Manual of Gynaecologic Oncology Sps Kochar
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Chemotherapy in Gynaecologic MalignanciesCHAPTER 1

In the malignant growth, cells do not cease multiplying when they reach a critical mass, and the uncontrolled growth leads to the death of the host. In the early phases of the growth, tumour cells appear to grow exponentially, but as tumour mass increases, the time that a particular tumour requires to double its volume appears to increase. The outcome of cancer chemotherapy is not fully predictable, but the chances of remission can be improved by judicious selection of patients, careful assessment of the tumour's growth pattern, and treatment of the neoplasm with the drug or drugs most likely to be effective.
Not all cancer patients can be treated with drugs. The suitability of a patient for chemotherapy depends on at least three critical criteria: (1) the nature of the neoplasm, (2) its extent of spread or stage, and (3) the patients clinical condition. Factors that determine a tumour's susceptibility include how the drug is distributed to the tumour, drug transport into the cell, whether a drug sensitive biochemical pathway is present in the tumour cell, and the relative rates of intracellular activation and deactivation of the drug.
At present, only disseminated neoplasia is regularly treated with chemotherapy; surgery, radiotherapy, or both are the current treatment choices for localized disease. These concepts are rapidly changing, and the use of adjuvant chemotherapy soon after eradicating surgery is increasing, especially in the treatment of ovarian and uterine cancer. Chemotherapy in a severely debilitated patient is usually futile and often dangerous, and thus should be avoided. Skipper and associates first described the “cell kill” hypothesis. A given dose of a drug kills a constant fraction of cells, not a constant number, regardless of the cell numbers present. This implies that the cell destruction by drugs follows first-order kinetics. The logical conclusion derived from this hypothesis is that the maximal opportunity for achieving cure exists during the early stage of disease. It is more difficult to eradicate disseminated disease than localized cancer, and it is much easier to control small tumours than large ones.
 
TUMOUR CELL BIOLOGY
The doubling time of the human tumour is the time it takes for the mass to double its size. The doubling time in squamous and adenocarcinomas vary from 50–150 days. If it is assumed 2that the malignancy starts from a single cell, then a 1 mm mass will have undergone approximately 20 tumour doublings. A 1 cm mass, so called very early lesion, would have undergone 30 tumour doublings. Metastasis generally has a shorter doubling time than has the primary lesion. Two basic factors that regulate the speed with which tumours grow are the growth fraction and cell death.
All dividing cells follow a predictable pattern for replication called the generation time. There are five basic phases. G1 phase lasts for a variable amount of time – usually lasts between 4 and 24 hours. The S phase is the phase of DNA synthesis and usually lasts between 10 and 20 hours. The G2 phase is a premitotic phase that lasts from 2–10 hours, and the M phase, when actual mitosis takes place, lasts between 0.5–1 hour. Tumours do not have faster generation times but have more cells in the active phases of replication than normal tissues. Normal tissues have a large number of cells in the G0 phase, wherein the cell is not actively committed to division or is “out of cycle”.
Some chemotherapeutic agents appear to act at several phases of the cell cycle. Alkylating agents appear to act in all phases from G0 to mitosis. They are called cycle-nonspecific agents. Drugs such as hydroxyurea, doxorubicin (Adriamycin), and methotrexate appear to act primarily in the S phase. Bleomycin appears to act in the G2 phase, and vincristine appears to act in the M phase. These drugs are called cycle-specific agents (Table 1.1).
Table 1.1   Cell cylce (phase)—specific drugs
Phase
Drugs
S phase dependent
Cytarabine
Doxorubicin
5-Fluorouracil
6-Mercaptopurine
Methotrexate
Hydroxyurea
Prednisolone
M phase dependent
Vincristine
Vinblastine
Paclitaxel
Etoposide
Teniposide
G2 phase dependent
Bleomycin
G1 phase dependent
Corticosteroids
The time that takes a cell to complete one cycle of growth and division is its generation time. However, the time a tumour takes to double in size depends on generation time and 3cell death rate. Chemotherapy of cancer requires an edge, a physiologic mechanism that can be exploited to differentially kill cancer cells but spare normal cells as much as possible. Tumour tissues have a more rapid growth rate than normal tissues, and this can be used against them. At any given time, large number of cancer cells will be in the DNA synthesis phase (S phase) of the cell cycle, the only time during which cycle-dependent agents can act. Thus, short-term high-dose chemotherapy with agents affecting DNA synthesis, such as methotrexate, is more effective in killing rapidly dividing tumour cells with relative sparing of normal bone marrow elements. A course of chemotherapy extending over a period of several days, or even weeks, may be required to kill a slow growing tumour in which only a few cells are in the stage of DNA synthesis at any one time. Agents that do not depend on DNA synthesis for their effects (i.e. cycle-nonspecific agents), such as alkylating agents, are most effective against bulky, slow-growing tumours.
The cells remaining after treatment tend to divide more rapidly and are more susceptible to attack by cycle-specific agents. The phenomenon of increased susceptibility of tumour cells during recovery from alkylating agents is the rationale for combining cycle-nonspecific and cycle-specific agents in many regimens. Each drug chosen for combination therapy should have antitumour activity when used alone.
The effectiveness of any cancer treatment is limited by the development of acquired drug resistance. It has been suggested that spontaneous mutation is a basis for drug resistance. The theory suggests that most of the malignant cell begin with intrinsic sensitivity to chemotherapeutic agents but develop spontaneous resistance at variable rates. The phenomenon of pleotropic drug resistance occurs when certain drug resistance mechanisms confer a cross-resistance to structurally dissimilar drugs with different modes of action. Genetic changes underlying drug resistance could be based on point mutation or gene amplification. Evidence suggests that gene amplification may play a role in clinical drug resistance.
CHEMOTHERAPY DRUGS USED IN GYNAECOLOGIC CANCER
 
CYCLE-NONSPECIFIC AGENTS
 
Alkylating Agents (Table 1.2)
Alkylating agents prevent cell division primarily by cross-linking strands of DNA. Because of continued synthesis of other cell constituents, such as RNA and protein, growth is unbalanced and the cell dies. Activity of alkylating agents does not depend on DNA synthesis in the target cells.4
Table 1.2   Alkylating agents
Drug
Dose and route of administration
Acute side effects
Toxicity
Cyclophosphamide
500–1500 mg/m2 single dose IV or 60–120 mg/m2 daily PO
Nausea and vomiting
Bone marrow depression, alopecia, cystitis
Chlorambucil (leukeran)
0.1–0.2 mg/kg/day PO
Nausea and vomiting
Bone marrow depression
Melphalan
0.2 mg/kg/day PO for 4 days every 4–6 weeks
Nausea and vomiting
Bone marrow depression
Thiotepa
0.2 mg/kg/day for 5 days
None
Bone marrow depression
Ifosfamide
7–10 g/m2 IV over 3–5 days every 3–4 weeks
Nausea and vomiting
Bone marrow depression, alopecia, cystitis
 
CYCLE-SPECIFIC AGENTS
 
Antimetabolites (Table 1.3)
Antimetabolites act by inhibiting essential metabolic processes that are required for DNA or RNA synthesis.
Table 1.3   Antimetabolites
Drug
Dose and route of administration
Acute side effects
Toxicity
5-Fluorouracil (5-FU)
12 mg/kg/day IV for 4 days
Occasional nausea and vomiting
Bone marrow depression, diarrhoea, stomatitis, alopecia
Methotrexate
1.5 mg/kg IV for 5 days
None
Bone marrow depression, megaloblastic anaemia, diarrhoea, stomatitis, alopecia, hepatic fibrosis, vasculitis, pulmonary fibrosis
Cytarabine
200 mg/m2 daily for 5 days by continuos infusion
Nausea and vomiting
Bone marrow depression, megaloblastosis, leucopenia, thrombocytopenia
Gemcitabine
800–1000 mg/m2 IV weekly every 3 weeks
Mild nausea, vomiting, malaise, maculopapular rash
Bone marrow depression
5
 
Antibiotics (Table 1.4)
Several cytotoxic antibiotics have come into use for chemotherapy of certain neoplasms. Those used in gynaecologic cancers are given in Table 1.4.
Table 1.4   Antibiotics
Drug
Dose and route of administration
Acute side effects
Toxicity
Actinomycin D (Dactinomycin)
15 μg/kg/day IV or 0.5 mg/day for 5 days
Pain on local infiltration with skin necrosis, nausea and vomiting, cramps and diarrhoea
Bone marrow depression, stomatitis, erythema, hyperpigmentation and desquamation in area of previous irradiation
Mitomycin C
0.05 mg/kg/day IV for 6 days, then alternate days until a 50-mg total dose
Nausea and vomiting, local inflammation and ulceration if extravasated
Neutropenia, thrombocytopenia, oral ulceration, diarrhoea
Bleomycin
10–20 mg/m2 IV or IM 1–2 times a week
Fever, chills, nausea, vomiting, local pain and phlebitis
Hyperpigmentation of skin, pulmonary: pneumonitis with dyspnoea, fibrosis, especially with more than 400 mg total dose
Doxorubicin (Adriamycin)
60–100 mg/m2 IV every 3 weeks
Nausea, vomiting, fever, local phlebitis, necrosis if extravasated, red urine
Bone marrow depression, alopecia, cardiac toxicity related to the cumulative dose, atrophy of the myocardia if a total dose of 450–500 mg/m2 is exceeded
 
Plant Alkaloids (Table 1.5)
The plant alkaloids arrest cells in metaphase by binding the microtubular protein used in the formation of the mitotic spindle.
 
MISCELLANEOUS DRUGS (Table 1.6)
Certain neoplastic agents are available that do not clearly fit into any of the above categories. These are given in Table 1.6.6
Table 1.5   Plant alkaloids
Drug
Dose and route of administration
Acute side effects
Toxicity
Vinblastine (Velban)
0.10–0.15 mg/kg/wk IV
Severe prolonged inflammation if extravasated, nausea, vomiting, headache, paresthesias
Bone marrow depression, alopecia, muscle weakness, peripheral neuropathy, mental depression and stomatitis
Vincristine (Oncovin)
0.4–1.4 mg/m2 IV weekly
Local inflammation if extravasated
Paraesthesias, weakness, loss of reflexes, constipation, hoarseness, footdrop, marrow toxicity, anaemia, alopecia
Etoposide (VP-16)
100 mg/m2 IV days 1,3,5; repeat in 4 weeks
Nausea and vomiting
Leucopenia, thrombocytopenia, alopecia, headache, fever, occasional hypotension
Paclitaxel (Taxol)
170–250 mg/m2 IV every 3–4 weeks
Allergic reaction, nausea, vomiting
Bone marrow depression, severe allergic like reactions with facial erythema, dyspnoea, tachycardia, hypotension, cardiotoxicity, alopecia, stomatitis, fatigue
 
CHEMOTHERAPY SCHEDULES
 
Adjuvant Chemotherapy
When an agent or group of agents produces a high number of responses in overtly metastatic tumours, efforts are made to incorporate them into the treatment of earlier stages of disease, particularly in the adjuvant setting. Residual micrometastatic tumour following definitive local therapy should be more susceptible to systemic therapy than clinically detectable tumour. The micrometastatic disease should have a better vascular supply, enabling better drug penetration. It should also have a higher proliferative rate, and there should be a smaller number of drug resistant cells. It is important to recognize that in an adjuvant setting it is impossible to predict recurrence definitively in the individual patient. The strategy is rather to select populations of patients who are known to be at high-risk of disease recurrence, and then to treat large number of these patients in order to produce increases in disease free and overall survival.7
Table 1.6   Miscellaneous chemotherapy drugs
Drug
Dose and route of administration
Acute side effects
Toxicity
Cisplatin (Cis-diamminedichloroplatinum)
50–100 mg/m2 IV every 3 weeks
Nausea and vomiting
Renal damage, moderate myelosuppression, neurotoxicity, severe renal damage can be avoided by not exceeding a total dose of 500 mg/m2 in any treatment course
Carboplatin (Paraplatin)
250–400 mg/m2 IV or by 24 hr continuous infusion every 2–4 weeks
Mild nausea and vomiting
Bone marrow depression, esp thrombocytopenia
Hydroxyurea
80 mg/kg PO every 3 days or 20–30 mg/kg/day
Anorexia and nausea
Bone marrow depression, megaloblastic anaemia, stomatitis, diarrhoea, alopecia
Hexamethylmelamine
4–12 mg/kg/day, PO in divided doses
Nausea and vomiting
Bone marrow depression, neurotoxicity, both central and peripheral
Hycomptamine (Topotecan)
1.5 mg/m2 daily for 5 days
Maculopapular pruritic exanthema
Bone marrow depression
Medroxyprogesterone acetate (MPA)
400–800 mg/week IM or PO
None
Liver function abnormalities, alpoecia and hypersensitivity reactions
Tamoxifen
10–20 mg PO twice daily
Nausea
Hot flashes, pruritis vulvae, occasional vaginal bleeding
Leuprolide
1 mg/day subcutaneously
Nausea
Hot flashes
 
Neo-adjuvant Therapy
The utilization of chemotherapeutic agents prior to surgery or radiation therapy is known as neo-adjuvant chemotherapy. This is especially useful in patients with advanced but locally confined malignancy. Chemotherapy given prior to radiation or surgery has several advantages. First, tumour vasculature has not been disturbed by surgery, radiation therapy or other local procedures. Secondly, the patient generally has maximum performance status and is not recovering from side effects of other treatment. Finally, by shrinking locally advanced tumours, 8neo-adjuvant chemotherapy may render them more amenable to treatment with surgery or radiation. The role of neo-adjuvant therapy has yet to be determined, but conceptually this strategy has great potential.
 
Intraperitoneal Chemotherapy
Intraperitoneal chemotherapy has been used primarily in recurrent ovarian cancer for last 20 years. It has been clearly shown that application of this technology (primarily with cisplatin) to patients with drug-sensitive disease and low-volume persistence or recurrence can reliably convert 35% of patients into a disease-free state. A recent randomized trial using this approach as part of initial therapy in patients with no residual intra-abdominal disease greater than 2 cm has shown a survival advantage and less toxicity with use of cisplatin intraperitoneally compared to its use intravenously. Paclitaxel has also been shown to be active via the intraperitoneal route.
 
Curative Chemotherapy
Patients with ovarian germ cell tumours, choriocarcinoma, childhood sarcoma, small percentage of those with epithelial ovarian carcinoma have potentially curable malignancies using current chemotherapeutic programmes. For these patients, administering the most effective agents in the highest dosage and at the most frequent intervals is essential. Since the goal of treatment is cure, the acceptance of greater short-term toxicity is justifiable because of the possibility of long-term benefit.
 
Palliative Chemotherapy
Palliation includes treatment of psychological as well as physical symptoms. For all patients receiving palliative therapy, the therapeutic index of the treatment programme, especially with regard to toxicity, is of prime importance. Clinical trials are essential in these patients, especially phase II trials aimed at identifying new agents or multimodality regimens. When it is feasible, such patients should always be offered the opportunity to participate in clinical trials.
 
DRUG TOXOCITY
The mechanism of toxicity is similar to the one producing the desired cytotoxic effect. Chemotherapeutic agents can damage even organs with limited cell proliferation. Chemotherapeutic agents must be used at doses that produce some degree of toxicity to normal tissue in order to be effective.9
 
Haematologic Toxicity
The most common haematologic adverse effects include myelosuppression, manifested primarily as leucopenia, thrombocytopenia and anaemia. The majority of chemotherapeutic agents produce myelosuppression. Most of these produce a maximum drop in leucocyte and platelet counts between day 7 and day 14 following drug administration, with recovery completed between day 21 and day 28. Patients with absolute granulocyte counts less than 500/mm2 for 5 days or longer are at a higher risk for sepsis. The practice of utilizing prophylactic broad spectrum antibiotics in febrile granulocytopenic cancer patients has significantly decreased the incidence of life-threatening infections in this group of patients.
Granulocytopenic patients should have their temperature checked every 4 hours, and they should be examined frequently for evidence of infection. Patients with sustained thrombocytopenia having platelet counts < 20,000/mm3 are at risk for spontaneous haemorrhage, particularly gastrointestinal or acute intracranial haemorrhage. Routine platelet transfusions for patients with platelet counts < 20,000/mm3 have significantly reduced the risk of spontaneous haemorrhage. A posttransfusion platelet count performed 1 hour after platelet administration should show an appropriate incremental increase. If no posttransfusion platelet increase occurs, it is likely that there has been previous sensitization to random donor platelets and such patients require single donor HLA matched platelets for future transfusions.
Table 1.7   Drug dose modification
Count before next course
Dose Modification
Leucocytes
> 4000
100% of the dose
3999–3000
100% of nonmyelotoxic agents
50% myelotoxic agents
2999–2000
100% of nonmyelotoxic agents
25% myelotoxic agents
1999–1000
25% of nonmyelotoxic agents
< 999
No drug
Platelets
> 100,000
100% of dose
50,000–100,000
100% of nonmyelotoxic drug
< 50,000
No drug
Haematopoiesis is regulated by a variety of haematopoietic growth factors (HGFs), which stimulate the proliferation, differentiation, and viability of haematopoietic progenitor cells and mature blood elements. Three HGFs, namely erythropoietin (EPO), granulocyte colony-stimulating 10factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) have been approved for amelioration of chemotherapy-induced myelosuppression.
In patients who develop febrile neutropenia and infections, it is not clear whether the addition of colony-stimulating factors to the standard treatment with antibiotics and supportive care has significant benefits. Several studies have shown that CSF-treated patients had a shorter neutropenia, fever and hospital stay.
Endogenous erythropoietin levels in anaemic cancer patients are inadequate for the degree of anaemia. The use of erythropoietin (EPO) in patients with anaemia of cancer as well as those with cisplatin-associated anaemia has been effective in raising the blood haemoglobin concentration and decreasing the transfusion requirements as well as improving the patient's symptoms. A staring dose of 50–100 U/kg given subcutaneously three times a week is sufficient. It may be raised up to 100–150 U/kg three times weekly. The treatment with EPO is very costly.
 
Dermatologic Toxicity
 
Extravasation Injury
The administration of chemotherapy generally involves the use of veins located between the dermis and the subcutaneous fat of the upper extremity. Extravasation of certain cytotoxic drugs into this space can cause a full thickness loss of skin and, in areas with little subcutaneous fat, damage to nerves, tendons and muscles as well. Several steps might be taken to minimize the risk of extravasation injury. First, areas such as the dorsum of the hand should be avoided if possible. Secondly, administration of bolus injections with normal saline through a freely flowing intravenous line both before and after the delivery of the drug will help. Thirdly, in patients who have poor veins, the use of special venous access devices such as Hickman catheters or subcutaneous ports should be considered. With the use of such measures, the frequency of extravasation should be less than 1% of drug injections.
Should extravasation occur, management is directed at minimizing damage. Reasonable initial approach is to place an ice-pack on the area. The area should be infiltrated with hydrocortisone (50–100 mg) ice-packs should be maintained for 24 hours. If injury is severe, eventual surgical debridement followed by excision of the affected area and skin grafting may be required.
 
Radiation Enhancement Effects
Certain cytotoxic drugs have the capacity to cause damage to previously irradiated tissue, particularly skin and mucous membranes. Drugs commonly associated with this type of reaction include actinomycin D, doxorubicin, 5-fluorouracil and hydroxyurea. The reaction assumes 11the form of an erythema followed by dry desquamation with occasional ulceration. Management ranges from topical steroids and cool soaks for mild to moderate reactions, to surgical debridement for more severe reactions associated with ulceration.
 
Alopecia
Hair loss associated with chemotherapy is a result of the effect of cytotoxic agents on the rapidly proliferating tissue of the hair follicle. Inhibition of the activities of the growth cycle results in a failure to maintain the size of the root and the diameter of the shaft of the hair. The resultant thinner shaft is more susceptible to breakage, with consequent loss of hair. Loss of scalp and facial hair without much loss of hair elsewhere is typical of alopecia associated with chemotherapeutic agents. Drugs that regularly induce loss of hair are anthracyclines danurubicin and doxorubicin, the plant alkaloids vincristine and VP-16, actinomycin D, and cyclophosphamide, paclitaxel and docetaxel.
Efforts have been made to prevent alopecia by using scalp tourniquets or hypothermia. Although, these methods have succeeded in reducing the frequency of alopecia, they carry a theoretical risk of increasing the frequency of scalp metastasis.
 
Gastrointestinal Effects
 
Nausea and Vomiting
Nausea and vomiting secondary to chemotherapy are mediated through the vomiting centre in the medulla. Stimulation of this centre arises from the chemoreceptor trigger zone, which lies close to the vomiting centre, or from stimuli transmitted from the cerebral cortex, gastrointestinal tract, heart and vestibular apparatus. The definitive management includes the use of anti-emetic drugs.
Effective anti-emetic drugs that should be considered include several dopamine antagonists, corticosteroids, and several of the cannabinoids. Metoclopramide in high-doses is also effective. The management of severe nausea and vomiting has been greatly improved by the introduction of potent and selective antagonists of the 5-hydroxytryptamine (5-HT) receptors. Two of these agents, namely ondansetron (Zofer) and granisetron, are now replacing traditional anti-emetic agents. The most commonly reported adverse effect with the use of either of the drugs is headache.
 
Mucositis
The term mucositis refers to the effect of certain chemotherapeutic agents on the epithelial lining of the gastrointestinal tract, and includes stomatitis, cheilosis, glossitis, esophagitis and 12oral ulceration. The likelihood of mucositis increases with higher doses and with factors that impair excretion of the drug.
The management of mucositis includes prevention of infection and maintenance of hydration. Preparations containing topical anaesthetics and warm saline mouth rinses afford symptomatic relief.
 
Diarrhoea and Constipation
Diarrhoea, particularly bloody diarrhoea, may be associated with those agents that produce mucositis, and is usually associated with severe mucositis in other portions of the gastrointestinal tract. In patients with protracted diarrhoea, the possibility of pseudomembranous colitis needs to be ruled out. Oral metronidazole or vancomycin should be initiated if the index of suspicion is high.
Constipation is most often seen in patients receiving vinca alkaloids, particularly vincristine, as a consequence of autonomic neuropathy. The problem usually occurs within 3 days of drug administration. Management is conservative, with resolution expected over a 2-week period.
 
Hepatotoxicity
Hepatic toxicity is uncommon. Mild elevations in transaminase, alkaline phosphatase, and bilirubin are seen with many agents, but rarely the condition is severe. The management of all these reported hepatotoxicities requires the cessation of the offending agent when the liver abnormality is detected.
 
Cardiac Effects
The principal chemotherapeutic agents associated with cardiotoxic effects are the anthracycline antitumour antibiotics, i.e. daunurubicin and doxorubicin. The arrhythmias and electrocardiographic changes may occur during or immediately after drug administration. Cardiomyopathy is directly related to the cumulative total drug dose. With doxorubicin, at total doses higher than 550 mg/m2, the incidence of cardiomyopathy associated with intractable congestive heart failure reaches 30%.
 
Pulmonary Effects
Pulmonary toxicity secondary to chemotherapy takes the form of a diffuse interstitial pneumonitis, which may eventually develop into pulmonary fibrosis. The drug first associated with these complications is bleomycin. Onset is heralded by a dry cough, dyspnoea and fine 13bibasilar rales. Other drugs associated with a similar picture are mitomycin C, the nitrosoureas, busulfan, and methotrexate.
 
Genitourinary Effects
 
Renal Effects
The drugs that most commonly produce direct renal toxicity include cisplatin, mitomycin C, mithramycin, methotrexate and the nitrosoureas. The most prominent of these agents producing renal toxicity is cisplatin. The frequency of nephrotoxicity can be reduced by the induction and continuation of a urine flow in excess of 100 ml/h prior to, during and for several hours after the drug administration.
Amifostine is an organic phosphate cytoprotective agent that is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin.
 
Bladder Effects
Significant toxicity to the lining of the urinary bladder has been reported with cyclophosphamide and the related compound, ifosfamide. The urotoxicity of ifosfamide, characterized by haemorrhagic cystitis, is due to the toxic metabolites 4-hydroxy-ifosfamide and acrolein. Mesna, a synthetic sulfhydryl compound, is used to inhibit haemorrhagic cystitis induced by ifosfamide.
 
Gonadal Effects
There have been no large scale, detailed studies of drug effects on gonadal function. The reported effects are testicular atrophy, failure of spermatogenesis, and amenorrhoea. These agents include mustard type alkylating agents, busulfan, the vinca alkaloids, bleomycin, hydroxyurea and procarbazine.
 
Neurologic Effects
Acute encephalopathic syndromes have been reported with a variety of different chemotherapeutic agents. Management requires the cessation of the drug and supportive care of the patient. Peripheral neuropathies are generally manifested by both sensory and motor components, and are dose related. Peripheral neuropathy is the principal non-haematologic dose-limiting side effect of paclitaxel. The incidence of neuropathy is dose dependent. Amifostine appears to have a neuroprotective activity.
 
EVALUATION OF NEW AGENTS
A number of trials are necessary to demonstrate the use of a new agent in regular medical practice. These trials are defined as follows:14
Phase I: These trials are designed to test new drugs at various doses to evaluate toxicity and determine the tolerance to a particular agent.
Phase II: These attempt to determine the therapeutic effectiveness as well as the extent of toxicity of the particular agent at doses expected to be effective against specific tumour types.
Phase III: These are designed to compare the drug to treatment currently in use. They are prospective randomised double blind trials.
BIBLIOGRAPHY
  1. Calvert AH et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748.
  1. DeVita VT, Hellman S: Cancer Principles and Practice of Oncology 4th ed. JB Lippincott,  Philadelphia,  1993.
  1. Goldie JH: Scientific basis for adjuvant and neoadjuvant chemotherapy, Semin Oncol 1987;14:1.
  1. Groopman JE et al: Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999;91: 1616–34.
  1. Sevin B et al: Chemosensitivity testing in ovarian cancer. Cancer 1993;71:1613.
  1. Sotrel G et al: Acute leukemia in advanced ovarian carcinoma after treatment with alkylating agents.
  1. Zucker S: Anemia in cancer. Cancer Invest 1985;3:249.