PRINCIPLES OF
CANCER CHEMOTHERAPY


The modern age of systemic chemotherapy dates from early 1940s, when Hoggins and Hodges showed that the patients with prostate cancer benefited from administration of estrogen. Drugs are now used at some time during the course of illness of most cancer patients. Cytotoxic drugs can cure some disseminated tumours and can be effective in decreasing tumour volume, alleviating symptoms and even prolonging life in many other types of metastatic cancer. Currently, chemotherapy has a role in four different clinical settings-

1) INDUCTION CHEMOTHERAPY - drug therapy given as a primary treatment for patients who present with advanced cancer for which no alternative treatment exists.

2) ADJUVANT CHEMOTHERAPY - use of systemic treatment after tumour has been controlled either with surgery or radiotherapy. The rationale of the treatment is to treat micrometastatic disease at a time when tumour burden is minimum, thereby enhancing the potential efficacy of drug treatment. In adjuvant setting relapse free survival remains the major end point.

3) NEOADJUVANT (PRIMARY) CHEMOTHERAPY use of chemotherapy as the initial treatment for patients who present with localised tumour, for which there is an alternative but less than completely effective local treatment. For neoadjuvant therapy there should be considerable evidence for the effectiveness of drug program in question against advanced disease of the same type. This approach allows preservation of vital normal organs like larynx , anal sphincter, bladder as the primary tumour is reduced in size and rendered easier to deal with by traditional local methods.

4) DIRECT INSTILLATION- into sanctuary sites or by site directed perfusion of specific regions of the body directly affected by the cancer.

CELL CYCLE

The concept of differential drug efficacy during specific phases of life cycle of malignant cells has important theoretical implications for cancer therapy, although the practical importance of this concept is uncertain.

The cycle of a normal and malignant cell starts with mitosis or cell division, which is followed by the G1 phase or the first gap phase. Cell stops proliferating and comes to rest in G1 phase. Occasionally, cells rest for a prolonged period of time and this is known as G0 phase. On emerging from G1 cells begin a phase of active DNA synthesis - S phase. In this phase the DNA content is doubled .This is followed by another phase of apparent cell rest - G2 phase and once the cell comes out of it, it undergoes cell division.

Agents which are effective only during a particular phase of cell cycle e.g. S phase of cellular DNA synthesis, are known as phase- specific. Whereas , the agents in which action is prolonged and independent of any specific phase are called phase- non specific.

Agents which are most effective during S phase are ineffective in a tumour with slow turnover and high percentage of dormant cells. Phase- specific drugs need frequent administration or even administration by continuous infusion. Conversely phase- non specific drugs like Doxorubicin are independent of cell cycle and effective even against tumour with low proliferative activity.

COMBINATION CHEMOTHERAPY

With exception of Choriocarcinoma and Burkitt's lymphoma, single drugs in clinically tolerable doses have been unable to cure cancer. Effective combination of wide array of active drugs, which were used initially for treatment of Lymphomas and Leukaemias have now been extended to the treatment of most solid tumors.

Combination chemotherapy provides maximal cell kill within the range of toxicity tolerated by the host for each drug as long as dosing is not compromised .It may also prevent or slow the subsequent development of drug resistance.

Principles for the selection of indivisual drug in the effective combination as given below.

1).Only drugs that are effective against tumour in question are included, with the exception of certain drugs that are inactive against tumors , but appear to minimise dangerous toxicity to human cells.

2).Drugs should have different mechanism of action.

3).They should have different toxic side-effects thus allowing the administration of full or nearly full doses of each agent.

CYCLES OF COMBINATION CHEMOTHERAPY

Drugs should be administered at frequent intervals and the treatment free intervals between cycles should be the shortest possible time necessary for recovery of most sensitive normal target organ,which is usually the bone marrow.

Omission of a drug from combination chemotherapy may allow overgrowth by a cell line sensitive to that drug alone and resistant to others. In addition arbitrary reduction in the dose of effective drug may dramatically reduce the dose below the threshold of effectiveness and destroy the capacity of combination to cure the disease. Reduction in dose often results in minimal decrease in toxicity,but major reduction in efficacy. Bone marrow has a storage compartment that supplies mature cells to the peripheral blood for 8 to 10 days. Following bone marrow toxicity leucopaenia and thrombocytopaenia are observed on ninth or tenth day after initial dosing.Nadir blood counts are noted between days 14 and 18,with onset of recovery by day 21 and complete by day 28. The highest risk of infection or bleeding occur with granulocyte count lower than 500 / mm3 and platelet count less than 10,000 / mm3. If nadir lasts for 4 to 7 days, it is tolerated by most patients without any further supplemental support.

The introduction of colony stimulating factors ( CSF ) has been significant advance for cancers therapy as they help to accelerate bone-marrow recovery and prevent occurrence of severe myelosuppression. They play instrumental role in decreasing incidence of hospitalisation and allow maintenance of optimal dose intensity of chemotherapy.

LOG CELL KILL HYPOTHESIS

The objective of cancer treatment is to reduce the tumour cell population to zero cell. However, with chemotherapy, this can not be achieved, because experiments using rapidly growing transplanted tumours in men have established the validity of fractional cell kill theory, which states that a given drug concentration applied for a defined time will kill a variable fraction of cells , from very few to about 99.999%. Subsequent doses will kill the same fraction of tumour cells. It has been proposed that the tumour cell killing is fractional in human beings as well. This concept is called the log cell kill hypothesis, because the kinetics of killing approximate a first order geometric process. As a result fractional cell kill observed is expressed in logarithmic terms. Since the body burden of tumour cells in human with advanced malignancies may be greater than 1012cells ( 1 kg ) and since the best one can hope with single exposure appears to be between 2 and 5 logs of cell kill, it is apparent that treatment must be repeated many times in order to achieve control.

GOMPERTZIAN MODEL OF TUMOUR GROWTH

According to this model growth fraction of tumour is not constant, but decreases exponentialy as the tumour grows. Exponential growth seen in initial stages of the tumour is matched by exponential retardation of growth as the tumour grows. The growth fraction peaks when tumour is approximately 37% of it's maximum size.

In Gompertzian model, when a patient with advanced cancer is treated, the tumour mass is large, growth fraction is low and the fraction of cells killed with each dose is small. Sensitive Gompertzian growing tumours respond to cytotoxic drugs in Gompertzian fashion. Conversely, when tumour is small or clinically undetectable, it's growth fraction would be largest and although numerical reduction in cell number is small, the fraction of cells killed would be higher than later in the tumour course.

DRUG RESISTANCE

GOLDIE - COLDMAN HYPOTHESIS

In 1979, Goldie and Coldman developed a mathematical model that predicted that tumour cells mutate to drug resistance at a rate intrinsic to genetic instablity of particular tumour. This model predicted that such events would begin to occur at a population sizes between 103 to 106 tumour cells, much lower than the mass of cells considered to be clinically detectable ( 109 or 1 billion cells ).

The probability that a given tumour will contain resistant clones, when patients disease is newly diagnosed would be function of both tumour size and and inherent mutation rate. If mutation rate is as infrequent as 10-6 , a tumour of 109 cells will contain at least one resistant clone. Therefore, such tumours will initially respond with partial or complete remissions, but would recur as the resistant clones expand to repopulate the tumour mass.

Since, resistant clones are present even in small tumours and the maximal chance of cure occurs when all available effective drugs are given simultaneously. Because, this would involve using eight to 12 drugs simultaneously, this option is not feasible in clinical practice. An alternative approach is to use two programs of equally effective, non cross resistant drugs in alternating cycles has been under evaluation since mid 1980s. But, so far alternating cycles have shown no advantage over conventional regimens. In 1986 Day and Norton suggested that sequential combination should outperform alternating cycles, because no two combinations are likely to be strictly non cross resistant. There have been clinical examples in which sequential therapies have outperformed alternating cycles of same program, if the dose intensity of two programs is carefully monitored.

APOPTOSIS AND ROLE OF p53

Apoptosis or programmed cell death, stars with interaction between cytotoxic drug and target receptor, which acts as a stimulus to initiate a cascade of events eventually resulting in apoptosis. This pathway involves detection of death inducing signal by a sensor, a signal transduction network and an execution machinery that facilitate process of cell deat p 53 is a tumour suppressor gene and critical transcriptional activator that causes both G1 and G2 arrest of cell cycle, when cells are exposed to DNA damaging agents. This step is necessary to repair of damaged DNA. In additioon p53 is a potent inducer of apoptosis within a cell, in which DNA damage has occurred.

Mutation of p53 gene with rsultant function loss associated with resistance to chemotherapy. Conversely some studies have revealed that cells with impaired p53 function can become sensitised to various cancer agents.

ROLE OF Bcl -2 FAMILY IN APOPTOSIS

Bcl -2 is potent suppressor of apoptotic cell death and a number of studies have shown that it is able repress cell death triggered by wide variety of anticancer agents. Further, treatment of cancer cells with a antisense strategy directed against Bcl -2 leads to reversal of chemoresistance. Bcl -x1 is a functional homologue of Bcl -2 has also antiapoptotic activity. In contrast some other members of this family including Bax and Bcl- x3 and Bak have been shown to promote apoptosis.

ROLE OF mdr-1 AND mpr GENES IN CHEMORESISTANCE

Both these genes cause efflux of certain drugs including anthracyclines, taxanes, vinca alkaloids and anti- folate analogues from the cells leading to low intracellular concentration of these drugs, ultimately leading to multi- drug resistance.

DOSE INTENSIFICATION

Dose response curve of cancer chemotherapy is usually sigmoidal in shape, with threshold, a lag phase, a linear phase and a plateau phase. The dose response curve is steep in linear phase. On an average dose reduction of 20% leads to loss of 50% of cure rate. The converse is also true. In tumours with high growth fraction, a two fold increase in dose often leads to ten fold increase in tumour cell kill ( 1- log ). Because anticancer drugs are often toxic, it is often appealing to avoid acute toxicity by either reducing the dose or increasing the time interval between two cycles. This kind of empiric dose reduction is a major reason for treatment failure in patients with sensitive tumours.

Hryunik et al analysed treatment outcome in various tumours as a function of dose intensity. Dose intensity is defined as drug delivered in millgrams per square meter per week regardless of schedule or route of administration. A positve relation between dose intensity and response rate has been demonstrated in several solid tumours including advanced ovarian, breast, lung and colon cancers and in the lymphomas.

An increase in dose intensity represents one approach to improve the effect of specific drug or drug combinations. But, in the presence of large tumour burden and at the low end of curability curve, an increase in dose doesn't improve treatment outcome, as the dose -response curve is flat and most often leads to unacceptable host toxicity. Further increasing the dose intensity in regimens that are already associated with curing nearly 100% of subset of patients would not be expected to be of clinical benefit.

Certain cancers which are otherwise refractory to combination chemotherapy, often respond to high dose chemotherapy combined with stem cell support ( Granulocyte and Granulocyte- Monocyte Colny Stimulating Factors ). These include refractory lymphomas, breast cancers, childhood sarcomas and neuroblastomas. This suggests that maximising dose intensity can improve response rates or cure in a drug responsive tumour.

IN VITRO DRUG RESPONSE ASSAYS

Several methods in use for in-vitro assessment of drug sensitivity of human cancer cells to various cytotoxic drugs include-

- clonogenic assay

- tritiated thymidine incorporation

- differential staining cytotoxic assay (DiSC )

- colorimeteric assay

- chemotherapeutic treatment of athymic mouse with human tumour xenografts

The advent of reliable in vitro drug response assays has raised possibility of selecting effective anticancer agent to be used either alone or in combination to treat patient's indivisual tumour. Identification of agents with extremely low probability of response makes it possible to eliminate the use of such agents and thus their potential for adverse events. In general these tests have an overall sensitivity of 85% and over all specificity of 80%. Although,in a review of 12 different clinical trials using in- vitro drug sensitivity as a guide to select the agents no survival benefits have been demonstrated , but they definitely help the clinician to avoid exposure of the patients to toxicity of drugs with little clinical benefit.