcinoid, GI
Calcitonin, Osteomalacia
Hypercalcaemia
Neuromuscular dysfunctions, irritability
Lung carcinoma (12%), Breast, Kidney
Hormonal mechanisms have been implicated in metastatic disease also. PTH like hormone
Miscellaneous
Hypoglycaemia
Growth hormones
Renin
Placental lactogens, Prolactin
Chorionic gonadotrophins
Hypoglycaemia
Acromegaly
Hypertension
Miscellaneous
Mesotheliomas, Hepatic
Carcinoid, Pancreas, Gastric
Tumours of juxtaglomerular system
Hypernephromas, Lung, Breast
Bronchogenic ca, Stomach,
Germ cell Tumours, Pancreas
Hepatoblastoma
Pro-IGF-2, Insulin like GH like substance Renin
Miscellaneous hormones HCG like
2. Haematological and coagulation paraneoplastic manifestations : Specific paraneoplastic dysfunctions of hemopoietic and coagulation factors are common in patients with malignancies. The low white cell and platelet counts could be due to infiltration of bone marrow with rumour cells. The recent research in effects of hormones and growth factors on regulation of haemopoiesis may unravel the mechanisms. However, causes other than malignancy need exclusion in each case.
Anaemia
Normocytic Normochromic
Normocytic normochromic anaemia
Thymoma, Others
? Low erythropoietin
Autoimmune haemolytic anaemia
Leukaemias, Lung, Breast, Ovarian, Renal cell, Testicular
? Autoantibodies
Microangiopathic haemolytic
Anaemia, azotaemia, thrombocytopenia anaemia
Mucinous adenocarcinomas
Plugging of microvessels with fibrin platelets. Sometime in
mitomycin therapy
Eosinophilia and Basophilia Erythrocytosis
Increased in red cell mass
Hodgkin's disease, Lymphoma
Renal cell, Hepatoma, Cerebellar haemangioblastoma Adrenal cortical rumour
Erythropoietin (Can be raised in benign lesions also) Androgens
Granulocytosis
Sometimes monocytosis
Gastric, Hepatoma
Granulocyte stimulating factors
Thrombocytosis
Hypercoagulable state
Hodgkin's disease, Lymphoma
? Cytokines
10
Thrombophlebitis
Fleeting phlebitis, hypercoagulable state, deep venous thrombosis
Pancreatic, Breast, Ovary, Prostate
Complex mechanisms
Coagulopathies
Intravascular clotting defect, haemorrhage
Pancreatic; Lung, Prostate
Complex mechanisms
3. Neurological paraneoplastic manifestations : The symptoms, which are distal effects of cancer on nervous system occurring more often are tabulated. The neurological paraneoplastic syndromes are seen in less than 1% of cancer patients. The symptoms/dysfunctions occur without direct invasion, metastasis or pressure by tumour mass of neural tissue. Not all patients with these symptoms/dysfunctions would have underlying malignancies, but possibility of malignancy must be kept in mind. Wide variety of neurotoxic agents, hormones, cytokines, autoantibodies, viral infection etc. have been implicated as mechanism of these manifestations. The subject is more complex than summarised here under.
Cerebellar degeneration
Symmetric ataxia of arms and legs, Increased cells and proteins in CSF, occasional oligoclonal band. Acute onset. 50% have underlying malignancy
Hodgkin's disease, Breast, Ovarian, Lung
Anti-Purkinje antibodies?
Eaton-Lambert syndrome
Proximal muscle weakness. Blurred vision, ptosis, diplopia. 40% patients have underlying malignancy
Lung (Small cell), Thymoma, Lymphoma
Limbic encephalitis
Personality changes, short-term memory loss, seizures hallucinations
Lung (Small cell), Hodgkin's disease
Uncommon. Autoantibodies?
Opsoclonus myoclonus
Focal myoclonus, involuntary chaotic eye movement. Acute onset. 20–50% patients have malignancy
Neuroblastoma (children)
Lung carcinoma (Adults)
Retinal degeneration
Photosensitivity, scotomatous visual loss, reduced colour vision, night blindness. Abnormal electroretinogram
Lung (Small cell), Melanoma
Autoantibodies to retina?
Stiff-Mann syndrome
Stiffness and spasm of muscles
Lung (Small cell), Breast, Hodgkin's disease
Autoantibodies?
Subacute motor neuropathy
Progressive weakness lower extremities
Hodgkin's disease
Subacute sensory neuropathy
Progressive distal sensory loss (numbness, tingling, dysesthetic pain). 20% patients have malignancy
Small cell ca of lung
4. Mucocutaneous paraneoplastic manifestations : A wide variety of mucocutaneous manifestations have been described which may precede, be concurrent, or follow the discovery of malignancies. Some mucocutaneous lesions are associated with specific malignant process others are common to neoplastic disease (benign or malignant) or can occur as idiopathic conditions. Both conditions start almost at the same time, though there may be delay in diagnosing the underlying malignancy and usually follow parallel course. The association of malignancy in certain dermatoses is so high that efforts to uncover the underlying malignancy are desirable.
Acanthosis nigricans
Small hyperkeratotic lesions in groin, submammary, neck and axilla. Hyperpigmented, velvety texture
Gastric, other intraabdominal adenocarcinomas
Insulin like growth factor
Acquired ichthyosis
White brown scales on trunk and limb
Hodgkin's lymphoma, Kaposi's sarcoma, Breast, Lung
Acquired tylosis
Palmer planter keratosis
Lung, Gastric, Oesophageal
Amyloidosis
Periorbital purpura, plaques, nodules, alopecia, nail changes
Multiple myeloma
Deposit of amyloid protein
11
Bazex's disease
Acral papulosquamous lesions, psoriasiform plaques Palmer-planter keratosis
Upper aerodigestive
Insulin like growth factor
Digital clubbing
10% of patients with clubbing have cancer
Lung, Mesothelioma
Many benign diseases produce digital clubbing
Erythema gyratum ripens
Erythematous lesion giving stripped appearance, 100% have underlying malignancy
Gl, GU, Breast
Extra mammary Paget's disease
Erythematous exudative dermatitis in apocrine gland (Groin, perineum)
Adnexal adenocarcinoma, GU
Cutaneous adenocarcinoma with underlying malignancy
Florid cutaneous papillomatosis
Suddenly appearing verrucose papillomas in extremities (back of hand and wrist) 100% incidence of malignancy
Stomach
Hypertrichosis lanuginosa
Pale colourless fine textured hair - forehead
Lung
Very high association of cancer
Lesser-Trélat syndrome
Clinical diagnosis. Skin involvement
Pancreas, Lymphomas
Uncommon
Necrolytic migratory erythema
Cyclic circinate and gyrate eruptions lower abdomen
Glucagonoma
Typical of the rumour
Pityriasis rotunda
6% of cases have underlying malignancy. Scaly circular pigmented patches
Hepatocellular, Gastric
Pruritus
11% of patients with severe pruritus have malignancy
Lymphoma, Polycythaemia vera
Cytokines
Tripe palm
Thickened palm and sole. 90% underlying malignancy
Lung, Stomach
Sweet's syndrome
Fever, neutrophilia, erythematous painful plaques
AML, GU, Breast
5. Musculoskeletal system : Large number of peptides, polypeptides and chemical mediators, either leak or abnormally produced, from the malignant tissue or the product of cell death, which are not dealt physiologically are presented to the host immune system. It is therefore expected that a variety of autoimmune phenomenon may present involving several organ systems. There is a definite higher incidence of malignancy in patients suffering with connective tissue diseases. Direct infiltration of vessels by lymphoid cells may produce symptoms like vasculitis (Angioimmunoblastic vasculitis lymphadenopathy; Lymphomatoid granulomatosis, etc.)
Idiopathic inflammatory myopathy
6–10% of patients have underlying malignancy. Muscle inflammation and weakness
Testicular, thyroid (Male) Ovarian (Female)
Autoimmune?
Rheumatoid arthritis
Symptoms of RA. (Felty's syndrome—Neutropenia, splenomegaly, skin ulcers in legs)
Haemopoietic (Western)
Immuno-dysregulation; Immune oropharyngeal (Japan) activation
Scleroderma and related conditions
Eosinophilic fascitis
Thickening of skin and fascia, orange like skin
Autoimmune? Hodgkin's disease
Erythromelalgia
Warm burning feet
Myeloproliferative
Palmar fascitis
Thickening of palmar skin, arthritis
Miscellaneous solid rumour
12
Reflex sympathetic dystrophy
Thickening of palmar skin, arthritis, contracture
Pancoast tumour
Werner's syndrome
10% of patients have underlying malignancy.
Mesenchymal
Premature ageing
Sjögren's syndrome
Xerostomia, xerophthalmia.
(44 fold increase). Enlargement of
parotid gland, pseudolymphomas
Lymphomas
EB virus, HIV infection?
Systemic Lupus erythematosus
5% of patients have underlying malignancy.
Lymphomas
Vasculitis
5% of patients have underlying malignancy.
Haematologic, Lung, Colon, Oesophagus, Head and Neck
6. Miscellaneous Fever
More often due to infection. Fever is presenting symptom in five per cent of patients with malignancy
Renal cell, Lymphomas, Hodgkin's disease, Hepatoma
IL-6, IL-1, Tumour Necrosis Factor etc. are likely pyrogens
Cachexia
Anorexia, weight loss, weakness, fatigue, impaired immunity
Miscellaneous solid tumours
Cachexia of some degrees present in 15% of cancer patients. Does not improve on forced feeding. Multifactorial causes.
Protein losing enteropathies Renal manifestations
Hypoproteinemia, oedema, confusion
Renal disorders associated with malignant disease vary in their clinical presentation and aetiologic mechanisms
Nephrotic syndrome
10% of cancer patients. Proteinuria, hypoalbuminaemia, oedema, hyperlipidemia
Colon, Prostate, Lung
Immune complexes
Microvascular thrombosis
Thrombotic, haemolytic ureamic syndrome
Hepatocellular carcinoma
Fluid electrolyte imbalance Tubular obstruction
Hyponatremia, hypouricaemia Progressive renal failure
Lung, Pancreas, Many solid tumours Multiple myeloma, Pancreas
Hormonal
Deposit of viscous material
Hypertrophic osteoarthropathy
Lung carcinoma
Note to Table 1.2
# The list is not designed to be exhaustive, only important paraneoplastic manifestations / dysfunctions and their association with malignant tumours is given. Single or few case descriptions producing paraneoplastic symptoms are not included. The aetiologic understanding of paraneoplastic symptoms will improve patient care and in some instances an early diagnosis. Important references (a-g) are given below for further reading.
a. Hall TC : Paraneoplastic Syndromes: Mechanisms. Semin Oncol 24 (3) : 269, 1997
b. John JW, Foon KA, Patcheil RA : Paraneoplastic syndromes pp 2397, In (Eds.) DeVita CT et al: Principles and Practice of Oncology, 5th Ed. 1997, Lippincott-Raven, Philadelphia, USA
c. Posner JB : Paraneoplastic syndromes. Neurol Clin 9: 919, 1991
d. Dell WB : Endocrine/Metabolic syndromes of cancer. Semin Oncol 24 (3): 277, 1997
e. Spivak JL : Cancer related anaemia : Its cause and characteristics. Semin Oncol 21: 3, 1994
f. Green KB, Silverstein RL : Hypercoagulability in cancer. Hematol Oncol Clin North Am 21 (Supp 3): 3, 1994
g. Posner JB : Neurologic Complications of Cancer. 1995, FA Davis, Philadelphia, PA
h. Posner JB : Paraneoplastic syndromes. Neurol Clin 9: 919, 1991
i. Cohen PR : Paraneoplastic dermatopathology : Cutaneous paraneoplastic syndromes. Adv Dermatol 11: 215, 1995 j. McLean DI : Cutaneous paraneoplastic syndromes. Arch Dermatol 122: 765, 1986
k. Carsons S : The association of malignancy with rheumatic and connective tissue diseases. Semin Oncol 24 (3): 360, 1997
13
Table 1.3   Hereditary Syndromes and Associated Neoplasms
Syndromes / Disorders
Manifestations
Associated Tumour
Mode/Comments
Ataxia-telangiectasia
Telangiectasia of conjunctiva - jaw - ears - palate, ataxia, apraxia of eye movements, etc.
Leukaemia Lymphoma; Ovarian; Stomach; Brain
Autosomal recessive (ATM), IgA with or without IgE deficiency. High incidence of malignancy
Bloom's syndrome
Photosensitivity, telangiectasia, erythema of face, stunted growth
Leukaemia; Carcinoma of tongue; Colon; Esophageal; Wilms
Autosomal recessive, hBLM; Cloned/testing available. High incidence of malignancy
Burton's sex linked agammaglobulinaemia
Recurrent pyogenic infections
Wilms; Lymphoma
Sex linked, over 5% incidence
Cowden's syndrome
Hypertrophic breast, hypoplastic mandible, thyroid nodules
Lymphoma, Thyroid
Dominant/PTEN/under study
Li-Fraumeni syndrome
Patchy pigmentation
Soft tissue sarcomas; Breast; Osteosarcomas, Brain; Leukaemias
Dominant/p53, testing available
Fanconi's anaemia
Unexplained fever, vomiting, polyuria, osteomalacia
Leukaemia Oesophageal, Skin Hepatoma
Autosomal recessive, FACA Cloned. High incidence of malignancy
Chediak-Higashi syndrome
Recurrent pyoderma, lightening of skin and hair color, giant melanosomes, photophobia
Lymphomas
Autosomal recessive. High incidence of malignancy
Gardner's syndrome
Bony exostoses, epidermal cyst, lipomas, fibromas, dermoid tumours, sebaceous cyst
Adenocarcinoma of large and small bowel
Autosomal dominant
Keratosis palmaris et plantaris Neurofibromatosis (von Recklinghausen)
Keratosis of palm and sole
Neurofibromas, cafe-au-lait spot
Esophageal
Pheochromocytoma
95% incidence
Autosomal dominant, few develop malignant tumour
Nevoid basal cell ca syndrome
Multiple basal cell ca, pits on sole and palms, cysts in jaw, skeletal anomalies
Medulloblastoma Fibrosarcoma (Jaw)
Autosomal dominant, infrequent development of malignant tumours
Peutz-Jeghers syndrome
Hamartomatous polyps of GI tract, pigmentation of lip, face and oral mucosa
Rare-Colon?
Autosomal dominant, benign or malignant neoplasms
Sturge-Weber syndrome (Encephalotrigeminal syndrome)
Hemangioma within the distribution of trigeminal nerve
Neurologic malignant tumours
Autosomal dominant, infrequent development of malignant tumours
Tuberous sclerosis (Bourneville syndrome)
Pigmented macules, adenomas fibromas, epilepsy, skin warts
Neurologic malignant tumours
Autosomal dominant, infrequent development of malignant tumours
Cerebello retinal hemangioblastoma (von Hippel-Lindau)
Retinal malformations, headache, unilateral ataxia, blindness
Neurologic malignant tumours, renal cell, pheochromocytoma
Autosomal dominant, infrequent development of malignant tumours
Werner's syndrome
Short stature, Scleroderma like changes, premature aging, leg ulcers, cataract
Sarcomas, Meningiomas
Autosomal recessive, >10% incidence of malignant tumours
Wiskott-Aldrich syndrome
Eczematous dermatitis, pyoderma, thrombocytopenia
Lymphomas
Sex linked, >10% incidence of malignant tumours
Xeroderma pigmentosa
Intolerance to radiation injury
Skin cancer; Melanoma
Recessive/testing available
14
Table 1.4   Genes-Relationship to Cancers
Gene
Tumour Types
Inheritance/Class
Testing
BRCA1,
Breast, Ovarian
Dominant/Suppressor
Available
BRCA2
Breast (Both sexes)
Dominant/Suppressor
Available
HPC1
Prostate cancer
Dominant
-
APC
Familial adenomatous polyposis
Dominant/Suppressor
Available
MSH2
Hereditary non-polyposis;
Dominant/Mismatch repair
Available
MLH1
Colon; Endometrium
Dominant/Mismatch repair
Available
MEN 1
Pancreatic islet cell
Dominant
-
Pituitary adenoma
MEN 2
Medullary thyroid
Dominant
Available
Pheochromocytoma
MTS 1 (CDKN2)
Skin (Melanoma)
Dominant/Suppressor
Available
NF1
Brain and others
Dominant/Suppressor
Available
NF2
Brain and others
Dominant/Suppressor
Available
Ret
Thyroid, others
Oncogene
-
VHL (von Hippel-Lindau)
Haemangioblastoma of retina,
Dominant/Suppressor CNS, Pheochromocytoma, Renal cell carcinoma
Available
WT-1
Renal cell carcinoma
Suppressor
-
PTCH (Gorlin's syndrome)
Basal Cell carcinoma
Dominant
-
Note for Table 1.3 and 1.4
The genetic predisposition constitutes a major risk factor either because of a higher risk of developing cancer (a small portion about 5%) or interaction with carcinogens (a higher portion but % unknown). At present we know of some 20 genes, which are involved in hereditary cancer and the number is sure to expand. Virtually any cancer type may appear in pedigree. The appearance of symptoms is age dependent for example FAP occurs in young age and familial prostatic cancer in old. Age at which the symptoms begin cannot be predicted. Further, interfamily variations are so high that one is compelled to consider environmental factors resulting in variation. Therefore, one can suggest that mutation alone is not sufficient but something more must happen for tumourigenesis. Even when penetration is complete there is a variation in expression that is, some may develop sarcoma and others breast carcinoma. This variation of expressivity is being identified for some hereditary cancers but much work is needed. It is also known that the parents of first affected person do not carry the mutation, but the patient carries the first germline mutation. Ninety percent mutations occur in male germline (father). Due to decreased fertility and increased mortality, a mutational equilibrium is kept. New mutant cases are seen in most hereditary cancers and evenly distributed in most population, suggesting spontaneousness of these mutations. There are known exceptions such as BRCA1; BRCA2 or HNPCC. This genetic equilibrium is more complex than can be stated here.
Different genes mutations affect cell proliferation (RB1) and cell death (P53). Further, different target tissues (embryonal, tissue growing in adolescence, etc.) for cancer may have different genetic logic. The most common gene mutated in germline is tumour suppressor gene, but others such as proto-oncogenes and DNA repair genes have their significance.
1. Thomas R : Laws for dynamics of regulatory networks. Int J Devel Biol 42: 479, 1998
2. Fearon ER : Human cancer syndromes: clues to the origin and nature of cancer. Science 278: 1043, 1997
3. Tomlinson IPM, Novelli MR, Bodmer WF : The mutation rate and cancer. Proc Natl Acad Sci, USA 93: 1480, 1996
4. Knudson AG : Hereditary Cancer: Themes and variations. J Clin Oncol 15 (10): 3280, 1997
5. Ad Hoc Task Force on Cancer Genetics Education: Resource Document for Curriculum Development in Cancer Genetic Education. J Clin Oncol 15 (5): 2157, 1997
7. Varmus H, Weiberg RA: Genes and Biology of Cancer. Scientific Library (W. H. Freeman), 1993
8. Vogelstein B, Kinzler KW: The Multistep Nature of Cancer. Trends in Genetics 9 (4), 138, 1993
Tumour volumes can be measured. Tissue diagnosis of small tumours within the chest or abdomen can be achieved by USG or CT-guided fine needle aspiration cytology or Tru-cut needle biopsy. Lesions in vertebrae or other bones also can be biopsied under CT-guidance.
Vascularity of tumours can be assessed. Surgical access to the tumour can be planned in advance. Tumour thrombus in vessels like inferior vena cava from renal cell carcinoma can be established preoperatively and surgeon can be prepared to handle such issues and the patient can be informed about the risks involved.
CT and US were developed in 1970s and continue to evolve in a manner that constantly expands their applications and value in the evaluation of cancer patients. MRI was introduced in 1980s and multiple fast-paced developments in each of these areas continue. MR spectroscopy promises gross physiologic information about tumours.15
 
Nuclear Medicine
Nuclear medicine is a functional imaging. With the advances in computer technology, the nuclear medicine techniques have greatly expanded the potential of contributing to oncologic imaging. The Gamma Camera has undergone a major change in the form of tomographic imaging capabilities. Single Photon Emission Computerised Tomography—SPECT—is able to generate 3-dimensional functional images of organs with improved resolution and finer details. Positron Emission Tomography (PET Scanning) has ability to image organs using Positrons like Fluorine-18, Oxygen-15, Carbon–14 etc. This technology, though expensive, has tremendous potential in imaging biochemical changes at molecular and receptor level. Hand held Gamma probe is being used in detection of sentinel nodes in breast cancer and melanoma during surgery to detect occult metastatic involvement.45,46 Continuing development of radiotracers and imaging techniques will play important adjunctive role for nuclear medicine in future.
 
ROLE OF SURGICAL PATHOLOGIST
Changes in concepts and options for treatment in cancer have brought significance of the biopsy techniques (fine needle aspiration cytology-FNAC, Tru-cut core biopsy, open biopsy and frozen section). It is important to emphasise proper handling of the specimen pertaining to its use for cytology, paraffin section, contact imprint, special staining, immunohistochemical staining, receptor assays, etc. A close cooperation between the surgeon and the pathologist is of immense importance. Mere presence or radiologic demonstration of mass lesion is not sufficient and it is obligatory to make a tissue diagnosis. The role of the surgeon is to provide adequate biopsy material for tissue diagnosis and of a surgical pathologist to provide maximum information crucial for the treatment planning. The following questions need to be clearly answered.
  1. Will the selected technique provide adequate (quantity) and representative (quality) material? For example, a large specimen of necrotic portion of the tumour in a sarcoma will fail to provide correct diagnosis,
  2. Is the correct type of biopsy technique followed? For example, it will be inappropriate to seek answer on FNAC of salivary gland mass or branchial cyst as to its malignant nature or a punch biopsy of an exophytic growth in oropharynx to answer the question of tissue infiltration. In these situations, a frozen section may be necessary,
  3. Is the biopsy specimen representative of the mass lesion? For example, a biopsy from the liver, suspected to have multiple space occupying lesions may be read as normal. From the pathologist point of view the specimen may be adequate and satisfactory but from clinical point of view such a report is misleading. Similarly the pathologist should establish a tumour size for the surgeon. For example a gross description of 2 × 2 × 1.5 cm of an excisional breast biopsy specimen is justified for the record but the lesion may only be 0.9 × 0.9 × 0.6 cm. Clinician needs the report to be more informative than just the diagnosis of tissue type,
  4. Handling of specimen irrespective of its method of obtaining is crucial? For example a crushed specimen (even when adequate) or a dried out cytology smear have no diagnostic value. The surgeon should respect the preference of the pathologist in the matter of making smear, use of fixative and manner of transport. On the other hand a pathologist should not indulge in answering questions on an inappropriate type of material, for example a pathologist should not be dogmatic on the question of invasiveness and grading on a limited tissue from a large liposarcoma, and
  5. Whether it is a “cancer” or “not a cancer” may be the only concern of the patient. Equivocal answer by the pathologist may be confusing and frustrating.
By no means, one can enlist all possible limitations of the surgeon to obtain an adequate specimen nor one can discuss all the pitfalls that a surgical pathologist faces. However, joint efforts can answer almost all questions required to provide adequate care. Simply providing a clear and adequate history could resolve a difficult pathological diagnosis. Efforts should be made to standardise pathological reporting.21
 
CURRENT CONCEPTS IN THE MANAGEMENT OF CANCER
The current concepts of treatment of cancer are built around two facets, viz. a) the systemic nature of cancer, which underscores the potential efficacy of chemotherapeutic agents that act at the systemic level and b) multimodal approach to therapy, even for so-called “early” cancers.16
Barely two decades ago, chemotherapy played only a restricted, palliative role in the treatment of widely disseminated cancers (stage IV), but today, anticancer drugs are employed as the primary therapeutic modality in certain cancers such as uterine choriocarcinomas etc. In addition chemotherapeutic agents can mop up the circulating cancer cells and micrometastatic deposits which has prompted the use of cancer chemotherapy along with primary locoregional treatment (adjuvant).
With the current knowledge of the biological behaviour of cancers, it is now being appreciated that the application of surgery, radiation therapy, chemotherapy and other modalities in appropriate sequence and combinations can yield better results. It is therefore necessary to plan the treatment protocol for each patient at the time of his initial diagnosis. The surgeon, radiation oncologist and a medical oncologist should see him jointly. This is not often achieved, even in large cancer centres. However, one should strive to invoke team approach to offer a patient, optimum chance of cure.
 
SURGICAL TREATMENT AND ITS EVOLUTION
Surgery, the oldest known method of treating cancer, remains the principal therapeutic modality for eradicating ‘localised’ malignant lesions. In 1853, Sir James Paget treated breast cancer by local excision of the tumour mass, with much loss of blood and wound infection. During subsequent years the principle of en bloc excision of the cancer bearing organ and the lymph nodes draining the area was evolved. It was assumed that cancer was a disease initially localised to a specific organ and that radical local excision would remove not only the primary growth but also all local extension of the disease and the lymph nodes draining the primary site.47,48
William Halsted at the Johns Hopkins Hospital, Baltimore, USA in 1882, took the final step in the evolution of the operation known as “Radical Mastectomy” (en bloc excision). In 1891, Willy Meyer of New York, evolved a similar operation which he presented at the New York Academy of Medicine (Section on Surgery), in 1894. The effect of the Halsted or Willy Meyer operation upon the cure rate of carcinoma of the breast was immediate and dramatic. In the pre-Halsted era, the local recurrence rate was nearly 82% and the 3-year cures rate a mere 5%. Halsted reported in 1898 a 10% local recurrence rate and a 41% 3-year cure rate. It seemed logical, in the past, to improve on the results of cancer surgery by evolving progressively more radical operative procedures. Advances in surgical techniques, anaesthesia and supportive care permitted the development of ultra radical cancer operations. With a very few exceptions, however, these supra radical procedures did not significantly increase the cure rates.48
Concepts of radical surgery also seem to differ in different situations and are under constant review. Amputation was routinely carried out for a malignant bone tumour, e.g. osteosarcoma, at least above the level of the joint proximal to the tumour and under no circumstances through the tumour-bearing bone. Local excision of tumour-bearing long bone and replacement with prosthesis has come into vogue with acceptance of adjuvant systemic chemotherapy in a well-defined group of osteosarcomas, such as small-localised tumour with few mitotic figures and parosteal variant. Soft tissue sarcomas arising in the extremities are best removed by excision of the involved muscle groups or amputation. However, such a radical excision is abandoned in embryonal rhabdomyosarcomas in children where chemotherapy and radiation therapy have either reduced the extent of surgical resection or completely eliminated it.
In squamous cell cancers of the oral cavity, wide excision of the primary lesion often required resection of the adjoining mandible or maxilla, in conjunction with radical neck dissection. Many procedures are now designed to preserve the mandible such as mandibulotomy and mandibular swing or marginal mandibulectomy (rim resection), to obtain cosmetic and functional advantage, without compromising the concept of radical surgery and jeopardising cure rate. Lymph node metastasis is often treated by modified neck dissection, preserving the accessory nerve and occasionally internal jugular vein.
Well-differentiated cancers of the thyroid, treated in the past by total thyroidectomy are currently treated by lobectomy to reduce the incidence of hypoparathyroidism and recurrent laryngeal nerve damage, in a well-defined low risk group. In nonseminomatous germ cell tumours (NSGCT) of the testes, retroperitoneal lymph node dissection (RPLND) was considered mandatory, irrespective of whether the lymph nodes were clinically involved or otherwise. Today, RPLND is under review with better understanding and general availability of tumour markers (alpha fetoproteins and beta HCG). Ability to diagnose and follow up RPLN enlargement with CT scan and effective combination of chemotherapeutic agents to control the systemic disease has changed our perception.17
 
 
Does Radical Surgery Cure Cancer
Currently, extended radical surgical procedures have been abandoned at the majority of cancer centres, since the morbidity and physical disability resulting from these heroic procedures are too high a price to pay for a questionable improvement in survival rates. With introduction of multimodal approach utilising radiation therapy and/or chemotherapy pre or postoperatively, there is a definite change in the approach of surgical oncologists.
The value of time-honoured “radical” surgical procedures for truly localised cancers is also being questioned.49 Experience has shown that 10–15% of patients with so-called “localised” cancer, e.g. in the breast, having uninvolved axillary lymph nodes, will develop metastases, despite a well-performed radical mastectomy. 60–80% patients with osteogenic sarcoma or Ewing's tumour, who did not have clinical or radiological evidence of metastases at the time of amputation or radiation therapy, usually develop multiple pulmonary metastases within a few months following such treatment.24 This suggests that subclinical or “micro” metastases are present, even in a number of so-called “clinically localised” cancers and points to our inability to detect microscopic metastasis or metastatic lesions of less than 0.5 cm in size.24
 
Preoperative Testing
There is increasing tendency to order a long list of investigations as a matter of routine, preoperatively, often as a defensive medicine in the event of medicolegal proceedings. Such a tremendous waste of limited resources in countries with poor economy cannot be justified. The importance of cost effectiveness is being appreciated even in rich countries. The frequency of unanticipated abnormalities or abnormalities shown to change patient management is too low to justify a detailed testing of all patients. Furthermore, little evidence exists that test result abnormalities are associated with reduced perioperative morbidity. Table 1.5 lists recommendations regarding routine preoperative testing.
Table 1.5   Test Recommendations Prior to Elective Surgery
Test
Recommendation
Complete Blood Count
All patients
Haemoglobin
White blood cell count
Platelet count
Renal function (creatinine or BUN)
All patients over 40 years
Glucose (random)
All patients
Electrolytes (sodium, potassium, bicarbonate, chloride)
Selective use
Hepatic enzymes
Selective use
Coagulation testing
Prothrombin time
Selective use
Partial thromboplastin time
Selective use
Bleeding time
All patients
Urinalysis
All patients
Chest radiograph
All patients over 45 years of age
Electrocardiogram
All patients over 45 years of age
* Order tests in patients believed likely to have abnormal results as judged from history and physical examination
 
RADIATION THERAPY
Radiation therapy is widely used modality to treat cancer besides surgery. It is often combined with surgery to achieve optimal control of localised cancer. However, radiation therapy has a limited role to play in the treatment of disseminated cancer. Radiosensitive tumour such as Ewing's sarcoma of bone may respond well to radiation therapy and could be controlled at the primary site but patient will succumb to pulmonary metastases and overall survival may be poor.24
During the first 25 years of the nine-decade history of this specialty, radiation therapists functioned under formidable handicaps. They had no standardised unit of dose delivered to the tumour. The energies delivered by the therapy machines available were low, lacking the power to deliver an adequate cancericidal dose at depths 18beyond 4 to 5 cm. Lack of knowledge of the biological effects of radiation led to a high mortality rates and poor end-results. Severe skin and subcutaneous tissue damage often prevented delivery of a cancericidal dose to a deep-seated tumour.
The 1920's saw the first major breakthrough, when Coolidge invented the sealed vacuum X-ray tube, which could be operated at the then unheard-of energy ranges of 180,000 to 200,000 volts, thereby introducing the kilovoltage era to radiotherapy. During this period, methods for adequate measurement of radiation dosage evolved. Physical unit of dose was designated as the “roentgen”, which was followed later by the word “rads”. However, the radiation oncologists of that era were severely hampered by the physical limitations of the dose distribution pattern of the 200-kilovolt photon beams.
Pioneering work of Claude Regaud, who convincingly showed that a small daily dose (fractionation) could inhibit spermatogenesis whereas a single large dose could not produce the same biological response. The fractionation of dose also reduced the injury to overlying skin. A new era in radiation therapy began with these developments, i.e. new kilovoltage equipment; ability to quantitate radiation dose and fractionation can produce the desired results. Extraordinary contributions to the care of the cancer patients have been made by radiation oncology since then.
It was obvious that X-rays with higher energies were needed. As a by-product of the development of the atom bomb, a cheap substitute for radium, “radioactive Cobalt-60”, an unstable isotope of cobalt was discovered. This man-made isotope soon found its way into the interstitial brachytherapy field and ultimately led to the development of the teletherapy unit, which ushered in the megavoltage era of radiation therapy.50 In the mid-50s the Betatron and the Linear Accelerator were introduced. Today the “LINAC” (linear accelerator of 6–20 mV) is widely used as the “workhorse” of the modern era of megavoltage radiation therapy.
High energy X-rays (photons) and electron (negative subatomic particle) beams offer many advantages over the conventional 200 kV X-ray: a) physical characteristics of the beam to target small lesions deep within the body, without radiating the skin and nearby vital tissues and organs; b) the beam can be widened to treat a much larger volume of tissue than was possible with the 200 kV unit and c) the problem of limitation of skin tolerance was solved by the skin sparing effect of the high energy beam. Increase in the versatility and precision of the physical dose distribution of the therapeutic beam led to improved 5-year survival rates for certain cancer type (superficial “early” squamous cell carcinoma of the skin, vocal cord, oral cavity, oropharynx and penis etc.), such high-voltage therapy gives results as good as those obtained by ablative surgery. These patients also enjoy a better quality of life, by retaining functional and cosmetic integrity.50
The use of microprocessor-controlled treatment planning system provides ability to deliver radiation to an asymmetrical field. Better fractionation schedules and use of radiosensitisers (substances capable of enhancing cancericidal effect) are the subjects of investigation. It is expected that further improvements and more rational use of external beam radiation therapy is sure to come.
 
 
Interstitial or Intracavitary Radiation Therapy (Brachytherapy)
In this method of treatment, radioactive sources of radium, cobalt, cesium or iridium are placed within the vagina or endometrial cavity or in contact with a cancer or inserted into tissues via plastic tubes, e.g. sarcomas of the limbs, cancer of the breast, etc. This strategy is also employed in the treatment of early cancers of the oral cavity, utilising a surface applicator, the radiation source being placed within a dental mould, made to measure for individual patients.
 
Radioactive Isotopes
Selective concentration of a radioactive isotope in tissue forms the basis of this therapy. The classical example is that of radioactive iodine (131I) in the treatment of well-differentiated carcinomas of the thyroid that selectively absorb radioactive iodine destroying tumour cells by internal radiation sparing other normal adjacent tissues. Similarly, radioactive strontium can be used for the treatment of bone metastases.
 
Complications of Radiation Therapy
Indiscriminate or incorrect administration of radiation can lead to undesirable systemic effects known as “radiation sickness”, characterised by anorexia, nausea, vomiting, anaemia, profuse perspiration, prostration and occasionally 19high fever in extreme cases. In the past, radiation injury to the skin from orthovoltage units was commonly encountered. The damaged skin often presented an alarming appearance, with erythema, oedema, ulceration and occasionally severe infection. Non-healing of a wound or surgical incision used to be a common complication of low-voltage radiation therapy. With the advent of supervoltage units, radiation could be directed to the deeper tissues with minimal or no damage to the skin (skin-sparing effect). After a heavy dose or radiation to a large area of tissue, bone marrow depression is likely to occur.
Delayed radiation induced injuries at various sites include radiation nephritis, strictures or chronic ulcers in the gastrointestinal tract, radiation pneumonitis leading to fibrosis of the lung, dryness of the mouth and throat due to loss of salivary secretions, ulceration and fistulae of the bladder and rectum (radiation cystitis and proctitis), transverse myelitis, constrictive pericarditis, cataract, etc. A serious long term (a decade or two following the initial irradiation) complication of radiation therapy is the occurrence of a second malignancy, particularly leukaemia. Surgery in radiated area is hazardous due to poor healing of the damaged tissues.
 
Supportive Care of Patients Receiving Radiation Therapy
 
Emotional Assistance
Many fears burden a patient undergoing radiation therapy; such as the fear of death, of being “burnt” or disfigured, of being unable to retain normal functions, anticipation of pain, sterility and loss of sexual power. Fear leads to major systemic responses, such as dryness of the mouth and throat, tremors of the hands, vomiting and alarming episodes of palpitation. Reassurance and if necessary tranquillisers in liberal doses may be given to such patients.
 
Nutritional Support
Intravenous hyperalimentation has proved to be of considerable benefit in maintaining and improving the electrolyte balance and general nutritional level in patients with dysphagia or gastrointestinal tract obstruction.
 
Skin
The skin should be kept dry and well aerated. Mild antiseptics are useful. For moist desquamation, an antibiotic ointment is beneficial. Topical application of a steroid cream will relieve the distressing symptoms of itching and pain.
 
Mucous Membranes
The mucous membrane of the upper respiratory and alimentary tracts is very sensitive to radiation. Severe mucositis gives rise to soreness and inability to masticate or swallow food. Irritants such as smoking, spicy food and alcoholic beverages should be avoided. Topical application of gentian violet, or an antifungal agent such as Mycostatin, should be used to control fungal infections caused by monilia, etc.
 
Tissue Support
Loss of tissue following radiation therapy may require prosthesis or plastic surgical repair of defect left behind by a cancer that had destroyed the part, e.g. basal carcinoma involving nose.
 
CHEMOTHERAPY
Local control of tumour was possible by surgery and radiation in some cases, but there was a need to find solution to control the systemic disease and the development of drugs was inevitable. The initial drugs were colchicine, Arsenic, Benzol, and Urethane and were used in chronic myeloid leukaemia. Most of these drugs are no longer in use, however observations with these drugs provided the basis to search for more effective drugs. A simultaneous development in experimental medicine of inbred mice and transplantable tumours (Walker 256, Ehrlich ascites, sarcoma 180, etc.) allowed the examinations of many drugs on animals prior to their testing in humans.
After World War II, a greater activity was witnessed in the development of newer drugs. The initial success of nitrogen mustard in 1946 in the treatment of leukaemia and lymphomas gave considerable stimulus and hope. 20Complete regression of metastatic gestational choriocarcinoma, following treatment with methotrexate (1956), was a source of great encouragement to oncologists and showed the effectiveness of chemotherapy in curing metastatic solid tumours, and monitoring the effectiveness of chemotherapy by serially testing tumour markers (beta HCG).51
The drugs developed were categorised in various groups, such as alkylating agents, antifolate, corticosteroids, antimetabolites and antibiotics. The reasons of their development, in most cases were other than cancer, but their use was soon discovered in various human malignancies. Following these initial developments, pre-planned drug development programs began. Several drugs, which are in current use such as vincristine, vinblastine (vinca alkaloids), procarbazine, cytosine arabinoside (Ara-C), Adriamycin, bleomycin, cisplatin were developed under such programs. 5-Fluorouracil on the other hand was a result of biochemical research. Several drugs such as Taxol and less toxic analogues of other drugs have been developed and these are finding their use in specific cancers.
At present there are dozens of anticancer drugs available for clinical use and the rate is steadily increasing. Specialty of medical oncology has shown phenomenal growth. Chemotherapy is accepted as a standard form of treatment and knowledge of the practical management of cytotoxic therapy is essential for surgical and radiation oncologist. Commonly used drugs are enlisted in Table 1.6. The impetus for the use of drug combinations, stemmed from the success obtained in the treatment of many cancers, understanding of cell kinetics and mechanism of actions of anticancer drugs. Thus, chemotherapy progressed from playing a purely palliative role, to the position of a definitive primary therapeutic modality for a number of cancers.
 
 
Mechanisms of Action of Anticancer Drugs
Cytotoxic drugs can be cytocidal that is these lead to a direct killing of the tumour cells or cytostatic, inhibiting the tumour cell proliferation. The cytocidal mechanism involves the blockage of protein synthesis and the cytostatic effect is due to the inhibition of DNA synthesis. Certain drugs are specifically active in tumours that have a high mitotic activity and are designated as being “cycle-specific agents”, mainly the antimetabolites. The resting tumour cells, however, constitute the major population of a tumour mass and are affected mainly by alkylating and antibiotics group of drugs, which are “non-cycle-specific”.
 
Methods of Drug Administration
Oral administration is preferred in drugs which are well absorbed and which do not irritate the gastrointestinal tract. Many alkylating agents can be administered orally. The intravenous route is essential for the administration of drugs such as Adriamycin, mitomycin or vincristine, as they are local irritants and can cause marked necrosis of the skin and subcutaneous tissues. Intracavitary therapy is primarily employed to control ascites and pleural effusion. Most of the anticancer drugs do not cross the blood-brain barrier and therefore, intrathecal therapy with methotrexate is employed to control meningeal leukaemia. Intra-arterial infusion is employed infrequently, in order to provide high concentration of a drug in a limited area or in a single organ.
 
Venous Access Devices (VADs)
The VADs are catheters inserted into the superior or inferior vena cava to provide ongoing and permanent venous access. There are two types of VADs: (1) indwelling Silastic catheters such as the Hickman, the Broviac, and the Groshong; and (2) implantable devices such as the Port-A-Cath, the Norport, and the Infuse-A-Port (Fig. 1.1). Patients requiring frequent access with prolonged treatment via continuous infusion with vesicant drugs or those in outpatient settings are the candidates for venous access devices.
Indwelling catheters are placed through the subclavian vein into the superior vena cava. They are tunneled through a subcutaneous pocket to an exit point in the area of the right nipple on the chest wall and “capped.”
zoom view
Fig. 1.1: Hickman subcutaneous port with a small venouscatheter for long term intermittent access
21
Table 1.6   Commonly used Agents for Systemic Therapy in Cancer
Category/Drugs / Dosage / Route
Common Indications
Unique - Side Effects
Special Instructions
A. Chemotherapy Agents Altretamine (Hexalen)
Capsule 50 mg; PO
(Misc.)
Recurrent ovarian cancer
Neuropathy and CNS toxicities, myelosuppression
May cause orthostatic hypotension Cimetidine can slow metabolism and increase toxicity. MOA inhibitors and antidepressants may cause hypotension
Aminoglutethimide (Cytadren)
Aromatase inhibitor Tablets 250 mg; PO
(Misc.)
Breast cancer, Prostate cancer
Drowsiness, severe nausea, dizziness, adrenal insufficiency maculopapular rash, hypotension
Replacement therapy with steroids, rash is not an indication to discontinue treatment
Asparaginase
Vial 10,000 U with mannitol
(Enzyme - Misc.)
ALL
Hypersensitivity reaction, reduced production of coagulation factors, hyperglycaemia, thrombosis, pancreatitis
Abolishes effect of methotrexate and increases toxicity of vincristine. Peripheral neuropathy. Administer dilute solution and keep emergency tray at bedside. Monitor glucose level. Highly vesicant - precautions required
Bleomycin
Vial 15 U with diluent; IM or IV
(Antibiotics)
Testicular tumour, Lymphomas, Head and neck cancers, Pleural effusion
Dose related pulmonary fibrosis, hypersensitivity reaction, nail bed changes. Raynaud's phenomenon, Mucocutaneous toxicity
Dose closely calculated. Chills, fever, hypersensitivity reaction - more common in lymphomas. Antihistamine and Acetaminophen administered prophylactically. Emergency tray at bedside
Busulphan (Myleran)
Tablets 2.0 mg; PO
(Alkylating)
Chronic myeloid leukaemia,
Myeloproliferative disorders
Hyperuricemia, hyperpigmentation gonadal suppression, alopecia
Allopurinol, hydration, administer on
an empty stomach,
Busulphan lung syndrome, cataract
Monitor: BUN, creatinine, for
myelosuppression
Carboplatin (Paraplatin)
Vial 50,150 mg; IV
(Alkylating)
Ovarian cancer, Testicular cancer, Head and Neck cancers, Lung cancer
Nephrotoxicity, ototoxicity, hypersensitivity, hepatotoxicity, cumulative myelosuppression
Avoid other nephrotoxic or ototoxic drugs. Infuse under hydration. Monitor: BUN, creatinine, Na, K, CI, magnesium, for myelosuppression. Aluminium needles should not be used for administration
Carmustine (BCNU)
Vial 100 mg with alcohol diluent; IV
(Nitrosourea)
Brain tumour, Hodgkin's disease, Non Hodgkin's lymphomas, Myeloma, Mycosis fungoides
Vesicant, pulmonary and cutaneous toxicities, delayed myelosuppression
Avoid skin contact, use antiemetic and hypnotics, oral hygiene, infuse dilute solution over 1–2 hours. Monitor: for renal function and myelosuppression
Chlorambucil (Leukeran)
Tablets 2.0 mg; PO
(Alkylating)
Chronic lymphocytic leukaemia, Hodgkin's disease, Ovarian cancer Breast cancer
Urticaria, gonadal suppression, pulmonary fibrosis, seizures
Administer on an empty stomach Monitor: for myelosuppression, renal and hepatic functions
22
Cisplatin (Platinol)
Vials 10 & 50 mg; IV
(Alkylating)
Ovarian cancer, Testicular cancer, Bladder cancer, Non-small cell carcinomas, Prostate cancer, Osteogenic sarcomas, Endometrial cancer, Head and Neck cancers
Anaphylaxis, uricemia, electrolyte imbalance, nephrotoxic, peripheral neuropathies
Avoid other nephrotoxic or ototoxic drugs. Infuse under hydration/ mannitol, do not use aluminium needles. Monitor: BUN, creatinine Na, K, CI, magnesium and renal functions
Cyclophosphamide (Endoxan, Cytoxan)
Tablets 25 mg, 50 mg; PO Vials 100 mg, 200 mg, 1.0 gm, 2.0 gm; IV
(Alkylating)
Breast cancer, Ovarian cancer, Lymphomas, Myeloma, Wilms tumour, Neuroblastoma,
Acute leukaemia, Testicular cancer
Hemorrhagic cystitis, nausea, vomiting, myelosuppression, cardiac toxicity with Adriamycin, haemolytic anaemia in CLL patients
Oral drug intake on an empty stomach. Don't administer drug late at night this is to avoid accumulation of drug in the bladder. Adequate hydration, phenobarb increases myelosuppression. Monitor: for myelosuppression, liver functions. Cyclophosphamide is secreted in the milk - caution nursing mothers
Cytarabine (Cytosar) Vials 100, 200 mg and 1 and 2 gm; IV
(Antimetabolites)
AML, CML (Blast crisis) Intrathecal in Leukaemia
Myelodysplasia
Vesicant. Pancreatitis, Pulmonary oedema, GI symptoms, keratitis, conjunctivitis
Avoid high dose cyclophosphamide. Discard if prepared solution not
Dacarbazine (DTIC)
Vials 100 mg and 200 mg; IV
(Alkylating)
Melanoma, Hodgkin's disease,
Sarcoma, Endocrine rumours
Vesicant, pain at injection site, flu like symptoms, hepatic venoocclusive disease, facial paresthesia, photohypersensitivity
Antiemetic, hydration to have good urine output, heating helps local pain, avoid sunlight, restrict food for 4–6 hours after medication
Dactinomycin
Vial 0.5 mg in mannitol; IV
(Antibiotics)
Wilms tumour, Rhabdomyosarcoma Sarcomas, Testicular cancer, Choriocarcinoma,
Local vesicant, radiation recall toxicity, hepatotoxicity, alopecia hypercalcaemia
Gloves to prepare, solution highly toxic, avoid contact with eyes, skin and mucous membrane, oral hygiene. Concurrent use of Adriamycin increases cardiotoxicity. Incompatible with preservatives
Daunorubicin
Vials 200 mg in mannitol; IV
(Antibiotics)
AML, ALL
Local vesicant, dose related cardiac toxicity, red urine, alopecia
Oral hygiene, Monitor: cardiac status, myelosuppression
Doxorubicin (Adriamycin)
Vial 10, 20, 50 mg in mannitol; D
(Antibiotics)
I
ALL, AML, Lymphomas, Breast - Ovarian - Endometrial cancers, Wilms tumour, Neuroblastoma, Rhabdomyosarcoma
Local vesicant, dose related cardiac toxicity, red urine, alopecia
Oral hygiene. Monitor cardiac status during and many years after the treatment and for myelosuppression
Etoposide (VP16)
Vials 100, 150, 500 mg; IV Capsules 50 mg store at 4°C; PO
(Plant alkaloids)
Refractory testicular tumour, small and non-small cell lung cancers, Lymphomas
Delayed myelosuppression, pulmonary and cutaneous toxicities, hypotension, serious hypersensitivity reaction
Have IV running, slow drip. Monitor for hypotension and hypersensitivity reaction, keep emergency tray at bedside. Contains polysorbate and can react with plastic devices
Floxuridine (FUDR)
Vial 500 mg for intra-arterial use
(Antimetabolites)
Intra-arterial infusion in metastatic cancer to liver
Cerebellar ataxia, myocardial ischaemia, cholangitis
Slow intra-arterial infusion
23
Fluorouracil (5-FU)
Vial 500 mg; IV
Topical preparation also
Gemcitabine
(Antimetabolites)
Breast cancer, GI tract cancer, Ovarian cancer, Endometrial cancer, Testicular cancer, Squamous-cell cancer, Lymphoma, Pleural effusion
Nausea, vomiting, stomatitis, oesophagitis, hand-foot syndrome
Maintain urinary output. Oral - drug intake on an empty stomach in the morning. Slow infusion or push
Hydroxyurea
Capsules 500 mg; PO
(Misc.)
CML, Ovarian cancer, Head and Neck cancer, Melanoma, Cervical cancer
Megaloblastosis, thrombocytopenia. Carcinogenic
Monitor for myelosuppression and renal functions
Ifosfamide
Vials 1.0 gm, 3.0 gm; IV
(Alkylating)
Second line therapy in testicular cancer, Non-Hodgkin's lymphoma, many solid tumours
Haemorrhagic cystitis, nausea, vomiting, myelosuppression, cardiac toxicity with Adriamycin, metabolic acidosis
Use antiemetics, drug intake on an empty stomach. Don't administer drug late at night this is to avoid accumulation of drug in the bladder. Adequate hydration, phenobarb increases myelosuppression. Monitor: for myelosuppression, hepatic function. Usually given with Mesna
Lomustine (CCNU, CeeNU) Capsules 10, 40, 100 mg; PO
(Nitrosourea)
Brain tumour, Myeloma, Lymphomas, GI cancer
Allergic reactions, hepatotoxicity, CNS toxicity, postural hypotension, dose related myelosuppression
Administer on an empty stomach, Monitor: for myelosuppression, BUN, creatinine, hepatic functions. Oral hygiene
Mechlorethamine
(Nitrogen Mustard, (Mustargen) Vial 10 mg; IV
(Alkylating)
Hodgkin's disease, Intracavitary for effusion, Mycosis fungoides, Intracavitary administration
Pain and sloughing at site of injection; gonadal suppression, myelosuppression
Concurrent use of Adriamycin increases cardiotoxicity, Highly toxic, special disposal of unused drug required
Melphalan (Alkeran) Tablets 2 mg; PO
(Alkylating)
Myeloma, Ovarian cancer,
Melanoma, Breast cancer
Pulmonary toxicity, hypersensitivity, vasculitis
Food and Cimetidine can reduce absorption. Interacts with muscle relaxants
Mercaptopurine
(Purinethol, 6-Mercaptopurine) Tablets 50 mg; PO
(Antimetabolite)
ALL, AML, Polycythaemia vera, Childhood Lymphomas
Skin rash, hepatotoxicity
Monitor liver functions. Reacts with allopurinol and dose adjustment required
Methotrexate
Tablets 2.5 mg; PO
Vials 20, 50, 100 mg; IV or Intrat
(Antimetabolite) Kecal
Choriocarcinoma, Lymphomas, ALL (Intrathecal), Gastric cancer Breast cancer, Head and Neck cancers
Vesicant, myelosuppressive Toxicity is dose related
Interacts with salicylates, NSAID, nonabsorbable antibiotics, folic acid. Monitor for myelosuppression
Mitomycin
Vials 5, 20 mg with mannitol; IV
(Antibiotic)
Stomach cancer, Pancreatic cancer, Head and Neck cancers
Vesicant, pulmonary toxicity, haemolytic ureamic syndrome not cause pain or burning and may result in sloughing
Monitor liver and renal functions. Protect from light. Extravasation may
Mitotane (Lysodren)
Tablets 500 mg; PO
(Misc.)
Adrenal carcinoma
GI symptoms, rash, CNS toxicity, dermatitis
Require replacement therapy with corticosteroid. May discontinue if side effects are intolerable and restart
24
Mitoxantrone (Novantrone) Vials 20, 25 mg; IV
(Antibiotic)
AML, Breast cancer, Hepatoma, Non-Hodgkin's lymphoma
Blue green urine, vesicant, myelosuppression, cardiomyopathy
Use gloves, high fluid intake, monitor for myelosuppression, antiemetic. Solution is slightly bluish
Paclitaxel (Taxol)
Vial 30 mg; IV
(Plant alkaloid)
Ovarian and breast cancer
Hypersensitivity, neuropathy, cardiac toxicity, mucositis, alopecia
High fluid intake, emergency tray at bedside, oral hygiene
Plicamycin (Mithracin)
Vial 2500 microgram; IV
(Antibiotic)
Testicular cancer, Hypercalcaemia of malignancy
Local vesicant, coagulopathy, nephro and hepato toxicities, bleeding epistaxis
Avoid drugs known to cause coagulopathies, produces local phlebitis
Procarbazine
Capsules 50 mg; PO
(Misc.)
Hodgkin's disease, Brain rumours, Lung cancer, Melanoma
Antabuse like effect, peripheral neuropathy, hepato and pulmonary toxicities
Has wide drug interactions (antihypertensive, narcotics, anticoagulants). Avoid food containing tyramine
Streptozocin (Zanosar)
Vial 1.0 gm; IV
(Nitrosourea)
Islet cell carcinoma
Glucose intolerance, cumulative renal toxicity
Monitor glucose levels, renal function. Highly vesicant
Teniposide (VM-26)
Ampules 50 mg with diluent; IV
(Plant alkaloid)
Childhood leukaemia,
Lymphomas, Neuroblastoma, Glioma, SCLL, Melanoma, Renal cell carcinoma
Vesicant. Chemical phlebitis, allergic reactions, hypotension
Use gloves, Monitor renal functions, emergency tray at bedside
Vinblastine (Velban)
Vial 10 mg; IV
(Vinca alkaloids)
Testicular cancer, Breast cancer,
Choriocarcinoma, Lymphomas, Sarcomas, Head and Neck cancers
Vesicant. Pain at rumour site, hypertension, gonadal suppression, peripheral neuritis, anaphylaxis reaction, constipation
Use gloves, stool softener,
Monitor fluid intake and electrolytes
Vincristine (Oncovin)
Vials 1.0 and 2.0 mg; IV
(Vinca alkaloid)
ALL, Neuroblastoma, Wilms tumour, Hodgkin's disease, Non-Hodgkin's lymphoma, Rhabdomyosarcoma, Breast cancer, Myeloma, Sarcoma
Vesicant. Pain at rumour site, hypertension, gonadal suppression, peripheral neuritis, anaphylaxis reaction, constipation, SIADH
Use gloves, stool softener,
Monitor fluid intake and electrolytes
B. Hormonal Agents Dexamethasone (Decadron) Available in many strength; PO, IV
ALL, Hodgkin's disease, CLL, Myeloma, Waldenstrom's macroglobulinaemia, Lymphangitic metastasis
Cushing appearance, fluid retention, hyperglycaemia, muscular weakness, peptic ulcer, osteoporosis, aseptic necrosis of the head of the femur
Anti ulcer regimen
Diethylstilbestrol (DES) Tablets 50 mg; PO Vial 250 mg; IM
Breast cancer, Prostate cancer
Feminisation, fluid retention, uterine cancer, thromboembolic phenomenon hepatic adenoma, hypercalcaemia
Esterified oestrogen Tablets 0.3, 0.625 mg; PO
Breast cancer, Prostate cancer
Feminisation, fluid retention, thromboembolic phenomenon, risk of endometrial cancer
Estramustine
Capsules 140 mg; PO
(Misc.)
Metastatic prostate carcinoma
Breast tenderness, water retention thrombophlebitis
Careful administration in diabetics, hypertensive and CHD
Flutamide (Antiandrogen)
Capsules 125, 250 mg; PO
Prostate cancer (with LHRH)
Increase bone pain, feminisation, diarrhoea
Monitor liver functions
25
Goserelin (Zoladex - LHRH)
Pellets for SC insertion
Prostate cancer, Breast cancer
Worsening bone pains, hot flushes
Contraindicated in pregnancy
Leuprolide
Pellets for SC insertion
Prostate cancer, Breast cancer
Worsening bone pains, hot flushes
Contraindicated in pregnancy
Megestrol acetate (Megace)
Tablets 20, 40 mg; PO
Endometrial cancer, Breast cancer
Weight gain, thromboembolic phenomenon
Prednisone
ALL, Lymphomas, CLL, Waldenstrom's macroglobulinemia, Lymphangitic metastasis
Cushing appearance, fluid retention, hyperglycaemia, muscular weakness, peptic ulcer
Anti-ulcer regimen
Tamoxifen
Tablets 10 mg; PO
Breast cancer
Significant effect of anticoagulant
Octreotide (Sandostatin)
Multidose vial 50 microgram/ml; IV
Carcinoid tumours producing active peptides
Potentiate effect of hypertensive agents
Corticosteroid may replace effectiveness
C. Biological agents
Aldesleukin (Human recombinant IL-2, Proleukin) Vial 22 million units
Renal cell carcinoma, Melanoma
Fever, chills, capillary leak syndrome, can produce cardiac - renal - pulmonary - endocrine toxicity
Delayed reaction to radiopaque media. Not use in less than 18 years of age
Interferon alfa − 2 B (Intron-A)
Vial 3 million units
Hairy cell leukaemia, Kaposi's sarcoma, Renal cell carcinoma, myeloma, Non-Hodgkin's lymphoma
Fever, flue like syndrome, cardiac and neurotoxicity, agranulocytopenia, haemolytic anaemia
Interactions with other drugs not fully evaluated
Erythropoietin (Epogen)
Vial 200–10,000 units/ml
Treatment induced anaemia
Generally well tolerated
Filgrastim (CSF-G, Neupogen) Vial 300 mcg/ml
Treatment induced myelosuppression, proliferation and differentiation of neutrophil
Pain at injection site, bone pain, arthralgia, allergic reaction
Generally well tolerated
Sargramostim (CSF-GM)
Treatment induced myelosuppression, proliferation and differentiation of neutrophil
Pain at injection site, bone pain arthralgia, allergic reaction capillary leakage syndrome
Generally well tolerated
D. Miscellaneous
MESNA (Sulfhydryl compound) Vial 100 mg/ml
Prevention of cystitis induced by Cyclophosphamide or Ifosfamide
Bad taste, diarrhea, allergic reaction
Can react in patients wit auto immune disease
Leucovorin (Citrovorum factor) oral and IV preparations
Prevention of myelosuppressive effects of antifolic acid compound
Flue like syndromes, neuralgic disorders
Excessive dosage may nullify the effect of chemotherapy
Notes:
Bold indicates tumour types primarily approved by the drug authorities. However, the drug is used in the treatment of other tumours is also suggested. Such tumour types have been found to be responsive in various studies. Leading cancer centres advocate a variety of protocols utilising various drug combinations. The protocols followed by the authors or commonly used are given in the respective chapters
Emergency tray (Epinephrin 1:1000, Benadryl, dexamethasone, oxygen)
Alkylating Agents — Interact with already formed DNA, non-cycle specific used singularly or in combination
Antimetabolites — Interfere with DNA synthesis, cell-cycle specific, mostly used in combination with other drugs
Antibiotics — Variable mechanism of action, including alkylation and direct DNA destruction, mostly used in combination with other cytotoxic agents
Miscellaneous — Variable mechanism of action, and origin of drugs
26
Table 1.6 contd. Agents available in India for Systemic Therapy in Cancer
Asparaginase
Leunase
(Biochem)
Bleomycin
Bleocin
(Khandelwal)
Busulphan
Myleran
(Wellcome)
Carboplatin (Paraplatin)
Oncocarbin
(TDPL)
Chlorambucil
Leukeran
(Wellcome)
Cisplatin (Platinol)
Cisplatin
(Biochem), Kemplast,
(Dabur)
Cyclophosphamide
Endoxan
(German Remedies)
Cycloxan
(Biochem)
Cytarabine
Cytarabine
(Biochem)
Doxorubicin (Adriamycin)
Doxorubicin
(Khandelwal), (Biochem)
Etoposide (VP16)
Lastet
(Khandelwal)
Etoside
(Cipla)
Floxuridine (FUDR)
Fluorouracil (5-FU)
Fluracil Fivefluro
(Biochem) (Biddle Sawyer)
Hydroxyurea
Neodrea
(VHB Pharma)
Mechlorethamine
Mustine Hcl
(Knoll)
Melphalan
Mercaptopurine
Purinethol
(Wellcome)
Methotrexate
Biotrexaate Neotrexate
(Biochem) (Biddle Sawyer)
Mitomycin
Mitomycin-C
(Biochem)
Mitoxantrone (Novantrone)
Oncotron
(TDPL)
Paclitaxel (Taxol)
Intaxel
(Dabur)
Vinblastine (Velban)
Cytrabin
(Biochem)
Cytroblastin
(Cipla)
Vincristine (Oncovin)
Cytocristin Neocristin
(Cipla)
(Biochem)
Dexamethasone (Decadron)
Diethylstilbestrol (DES)
Honvan
(German Remedies)
Esterified estrogen
Lynoral
(Infar)
Estramustine
Flutamide (Antiandrogen)
Prostamid
(BDH)
Prednisone
Tamoxifen
Tamoxifen Nolvadex
(Lyka)
(ICL)
MESNA
Uromitaxen
(German Remedies)
Leucovorin (Citrovorum factor)
Aldesleukin (Proleukin)
Interferon alfa − 2 B (Intron-A)
Erythropoietin (Epogen)
Filgrastim (CSF-G, Neupogen)
Sargramostim (CSF-GM)
The catheter must be flushed daily with heparin and the injection cap changed weekly. The advantages of Silastic catheters relative to other devices are their slightly larger lumen, the availability of multilumen devices, and their easy removal when therapy is completed. Implanted access devices (Port-A-Cath, the Norport, and the Infuse-A-Port) are also threaded to the superior vena cava; however, the proximal end is composed of a small reservoir that is implanted in the subcutaneous tissue of the upper chest. It is felt as a small, raised area and, although implanted under the skin, is visible as a rounded “lump.” These ports are made of medical use silicone that is hypothrombogenic. The large self-closing radiopaque silicone septum remains watertight after more than 1000 punctures per cm2 from 22 G needles. The port/catheter connection is armored and anti-kinking in whatever position the port is placed. The catheter causes minimal interference in the vessel in which it is placed.27
Central venous catheterisation has become an integral part of care of patients requiring prolonged intravenous anticancer drugs. During 1970s considerable experience was gained with use of central venous access for nutritional support, ICU monitoring and cardiac catheterisation. Besides, chemotherapy drug delivery, blood samples can be withdrawn, and transfusions and nutritional fluids delivery can also be achieved through use of these ports.
The lifelines of the patients receiving chemotherapy are the veins, which should be protected to the maximum possible extent.52 Close attention should be paid to adequate dilution of those drugs that have a sclerosing potential, to minimise local necrosis through extravasation. Injections of corticosteroids and procaine are often salutary.
 
Combination Chemotherapy
The rationale for employing multiple drugs is a) to prevent the development of drug resistance, b) to minimise the toxicity of high-dose of a single drug and c) to attempt to interrupt the cell cycle at various stages. The classic examples of evolution of combination chemotherapy are, the MOPP protocol (Mustard, Oncovin, Procarbazine, Prednisone) for Hodgkin's disease and the CMF (Cytoxan, Methotrexate, 5 Fluorouracil) combination for breast cancer. The MOPP schedule led to an 80% response rate in disseminated Hodgkin's disease, compared to 25% in patients treated with any single drug. At present, combination chemotherapy is extensively used in treatment of malignancy. Generally speaking, drug therapy is preferably given intermittently to allow for adequate recovery of bone marrow. The terminology commonly applied in modern day chemotherapy is given below:
 
Induction
High dose usually combination chemotherapy, given with the intent of inducing complete remission when initiating a curative regimen. The term is usually applied to haematologic malignancies but is equally applicable to solid tumours.
 
Consolidation
Repeating of the induction regimen with the intent of increasing cure rate or prolonging remission after induction regimen.
 
Intensification
Chemotherapy, after complete remission with higher doses of the same agents used for induction or with different agents at high-doses with the intent of increasing cure rate or remission duration.
 
Maintenance
Long term chemotherapy (low dose, usually combination) in a patient, who has achieved a complete remission, with the intent of delaying the regrowth of residual tumour cells.
 
Palliative
Chemotherapy given to control symptoms or prolong life in a patient in who cure is unlikely.
 
Salvage
A potentially curative, usually combination and high dose, regimen given in a patient who has failed to respond or recurred following a different curative regimen.
 
Adjuvant
Chemotherapy administered to a patient with no evidence of residual cancer after surgery or radiation therapy, given with the intent of destroying micrometastases.28
 
Neoadjuvant
Chemotherapy given prior to surgery or radiation therapy. Primarily given to reduce the tumour size to downgrade the stage of tumour.
 
Miscellaneous Issues
High dose chemotherapy with drugs attenuating their toxicities or bone marrow transplantation is very specialised treatment modalities and are beyond the scope of this book. The use of anticancer drugs either prior to or after surgical treatment is discussed when applicable, in the respective chapters. There appears to be no safe anticancer drug during the period of pregnancy.
 
Toxicity of Chemotherapy
The major drawback of cancer chemotherapeutic agents is their lack of tumour specificity, affecting not only the tumour cells but certain normal cells, as well. The susceptible tissues are those with continuous renewal of cells, such as bone marrow, lymphoid cells, mucosal surfaces, hair follicles and others are specific for the drugs (Table 1.5).53 Increased susceptibility to infection due to low white cell count and bone marrow depression is common concern. The fear of hypersensitivity is common to all drugs.54
 
Hypersensitivity
The type 1 hypersensitivity reaction (fever, chill, urticaria, bronchospasm, abdominal cramps, hypotension and angioedema) can occur with any of the drugs. These are more commonly reported with L-asparaginase (6–43%) and cisplatin (1–6%) and to a lesser degree (1–4%) with Anthracycline, VP-16 and bleomycin. Bleomycin can give rise to symptoms similar to that observed in Raynaud's phenomenon. These reactions can be treated with corticosteroids and antihistamines. However, if serious enough, alternate drug protocols should be selected. Granulocyte infusion should be avoided, simultaneously to or soon after the administration of anticancer drugs.
 
Drug Extravasation
Although every care is taken while administering anticancer drugs, extravasation at the site of venepuncture occurs in 1 in 1000 patients. Immediately discontinue infusion, inject short acting hydrocortisone in local site, apply ice pack for 30 minutes—2 hours. If sloughing occurs, it may take a long time before the site is ready for skin grafting or may need major flap reconstruction.
 
Cardiac Toxicity
This is a concern in patients receiving Adriamycin or daunorubicin. The toxicity manifests in the form of cardiac arrhythmias or congestive heart failure. The dose of Adriamycin should never exceed 550 mg/m2 and drug is contraindicated in patients with ECG evidence of conduction defects.
 
Cystitis
Cyclophosphamide can cause haemorrhagic cystitis and require discontinuation of the treatment. The patient receiving cyclophosphamide should be advised to take plenty of fluid or should receive intravenous hydration. The use of cyclophosphamide in patients who have received pelvic irradiation should be carefully judged.
 
Neurotoxicity and Gonadal Dysfunctions
These side effects of cancer chemotherapy are debilitating and should be looked for. Many of these effects will diminish with time and patient needs to be assured. However, if these are pronounced, alternate drugs should be selected. Vincristine over 2 mg in a single dose is contraindicated.
 
Miscellaneous Effects
Photosensitivity is seen with dacarbazine and can easily be avoided with appropriate advise.29
 
HORMONAL THERAPY
Certain organs are hormone dependent for their proliferation and function such as breast, prostate and uterus. Physiologic hormonal imbalance has been implicated in the development of malignant changes, particularly in breast and uterus. It was natural to explore if hormonal manipulation could affect the growth of cancer of these organs.
Hormonal manipulation influencing the course of carcinoma of the breast has been known since 1896 when oophorectomy was first performed. Oestrogen stimulates breast tumour cell growth; therefore, the goal is to deny availability of oestrogen.55 Therapeutic oophorectomy performed at the time of appearance of recurrent cancer was equally effective. Early attempts at treatment centered on hormonal manipulations by bilateral oophorectomy, later by the use of radiation to sterilise the ovaries or treatment by androgens to oppose the oestrogen related effects. With the discovery and widespread use of oestrogen and progesterone receptor estimations,56 there has been a revival of interest in hormonal therapy. Adjuvant tamoxifen (an antioestrogen) is used widely after primary treatment of postmenopausal patients with node positive operable breast cancer and patients with locally advanced disease.
Adult normal prostatic epithelium atrophies in the absence of androgenic hormones. The testes normally produce 90% of the circulating androgens, rest being produced by the adrenal glands. Approximately 60% of circulating testosterone is bound to testosterone binding globulin, 37% is bound to albumin and 3% circulates unbound in the plasma. Only this unbound fraction is biologically active. If androgen is removed from the physiologic environment, the prostate cells are unable to function properly.51 Prostate cancer cells are variably dependent on androgen, some being highly dependent while others are minimally so. Adrenal androgens alone cannot sustain the prostate. Hormonal manipulation in a prostate cancer patient can be achieved in different ways such as bilateral orchiectomy, bilateral adrenalectomy, hypophysectomy, and administration of oestrogens, Luteinising hormone releasing hormone agonists, antiandrogens, etc. The hormonal treatment is discussed in the respective chapters dealing with these organ systems.
 
BIOLOGICAL THERAPY
The deficiency with both surgery and radiation therapy is in their inability to effectively deal with tumour spread outside the areas directly accessible to these treatments. Chemotherapy has low therapeutic ratio for many tumours and the fact that drug resistance may rapidly develop or even be present from the start. The clinical applications of immunological principles can be vaguely perceived at present, though much hopes rest on this field.27
The “aberrant” cells are appearing continuously in the host, however body mechanisms are successful in eliminating such cells. Such malignant cells have qualitative, quantitative and physical characteristics, distinct from the normal cells. The presence of surface glycoproteins capable of producing immune reaction in the host can be demonstrated. However, why such immune reaction cannot eliminate these cells remain unexplained, though many theories have been proposed.51 The presence of tumour associated antigens was demonstrated in the early 1960s. Subsequent work could demonstrate the presence of both circulating antibodies in the blood, specific sensitised cells and antibody on the surface of the tumour cells. However, the potential of these findings could not be applied either for diagnosis or prognosis or for treatment of cancer patients and remains in experimental domain. Manipulation of immune system by many methods such as nonspecific stimulation, passive transfer of activated cells, removal of substances capable of inhibiting cellular immunity, infusion of cytotoxic antibodies, etc. show their effects in syngeneic tumour, particularly at the time of implantation but could not eradicate tumours which are well established and with metastases. Much more work is required for the newer concepts to be tested.59
Biological therapy for cancer may be defined as a treatment that uses biological materials, usually cell or cell products, which either have direct effects on tumour cell proliferation or differentiation or modify the host biological response to the malignant disease. At the turn of the century, Dr. Cooley reported tumour regression induced by a crudely prepared vaccine. He observed complete regression in a recurrent, inoperable sarcoma of the neck, after the patient had erysipelas. On the basis of this observation, Cooley developed a mixed vaccine of killed bacteria which he injected directly into the tumour or gave intravenously. A few impressive regressions and long term cures were noted, but the responses were very inconsistent, and interest in the so-called “Cooley's Toxin” diminished over a period of time.30
About four decades back, BCG was demonstrated to have significant antitumour activity against a wide variety of animal tumours. Since then, a number of investigators have utilised BCG vaccination, especially in the treatment of malignant melanoma, and have reported long periods of disease-free survival in many cases. In the 1970s immunotherapy with BCG and allogeneic or autologous tumour cells was widely investigated, but carefully performed clinical studies failed to show consistent success.
The rekindling of interest in biological therapy for cancer followed inevitably from the development in biology in the 1970s and 1980s. The identification of the molecular basis of many biological processes has presented new ideas for biological treatment. The best example of this lies in the characterisation of the T cell growth factor interleukin, which promotes the proliferation of T lymphocytes as well as stimulates other cytotoxic cell populations and macrophages. The biology of IL-2 led to experimental cancer therapy, and Rosenberg et al at NIH, USA introduced it into the clinic to enhance immune responses against tumours with limited success.
DNA recombinant technology has allowed the expression of genes for many potent biological materials, resulting in the production of large quantities that can readily be purified for clinical use. Some of the agents now available have direct anticancer effects: Interferons have antiproliferative effects; tumour necrosis factors have a direct cytotoxic effect. However, others such as IL-2 or IL-6 may act by enhancing naturally occurring responses to cancers.
Other biological factors may be useful in reducing the toxicity of conventional chemotherapeutic drugs, e.g. haemopoietic growth factors ameliorate bone marrow toxicity of some cytotoxic drugs. The interaction of biological treatment with chemotherapy or radiation therapy offers valuable combined approaches, which already have shown some promise. Other biological approaches including monoclonal antibodies, active immunisation and adoptive cellular therapy are being studied. Monoclonal antibodies directed against tumour associated antigens have been used as anticancer agents and tumour regression has been described. Recently drugs capable of inducing selective anticancer immune response are in preclinical trials.60 Active immunisation with melanoma tumour antigens can apparently produce tumour regression. These exciting developments are slowly trickling in the clinics, both in diagnosis and treatment.61
 
NORMAL TISSUE PROTECTION
There is conclusive evidence that haemopoietic growth factors can stimulate the bone marrow in man and reduce myelosuppression by cytotoxic drugs. Infusion of haemopoietic colony stimulating factors (CSF) can be used to support bone marrow function in cancer patients undergoing chemotherapy. These molecules include CSF for granulocytes, macrophages and granulocyte-macrophage and erythropoietin for red cells.
The production of cytotoxic-drug-resistant stem cells may be a mechanism by which normal cells could be protected from treatment related toxicity, allowing much larger dosages to be used. The proposed transgene can render stem cells resistant to some specific drugs, e.g. methotrexate by use of dihydrofolate reductase (DHFR) or confer on them more widespread multidrug resistance (MDR) by the expression of the MDR1 gene.
 
THE PROBLEM OF CANCER CONTROL
The spectrum of activities being undertaken to control cancer today has three main facets: research, prevention, and early detection, which mandates public and professional education. Our discussion will be limited and confined to the prevention and diagnosis of early cancer.
 
 
Epidemiology
A cancer registry is defined as an organisation for the collection, storage, analysis and interpretation of data on persons with cancer. A hospital-based registry undertakes these tasks within the confines of a hospital or a group of hospitals. A population-based registry is concerned with all newly diagnosed cases of cancer occurring in a population of well-defined composition and size. Registries can provide information on cancer burden in a community, providing the data needed to uncover the causes of cancer in humans and for evaluation of the effects of steps taken to control the disease. Cancer control activities include: a) continued assessment of the incidence of cancer in the population; b) provision of the personnel, hospital and other facilities and equipment needed for the diagnosis, treatment and rehabilitation of the cancer patient; c) evaluation of the effect of early diagnosis and treatment; and d) identification by epidemiological and laboratory studies of the initiating and promoting agents that cause cancer.31
 
Prevention of Cancer
Sir Newton's Principia Mathematica was published in 1687, describing the classical theory of gravity, however, his prediction that it should be possible to place a satellite into the earth orbit given a sufficient force to achieve proper distance, could be realised three centuries later. The expectations from science have not realised at a pace desired of it, thus produced pessimism towards this disease. We better appreciate the molecular mechanisms of cell-cycle control pathways and cellular suicide, which are mostly disrupted in cancer. The cancer may develop due to spontaneous somatic mutation (15%), inheritance predisposition to cancer (5%) and exposure to environmental agents with or without hereditary susceptibility (80%). To prevent cancer it will be important to have clear understanding of associated risk factors, both genetic and environmental. A family history constitutes the most important genetic risk factor for majority of common cancers such as breast, colon, ovaries and prostate.
It has been estimated that 65–80% of all cancers are due to non-shared environmental exposure, attributable to the life-style and are thus preventable. Some of the cancers involving the skin, upper respiratory tract, lungs and urinary bladder, have been associated with occupational hazards. A variety of carcinogens present in the environment of the present day industrial worker are held responsible for the occurrence of cancer. Through adequate legislation and rigid implementation of preventive measures, the incidence of such cancers can be minimised. Much remains to be done however, in controlling air pollution in our major cities.
The high incidence of cancers of the oral cavity and oropharynx in the Indian population is undoubtedly linked with the manner and degree of tobacco consumption in the presence of poor oral hygiene. Unless inherent harmful social customs are curbed or eliminated through education, we cannot expect to prevent this large group of cancer from afflicting those addicted to these habits. As of today, not a single specific program has been planned by the public health authorities to prevent cancers of the oral cavity and oropharynx in India. The phenomenal rise in the incidence of bronchogenic carcinoma in Western countries has been shown to be directly proportional to the quantum of cigarette smoking. In the United States and Northern Europe, the disease has assumed epidemic proportions. Heavy alcohol consumption has also been implicated in the genesis of cancer of the tongue and oesophagus.
 
Tobacco, Diet and Premalignant Conditions
Wide spectrum of tobacco products are available for human consumption. They can be classified into tobacco smoking and oral use of un-burnt tobacco (smokeless tobacco). Irrespective of its mode of consumption, tobacco is carcinogenic. Patients with premalignant conditions such as oral submucous fibrosis, erythroplakia, atrophic glossitis must be advised to change their life-styles especially avoid tobacco, Areca nut and betel quid, and should go for cancer check ups annually. Diet rich in high residue fibre of leafy green and yellow vegetables and fruits protects from GI tract cancers. Reduction in red meat in diet and replacing with high fibre content has reduced GI tract cancers in USA. It is virtually impossible to curb addictive human habits and customs by any means known today, hence prevention of a majority of cancers yet remains an allusive dream. Meditation can help to change habits. Positive thinking can help remove addictions and instill healthy lifestyle.
 
Early Detection of Cancer
If cancer cannot be truly prevented, it should at least be detected in the early treatable stages. What evidence is there of the value of early detection? The best answer would be to compare the mortality rates of patients treated for localised cancers with those of advanced disease.6163 The twelve types of cancers shown in Chart 1.1 represent approximately 80% of all cancers and are responsible for 70% of the overall mortality. Experience at the major cancer centres today has conclusively demonstrated the fact that negligible morbidity, low mortality and a better quality of life are the end results obtainable if only cancer patients are treated in the early stages of the disease. When patients seek medical advice for vague symptoms, which could be due to a possible malignant tumour at a particular site, the alert clinician should investigate the patient immediately, to exclude cancer. At this stage, cancer is usually not significantly advanced. Early diagnosis, then, refers to detection of cancer in the more or less asymptomatic, apparently healthy subjects (Chart 1.1)
An early detection drive involves mass screening of a high risk but healthy population, carried out by means of: a) cytology smear tests; b) clinical examinations; c) a variety of roentgenological examinations; and d) biochemical tests. The expense involved in such mass screening can be prohibitive, even for affluent countries. In the past, mass screening programs were beset with problems of low yield, inadequate follow up, poor physician utilisation and the wrong group of people being screened.32
zoom view
Chart 1.1: Comparison of long-term survival rates in patients with localised and non-localised cancer. Miller DG : Cancer 37: 426, 1976. Copyright American Cancer Society. Reprinted by permission of Wiley-Liss Inc., a subsidiary of John Wiley & Sons Inc.
Hence the program of screening could be restricted to cover a population at known higher risk of developing cancer at a given site. For example, workers in the dye industries could be specifically screened for urinary bladder cancers, workers in the asbestos industry for bronchogenic carcinoma, men who chew or smoke tobacco for oral, pharyngeal, laryngeal and lung cancers, women at known risk for breast and uterine cervix cancers. Details of some of the screening programs for common cancers are given below:
 
Uterine Cervix
Mass screening in its truest sense has been employed in a number of countries for the detection of early cervical cancer. In certain parts of the United States, UK, Europe, Canada and the USSR, most women above the age of 25 years voluntarily undergo a yearly or two-yearly “Pap” test. Many such countries have demonstrated a 50% drop in the mortality from cervical cancer. As a result of such mass screening of apparently healthy women, the proportion of carcinoma-in situ (of the uterine cervix) have risen sharply and that of invasive carcinoma has fallen proportionately.
In India, large-scale mass cytological screening is not a feasible proposition economically. Hence the screening program has been restricted to those patients who voluntarily report for such tests. The Indian Academy of Cytology is making effort to have the Pap test included in the gynaecological examination of women who report to Primary Health Centres for advice on family planning.
 
Breast
Mammography, coupled with clinical examination, is today being employed for the early detection of breast cancer. A yearly mammogram of all the adult (normal) female population is not recommended, because of the radiation hazard. In most countries, therefore, this test is confined to women above the age of 45. However, self-examination is inexpensive and women should be educated to adopt this simple screening measure. Mammography should however be undertaken whenever indicated, e.g. in those women who report with complaints referred to the breast, where the diagnosis remains doubtful and in those who belong to known high-risk groups in the 33population. The American Cancer Society's experience in this regard is worth noting. Low-dose units for mammography may lead to more universal use of this efficient detection technique.
 
Oral Cavity and Oropharynx
The oral cavity can be inspected easily. Dentists and physicians should not spare any efforts to locate precancerous lesions such as the leukoplakias, erythroplakia, submucous fibrosis or early non-healing ulcers.
 
Prostate
Wide spread use of PSA testing above the age of 50 years is bringing patients with localised disease more often and posing a new problems to handle patients with borderline findings. This issue is discussed in the chapter dealing with prostate cancer.
The efforts have made significant inroad to improve the survival and the future is hopeful.6163 We need similar efforts in India by taking note of those already made in the other countries.
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