Chemotherapy in gynaecological malignanciesPresentation Transcript
Prof. Dr M. C. BANSALM.B .B.S. FRCOG. MRCOG
Chemotherapy should be restricted to the patients in whom diagnosis of cancer has been confirmed by either biopsy or cytology . All chemo-therapeutic agents have potential side effects, and it is important to ascertain whether the patient has measurable disease and / or elevated tumor markers , Particularly before starting therapy in patients with metastatic disease , so that response can be assessed objectively.
ISSUES TO BE DISCUSSED1. Natural History of the Particular Malignancy a. Diagnosis of a malignancy made by biopsy b. Rate of disease progression c. Extent of disease spread2. Patients Circumstances and Tolerance a. Age, general health, underlying diseases b. Extent of previous treatment c. Adequate facilities to evaluate, monitor, and treat potential drug toxicities d. The patients emotional, social, and financial situation
ISSUES TO BE DISCUSSED3. Likelihood of Achieving a Beneficial Response a. Cancers in which chemotherapy is curative in some patients (e.g., ovarian germ cell tumors) b. Cancers in which chemotherapy has demonstrated improvement in survival (e.g., epithelial ovarian cancer) c. Cancers that respond to treatment but in which improved survival has not been clearly demonstrated (e.g., metastatic cervical cancer) d. Cancers with marginal or no response to chemotherapy (e.g., melanoma)
To achieve complete cure. To achieve best possible survival. To relieve agony by palliation in terminal cases. To Prevent recurrence. To reasonably reduce distant and regional metastasis and if present, to treat them. To improve result of surgery , radiotherapy and immunotherapy. To minimize the side effects
1. Highly chemo sensitive - curative results. Ovarian germ cell, gestational trophoblastic tumor.2.Chemosensitive - cure is uncommon . Epithelial cancer of ovary with 70-89% response butmost patients will have relapse. Chemotherapyimproves survival but does not restore a normal lifeexpectancy.3.Low sensitivity - Uterine leiomyo-sarcoma impact oftherapy over survival rate is not clear.4.Chemo resistant - metastatic melanoma, low orunpredictable response.
Chemo therapeutic agents must have greater activity against tumor cells as compared to normal tissue, thus cause less toxicity and possess wider therapeutic window. Most chemo therapeutic agents act by disturbing DNA or RNA synthesis, affecting crucial enzymes or altering protein synthesis. Normal cell growth also uses similar vital pathways as the malignant cells, particularly regenerating normal cells i.e. GIT mucosa , bone marrow, hair follicles, skin etc.. Hence differential sensitivity of anti neoplastic drugs by normal VS tumor cells is quantitative rather than qualitative.
Therapeutic Index =Ratio of drug dose needed forTherapeutic effect and drug dose whichwill result in toxicity. Because window of toxicity is very narrowfor available drugs , useful therapeuticresponse depends on pharmacology andbiological factors.
1. Cell cycle. 2. Pattern of normal growth 3. Cell Kinetic Concepts 4. Cancer cell growth.
Cell CycleM-mitotic phase- phase of division.G1-Post mitotic Phase – differentiation or continue inproIiferation.S phase-DNA synthesis phase – New DNA Replication occurG2Phase-postsynthetic phase Cell has diploid No of chromosomes, Twice DNA Content of normal cell.G0 phase-resting phase. Cells do not divide. Cell may move in or out of the G0 phase.
Generation time is duration of cycle from M phase to M phase. Variation occurs in all phases of cell cycle , but it is maximum in G0 phase. Causes of variation are complex and not completely understood. Dividing cells that are actively traversing the cell cycle are most sensitive to chemotherapy.
All normal tissues have the capacity for cellular division andgrowth . There are 3 general types of normal cell growth 1. Static population comprises of relatively well differentiated cells that after initial proliferative activity in embrionic and neonatal period , rarely under go cell division like striated muscle and neurons. 2. Expanding Cell population is characterized by ability to divide under special circumstances e.g. tissue injury stimulate growth in liver and kidney. 3. Renewing Population of cells is constantly in proliferative state .cell division is constantly going on. There is high degree of tissue turnover and cell loss ., this occurs in bone marrow, skin, GI mucosa etc.
Only small proportion of tumor cells are in active cell division at any time. 2 major factors that affect the rate at which growth occurs — (a) Growth Fraction (b) Cell Death. (a) Growth Fraction No. of tumor cells that are actively and rapidly dividing , ranging from 25 - 95 % of cell mass. Cancer Stem cells make a very small population of tumor, these are relatively chemo- resistant . These stem cells play an important role in the development and progression of tumor growth even after chemotherapy is stopped.
Tumor growth may be altered in followingways 1. Cytotoxic chemotherapy-- alters both generation time and growth fraction of tumor. 2. Hormones—alter the growth fraction, have no effect on generation time. 3. Radiation therapy--alters both growth fraction and generation time. 4. Altering O2 tension and Vascular supply--alter growth fraction only. 5. Immunotherapy-- it alters both .
Cell Cycle : specific / non specific agents Cell cycle - Non specific agents - Kill the cell in all phases of cycle and are not too dependent on cellular division or proliferation. Cell cycle - specific agents – Hydroxyurea , its cell killing effect depends on cell proliferative activity . They kill in only one phase of cell cycle - most active in S phase. In addition to cell cycle and proliferative sensitivity; different chemo therapeutic drugs may exert a greater effect, in different phases of cell cycle, hence combination of various chemo therapeutic agents may give greater killing effect on tumor cells with reduced toxicity, as compared to single drug treatment.
Tumor cell growth represents a disruption in the normal cell growth check / control mechanism resulting in continued proliferation at the cost of normal cell and eventual death of host. Gompertzian growth this means exponential growth spurt and exponential growth retardation over entire duration of tumor growth e.g. as the tumor size increases rapidly then the time required in doubling its size also increases.
Doubling Time of tumor is the time taken by tumor to enlarge to double it’s size. For example Embyronal tumors, lymphomas and some mesenchymal cancers have relatively fast doubling time (20-40 days) in comparison that of Adeno / Squamous cell carcinomas ( 50-150 days). In general metastasis have faster doubling times than primary tumor.
It is assumed that a tumor starts from a single malignant stem cell, then exponential growth occurs at an early stage. 1. a 1-mm will have under gone approximately 20 tumor doublings. 2. a 5 mm size tumor ( first time might be identifiable on a radiograph) will have under gone 27 doublings.
3. a 1 cm tumor mass will have undergone 30 doublings. Once tumor is palpable or detectable (1cm in diameter) then 3 more doublings will produce a mass measuring 8 cm. Metastasis have usually taken place by this time. That is why patient seeks medical consultation at late stages and currently available diagnostic methods detect tumour growth in late stage only
Chemo therapeutic drugs appear to work by 1st order kinetics , that is , they kill a constant fraction of cells rather than a constant number. The cure rate will be significantly increased if tumor mass is small, but cell masses of 1o raise to power one to 10 raise to power four cells are too small to detect clinically. This is the basis of using adjuvant chemotherapy in early stage of disease when sub clinical metastasis are likely to be present in many patients.
Chemotherapeutic agents are best effective when initially used in cancer treatment.. Later the tumor develop resistance and tumor cell killing effect is blunted . Hence patient often have initial remission followed by recurrence after variable time interval. Various mechanisms operate in development of drug resistance. Resistant tumor may display increased rate of drug deactivation or decreased killing activity of drug., increased drug efflux, or decreased drug intake by tumor cells. Altered efficacy of inhibiting enzymes , or increased production of drug target enzymes occur to explain the development of drug resistant after some time.
Goldie Coldman Hypothesis : The proportion of resistant cells in any untreated tumor is likely to be small , and the initial response to treatment will not be influenced by the small number of resistant cells. Hence remission can be achieved initially even though the resistant cells are present in tumor. This model of spontaneous resistance implies that 1. Tumors are curable with chemotherapy if no permanently resistant cells are present or drug therapy is begun before resistance develop.2. If only one antineoplastic drug is used , than probability of cure diminishes rapidly with development of a single resistant line.
3. Minimizing the development of drug resistantclones require multiple effective drugs at the time ofstarting treatment. 4.The rate of spontaneous mutation to resistantoccurs naturally at the frequency of 1 in 10,000 to 1in 1,ooo,ooo.cell division. This model predicts that alternative cyclesof treatment should be superior to sequential useof particular drug because sequential use ofantineoplastic agent would allow for developmentof resistance and regrowth of doubly resistantline.
It focuses on the Gompertzian growth rate exhibited bymalignant tumors.It suggests that treatment of cancer cells exhibiting sensitivity toparticular chemotherapeutic agents will be enhanced if single ormultiple drug regimens are delivered at their optimal doselevels in so called in a dose dense manner rather alternatingregimens.High risk gestational trophoblastic tumors are very sensitive toEMA-CO every 6to 7 days is an example of dose dense regimen. The difference between two is--- 1.Goldi Coldman focusses on rapid administration of as many active agents as possible, doses of individual agent need frequent modification because of overlapping drug toxicities. 2.Nortonand Simon theory---individual drugs are given in sequence at their optimal dose to produce their cytotoxic effect
Itoccurs when certain drugs develop cross resistance even of being dissimilar in their pharmaceutical structure and different mechanism of action.
Studies in human solid tumors in vitro frequently demonstrate steep dose response curves suggesting the importance of giving full dose . Several prospective randomized studies in epithelial ovary tumors have failed to demonstrate improved results either by increasing dose of cisplatin or Carboplatin per cycle or extending the duration of treatment beyond 5-6 cycles. In general , the goal should be to maintain dose intensity consistent with acceptable toxicity profile on each individual patient.
Drug effect = Drug concentration x durn of exposure = C (plasma concentration) x T (Time)Factors 1.Route of administration & absorption. 2. Transportation and drug distribution. 3.Drug metabolism, biotransformation. 4.Inactivation and Excretion. 5.Drug interactions
Drug may be given orally, IM, IV, intra cavitary , intra tumor , regional Studies of wide variety of chemotherapeutic agents have demonstrated a differential concentration of 30- 100 fold , depending on molecular weight , charge and lipid solubility of agent. Several studies have revealed that intra peritoneal administration of Cisplatin as a primary therapy in cases of small volume advanced ovarian cancer is highly effective
Antineoplastic drugs produce their antitumor effect by interacting with intracellular target molecules. It is critically important that drug in its active form should reach in side the cancer cell in appropriate concentration. After absorption from the site of administration , drugs may be bound to albumin or other blood components, their ability to enter various body compartments , vascular spaces, and extra cellular sites is highly influenced by plasma protein bindings, relative ionization at body fluid’s pH , molecular size and lipid solubility.
Sanctuary Site These are areas where the tumor is inaccessible to anticancer drug., hence ineffective like CSF, center of large tumor masses (avascular). Cell Penetration it may be by simple diffusion or by active transportation across cell membrane. Alkylating drugs depend on a carrier transport for cellular penetration . For Macromolecules it may be necessary for pinocytosis to accomplish cellular entry.
Mani drugs are active as intact molecule but some require metabolism / transformation to active form. Many anti metabolite drugs need phosphorylization for cell entry. Alkylating agent Cyclophsphamide requires absorption and liver metabolism to be activated , while thiotepa or nitrogen mustard need no metabolism for activation . Not only initial activation is important but rate of metabolic degradation of active drug or its active metabolite form is important in determining antitumor activity . Eg. is increased intracellular enzymes (glutothione-s-Transferase) hasten the degradation of metabolites of Alkylating drugs - development of drug resistance in short time .
Most chemotherapeutic drug or their metabolites are excreted by kidney or liver ., their normal function are critical to normal drug excretion thereby minimizing side effects. Vincristn, Doxorubicin,Paclitaxel are excreted primarily and exclusively by liver. while other drugs like Methotrexate is excreted almost entirely by the kidney.
Drug interaction may increase or decrease the antitumor activity of a particular drug or they may increase or modify its toxicity. Important drug interactions are - 1.Alkylating agents are highly reactive compounds and may produce direct physical or chemical inactivation when multiple drugs are used . 2.Intestinal absorption of drugs is altered by concurrent use of oral antibiotics that suppress bacterial flora , example Methotrexate..
3.Cisplatin / methotrexate bound to albumin and may be displaced from their binding site by drugs like aspirin and sulfa , thereby increasing free and higher concentration of these anticancer drugs - increased toxicity .4.Alteration in drug interaction may occur , as when methotrexate increases 5 fluorouracil activation., while % fluorouracil impairs the antifolate activity of methotrexate.5.Nephrotxic antibiotics frequently alter methotrexate excretion and may increase renal toxicity of cisplatin.
Sound basis for combination chemotherapy is from knowledge of cellular kinetics , drug metabolism , drug resistance and tumor heterogeneity. Limitations of Single drug therapy 1. Toxicity limits the dose and duration of drug administration thus restricts the tumor cell kill achievable. 2. Adaptive mechanism allow cell survival and eventual tumor regrowth of drug resistant tumor cells in spite of initial lethal effect on bulk of tumor mass. 3. Drug resistance may develop spontaneously. 4. Multi drug or Pleiotropic drug resistance may develop.
Different chemotherapeutic agents may act in different phases of tumor cell cycle. With identification of appropriate combinations and proper dose schedule and sequence, sufficient log kill can be achieved. Drug Resistance Probability of emergence of drug resistance cells have reduced if 2or more drugs with different mechanism of action are used in tight sequenced treatment scheme .
DRUG INTERACTION It may be additive, synergistic or antagonistic.Additive therapy produce enhancedantitumor effect equivalent to sum ofactions of combined drugs.Combination that results in improvedtherapy due to increased antitumor actionand decreased toxicity are said to besynergistic .
SCHEDULE DEPENDENCY = Drugs used indifferent sequence may produce a widely variedeffect, example is the reduced cardiac toxicity whenweekly low dose Doxorubicin compared to highbolus dose.REMISSION Complete remission (response) withsignificant prolongation of survival.Partial / Incomplete remission (response) : 30-50%reduction in size of tumor along with variablesubjective improvement and absence of new lesiondevelopment during therapy.
RECIST : DEFINITION OF RESPONSE
Dose (mg) = target AUC x sum of GFR + 25 %(AUC is area under curve)
DRUG DOSE ADJUSTMENT – COMBINATION CHEMOTHERAPY SLIDING SCALE BASED ON BONE MARROW TOXICITY
Antitumor drugs are most toxic agents used in modern medicine. Mechanism of toxicity is similar to their killing action on neoplastic cells. Organ systems which are rapidly proliferating as a normal physiological phenomenon are most affected.,e.g. skin, hair, bone marrow , GI mucosa . Even organs with limited cell devison may be affected either dose related or idiosyncratic fashion. Severe debility, advanced age, poor nutritional status, direct involvement of organ system can result in unexpectedly severe side effects.
The proliferating cells of erythroid, myeloid, megakaryocytic series of bone marrow are highly susceptible to damage by commonly used anti- neoplastic agents. Granulocytopenia develops with in 6 -12 days and recovery occurs in 3-4 weeks, while thrombocytopenia develops 4-5 days later , with recovery after white cell recovery. Patient with absolute granulocyte count <500/cmm for 5 days are prone to have sepsis . Quickly initiating broad spectrum antibiotics in presence of fever can be a wise policy
Platelets count < 50,00 are at risk of spontaneous bleeding particularly from GIT or intracranial hge. Platelet concentrate transfusion is indicated 1. If patient manifests active bleeding 2. If patient has active peptic ulcer. 3. Before and during surgical procedure. Recombinant interleukin 11 can be used in patientswith or anticipated to develop, severethrombocytopenia. Drug is administered 50 ug / KgSc once a day till platelet count return to > 50,000 /cmmIt is discontinued at least 2 days before nextchemotherapy.
Mucositis - 2-3 days before myelo- suppression. Increased bacterial and fungal infection leading to septiceamia. Oral candidiasis/ herpes simplex infection. Esophagitis , GIT Hemorrhage. Impaired intestinal motility(Resulting from neuropathic effect of vinca alkaloids ). Nausea and vomiting. Necrotizing enterocolitis - Severe Diarrhoea, illness that can be fatal in a granulocytopenic patient.
Most anti cancer drugs are capable of suppressing immune (Cellular as well as humoral) system , later being less affected. Most of immune suppression effects do not persist beyond 2-3 days after completion of chemotherapy. This short term immunosuppressive effect has led to increased use of intermittent chemotherapy course regimens to allow immunologic recovery during courses of treatment.
Skin necrosis and sloughing may result from extravasation of certain irritating agents , such as actinomycin-D, mitomycin , vincristin , vinblastin and nitrogen mustard. Alopecia is most common side effect. Generalized allergic skin reaction. Liposomal Doxorubocin, an agent is effective in platinum refractory cases of ovarian cancer. It can produce a painful acute dermatological syndrome characterized by desquamation of the skin , most often of feet and hands . Focal or disseminated blistering may also develop.
Increase in SGOT, SGPT, Alkaline/ Acid Phosphatase and serum bilrubin is common with most chemotherapeutic agents. These enzymes return to normal level after stopping drug administration. Long term use of methotrexate may cause liver fibrosis – progress to cirrhosis. Pre existing liver disease / exposure to hepatotoxins can increase risk . Antimetabolites like mercaptopurine , 6-thioguinine can cause reversible cholestasis.
Respiratory compromise resulting from lung metastasis , embolism , infection , radiation pneumonitis and tumor/ drug induced neuromuscular dysfunction etc may be significant complications. Interstitial Pneumonitis with pulmonary fibrosis is the usual pattern of lung damage associated with chemotherapy . Agents likely to cause it are bleomycin , gemcitabin , nitrosurea. Management of drug induced interstitial pneumonitis includes discontinuation of drugs , supportive care and steroids.
Anthracyclines and paclitaxel can cause cardiac arrhythmias. Doxarubicin and daunomycin can cause severe cardiomyopathy. massive dose of cyclophosphamide can cause cardiotoxicity. 5 flurouracil can cause angina pectoris. A major toxicity of the angigenic agent bevacizumab is development of hypertension.
In addition to anti cancer drugs , other cancer related complications may produce chronic azotemia, acute renal failure, including body fluid depletion, infection, metastasis , ureteral obstruction, radiation damage and tumorlysis syndrome. Drugs that can cause impaired renal function are cisplatin produce renal tubular toxicity, methotrexate can precipitate in tubules causing in acidic pH , nitrosourea cause chronic interstitial nephritis , mitomycin causes systemic microangiopathic hemolysis - Ac. Renal failure. Metabolites of cyclophosphamide irritate bladder mucosa - hemorrhagic cystitis . N-acetylcystine or mesna along with cyclophosphamide is used to prevent cystitis E –aminocapric acid can also be used.
Vinca alkaloid therapy is associated with reversible motor , sensory, autonomic neuropathy. Cisplatin cause progressive ototoxicity, peripheral neuropathy and rarely retro bulbar neuritis. Paclitaxel - peripheral sensory neuropathy. 5-flurouracil - acute cerebellar toxicity. Vit. B supplementation - improve the neuropathies but decrease the drug effectiveness.
Anaphylactic reaction has been associated with cyclophposphamide , cisplatin , doxorubicin , melphalan , etopside , teniposide and high dose methotrexate . It can be ameliorated with IV Dexamethasone (20mg), diphenylhydramine(50mg) and 1: 1000 diluted subcutaneous injection of Adrenalin.
Many anti cancer drugs are mutagenic and teratogenic. Have profound and lasting effect on testicular and ovarian function. Male develop testicular dysfunction - oligo / azoospermia. Onset of premature ovarian failure - amenorrhoea elevated FSH , LH levels and decreased serum estrogen.
Inappropriate Antidiuratic Hormone secretion - results in electrolyte and fluid imbalance documentable by 1.Hyponatremia 2.Hypertonic urine (more than plasma). Exclusion of hypothyroidism and adrenal insufficiency. Hyperuricaemia—when rapid tumor lysis is occurring it releases intracellular ions and uric acid resulting in life threatening hyper kalemia hyperphosphataemia , hypocalcaemia and acute renal failure. Hyperuricaemia can be prevented by maintenance of high urinary out put , high urinary pH(above 7.0) and prophylactic use of xanthine oxidase inhibitorAllopurinols
Many antineoplatic agent s are mutagenic and teratogenic. Alkaylating agents seem to be major offender in developing another malignancy . High risks are associated with 1. Extensive radiotherapy along with chemotherapy. 2. Prolonged alkylating drug therapy > 1year. 3. Age > 40 years at initial treatment.
Risk of congenital malformation , Abortion is highest in 1st trimester. Chemotherapy given during 2nd and 3rd trimester is usually not associated with malformation of fetus. Its ill effect on physical and intellectual growth of fetus ??
1 . Alkylating Agents.2 . Anti Tumor Antibiotics.3 . Anti Metabolites.4 . Plant Alkaloids.5 . Topoisomerase-1 Inhibitors.6 . Other Agents. 7 . Miscellaneous Agents. 8 . New Drug Trials.
ALKYLATING AGENTS USED IN GYNAECOLOGICAL CANCERS
ALKYLATING AGENTS USED IN GYNAECOLOGICAL CANCERS
These agents act primarily by chemical binding with DNA , they react with nucleophillic (electron rich) site on many important organic compounds such as nucleic acid, proteins and amino acids. These interaction produce cytotoxic effects. Mechanism of action Alkylating agents commonly bound to N-7 position of Guainine and other Key DNA sites . They interfere with accurate base pairing , cross linkage of DNA , produce single or double standard breaks, inhibiting DNA, RNA and protein synthesis required for cell proliferation and growth.
ALKYLATING – LIKE AGENTS USED IN GYNAECOLOGICAL CANCERS
These are antibiotics , isolated as natural products from Fungi. They act by forming complex with DNA. Mechanism of actionAntibiotics get inserted between DNA base pairs.Production of free radicals capable of damaging DNARNA and vital proteins essential for cell proliferationand growth.Thirdly they cause metal ion chelation and alterationsin cell membrane .These are ― cell cycle nonspecific Drugs.―
ANTI-TUMOUR ANTIBIOTICS USED IN GYNAECOLOGICAL CANCERS
ANTI-TUMOUR ANTIBIOTICS USED IN GYNAECOLOGICAL CANCERS
Interact with vital intra cellular enzymes .Their structure resembles purines and pyrimidines . Some of them act directly as intact molecule while other need biotransformation into active compound.Mechanism of actionMany drugs act in different ways at different sites inbiosynthetic pathways. There by interfering with cellfunction crucial to viability of cells particularly theactively proliferating cells.
Derived from plant Vinca Rosea are vinca alkaloids,.have single methyl group on one side chain. Plaxitaxe and epipodophyllotoxins are also used in treatment of gynaecological cancers. Like most natural compound complex thesse are large and molecules.Mechanism Vincristin and vinblastin act by binding to vitalintracellular proteins particularly to Tubulin. It inhibitsmicrotubule assembly and destruction of mitoticspindle, cell mitosis is arrested. These are cell cycle specificagents . Paclitaxel combines with microtubules resulting inpolymerization and destabilization , disruption of theirfunction and cell death.
These compounds exert their cytotoxic effect through inhibition of enzyme topoisomerase-1. It is important enzyme in DNA replication , repair and transcription. Agent binds to enzyme –DNA complex leading to permanent strand breaks and cell death.
TOPO-ISOMERASE – 1 INHIBITORS
Anti angiogenic drugs like bevacizumab exert their effect on normal / abnormal blood vessel delivering nutrients to malignancy.
Phase 1 trial These studies define spectrum of toxicity of any chemotherapeutic agent and are complete when the dose limiting toxicity of any particular dose and schedule has been defined. Phase 2 Trials studies usually use the dose and schedule established from phase 1 trials and apply this to selected tumor types of importance. Phase 3 These studies compare one effective treatment with another in a randomized fashion