PRINCIPLES OF CHEMOTHERAPY

DR.ASHIRWAD KARIGOUDARPG-3RD YEARDR.C K DURGA UNITDR.RML HOSPITAL, NEW DELHI

REFERENCE: DEVITA, HELLMAN AND ROSENBERG’S CANCER PRINCIPLES AND PRACTICE OF ONCOLOGY 8TH EDITION.

INTRODUCTION AND HISTORICAL PERSPECTIVE

Chemotherapy, which includes newly developed targeted treatments, is the principle tool of the medical oncologist.

The development of effective combination chemotherapy programs

for childhood leukaemia and lymphomas in the 1960s provided curative therapeutic strategies for patients with advanced malignancies of all types.

These advances confirmed the principle that chemotherapy could indeed cure advanced cancer and provided the rationale for using chemotherapy in the adjuvant setting following surgical resection and for integrating chemotherapy into combined modality programs with surgery and radiation therapy in locally advanced disease.

The principal obstacles: toxicity to the normal tissues of the body and cellular drug resistance.

Paul Ehrlich, coined the term chemotherapy.

First class of chemo-therapeutic: Alkylating agents

Alkylating agent were a direct product of the secret gas program of the United States during both world wars.

Sidney Farber report on folic acid led to the development of folic acid analogues as cancer drugs.

This work initiated the era of cancer chemotherapy.

Current targeted treatments, focus on elements of the cellular signalling apparatus uncovered since then.

CLINICAL APPLICATION OF CHEMOTHERAPY

Currently chemotherapy is used in four main clinical settings:

1. Primary induction treatment.

2. Neo-adjuvant treatment.

3. Adjuvant treatment.

4. Direct instillation into sanctuary sites or site-directed perfusion.

PRIMARY INDUCTION CHEMOTHERAPY

-It is drug therapy administered as the first treatment for patients who present with advanced cancer for which no alternative treatment exists.-This approach applies for patients with advanced, metastatic disease.

-Neoplasms for which there is an expanding role for primary chemotherapy of advanced disease are:

Bladder, Head and neck , Breast, Nasopharyngeal, Cervical, Non-small-cell

lung, Colorectal, Ovarian, Oesophageal, Pancreatic, Gastric, Prostate cancers.

NEO-ADJUVANT CHEMOTHERAPY

- Refers to the use of chemotherapy as the primary treatment in patients who present with localized cancer for which local therapies, such as surgery and/or radiation, exist but are less than completely effective.

-Clinical benefit is usually optimized when chemotherapy is administered in combination with radiation therapy, either concurrently or sequentially.

-One additional goal of neo-adjuvant therapy is to reduce the size of the primary tumour.

-Neo-adjuvant chemotherapy may allow for preservation of vital organs.

-Neoplasms for Which neo-adjuvant chemotherapy is indicated for locally advanced disease are:

Anal cancer, Head and neck cancer, Bladder cancer, Ovarian cancer, Breast

cancer, Osteogenic sarcoma, Cervical cancer, Rectal cancer,

Gastroesophageal cancer, Soft tissue sarcoma and Lung cancer .

ADJUVANT CHEMOTHERAPY

-One of the most important roles for cancer chemotherapy is as an adjuvant to local treatment modalities such as surgery and radiation therapy, and this approach has been termed adjuvant chemotherapy.

-The development of disease recurrence is mainly due to the spread of occult micro-metastases.

-The goal of adjuvant therapy is to eradicate micro-metastases.

-Neoplasms for which adjuvant therapy is indicated after surgery are:

Anaplastic astrocytoma, Breast cancer, Colorectal cancer, Gastric cancer,

Melanoma, Non small-cell lung cancer, Osteogenic sarcoma, Pancreatic

cancer.

PRINCIPLES OF CANCER KINETICS

-Cytotoxic effects of anticancer drugs are predicted to follow logarithmic cell-kill kinetics – Murine L1210 model.

-Thus, if an individual drug leads to a 3 log kill of cancer cells and reduces the tumour burden from 1010 to 107 cells, the same dose used at a tumour burden of 105 cells reduces the tumour mass to 102.

-Mathematical modelling data suggest that most human solid tumours follow Gompertzian model of tumour growth.

-In Gompertzian kinetics, the growth fraction of the tumour is not constant but decreases exponentially with time.

-Under the Gompertzian model, the growth fraction peaks when the tumour is approximately 37% of its maximum size.

-When patients with advanced solid tumours are treated, the tumour mass is larger, its growth fraction is low, and the fraction of cells killed is therefore small.

-An important feature of Gompertzian growth is that response to chemotherapy in drug-sensitive tumours depends, to a large extent, on where the tumour is in its particular growth phase.

-When the tumour is clinically undetectable, its growth fraction is at its highest level.

-Although the numerical reduction in cell number is small, the fractional cell kill from a known-to-be-effective therapeutic dose of a chemotherapy agent would be significantly higher than later in the tumour course.

-The Gompertzian model for tumour growth is important because it can also predict patterns of regrowth of residual tumour cells.

PRINCIPLES GOVERNING THE USE OF CHEMOTHERAPY

-With rare exceptions (e.g., choriocarcinoma and Burkitt's lymphoma), single drugs at clinically tolerable dosages are unable to cure cancer.

-In 1960s and early 1970s, drug combination regimens were initially developed based on known biochemical actions rather than on their clinical efficacy.

-Combination chemotherapy using conventional cytotoxic agents accomplishes several important objectives not possible with single-agent monotherapy which include:

1. Maximal cell kill within the range of toxicity tolerated.

2. Broader range of interaction between drugs and tumor cells with different genetic abnormalities in a heterogeneous tumour population.

3. May prevent and/or slow the subsequent development of cellular drug resistance.

-There should be a clear understanding of the biochemical, molecular, and pharmacokinetic mechanisms of interaction between individual drugs in a given combination, to allow for maximal effect.

-Most standard treatment programs were designed around the kinetics of recovery of the bone marrow in response to chemotherapy exposure.

-Introduction of the filgrastim and the long-acting molecule pegfilgrastim, has been a significant advance.

-One final issue relating to chemotherapy relates to the optimal duration of drug administration.

-Several RCT of the AT of breast and colorectal ca have shown that short-course treatment on the order of 6 months is as effective as long-course therapy (12 months).

-Progressive disease during CT is a clear indication to stop treatment in the advanced disease setting.

-There is no evidence of clinical benefit in continuing therapy indefinitely until disease progression.

-It appears that patients with good prognostic features may derive greater benefit from a chemotherapy-free interval than those patients whose tumours show a more aggressive phenotype.

-Several requirements must be met, however, for such an intermittent treatment approach to be adopted into clinical practice which include: 1. The induction chemotherapy regimen must be of sufficient clinical efficacy and duration.

2. Good response must be shown to re-initiation of the same chemotherapy or to administration of an effective salvage chemotherapy regimen.

3. There should be a sufficient time interval between the termination of primary induction chemotherapy and the onset of progressive disease.

4. Finally, patients who are taken off of active chemotherapy must be closely followed to ensure that treatment can be reinstituted at the first sign of disease progression.

BIOLOGY OF DRUG RESISTANCE

-The main obstacle to the clinical efficacy of chemotherapy is the development of or pre-existence of cellular drug resistance.

-In 1943, Luria and Delbruck observed that the bacterium Escherichia coli developed resistance to bacterial viruses (bacteriophages) not by surviving exposure but by expanding clones of bacteria that had spontaneously mutated to a type inherently resistant to phage infection.

-In 1979, Goldie and Coldman applied this principle of to the development of resistance to anticancer drugs and proposed that It was due to development of non-random cytogenetic changes.

-They developed a mathematical model that predicted that tumour cells mutate to drug resistance at a rate intrinsic to the genetic instability of a particular tumour.

-Their model predicted that such events would begin to occur at population sizes between 103 and 106 tumor cells (1,000 to 1 million cells), much lower than the mass of cells considered to be clinically detectable (109, or 1 billion cells).

-The probability that a given tumor contains resistant clones when a patient's disease is newly diagnosed is a function of both tumor size and the inherent mutation rate.

-But drug resistance occurs in a different fashion in human cancers.

Genetic instability of tumor cells and/or to alterations in key pathways involved in cell-cycle – cause for resistance to chemotherapy.

Important factors for genetic instability and chemo-radio resistance include p53, Bcl-2 family members, Death executioner pathway and NF-KB signalling pathway.

ASSESMENT OF CLINICAL RESPONSE

Response Evaluation Criteria in Solid Tumors (RECIST) Criteria:

1. Complete response

2. Partial response (PR)

3. Stable disease

4. Progressive Disease (PD)

RECIST criteria cannot be applied in:

1.In tumours with no target lesions such as early stage carcinoma, cystic lesions, necrotic masses etc.

2.The novel biologic agents, such as bevacizumab, sorafenib, and erlotinib.

Other modalities for assessment are:

a. Positron emission tomography (PET)

b. CT contrast perfusion and dynamic-contrast MRI techniques.

CELL CYCLE , CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS AND SIDE EFFECTS

CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS

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