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.5–8
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.9–10
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.11–12 This definition brings out three cardinal features of cancer:
- 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.
- 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.
- 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:
- The 5 and 10 years survival rates of patients treated by surgery, radiotherapy or chemotherapy are much higher than those of untreated patients.
- 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.
- The biological behaviour of certain cancers can be modified by hormonal manipulation.
- 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.
- 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
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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.22–25
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
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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.
- 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,
- 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,
- 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,
- 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
- 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.
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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.”
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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
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.61–63 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
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.61–63 We need similar efforts in India by taking note of those already made in the other countries.
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