Several mechanisms of resistance to topoI inhibitors have been described in in vitro systems. These include: (cid:2) Factors that affect the stabilization of the topoI \200\223DNA complex (cid:2) Alterations in drug accumulation (cid:2) Decrease d activation of CPT-11 (cid:2) Decreased cellular content/activity of topoI (cid:2) Mutatio ns of the topo I enzyme OHO-09(135-180) 11/16/02 11:20 AM Page 161 TOPOISOMERASE INHIBITORS 161 Little is know about mechanisms of resistance to CPT or its analogs in human tumors. Topoisomerase II inhibitors In the 1960s, podophylin derivatives \200\224etoposide and teni poside \200\224 were found to have a unique mechanism of action, subsequently identi \201e d as inhibition of topoII. Etoposide and teniposide exert their action on topoII by: Inhibiting the ability of the enzyme to relegate the cleaved DNA complex (cid:2) (cid:2) Generating high levels of DNA with potentially toxic double- stranded breaks (cid:2) Promoting mutation (cid:2) Permanent double-stranded breaks Illegitimate recombination (cid:2) (cid:2) Apoptosis Chemically, teniposide only differs from etoposide in the substitution of a thenylidene ring in place of a methyl group. However, teniposide is approximately 10% mo re potent then etoposide, in terms of both in vitro cytotoxicity and DNA strand breakage, b ut the difference is less apparent in vivo where teniposide is only 1.5 \200\2233 times mor e potent. Etoposide and teniposide are poorly water-soluble and are formu- lated with a num ber of excipients including polysorbate (etoposide) or cremophor EL (teniposide). Etoposide can be administered by either oral or intravenous routes, teniposide only by intravenous i njection. Recently, etoposide phosphate was introduced, a more solu- ble yet bioequivalent form of etoposide designed to decrease infusion- related toxicity. Teniposide and etoposide are widely used in treatment of adult and pediatric malignancies. Etoposide has been more broadly used in front-line therapy for: (cid:2) Small-cell lung can cer (cid:2) Germ-cell tumors (cid:2) Kaposi \200\231s sarcoma (cid:2) As part of preoperati ve regimens for bone marrow transplantation Both agents are used in front-line therapy for childhood cancer, including: (cid:2) Acute lymphoblastic leukemia (cid:2) Neuroblastoma (ci d:2) Rhabdomyosarcoma The pattern of toxicity is very similar between both agents and inclu des: OHO-09(135-180) 11/16/02 11:20 AM Page 162 PRINCIPLES OF CHEMOTHERAPY 162 (cid:2) Neutropenia (cid:2) Alopecia (cid:2) Mucositis Infusion-related blood pressure changes (cid:2) (cid:2) Hypersensitivity reactions Clinical pharmacology Oral etoposide capsules have bioavailability of 60% with extensive va riation. Etoposide absorption appears to be non-linear with decreased bioavailability at do ses above 200 mg. Etoposide phosphate has a similar degree of bioavailability and suggestio ns of non-linear absorption. Both etoposide and teniposide are heavily protein-bound; use in patients with low albumin c oncentrations will result in greater than expected systemic toxicity due to the larger free (unbound) drug con- centrations. Although both etoposide and teniposide are distributed in to the CSF, they achieve concentrations of 0.1 \200\2234% of that measured simultaneously i n plasma. Both etoposide and teniposide are extensively metabolized. Production of a catechol metabol ite is mediated through P450 3A4 and may have intrinsic cytotoxic activity. Etoposide glucu ronide has been found to account for up to 30% of the administered dose. Etoposide is more rapidly eliminated than teniposide with: (cid:2) Faster systemic clearance (cid:2) Greater renal clearance (cid:2) Shorter eliminati on half-life Linear relationships between etoposide systemic clearance and creatinine clear ance have been described for both adult and pediatric patients. Both etoposide and teniposi de have demonstrated pharma- codynamic relationships, where measures of systemic exposure ( AUC, Css, trough concentrations, etc.) are correlated with hematological toxicity. OHO-09(135-180) 11/16/02 11:20 AM Page 163 ANTI-MICROTUBULE AGENTS 163 Anti-microtubule agents Tubulin-interactive agents, commonly known as \200\230spindle poisons \200\231 have a long history of use in cancer treatment. They act by binding to speci \201c sites on tubulin, a protein that polymerizes to form cellular microtubules. Microtubules are important struct ural units involved in a number of cellular activities, including formation of the mitotic spindle. Agents that bind to tubulin can be categorized according to their main tubulin binding site: (cid:2) Vinca alkaloid binding site (cid:2) Colchicine binding s ite (cid:2) Rhizoxin/maytansine binding site (cid:2) Tubulin sulfhydryl groups (cid:2) A se parate class of as yet uncharacterized binding sites The table focusses on important anti-m icrotubule agents in pre-clinical and clinical development, grouped into families to summar ize: (cid:2) Mechanism of action (cid:2) Major indications (cid:2) Administration (cid:2) P harmacokinetic data for clinical practice (cid:2) Selected important information for the cl inic Tubulin is an important target for anti-cancer drug development; several anti-tubulin agents have signi \201cant anti-cancer activity in the clinic. Taxanes were the most encou raging development in anti-cancer chemotherapy of the 1990s; paclitaxel, when incorporated in a \201rst- line chemotherapy regimen for advanced ovarian cancer leads to signi \201c ant prolongation of survival, while docetaxel can make a small but signi \201cant impact o n survival of metastatic breast cancer patients, even when given in a second- or third-line setting to heavily pre-treated patients. Recent progress observed with taxanes has led to renewed interest in anti-microtubule analo gs or drugs interacting with different sites on tubulin. In particular, agents with an impr oved pharmacological pro \201le and/or activity in vinca/taxane-resistant cell lines are o f interest. Several new anti-tubulin agents are in pre-clinical development. Most of the basic research into drug resistance has involved using pairs of sensitive and r esistant tumor cells derived from the same parental cell line, usually by serial passage in increasing concentra- tions of the drug under investigation. This is an arti \201cial sit uation O H 1 6 4 O 0 9 Table 9.1 Anti-microtubule agents ( 1 3 Class of spindle poison Useful indications (mechanism of action) Drug administration (IV doses in mg/m2) Main toxicities Pharmacokinetics and Comments of clinical 5 metabolism interest 1 8 Vincristine (VCR) (destabilization of polymerised tubulin ((cid:2)-tubulin)) 0.5 \200\2231.4 q 1 \200\2234 w Metabolized in the liver VCR induces multi-drug Neuropathy Leukaemias, lymphomas, pediatric (total individual dose: tumors, small-cell lung cancer, mu ltiple myeloma 0 ) resistance (MDR) by P-glycoprotein (PgP). Mutations in (cid:3)and (cid:2) tubulin proteins enhance stability against depolymerization. 2 mg) 1 1 / 1 6 / 0 2 Vinblastine (VBL) (same as VCR) Neutropenia, neuropathy Lymphomas, germ cell 6 \200\22310 q 2 \200\2234 w tumors, Kaposi \200\231s sarcoma, breast cancer Metabolized in the liver Neuropathy occurs less frequently than with VCR 1 1 : 2 Vindesine (VDS) same as VCR) prostate, 2 \200\2234 q 1 \200\2233 w Neutropenia, neuropathy Non-small-cell lung cancer (NSCLC), Metabolized in the liver Randomized trials (breast, 0 NSCLC, sarcomas, A M breast cancer, lymphomas and melanoma) with VDS showed no advantage over treatments without VDS. P a g e 1 Vinorelbine (NVB) (same as VCR) NSCLC, breast cancer 25 \200\22330 / w combinations: Neutropenia, constipation, neuropathy Metabolized in the liver Selective binding to the Tau 6 cisplatin (NSCLC) and doxorubicin or 5FU (breast). Oral form in clinical development family of microtubule \200\224 associated proteins \206\222 tubulin aggregation into spira ls and paracrystals. 4 O H O 0 9 ( Table 9.1 (continued) 1 3 5 Class of spindle poison Useful indications (mechanism of action) Drug administration Main toxicities Pharmacokinetics and Comments of clinical (IV doses in mg/m2) 1 interest metabolism 8 0 NVB not active and associated with severe neurotoxicity in paclitaxed pre-treated breast ca ncer patients. ) 1 1 / 1 6 / 0 Paclitaxel (P) (microtubule stabilizer) (also anti-angiogenesis effect, disruption of Ki-Ra s function, apoptosis induction by phosphorylation of bcl-2) 135 (24 h) \200\223175 (3 h) Neutropenia, q 3 w. Weekly schedule neurotoxicity is under inv estigation. Combinations: mainly Toxicities are sequence- and schedule-dependent. Steroid Ovarian, breast, and lung cancers (other tumors). Reproducible anti-tumor activity (respons e rate 15 \200\22325%) with cisplatin or in platinum-resistant ovarian cancer stimulated do xorubicin (breast) further clinical development. Metabolized in the liver. Cisplatin \206\222 P: severe neutropenia; pre-medication is used to P \206\222 doxorubicin: more mucositis than the reverse sequence. 2 1 1 reduce hypersensitivity reactions. Water-soluble analogs and derivatives active in resistan t cells of P are under development. Mutations in P53 cell lines confer sensitisation to P. Resistance to P due to PgP and/or alterations in the expression or structure of (cid:2)-tub ulin. : 2 0 carboplatin (ovary) and A M P a g e 1 6 5 1 6 5 O H 1 6 6 O 0 9 Table 9.1 (continued) ( 1 3 Class of spindle poison Useful indications (mechanism of action) Drug administration Main toxicities Pharmacokinetics and Comments of clinical (IV doses in mg/m2) 5 interest metabolism 1 8 Docetaxel (D) (microtubule stabilizer) Breast cancer, lung cancer 100 (1 h) q 3 w, (other tumors) Reproducible anti-tumor activity (response rate 35 \200\22350%) in anthracycline-resistant breast cancer stimulated further clinical development. Metabolized in the liver Steroid pre-medication reduces and delays FRS. Tau and (cid:2)4-tu bulin expression correlate with D sensitivity in adenocarcinoma models. Neutropenia, retention syndrome (FRS) 0 ) 75 q 3 w (if elevated liver function tests). Weekly schedule is under investigation. 1 1 / 1 6 / 0 2 1 1 : Estramustine phosphate (EP) (binds to the microtubule- associated proteins to promote micro tubule disassembly) 560 mg \227 2/d orally (with meal) Gastrointestinal 75% of oral EP is absorbed. Terminal half-life: 20 \200\22340 h Most responses observed in prostate cancer were subjective (objective response rate 10%). EP has been combined with other antimicrotubules (P, VBL) and etoposide with a clinical be ne \201t in 30 \200\22360% of patients. Overexpression of beta (III & IVa)-tubulin and Tau may play a role in resistance to EP. Prostate cancer 2 0 A M P a g e 1 6 6 OHO-09(135-180) 11/16/02 11:20 AM Page 167 ANTI-MICROTUBULE AGENTS 167 which often results in resistance which is really very substantial with concentration varia nts in excess of 40 \200\223100-fold sometimes required to overcome such resistance. It is unclear whether this laboratory- derived resistance correlates with the types of clinical r esistance which are outlined above. Pharmacological resistance The underlying concept of pharmacological resistance is that the dose of chemotherapy that can be safely given is insuf \201cient to result in an effectiv e concentration of the active drug at its target site. This may be due to: (cid:2) Toxicity in other organs (cid:2) Enhanced clearance of drugs (cid:2) Physical barrier between blood stream and tumor cells (many tumors have avascular centers) (cid:2) De novo resistance \200\224tumor does not respond despite full-dose chemotherapy (cid:2) Acquired resistance \200\224initial response to chemotherapy, then tumor fails to respond and regrows (cid:2) Combination of de novo and acquired. Alteration of target or transportation mechanisms Tumor cells have the ability to mutate su ch that the drug is either not taken up by the cell or having been taken up is detoxi \201 ed more rapidly than normal. Alternatively, the actual target of the drug may change by mut ation such that it becomes impervious to the form of attack. Or the normal repair mechanism s which are present in all mammalian cells may become more active and repair damage is prod uced by a cytotoxic agent in a more ef \201cient manner, resulting in overall resis- tance to the agent. Classical multi-drug resistance \200\230Classical \200\231 drug resistance has been the mo st studied form of this phenomenon in the laboratory and results from overexpression of 170 KD glycoprotein known as p-glycoprotein. This spans the outer cell membrane and acts as an energy-dependent drug ef \202ux pump. Thus, as the drug enters the tumor cell, by diffusi on or transportation, the drug in the interior of the cell is picked up and is ef \202uxed into the extracellular environment. This reduces the effective concentration of the drug w ithin the cell and allows the cell to express resistance to the agent in question. The development of this form of resistance is most commonly asso- ciated with exposure to t he anti-tumor antibiotics, the anthra- cyclines, taxanes and etoposide. In fact, resistance to one of this group OHO-09(135-180) 11/16/02 11:20 AM Page 168 PRINCIPLES OF CHEMOTHERAPY 168 of agents usually confers resistance to the other groups in addition, thereby leading to th e phenomenon of \200\230multi-drug resistance \200\231. P-glycoprotein: (cid:2) Found in tissues \200\224used for transportation e.g. steroids \200\224protection against external toxins (cid:2) Overexpression leads to drug resistance (cid:2) Hematological malignancy \200\224early trials of low-molecular-weight inhibitors of P-glycoprotein encouraging \200\224but affects normal cells also and therefore more sensitive to chemotherapy Multi-drug resistance protein (MRP) This protein is one member of a family of proteins whic h also act as energy-dependent pumps, in this case resulting in drug ef \202ux or sequestr ation of the drug, within intracytoplasmic organelles or vacuoles. The most studied member of this family of proteins is 190 kilodalton protein which has a similar substrate speci \201city to p-glycoprotein but is usually associated with less resistance to the taxanes. T he clinical relevance of this form of resistance is less clear than with the p-glycoprotein ; clinical trials looking at inhibition of MRP are at an early stage. Glutathione Glutathione is the predominant cellular thiol and participates in a complex bio chemical pathway which interacts with the alkylating function of some agents (including cis platin). Glutathione over- expression in cell lines results in relative resistance to alkyl ating agent attack. In addition, glutathione is able to detoxify free radicals which may be an important pathway of action for some cytotoxics, including doxorubicin. Clinical trials of glutathione depletion have been performed with somewhat equivocal results. Failure to engage apoptosis The common \201nal pathway of cell death for many cytotoxics is apop- tosis. This is an active process within cells, somewhat akin to \200\230cell suic ide \200\231. The engagement of the apoptosis program is a complex inter- acting pathway. A t the center of this is p53, the so-called \200\230guardian of the genome \200\231. In cel ls which are unable to engage apoptosis, the damage done by cytotoxics can be \200\230igno red \200\231 and cell division continues. This results in clinical drug resistance. Gene-th erapy approaches to correct this apoptosis failure are being actively investigated. OHO-09(135-180) 11/16/02 11:20 AM Page 169 ANTI-MICROTUBULE AGENTS 169 Summary Clinical drug resistance is a major problem in oncology and the underlying mechanis ms are multifactorial. In any one patient it is unclear to what extent each mechanism contr ibutes. Nevertheless, the potential clinical bene \201ts of mechanisms to circumvent drug resis- tance are enormous. Undoubtedly, other mechanisms of drug resis- tance will be found as we come to understand more about the regulation of cell cycle, cell life, and cell deat h. OHO-09(135-180) 11/16/02 11:20 AM Page 170 PRINCIPLES OF CHEMOTHERAPY 170 Dose intensi \201cation Dose response and dose intensity The strategy of therapeutic dose intensi \201cation in on cology has been largely driven by the incomplete chemotherapy sensitivity exhibited by many tumors. Experimental evidence suggests that the drug resistance of cancer cells is often r elative; it can be overcome by expos- ing the \200\230resistant \200\231 cell to higher co ncentrations of the drug to which it has become \200\230resistant \200\231. In most labora tory models, extreme degrees of dose escalation are needed to overcome drug resistance. The concept of dose intensity takes into account time variables. Thus a regimen might be in tensi \201ed either by increasing the dose or by abbreviating the inter-treatment interval . The biological impact of these two strategies may be very different. There is a distinction between maintenance of a standard dose and true dose intensi \201ca tion: the shape of the dose \200\223response curve may not be \202at i.e. the mathematica l relationship between dose and response may vary at different points. It is possible that dose escalation may increase anti-tumor activity only up to a certain point, after which th e dose-response curve \200\230 \202attens \200\231 and further dose increases will be fut ile. Results of studies indicate that arbitrary dose reduction should be avoided, and suggest th at clinicians should consider use of prophy- lactic antibiotics, haematopoietic growth fact ors, etc. in situations where neutropenia and its complications threaten to undermine timel y delivery of potentially curative chemotherapy. High-dose chemotherapy (HDC) with haematopoietic support In the clinic, dose escalation wit hin a \200\230conventional \200\231 range has an inconsistent effect on response rates, an d with some exceptions, a negligible survival impact. Clinical dose escalation is complicat ed by a greatly increased toxicity, seen when these relatively non-speci \201c toxins are administered to patients. Substantial advances in haemato- poietic support have allowed inv estigation of very high doses of chemotherapy in the clinic. Autografting, using either aut ologous marrow or cytokine-mobilized peripheral blood progenitors, is seen to facilitate ad ministration of very high doses of those drugs dose-limited by myelosuppression. \200\230High-dose chemotherapy \200\231 (HDC) is therapy administered in doses clearly out side the standard range and which, with exceptions, require some form of haematopoietic cel lular support (some drugs, e.g. cyclophosphamide and etoposide are stem-cell sparing, and i t is pos- OHO-09(135-180) 11/16/02 11:20 AM Page 171 DOSE INTENSIFICATION 171 sible to administer them with growth factors as sole support). For drugs primarily dose-lim ited by myelosuppression, haematopoietic support allows the clinician to mimic the extreme dose escalation studied in the laboratory. Thus, thiotepa can be dose escalated by 30 \200 \22340-fold, carboplatin by 4 \200\2236-fold, etc. In early studies of HDC with bone marrow autograft support, high rates of objective respons e were seen in patients with chemotherapy- resistant lymphomas and solid tumors. Toxicity w as also formidable, and up to 20% of patients so-treated died from complications of therapy , especially from infections during the prolonged neutro- penic phase that inevitably occur red, and also from organ-failure syndromes. The introduction of the haematopoietic growth factors changed high-dose chemotherapy. Admin istration of these cytokines following bone marrow re-infusion resulted in a dramatic abbre viation of dura- tion of neutropenia. It was also discovered that administration of these f actors, either at steady state or following myelosuppressive chemotherapy, resulted in mobi lization of haematopoietic pro- genitors from the bone marrow into the peripheral blood. Th ese \200\230peripheral blood progenitors \200\231 (PBP) could be harvested by leuco- phere sis, then re-infused as haematopoietic rescue following sub- sequent HDC. PBP autografting is superior to marrow autografting, with shortened neutropenia and thrombocytopenia, and re duced mortality and morbidity. Historically, HDC has generally been given as a form of consolida- tion following conventio nal chemotherapy. Less frequently, it has been studied as primary treatment. It can be admi nistered in single or in multiple cycles. Role of HDC in the treatment of speci \201c tumors (cid:2) Relapsed aggressive lymphoma \200\224proven salvage treatment (cid:2) Refractory ly mphoma \200\22410% remission (cid:2) Poor prognosis NHL \200\224 \201rst-line treatment (c id:2) Multiple myeloma \200\224 \201rst-line treatment (cid:2) Relapsed refractory Hodgkin \200\231s disease \200\224 \201rst-line treatment (cid:2) Acute leukemia \200\224especial ly if no donor (cid:2) Metastatic testicular germ-cell tumors \200\224relapse after second remission \200\224failure to achieve complete remission (cid:2) Breast cancer \200\224salvage treatment for relapsed metastatic breast cancer \200\224(controversial) initial chemotherapy for metastatic disease (50% remission) \200\224(controversial) early-stage, poor-risk breast cancer OHO-09(135-180) 11/16/02 11:20 AM Page 172 PRINCIPLES OF CHEMOTHERAPY 172 (cid:2) Ovarian cancer \200\224early data encouraging (cid:2) Small-cell lung cancer \200 \224early data encouraging Future directions The immediate priority is to determine whether there is a role for HDC in the therapy of breast cancer and other solid tumors. Developmental work is needed to addre ss other important questions e.g. role of late intensi \201cation versus primary high dose , graft manip- ulation, and purging. Newer biological anti-cancer agents may pro- duce maxi mum impact in the setting of minimal disease, and the proven ability of HDC to produce freq uent CRs suggests future inves- tigations may involve both these modalities of treatment. OHO-09(135-180) 11/16/02 11:20 AM Page 173 CHEMO-IRRADIATION 173 Chemo-irradiation Chemotherapy and radiotherapy are complementary; integration of these treatment modalities underpins successful treatment of a num- ber of tumors. Chemotherapy reduces the burden of local diseases and eradicates systemic micrometastases, but effective loco-regional tumor c ontrol requires irradiation. Sequential combined therapy The traditional approach to combining chemotherapy and radio- t herapy has been to attempt to predict whether eradication of sys- temic disease or local tu mor control is of most immediate concern, then deliver the appropriate treatment \201rst; the other treatment is delayed until completion of the \201rst. The main dif \201cultie s are the uncertain behavior of individual tumors and the inevitable delay in delivery of o ne treatment. Chemotherapy as the \201rst-line treatment has the added potential bene \201t that in downstaging the tumor it may reduce both the volume of tissue which requires irradiation and the radiation dose required to control the tumor. Concurrent combined therapy Problems are avoided by delivering chemotherapy and radiotherap y together. This approach has advantages and some disadvantages (see Table 9.2). Ideally, cytotoxics chosen for chemo-irradiation regimens will have known activity against the tumor but will not have toxicities that overlap the effects of irradiation of the relev ant region. Anthracyclines are avoided because of their effects on skin and mucosa; methotr exate can increase the damage to the normal lung following radiotherapy. Agents such as cis platin and 5- \202uorouracil are particularly attractive Table 9.2 Bene \201ts and problems of concurrent combined therapy Advantage Disadvantage No delay in either therapy Increased toxicity Additive cell kill by two therapies Compromised dose of one or both treatments Enhanced cell kill by radiosensitizing Large volume irradiated effects of chemotherapy Reduced likelihood of evolution of resistance to either therapy Pharmacodynamic interactions (e.g. cell-cycle effects) OHO-09(135-180) 11/16/02 11:20 AM Page 174 PRINCIPLES OF CHEMOTHERAPY 174 because of their radiosensitizing effects. At least, in vitro, the inter- actions of chemot herapy and radiotherapy are complex and schedule- dependent: e.g. irradiation of cells may lead to cell-cycle arrest and this may confer relative resistance to subsequent exposure to phase- speci \201c cytotoxics such as taxanes; conversely, exposure to taxanes can lead t o radiosensitization. An attempt must be made to minimize the normal tissue damage of radiation during combined t herapy. Treatment times are often a mini- mum of 6 weeks (to reduce early normal reactions) and the dose per fraction is 2 Gy or less (to reduce late damage). Anal and bladder carcinomas For both these pelvic malignancies chemo-irradiation offers the possi- bility of organ preservation and avoidance of a stoma. There is good evidence that pelvic irradiation with concurrent 5- \202uorouracil and mitomycin is the best-established therapy for anal carcinoma. The combination of pelvic radiotherapy and cisplatin-based che mo- therapy has proven successful in large phase II studies in muscle- invading transitiona l cell carcinoma of the bladder. Small-cell lung cancer and oesophageal cancer Chemo-irradiation of intra-thoracic tumors is hindered by risk of serious morbidity, in particular pneumonitis and oesophagitis. Nonethe less, small cell-lung cancer is an excellent target for this approach; although chemosensit ive local failure is inevitable with chemotherapy alone, and even with conventional consoli dation radiotherapy, 40 \200\22350% of these patients have locally recurrent disease. The r esults of combination etoposide, cisplatin, and thoracic irradia- tion are promising. Toxic ity, especially oesophagitis, is considerable. Chemo-irradiation is superior to radiation therapy alone for oesophageal cancer but local f ailure rates remain high. Surgery after combined treatment may be the answer to this proble m, but the potential for morbidity is increased further. Ewing \200\231s tumor Chemo-irradiation is incorporated in the regimens under study in EICE SS 2, but a major concern in this type of curable cancer is the legacy of treatment-related problems in young patients, in particular the risk of second malignancy. OHO-09(135-180) 11/16/02 11:20 AM Page 175 PHARMACOKINETICS/PHARMACODYNAMICS OF ANTI-CANCER DRUGS 175 Pharmacokinetics/ pharmacodynamics of anti-cancer drugs Terminology Pharmacokinetics is the study of processes that a drug undergoes between time o f administration and time of elimination from the body. The most common pharmacokinetic dat a is a plot of plasma drug concentration versus time. The administered dose and para- meter s corresponding to rate and extent of the pharmacokinetic processes determine peak drug con centration, half-life, and drug exposure (the area under the plasma concentration versus ti me curve or AUC). These processes are: (cid:2) Bioavailability, for drug absorption (cid:2) Clearance, for elimination (cid:2) Apparent volume of distribution, for distribution Pharm acodynamics describe the relation of both the therapeutic and toxic effects of a drug to th e pharmacokinetic parameters. Pharmacokinetics/pharmacodynamics in clinical oncology Most drugs have a narrow therapeutic index \200\224dosages required for anti-tumor ef \201cacy usually cause some side-effects and a small increase above the therapeutic dose may be suf \201cient to cause life- threa tening toxicity. Variations in pharmacokinetic parameters of anti-cancer drugs between pati ents are frequently observed. These variations are caused by diversity in renal or metaboli c functions (which are themselves due to advanced disease), drug \200\223drug inter- action s, and toxic effects of previous chemotherapy on organ func- tions. These all contribute to variations in drug concentration in patients treated with a similar dose of cytotoxic. Since the amount of drug reaching the site of action (tumor cells or the tissue expressing toxicity such as bone marrow stem cells) is dependent on the systemic concentration, correl ation between pharmacokinetic parameters (e.g. peak concentration, AUC) and pharmacodynamic s endpoints is closer than that between adminis- tered dose and pharmacodynamics. The ultim ate goal of pharmaco- kinetically-guided dosing will be to maximize the likelihood of produ cing the antitumour response with minimum normal tissue damage. OHO-09(135-180) 11/16/02 11:20 AM Page 176 PRINCIPLES OF CHEMOTHERAPY 176 Parameters of in pharmacokinetics/ pharmacodynamics relationships In terms of pharmacokinet ic pharmacodynamic relationships of the anti-cancer drugs, the relevant pharmacokinetic par ameter is usually the AUC, which represents total systemic exposure of the body to the drug . AUC results from the bioavailable dose (administered dose weighted in case of extravascul ar administration by the bio- availability) and the patient plasma clearance (CL) which rep resents the elimination capacity for the drug: AUC = F \227 Dose / CL (F=bioavailability) Since anti-cancer drugs are administered intrav enously, F is equal to 1 and the dose required to provide an optimum AUC may be calculated with knowledge of individual plasma clearance. Then, variability in elimination becomes the more determinant pharmaco- kinetic process involved in pharmacokinetics/pharmacodynamics. The modi \201ed Hill equation, which corresponds to a sigmoidal curve, is frequently used to describe the relationship between a pharmacokinetic parameter (e.g. AUC) and a pharmacod ynamic effect (E): E = Emax . AUCH / (AUC50H + AUCH) Patient A: CL = 66 s n o i t a r t n e c n o c a m s a l P AUC = 3 Time therapeutic toxic Patient B: CL = 100 s n o i t a r t n e c n o c ) % e s o d a m s a l P ( t c e f f e m a S E AUC = 2 Time AUC Patient C: CL = 200 s n o i t a r t n e c n o c a m s a l P AUC = 1 Time Pharmacokinetic profiles of three individual patients with variation in profile resulting i n variable clinical effect (pharmacodynamics). OHO-09(135-180) 11/16/02 11:20 AM Page 177 PHARMACOKINETICS/PHARMACODYNAMICS OF ANTI-CANCER DRUGS 177 Emax represents the maximum possible effect and AUC50, the AUC that induces 50% of Emax. H is Hill \200\231s constant (or shape factor) which de \201nes the degree of sigmoidicity o f the model. The relationship between AUC and hematological toxicity is closer than that between pharmac okinetic parameters and clinical out- come. This observation is explained by numerous other causes of variation in tumor-cell response to a drug (cellular metabolism, drug resistance , biochemical and molecular factors, etc.). Other pharmacokinetic parameters such as duration of concen- tration above a threshold may be more relevant than AUC, especially for drugs having a schedule-dependent cytotoxicity. Inter-patient variability in elimination of anti-cancer drugs The traditional method for in dividualizing an anti-cancer drug dose is based on body-surface area (BSA), calculated acco rding to the Dubois formula using height and weight. In children, morphological criteria (B SA or weight) are a major component of inter-individual pharmaco- kinetic variability. In a dults, clearance of anti-cancer drugs is poorly correlated with BSA, leading to wide variat ion in drug exposure within patients dosed by this method. Hepatic and renal functions are the major determinants of drug elimination and have to be e xplored before administration of anti- cancer drugs. Renal dysfunction is easily assessed b y determining serum creatinine, measuring or calculating creatinine clearance, or most accu rately, by determining the clearance of radio-labeled EDTA. The impact of hepatic dysfuncti on on the drug elimination or metab- olism is more dif \201cult to estimate. Because of co mplex pathophysio- logical mechanisms of liver insuf \201ciency, hepatic enzymes and serum bilirubin levels are often poor indicators of metabolic activity. Alternative hepatic func tion tests have limited value in predicting pharmacokinetics of chemotherapeutic drugs: Indocyanine green (a marker of hepatic blood \202ow) (cid:2) (cid:2) Antipyrine (a substrate marker for cytochrome P450 activity) (cid:2) Lorazepam (a s ubstrate marker of hepatic glucuronidation) Practical considerations make these dynamic liv er functions inappro- priate for routine clinical practice. When metabolism of a drug is la rgely dependent on a unique catalytic enzyme, subpopulations of poor metabolizers may resul t from polymorphism in gene coding for the drug-metabolizing enzyme. Advancing age also represents a cause of pharmacokinetic variability of many drugs. Ageing is characterized by a combination of various physiological disorders, including reduction o f hepatic or renal blood \202ow, possible declines in microsomal activity, and frequent c o-medication. OHO-09(135-180) 11/16/02 11:20 AM Page 178 PRINCIPLES OF CHEMOTHERAPY 178 For some drugs, such as carboplatin, anthracyclines, and docetaxel, close relationships bet ween patient characteristics and drug clearance have been established. Then, priori adap tive dosing based on these characteristics is possible. For other drugs, such as methotrexa te, 6-mercaptopurine, and 5- \202uorouracil, dose optimization requires determination of p lasma concentrations in each patient in order to adjust subsequent doses or to modulate cur rent dose in case of continuous therapy. This approach \200\224 \200\230adaptive dosing wit h feed- back control \200\231 \200\224requires certain logistics which limit its use for al l drugs. Examples of dosing strategies for individual therapy Carboplatin Carboplatin is mainly eliminated by the kidney. Egorin \201rst estab- lished two relationships: (cid:2) First: between carboplatin clearance and measured creatinine clearance. (cid:2) Second: between the AUC and the percentage decrease in platelets following carboplatin administration as a single agent. By combining these, a formula was derived for individual dose cal- culation according to me asured creatinine clearance and desired platelet count at nadir. The concept of optimum AUC for carboplatin was demonstrated for treatment of ovarian and testicular cancers. Calvert developed a formula to allow a dose of carboplatin to be calculated in order to achieve a target AUC: Dose (mg) = AUC \227 (GFR + 25 ml/min) with GFR determined by isotopic measurement of 51Cr -EDTA clear- ance. The value of 25 ml/min corresponds to the mean non-renal clearance of ca rboplatin. The carboplatin target AUC must be chosen with reference to any other cytotoxics given in c ombination. Drugs (e.g. cyclophos- phamide) potentiate the hematological toxicity of carbop latin, but with others such as paclitaxel it is safe to administer an AUC similar to that o f carboplatin administered alone. Moreover, patients without prior exposure to chemotherapy may support a larger AUC than those who are heavily pre-treated. Anthracyclines and taxanes In the case of impaired hepatic function, guidelines have been p ro- posed for doxorubicin dosage reduction as a function of serum biliru- bin level: dose r eductions by 50%, 75%, or 100% are recommended when bilirubin exceeds 12, 30, or 50 mg/l. F or docetaxel, \201ve co- variables (age > 70 years, hypoalbuminaemia, elevation of (cid:3 )1-glyco- OHO-09(135-180) 11/16/02 11:20 AM Page 179 PHARMACOKINETICS/PHARMACODYNAMICS OF ANTI-CANCER DRUGS 179 protein, and raised ALT and AST) are predictive of reduced clearance. Since correlation was found between docetaxel clearance and risk of severe neutropenia, these parameters may all ow prediction of patients with high risk of toxicity and application of rational dose reduc tion. Methotrexate Monitoring of plasma drug concentration in patients receiving high- dose metho trexate is routinely performed. High levels 48 hours after the intravenous infusion and the reafter are associated with a risk of serious toxicity. For these patients with decreased m ethotrexate clear- ance and/or a large volume of distribution of the drug (generally due to the presence of a \200\230third space \200\231 \200\224pleural effusion or ascites), foli nic acid rescue is administered at a dosage adjusted according to methotrexate plasma level s. Mercaptopurine The effect of mercaptopurine is dependent on formation of the active 6-thiog uanine nucleotide (6-TGN) metabolites. This anabolic path- way competes with the catabolic pathway mediated by thiopurine methyltransferase. The latter enzyme expression is subject t o genetic polymorphism with about 10% of patients having intermediate activity and about 1 in 300 inheriting a de \201ciency who are exposed to prohibitive toxicity if standard merc aptopurine dosage is adminis- tered. The concentration of 6-TGN inside red blood cells has been shown to be an independent and important predictor of treatment outcome of patients ta king daily oral mercaptopurine. Although no de \201nite recommendation on how to individualize treatment can be given, mon itoring of erythrocyte 6-TGN should identify patients with a high-risk pharmacokinetic pro \201le (low levels of 6-TGN), allowing assessment of patient compliance. Summary Although prospective clinical studies comparing standard (in mg/m2) versus individu alized dosing have yet to be performed, it is likely that individualized dosing of some ant i-cancer drugs, based on pharmaco- kinetics, could increase the probability of tumor respon se and decrease the probability of major toxicity. In the absence of routine therapeutic dr ug monitoring, adjustment of the dose of subsequent treatment cycles according to the prese nce or absence of toxicity should be implemented more systematically. OHO-09(135-180) 11/16/02 11:20 AM Page 180 PRINCIPLES OF CHEMOTHERAPY 180 Further reading Cleton, F.Y. \200\230Chemotherapy: general aspects \200\231 in Peckham, M., Pinelo, M.M. a nd Veronesi, V. (eds.) Oxford Textbook of Oncology, pp. 445 \200\22353. OHO-10(181-188) 11/16/02 11:23 AM Page 181 Chapter 10 Hormone therapy Introduction 182 Types of endocrine therapy 183 Predictive indices of response 186 Resistan ce to hormone therapy 187 Controversies 188 OHO-10(181-188) 11/16/02 11:23 AM Page 182 HORMONE THERAPY 182 Introduction Hormones have been implicated in the development and behavior of many malignant tumors (inc luding vaginal, ovarian, laryngeal, pan- creatic, gastrointestinal, melanomas, and meningio mas). The best evidence that hormones maintain the growth of cancers relates to sex steroid hormones and tumors of their target organs, namely oestro- gens and progestins in breast a nd endometrial cancer and androgens in prostatic cancer. The effects of endocrine therapy are generally con \201rmed to target organs, and there ar e side-effects outside these sites. This accounts for the increased tolerability of this tr eatment in comparison with cyto- toxic chemotherapy. However, many tumors appear resistant to endocrine therapy, even at \201rst presentation, and more become insensitive during th e selective pressure of treatment and progression. Thus, most patients with breast and pros tate cancers die with hormone-independent disease.