A review of the pharmacology and clinical activity of new chemotherapeutic agents in lung cancer

A review of the pharmacology and clinical activity of new chemotherapeutic agents in lung cancer

CANCER TREATMENT ANTITUMOUR REVIEWS 1998: 24: 35-53 TREATMENT (%zi& A review of the harmacology and clinical activity of new c I! emotherapeuti...

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CANCER

TREATMENT

ANTITUMOUR

REVIEWS

1998: 24: 35-53

TREATMENT

(%zi&

A review of the harmacology and clinical activity of new c I! emotherapeutic agents in lung cancer S. V. Rajkumar

and A. A. Adjei

Division of Medical Oncology, Mayo Clinic and Mayo Foundation, 55905, U.S.A.

Lung cancer is the most common cause of cancer death in the United States, with an estimated annual mortality in excess of 160,000 (1). The vast majority of patients with lung cancer are not cured, and the overall 5-year survival rate is ll-14% (1). Most patients with lung cancer have non-smallcell lung cancer (NSCLC), and the mainstay of treatment for these patients is surgical resection. Only 25-30% of patients with NSCLC have resectable disease (stage I or II) at the time of diagnosis (2). The 5-year survival rate with surgical treatment in these patients approaches 40% (2). Patients with stage IIIA disease have been treated with either radiation or, in selected cases, surgical resection. Median survival with radiation alone is only 9-13 months, and the 5-year survival rate is only 5-10% (3-7). Due to the poor curative potential of radiation therapy, surgical approaches and combined chemotherapy and radiation therapy are used commonly. There is also considerable interest in pre-operative chemotherapy in stages II and III NSCLC in an attempt to increase surgical curability (8-10). Palliative treatment (supportive care only or palliative radiation or chemotherapy) is the main option for most patients with advanced unresectable NSCLC. Three recent meta-analyses evaluated the role of chemotherapy in NSCLC (11-13). The metaanalysis by the NSCLC Collaborative Group reported a 13% reduction in the risk of death at 5 years when chemotherapy was added to surgery or radiation therapy (11). A 27% reduction in the risk

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of death at 1 year favoring cisplatin-based chemotherapy over supportive care alone was also reported (11). This reduction corresponded to an increase in the l-year survival rate from 5 to 15%. The estimated improvement in median survival was about 6 weeks. Marino et al. (12) reported an estimated increase in median survival from 3.9 months for best supportive care to 6.7 months for chemotherapy. In their study, Grilli et ~2. (13) reported an increase in median survival of about 6 weeks (95% confidence interval, l-10 weeks) with chemotherapy in comparison to the best supportive care. Initial phase II trials in NSCLC using various chemotherapeutic combinations reported response rates that ranged widely from 10 to 50%, with response rates in stage III disease superior to those in stage IV disease. Response rates in larger phase III trials are about 25% (14,15). In two large studies in which the combination of cisplatin and etoposide was used (as one of the arms in a phase III trial), response rates ranged from 20 to 30% (16, 17). Median survival was 7-8 months. Response rates have not always correlated with better survival. In a randomised trial comparing five different regimens, single-agent carboplatin was associated with the best survival (31.7 weeks) despite having a very low response rate (9%) (18). The combination of mitomycin C, vinblastine and cisplatin had the best response rate (20%) but was associated with the poorest survival (22.7 weeks). Clearly, more active agents and more effective combinations are needed in the treatment of NSCLC. About 25% of patients with lung cancer have small-cell lung carcinoma (SCLC) (19). Chemotherapy is the mainstay of treatment in these patients 0

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36

for both limited-stage and extensive-stage disease. Most patients with SCLC have extensive-stage disease at presentation, and median survival, despite treatment, is only 10 months (19). Response rates in the BO-90% range have been reported for platinumcontaining combinations in SCLC, including a complete response rate of lO-50% (20, 21). However, only 5-10% of patients survive for 5 years despite intensive treatment (2). Chemotherapeutic agents with single-agent activity in NSCLC are cyclophosphamide, vincristine, cisplatin, mitomycin C, vinblastine, vindesine, carboplatin, etoposide and ifosfamide (2,14,22). Agents active in SCLC include cyclophosphamide, cisplatin, carboplatin, etoposide and doxorubicin. The most widely used combinations in NSCLC have been mitomycin C-vinblastinecisplatin+toposide, cisplatin and vinblastine-cisplatin (15). Combinations used frequently in SCLC include cyclophosphamidedoxorubicin-vincristine, cyclophosphamide-doxorubicitoposide and cisplatinetoposide. The dismal outlook for patients with advanced lung cancer despite the best available therapy has prompted a search for new chemotherapeutic agents. In the past few years, a number of new agents have been shown to have significant activity in both SCLC and NSCLC. These include the taxanes, camptothecins, gemcitabine and vinorelbine. This paper reviews the pharmacology and the published clinical activity of these four classes of drugs in lung cancer.

TAX01 DS The taxoids (Figure 1) are a new class of anticancer drugs that include paclitaxel(5/?,2O-epoxy-1,2a,4,7/l, 10/3,13a-hexahydroxytax-11-en-9-one 4,10-diacetate 2 benzoate 13-ester with [2R,3S]-N-benzoyl-3-phenylisoserine; Taxol) and docetaxel (5b,20-epoxy-1,2a,4, 7/?,10/?,13cr-hexahydroxytax-ll-en-9-one 4 acetate 2 benzoate trihydrate 13-ester with [2R,3S]-N-carboxy3-phenylisoserine, N-tert-butyl ester; Taxotere). Paclitaxel was discovered during the screening of over 30,000 natural products by the National Cancer Institute in the 1960s. A crude extract from the bark of the Pacific yew (Tams brevifolia) had cytotoxic activity against many tumors (23). Paclitaxel was determined to be the active constituent of this extract in 1971. Horwitz (24) later described the unique mechanism of action of paclitaxel. Despite initial problems of solubility and unexpected toxicities, several phase I trials were completed, and phase II trials were begun in the 1980s. Paclitaxel is now approved in the United States for use in the treatment of ovarian and breast cancer. In 1986, a semisynthetic

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taxoid was prepared through use of a precursor, lodeacetyl baccatin III, obtained from the needles of the European yew (Tams baccafa). The active constituent of this extract is docetaxel, which has two chemical modifications of paclitaxel’s structure. A hydroxy group replaces an acetyl group at the loposition of baccatin III, and an OC (CH,), moiety replaces a benzamide phenyl group in the 3’ position of the C-13 side-chain (25). Docetaxel has been approved for the treatment of recurrent breast cancer in the United States. Both paclitaxel and docetaxel have been evaluated for the treatment of lung cancer, with numerous studies yielding promising results. Docetaxel also seems to have an unexpectedly high level of activity in platinum-refractory NSCLC.

Mechanism

of action

Both drugs have similar mechanisms of action. They enhance both the rate and extent of microtubule assembly in vitro and inhibit the disassembly of microtubules, thereby leading to bundles of microtubules in the cells (25-27). Microtubules are eukaryotic cell components that perform important functions, including regulation of cell morphology, signal transmission, intracellular transport, formation of the mitotic spindle during cell division, cellular motility and anchorage of receptors in the cell membrane. Microtubules are assembled from tubulin, which is alOO-kDa protein comprising two subunits, M:and j?, of 50 kDa each. Structurally, microtubules are a collection of 13 protofilaments arranged longitudinally to form hollow cylinders, which are in equilibrium with free tubulin. The equilibrium shift between microtubule assembly and disassembly is controlled by various factors, such as free guanidine triphosphate, calcium ions, temperature and proteins (including microtubule-associated proteins), and can also be modified by drugs (28). Paclitaxel binds to the N-terminal 31 amino acids of the /I-tubulin subunit in the microtubule in a specific reversible and saturable manner, with a stoichiometry of approximately one molecule per a- or p-tubulin dimer. The microtubules formed in the presence of the taxoid are dysfunctional, causing the death of the cell by disrupting the normal microtubule dynamics of assembly and disassembly required during the cell cycle. The stable, abnormal microtubules formed with taxoid therapy lead to cell cycle arrest in the G2 and M phases of the cell cycle, since the cells are unable to form normal mitotic spindles and divide. Mechanistically, docetaxel differs from paclitaxel by being twice as potent an inhibitor of microtubule depolymerisation and promoter of tubulin assembly

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37 HO

HO

H

Doxetaxel

Paclitaxel

CH3

Figure I

Structures of the taxoids.

(29). Docetaxel binds to the same site on assembled tubulin as paclitaxel but with a 1.9-fold higher affinity. This difference may account for the differences in in vitro potency. The taxoid-binding site does not overlap with those of other antitubulin agents, such as the vinca alkaloids and colchicine (30). In vitro uptake studies have revealed a three-fold higher intracellular concentration of docetaxel than of paclitaxel for the same initial extracellular concentration of 0.1 pm (31). In comparative studies, docetaxel has been found to be 1.3- to 12-fold more cytotoxic in vitro than paclitaxel (32). In addition to its effect on microtubules, paclitaxel has exhibited other properties that may contribute to its cytotoxicity. Recent investigations have suggested that pa&axe1 may have significant anti-angiogenic activity. Non-cytotoxic doses of the drug were found to inhibit the angiogenic response induced by tumor cell supernatant in mice experiments. In vitro experiments also showed inhibition of endothelial cell proliferation, motility and invasiveness in a dosedependent manner (33). Paclitaxel also inhibits the production of matrix metalloproteinases, which are enzymes that degrade matrix and thereby continue to tumor invasiveness (34, 35). Further, paclitaxel has been shown to induce the expression of the gene for tumor necrosis factor CL.However, it is not clear

what relevance these effects have in the clinical activity of the drug. Paclitaxel has a radiosensitising effect, most likely related to its ability to cause cell cycle arrest in the G, and M phases of the cell cycle, when tumor cells are highly susceptible to the effects of radiation. Preclinical studies on human adenocarcinoma cell lines such as MCF-7 (breast), PC-Sh (pancreas), A549 (lung), DUT-145 (prostate), HT-29 (colon) and OVG-1 (ovary), show that paclitaxel is a radiosensitising agent in some, but not all, tumor cells (36-38). Radiosensitisation was observed in ovary, breast, prostate and colon cancer cell lines. In contrast, radiosensitisation was not seen in the A549 lung cancer cell line at any dose. However, trials combining paclitaxel and thoracic radiation in NSCLC are continuing, and preliminary results indicate response rates greater than 80% with acceptable toxicity (39, 40). Preliminary data also indicate that combined radiotherapy and docetaxel administration is feasible and safe in locally advanced NSCLC (41). However, because of a concern that pulmonary toxicity is increased with the concurrent administration of taxoids and radiation, more definitive results from combined modality trials in progress are awaited.

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Toxicity Major toxicities of the taxoids are neutropenia, mucositis, thrombocytopenia, peripheral neuropathy, alopecia and myalgias (42). The dose-limiting toxicity of both paclitaxel and docetaxel is usually neutropenia, which tends to be reversible and noncumulative. Reducing the infusion time of paclitaxel from 24h or greater to 3h reduces the incidence of neutropenia (43). Severe acute hypersensitivity reactions occurred in 20-30% of patients treated with paclitaxel in early phase I trials. These included hypotension, dyspnea, flushing angioedema and an erythematous rash. Hypersensitivity was thought to be related to the polyoxyethylated castor oil (Cremophor) vehicle in which the water-insoluble drug was dissolved (26). Since the reactions with paclitaxel resembled those with iodinated contrast dye, a similar schedule of premeditation was adopted. This consisted of dexamethasone, 20mg administered 12 and 6 h before chemotherapy, as well as cimetidine, 300mg, and diphenhydramine, 50mg, both given intravenously preceding administration of paclitaxel; the incidence of hypersensitivity reactions was reduced to less than 5%. The need for routine use of dexamethasone 6 and 12h before paclitaxel administration has been questioned recently (44, 45). Some investigators have used a single dose of dexamethasone, 16-20mg, given intravenously 30 min before paclitaxel infusion, with no increase in the incidence of hypersensitivity reactions (46,47). Anaphylactic reactions are rare with premeditation. Neurotoxicity, which has been better characterised for paclitaxel, occurs with both agents. It is a result of the toxicity of these drugs to nerve cell bodies or axons. Peripheral neuropathy follows a ‘stocking and glove’ distribution, tends to be symmetrical, and is mainly sensory. Motor abnormalities have been described in a minority of patients. Paclitaxelinduced neurotoxicity can be dose-limiting and tends to occur more frequently in patients with preexisting neuropathy. It is reversible, dose-dependent and related to cumulative dose. In a randomised trial of 471 patients with metastatic breast cancer, neuropathy occurred in 46% of patients treated with paclitaxel at a dose of 135mg/m*, and in 70% of patients treated with paclitaxel at 175mg/m2 (48). In this trial, however, only 5% had grade 3 or 4 neuropathy and only 1% had to discontinue treatment as a result of neurotoxicity. Neuropathy is also more frequent in patients receiving paclitaxel in combination with other neurotoxic agents, such as cisplatin (49). The most striking, unusual toxicity noted with docetaxel is a fluid-retention syndrome characterised

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by both peripheral and general&d edema. Pleural effusion, ascites, pericardial effusion and increased capillary fragility also can occur. The incidence was 30-50% in patients receiving 75-lOOmg/m* of docetaxel every 3 weeks, and rapidly increased at cumulative doses above 400mg/m2. This toxicity has been decreased by premeditation with oral dexamethasone, 4-8mg given twice daily 48-72h before and after docetaxel administration. With this schedule, the median cumulative dose to onset of fluid retention was 500mg/m’, whereas it was 400mg/ m2 without premeditation (50). When fluid retention occurs, it is treated with diuretics, dose reduction or discontinuation of treatment, and it is slowly reversible. Since hypersensitivity reactions appear to be less frequent with docetaxel, and since patients receive dexamethasone routinely to minimise fluid retention, premeditation with histamine antagonists, as with paclitaxel administration, is unnecessary.

Clinical pharmacology Paclitaxel Paclitaxel is extensively bound to plasma proteins (95-98%) and has a large volume of distribution. Single intravenous doses of paclitaxel, 135-350mg/ m’, produce mean steady-state drug concentrations (0.20-8.54mg/l) higher than those producing antimicrotubule effects in vitro (20.08mg/l) (51). Its clearance appears to be linear in studies of prolonged infusions, but when the drug is infused for shorter periods, the clearance may be non-linear and appears saturable (26, 52, 53). With 24-h infusions, a 30% dose increase (130-175mg/m*) resulted in a rise in the maximum concentration (C,) by 87%, but the change in area under the curve of plasma concentration ZIS time (AUC) remained proportional. However, with 3-h infusions, a similar 30% dose increase resulted in C, and AUC increments of 68 and 89%, respectively, suggesting dose-dependent kinetics at the more rapid infusion rates. Studies in mice indicate that the non-linear pharmacokinetics of paclitaxel may be related to the polyoxyethylated castor oil vehicle in which it is administered (54). Both C, and AUC show marked interpatient variability (51). Paclitaxel has a three-phase kinetic behavior, described as the a, #I and y phases of elimination. There is a wide interpatient variability in half-lives T1,= 0.04-0.5h for T1,2 u and 3.8-16.5h for T1,* B. The major routes of systemic clearance in humans have not been fully elucidated but, on the basis of animal studies, appear to be hepatic metabolism, biliary excretion and extensive tissue binding. Some

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human studies have implicated the cytochrome P450 isoenzymes CYP2C and CYP3A in the hepatic metabolism of paclitaxel (55). The dosage of paclitaxel in hepatic dysfunction has not been well studied, but in patients with significant liver dysfunction (total bilirubin >3mg/dl), the dose needs to be reduced by 50%. Since renal clearance of the drug is less than lo%, dose modifications are not necessary in renal failure (26, 56, 57). The optimal dose, schedule and duration of infusion of paclitaxel are yet to be determined. The usual dose of paclitaxel ranges from 135 to 250mg/ m2 infused over 1, 3, 24 or 96h. Initially, the 24-h infusion was widely used in clinical trials. Subsequent studies with standard premeditation revealed no greater incidence of hypersensitivity reactions with shorter infusion (43). A large randomised trial in women with relapsed ovarian cancer found that 3-h infusions were as effective as 24-h infusions and had fewer side-effects of granulocytopenia and stomatitis (43). The 3-h infusion is convenient and practical in ambulatory care. Since paclitaxel has a short half-life and is specific to the cell cycle, longer infusions may be more effective. Consistent with this theory, patients with metastatic breast cancer in whom treatment with short (l- to 3-h) infusions of paclitaxel had failed have had a response to more prolonged (96-h) infusions (58). A randomised clinical trial is underway comparing 3-h with 96-h paclitaxel infusion in metastatic breast cancer (59). A dose-response relationship has been observed withpaclitaxelinNSCLC. InaphaseIIstudybyHainsworth et al. (60), patients who received 200mg/m2 of paclitaxel had a higher response rate than those who received 135mg/m2 (31 and 12%, respectively). Six of 16 patients (38%) treated previously with cisplatin-based regimens had responses to 200mg/ m* of paclitaxel. A similar dose response was also noted in an Eastern Cooperative Oncology Group (ECOG) advanced NSCLC trial. In this study, the response rate with paclitaxel was 26.5% with 135mg/m2 and 32.1% with 250mg/m2 (with granulocyte-colony-stimulating factor [G-CSF] support) (61). In breast cancer, response rates with paclitaxel have tended to be better with 175 than with 135mg/ m2 (48). Such a dose response has not been seen in ovarian cancer (43). At present, superior responses with higher doses of paclitaxel have not been translated into improved overall survival. Synergistic cytotoxicity occurs in vitro when exposure to paclitaxel precedes cisplatin, melphalen, thiotepa or 5-fluorouracil. Synergism also occurs when cells are exposed to doxorubicin or edatrexate before exposure to paclitaxel, and when vinorelbine or estramustine is coadministered with paclitaxel (51).

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Docetaxel The pharmacokinetic behavior and elimination patterns of docetaxel are very similar to those of paclitaxel. Docetaxel is also highly protein-bound (>90%) and is excreted primarily by the liver. Clearance of docetaxel is decreased in patients with mild-to-moderate hepatic impairment. A reduction in the in vitro metabolism of docetaxel has been reported after incubation with drugs that are substrates of the CYP3A isoenzyme, such as erythromycin, ketoconazole, nifedipine, testosterone and midazolam. Substrates of the CW2C isoenzyme had little effect (62). Human docetaxel pharmacokinetics have been investigated in several phase I clinical trials of various doses and schedules of administration. The kinetic profile is consistent with a three-compartment model independent of dose or schedule. Mean pharmacokinetic values obtained from a population analysis of various studies were triphasic plasma half-lives of 4 min, 36 min and 11.1 h. Plasma clearance was 35.3 l/h (21 l/h/m2), and steadystate volume of distribution was 113 l(67.3 l/m2). Frequent dosing did not alter efficacy, an indication of lack of schedule dependency (63). The usual dose of docetaxel is 70-100mg/m2 over l-2h, given every 34 weeks. As with paclitaxel, dose reductions are not necessary in renal failure but are necessary in hepatic impairment. Preclinical studies in murine models show synergistic antitumor activity when docetaxel is administered simultaneously with agents such as vinorelbine, etoposide, cyclophosphamide, 5-fluorouracil and methotrexate (25).

Mechanisms

of resistance

The mechanisms of inherent or acquired resistance to the taxoids have not been fully elucidated. Some tumors possess tubulins with an impairment ability to polymerise into microtubules that makes them resistant to the taxoids (26, 64). In fact, their abnormally slow rate of microtubule assembly is normalised by the taxoids. The second mechanism of resistance involves amplification of p-glycoproteins coded for by the multidrug-resistance gene (26, 65, 66). These proteins function as drug-efflux pumps. Clinically relevant concentrations of polyoxyethylated castor oil have been shown to reverse multidrug-resistance gene-mediated resistance in some cell types (67).

Clinical activity Both drugs have shown activity in patients with advanced ovarian carcinoma, metastatic breast cancer, lung cancer and a variety of solid tumors. The

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S. V. RAJKUMAR Table

I

Phase

II trials

of the

taxoid

Docetaxel* Single-agent Single-agent Combination

activity in NSCLC activity in SCLC chemotherapy (carboplatin) chemotherapy chemotherapy in SCLC

(cisplatin) (carboplatin

activity in NSCLC activity in SCLC chemotherapy (cisplatin)

NSCLC, non-small-cell *Single-agent reported patients, leading to lower

A. A. ADJEI

in lung cancer

Treatment

Paclitaxel Single-agent Single-agent Combination NSCLC Combination Combination etoposide)

AND

Response

rates

Ref.

No. of studies

No. of patients

in

5 2 8

203 89 318

in NSCLC and

3 2

79 65

2347 7693

81-83 84, 85

in NSCLC

6 I 3

249 28 63

19-38 25 25-53

86-9 I 92 93-95

lung cancer: SCLC. small-cell for docetaxel includes two response rates.

lung cancer. trials in NSCLC

activity of paclitaxel and docetaxel in lung cancer is summarised in Table 1. The table illustrates the activity of the drugs in phase II trials, both as single agents and in combination chemotherapy. Phase III studies, discussed in detail in the text, are excluded from the tables. Paclituxel in NSCLC In most studies, the single-agent activity of paclitaxel in NSCLC is about lO-25% (Table 1). The inferior response rate of 10% observed by Millward ef a2. (71) may be related to the 60% exposure to previous radiotherapy in the patients studied. The combination of paclitaxel and carboplatin has been studied in several phase II trials, with response rates of 2663% (Table 1). Doses used were paclitaxel, 135250mg/m2, and carboplatin, AUC 5-7.5, administered every 3-4 weeks. Three phase II studies combined paclitaxel and cisplatin, and response rates ranged from 23 to 47% (Table 1). Doses used were paclitaxel, 135225mg/m*, and cisplatin, 80-lOOmg/ m* every 3 weeks in two studies. One study used a regimen of paclitaxel, llOmg/m*, and cisplatin, 60mg/m*, every 2 weeks. Most of these combination phase II studies used a l- to 3-h paclitaxel infusion. No definite differences in response rates occurred with duration of paclitaxel infusion. A recent randomised trial by the ECOG involving 536 patients compared cisplatin and etoposide (lOOmg/m’, l-3 days) with cisplatin and paclitaxel (135mg/m*) or with cisplatin, paclitaxel (250mg/ m2), and G-CSF (61). The cisplatin dose was 75mg/ m2 on Day 1 in all three arms. Paclitaxel was administered over 24h on Day 1. Each regimen was repeated every 3 weeks. Preliminary results presented in abstract form showed superior response

and one trial

(%I

I G25 53-68 26-63

in SCLC

that

studied

60, 68-71 72, 73 46, 7480

previously

treated

rates in the paclitaxel-containing arms (26.5% with 135mg/m2 and 32.1% with 250mg/m2) compared with cisplatin and etoposide (12%) (p
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a higher overall response rate of 93%, with a 54% complete response rate (85). Although these results are promising, the problem in SCLC has been maintaining these responses for the long term, and randomised controlled trials with good follow-up are needed to assess the contribution of paclitaxel in the treatment of SCLC. OH Compound

Substitutions

Docetoxel in NSCLC

c-10

c-9

C-7

H

H

H

Camptothecin

Docetaxel is active in previously untreated patients with NSCLC; response rates are 19-38% (Table 1). Phase II studies of docetaxel in patients previously treated with cisplatin for NSCLC have shown response rates of about 20% and appear encouraging (89, 91). Data from three phase II trials indicate that the combination of docetaxel (75mg/m*) and cisplatin (75 to lOOmg/m’) administered every 21 days is feasible and active in NSCLC, with response rates of 2553% (93-95) (Table 1). Several studies in progress are looking at combinations of taxoids and platinum compounds in advanced lung cancer and in combination with radiation in stage III NSCLC.

Docetaxel in SCLC Docetaxel is also being studied in SCLC. In a study conducted by the EOETC, a 25% response rate was seen in a group of mostly previously treated patients (98).

Topotecan

OH

Irinotecan

Figure

2

CN~N-

Structure stitution

I INHIBITORS

Topoisomerases are enzymes that uncoil DNA before replication. There are two classes of topoisomerases: topoisomerase I and topoisomerase II. Topoisomerase II inhibitors, such as the anthracyclines and epipodophyllotoxins, have been widely used in chemotherapy. Camptothecin, a plant alkaloid derived from the tree Camptotheca acuminatu, was the first mammalian topoisomerase I inhibitor to be identified, and showed impressive activity in a number of clinical studies. However, during phase I trials in the early 197Os, severe and unpredictable toxicity, including hemorrhagic cystitis, myelosuppression, nausea and vomiting, halted its further development. The water insolubility of camptothecin was thought to contribute to its unpredictable toxicity. Irinotecan (7-ethyl-lo-[4-(l-piperidino)-l-piperidinolcarbonyloxycamptothecin; CPT-11; Camptosar) and topotecan ([s]-dimethylaminomethyl-lohydroxycamptothecin; Hycamtin) are topoisomerase

?

c=o

of the camptothecin sites for irinotecan

H

H CHsCH,

molecule and the and topotecan.

sub-

I inhibitors that are semisynthetic, water-soluble analog of camptothecin. The structure of the parent compound with the substitutions for topotecan and irinotecan is shown in Figure 2. The analogues have greater in vim and in vitro activity and less severe and more predictable toxicity than camptothecin. Both have shown activity in a wide variety of solid tumors. Irinotecan and topotecan were recently approved in the United States for use in recurrent colon cancer and recurrent ovarian cancer, respectively.

Mechanism

TOPOISOMERASE

(CH,),NHCH,

of action

The cytotoxicity of irinotecan and topotecan depends on the inhibition of the eukaryotic nuclear enzyme DNA topoisomerase I. This enzyme, which is critical for DNA replication and transcription, causes transient breaks in a single strand of DNA by forming a transient DNA-enzyme ‘cleavable complex’. These breaks release the torsional strain caused by strand separation required for synthesis of a new strand of DNA or RNA. The camptothecins target this DNAtopoisomerase I complex, preventing the reannealing of the nicked DNA strand. This inhibition results in intracellular accumulation of drugstabilised topoisomerase I-DNA cleavable complexes, arrest of DNA replication and subsequent cell death (99). Irinotecan is a water-soluble prodrug that is rapidly hydrolysed to its active form, 7ethyl-lo-hydroxycamptothecin (SN-38), primarily by hepatic microsomal carboxylesterases. The topoisomerase I inhibition of irinotecan is accounted for by the intracellular concentrations of SN-38, which is about 3000 times more potent than the parent drug. An intact lactone ring in camptothecin and

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42

related compounds, including irinotecan and topotecan, enhances antineoplastic activity. The lactone functional group undergoes a pH-dependent hydrolytic ring opening to the relatively inactive hydroxy acid form, with the closed ring form predominating at low pH (100). A new inactive 5aminopentanoic acid metabolite of irinotecan has been identified. This metabolic pathway may involve hepatic cytochrome P-450 enzymes, and may in part account for the large individual variability seen in the kinetics of irinotecan and SN-38 (101). -

I oxlclty

The major dose-limiting toxicity of both irinotecan and topotecan is neutropenia. The incidence of grade 4 neutropenia with irinotecan is approximately 6%. This neutropenia is reversible, lasts mostly for less than 5 days, and is usually asymptomatic. Non-hematologic toxicity is generally mild with topotecan. In contrast, irinotecan has significant nonhematologic toxicity, including diarrhea, nausea and vomiting, abdominal cramps and flushing. Diarrhea is a dose-limiting toxicity of irinotecan. Several phase I studies have demonstrated that the dose-limiting toxicities of irinotecan are schedule-independent. Early onset of diarrhea, during or within 30 min after irinotecan infusion, has been identified. This is due to a cholinergic response and is easily controlled with anticholinergic therapy, such as atropine, 0.5 to l.Omg intravenously. Late onset of diarrhea, 5-10 days after drug administration, is difficult to treat and has an unclear cause. Early recognition and prolonged administration of loperamide are effective for late-onset diarrhea, having decreased the incidence of grade 4 diarrhea from 20-30% to 5-10% in different studies (102). The appearance of concomitant severe neutropenia and diarrhea has been fatal in a few cases (103). Some studies have also reported pulmonary toxicity, probably a hypersensitivity reaction, in some patients. Other toxicities with irinotecan are asthenia and alopecia. Topotecan is associated with severe grade 4 neutropenia in more than 80% of patients. Grade 4 thrombocytopenia has been noted in 26% of patients, and severe anemia (<8/g.d1) in 40% of patients. Nonhematologic toxic reactions are mainly nausea, vomiting, diarrhea, constipation, alopecia, fatigue, and abdominal pain.

CLINICAL PHARMACOLOGY lrinotecan After an intravenous infusion, irinotecan concentrations decline multiexponentially,

plasma with a

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mean terminal half-life of 6h (range P12h). The systemic clearance for total irinotecan and the lactone form are 13 and 451/h/m’, respectively (104). Maximum plasma SN-38 levels, which range from 2 to 5% of peak irinotecan concentrations, are generally achieved 1 h after irinotecan infusion. SN-38 AUC values range from 2 to 8% of those observed for irinotecan. There is a significant correlation between reduction in neutrophil counts and the AUC of both irinotecan and SN-38, but no relationship is noted with delayed diarrhea or clinical activity (105). The mean terminal half-lives of the total and lactone forms of SN-38 are longer than those for irinotecan (13.0 and 7.9h for total, 11.5 and 6.3h for the lactone form). The pharmacokinetics of irinotecan show interpatient variability but are linearly related to administered dose over the dose range of 50-350 mg/m’. The disposition of irinotecan has not been fully elucidated in humans. Renal excretion appears to play a minor role in the elimination of irinotecan and its two major metabolites (l-15%). The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38) and SN-38 glucuronide) during the 48h after drug administration ranges from 25 to 50% (106, 107). In earlier studies from Japan and the United States, the maximum tolerated dose (MTD) was defined as 240-250mg/m2 with a once-every-3-weeks schedule and 100 and 150mg/m* with a weekly intermittent schedule (108). The dose-limiting toxic effects in these studies were diarrhea and neutropenia. In the United States, the weekly intermittent schedule was thought to represent greater dose intensity and was therefore chosen for further studies. The usual dosage of irinotecan by this schedule is 125mg/m* weekly for 4 weeks, with repetition every 6 weeks. Studies from Europe on administration of irinotecan once every 3 weeks found that diarrhea was doselimiting at 350mg/m2. However, doses of up to 600mg/m2 were then given with concomitant administration of high doses of loperamide (108). In a confirmatory phase I trial at the Mayo Clinic, the recommended phase II dose of irinotecan on a 3week schedule was 320mg/m2 (109). In Europe, this once-every-3-weeks schedule was thought to be better tolerated and to have better dose intensity than the weekly schedule, and it was chosen for further studies there. Alternative dosage schedules that have been studied are continuous infusion for 5 days and daily infusion for 3 days (110). These studies have demonstrated that the dose-limiting toxicities and clinical activity of irinotecan in colon cancer are similar regardless of the administration schedule. The dosage of irinotecan in renal and hepatic failure is unclear. However, since the drug is metabolised in the liver, dose adjustments are

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probably necessary in patients with hepatic dysfunction. Interaction between irinotecan and 5-fluorouracil is schedule-dependent. Synergistic cytotoxicity occurs in vitro when exposure to SN-38 precedes 5fluorouracil and leucovorin in HCT-8 human colon cancer cells (111). Synergism with etoposide (a topoisomerase II inhibitor) and additive effects with cisplatin have been observed in studies using the A460 lung carcinoma cell line (112).

Topotecan At physiologic pH, the closed-ring lactone species of topotecan (active form) is predominant over the open-ring hydroxy acid species (less potent form). In preclinical studies, 90% of the administered dose was excreted within 96h. Fecal and urinary excretion of the drug were equivalent. Human studies indicated that urinary excretion accounts for 26-68% of drug elimination (113). In clinical studies, after a single intravenous infusion of topotecan, 2mg/m* over 30 min, the mean (*standard deviation) AUC of total topotecan in plasma were and C,, 8.64 + 3.58mg min/l and 50 + 18mg/ml, respectively (114). The AUC and C,, of the active lactone species were 0.27fO.O9mgmin/l and 7+3mg/ml, respectively. No good correlation was found between the absolute neutrophil counts and AUC (or C,,) of total topotecan. Similarly, tumor response also failed to correlate with AUC or C, of total topotecan. Phase I and pharmacokinetic studies by O’Reilly et al. (113, 115) indicated that dose adjustment does not appear to be necessary in patients with liver impairment but is required in patients with moderate renal impairment (creatinine clearance, 20-39ml/min). Patients with mild renal impairment (creatinine clearance, 40-59ml/min) also do not need dose adjustment. The usual dosage of topotecan is 1.5mg/m2 for 5 days every 21 days. The dosage recommended for patients with moderate renal dysfunction is 0.75mg/m2 for 5 days every 21 days. Additive or synergistic effects have occurred with the combination of topotecan and cisplatin in NCIH82ras(H) and A549 lung cancer cell lines (116).

Mechanisms

of resistance

Several mechanisms of resistance to these drugs have been reported. These include p-glycoproteinmediated drug efflux (topotecan), decreased metabolic activation (irinotecan), decreased levels and functions of topoisomerase I in the tumor cells, and enhanced DNA repair.

43

Clinical activity lrinotecan in NSCLC Irinotecan is active in NSCLC, with a response rate of 41% in a single-agent study involving 22 patients (Table 2). The dose used was 100mg/m2 weekly, administered intravenously by 90-min infusion (117). This agent has also been studied in combination with cisplatin, and response rates range from 48 to 54% (Table 2). The optimal dose of irinotecan in combination with cisplatin was 60mg/m2 weekly for 3 weeks, repeated every 4 weeks; the cisplatin dose was 80mg/m2 every 4 weeks (120, 121). At these dose levels, the combination was well tolerated.

hnotecan in SCLC Irinotecan has shown response rates of 25-47% in patients with SCLC treated previously with cisplatin (Table 2). Preliminary results from a Japanese phase II trial of combined irinotecan and cisplatin in 32 previously untreated patients with SCLC indicated an overall response rate of 78% and a complete response rate of 22% (122) (Table 2). Randomised controlled trials will be needed to define the role of irinotecan in lung cancer.

Topotecan in SC/L Topotecan has only limited activity in NSCLC but seems active in SCLC (Table 2). Schiller et al. (114) reported on the activity of topotecan (2mg/m* daily for 5 days, repeated every 3 weeks) in 48 previously untreated patients with extensive-stage SCLC. Most patients received G-CSF support. No complete responses occurred, but 19 of 48 patients (39%) had a partial response, lasting for a median duration of 4.8 months. In another trial, a 35% response rate was reported with topotecan in mainly previously treated patients with SCLC (125).

GEMCITABINE Gemcitabine (2’,2’-difluorodeoxycytidine; dFdC; Gernzar) is a fluorinated analog of deoxycytidine (Figure 3). In human trials, it has shown singleagent activity in solid tumors, including pancreatic, ovarian, lung, breast, bladder, and head and neck cancer (126-131). It is now approved for use in the treatment of metastatic pancreatic carcinoma in the United States. Gemcitabine has major differences in activity and clinical effects compared with those of other deoxycytidine analogs, such as cytosine

S. V. RAJKUMAR

44 Table

2

Phase

II activity

of irinotecan

and topotecan

Treatment

ltinotecan Single-agent Single-agent Combination Combination

activity in NSCLC activity in SCLC* chemotherapy (cisplatin) chemotherapy (cisplatin)

Topotecan Single-agent Single-agent

activity activity

Figure

3

Structures

No. of patients

w?

of deoxycytidine

Response

rates

References

I 2 2 I

22 50 95 32

41 2547 48-54 78

I I7 118, II9 120, I21 122

2 2

60 38

O-15 35-39

123, 124 114, 125

(%)

lung cancer.

and gemcitabine.

arabinoside. The drug was initially synthesised as an antiviral agent, but because of lack of a good therapeutic index, the compound was not evaluated further. Gemcitabine has a broad spectrum of antineoplastic activity in tumor cell cultures in vitro and in animal tumor models (132). It has been studied extensively in NSCLC.

Mechanism

No. of studies

in NSCLC in SCLC

NH,

A. A. ADJEI

in lung cancer

in NSCLC in SCLC

NSCLC. non-small-cell lung cancer; SCLC. small-cell *Both studies were on previously treated patients.

AND

of action

Gemcitabine is prodrug, transported as a fraudulent nucleotide into cells via the facilitated diffusion nucleoside transport carrier and phosphorylated to the monophosphate, diphosphate and triphosphate forms. The rate-limiting enzyme in the phosphorylation is deoxycytidine kinase. The first anabolite is 2’,2’-difluorodeoxycytidine monophosphate (dFdCMP), which is subsequently phosphorylated to 2’,2’-difluorodeoxycytidine diphosphate (dFdCDP), which in turn is phosphorylated to 2’,2’-difluorodeoxycytidine triphosphate (dFdCTP). In comparison to cytosine arabinoside, gemcitabine is a better substrate for the nucleoside transporter of tumor cells and has greater affinity for deoxycytidine kinase. In HL-60 cell lines, the K, (pmol/l) values

of deoxycytidine kinase for gemcitabine and cytosme arabinoside are 4.6 and 14.8, respectively (133,134). The principal cytotoxic metabolite of gemcitabine is dFdCTP. It directly competes with deoxycytidine triphosphate (dCTP) for incorporation into the elongating DNA strand. Incorporation of dFdCTP results in termination of DNA chain elongation and inhibition of DNA synthesis. These events are thought to be responsible for cytotoxicity from gemcitabine. Critical to the cytotoxic effect is the prolonged intracellular retention of dFdCTP that is related to its self-potentiation through various mechanisms. As dFdCDP inhibits ribonucleotide reductase for phosphorylation, competing endogenous deoxyribonucleotide pools (including dCTP) are reduced. In addition, dFdCTP inhibits its own catamonophosphate bolising enzyme, deoxycitidine deaminase, an enzyme that converts dFdCMP to 2, 2’-difluorodeoxyuridine monophosphate (dFUMP), which is then metabolised to 2’,2’-difluorodeoxyuridine (dFdU), an inactive catabolite (13.5 136, 137). The metabolic pathway of gemcitabine is surnmarised in Figure 4. The preclinical finding that prolonged exposure to gemcitabine leads to dramatically greater antitumor effect is consistent with the concept of self-potentiation leading to prolonged intracellular concentrations of dFdCTP (137). The solid tumor selectivity of gemcitabine, in contrast to other nucleoside analogs, is also thought to be related to the prolonged intracellular retention of dFdCTP. In vitro studies have demonstrated that prolonged exposure of various cultured neoplastic cells to gemcitabine results in potent radiosensitisation (138). This radiosensitisation is dose- and time-dependent and is maximal when radiation follows gemcitabine exposure. However, clinical trials investigating combinations of radiation therapy and conventional weekly doses of gemcitabine have shown significant toxicity. Trials are under way to evaluate the combination of radiation with lower doses of gemcitabine.

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Gemcitabine

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(dFdC)

deoxycytidine

kinase

Endogenous dCTP

1

Incorporation into DNA

45

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/

- - - + Inhibition Figure 4 Schema of gemcitabine metabolism. CDP, cytidine diphosphate; dCMP, deoxycytidine monophosphate; dCTP, deoxycytidine triphosphate; dFdCDP, 2’,2’-difluorodeoxycytidine diphosphate; dFdCMP, 2’,2’-difluorodeoxycytidine monophosphate; dFdCTF’, 2’.2’-difluorodeoxycytidine triphosphate; dFdU, 2’,2’-difluorodeoxyuridine; dFUMP, 2’,2’-difluorodeoxyuridine monophosphate.

Toxicity Gemcitabine is well tolerated. In phase I studies, the side-effects were predominantly scheduledependent flu-like syndrome, fever, hypotension, myelotoxicity and liver toxicity (139). Abnormalities in liver enzymes are noted in more than 60% of patients. Grade 3 or 4 myelosuppression occurs in 25% of patients. The flu-like syndrome is doselimiting when the drug is used for 5 consecutive days every 3 weeks. Other toxic reactions are nausea and vomiting, mild hematuria, dyspnea, edema, rash and somnolence. These side-effects are mild and are usually easily controlled. Most patients (>85 to 90%) do not experience hair loss or mucositis (140). Lifethreatening infections are rare.

Clinical pharmacology In phase I trials, plasma concentrations of gemcitabine after doses of 800-1000mg/m2 exceeded 50pmol/l(l41). Elimination of gemcitabine is largely through deamination, and the plasma half-life of gemcitabine is less than 60 min. Apparently sex differences in the half-life and clearance of gemcitabine most likely are related to differences in activity of the enzyme cytidine deaminase. The halflife of gemcitabine ranged from 40 mins with short (<1.2h) infusions to 295 min with long (1.2-5.0h) infusions in men, and 50-371 min in women (142).

The inactive deamination product (dFdU) has a biphasic elimination, with a terminal half-life of 14h. The active metabolite (dFdCTP) accumulates in cells and reaches high concentrations. It also has a biphasic pattern of elimination, with a terminal halflife of 12h in animal models (143). Preclinical studies indicate that gemcitabine and its metabolites are eliminated mainly through the urine, and 76-86% of the administered dose is excreted in the first 24h ww. Most groups have used gemcitabine at a dose of 800 to 1250mg/m2 intravenously every week for 3 weeks followed by a l-week rest (145). When the drug is given on this schedule, which is well tolerated, the primary dose-limiting toxicities are reversible hepatotoxicity and myelosuppression. Gemcitabine exhibits striking schedule-dependent toxicity. The MTD of the drug given weekly for 3 weeks every 4 weeks ranges from 790 to 2400mg/ m2 (146, 147). The MTD on an every other week schedule exceeds 3000mg/m2, whereas the MTDs for schedules of twice a week and 5 days a week every 4 weeks are 65 and 12mg/m2, respectively (148-150). Toxicity is also affected by duration of drug exposure. The MTD of a 24-h continuous infusion is 180mg/m2 (151). The combination of gemcitabine and cisplatin has shown synergistic preclinical activity in cultured human carcinoma cell lines and human tumor xenografts in nude mice (152). Several trials are underway evaluating the combination of gemcitabine with cisplatin and with other agents that have activity in lung cancer, such as irinotecan and the taxoids.

Mechanisms

of resistance

Gemcitabine resistance has been demonstrated in vitro by deficiency of deoxycytidine kinase, the ratelimiting enzyme responsible for the formation of the active metabolite, dFdCTP (153). Another potential mechanism for gemcitabine resistance is overexpression of cytidine deaminase (154). Tumors with relatively few cells in the S phase of the cell cycle may also contribute to gemcitabine resistance (155).

Clinical activity Gemcitabine in NSCLC Gemcitabine administered as a single agent has shown response rates of over 20% in NSCLC (156) (Table 3). Five separate phase II studies from the United States, Italy, Spain, Canada and South Africa have

S. V. RAJKUMAR

46 Table

3

Single-agent

phase

II activity

of gemcitabine

NSCLC,

activity in NSCLC activkty in SCLC chemotherapy (cisplatin) non-small-cell

lung cancer;

No. of patients

4 I 5

594 26 205

Response

rates

Ref.

(%) 156-159 160 161-165

20-26 30 30-54

lung cancer.

recently reported significant activity with gemcitabine in combination with cisplatin in the treatment of NSCLC (Table 3). In these studies, 203 previously untreated patients were treated, and response rates ranged from 30 to 54%. Toxicity was of gemcitabine was acceptable. The dose lOOO-1500mg/m2 given weekly for 3 weeks every 4 weeks. In four of these studies, cisplatin was administered at a dose of lOOmg/m* every 4 weeks (161-163, 165). One study used cisplatin at a dose of 30mg/mz given with each dose of gemcitabine (164). Median survival reported in one study was 13 months (165). Gemcitabine is currently approved for the treatment of NSCLC in Europe. A randomised trial by the ECOG comparing gemcitabine and cisplatin with paclitaxel and cisplatin, or docetaxel and cisplatin, or paclitaxel and carboplatin will help elucidate the role of gemcitabine relative to the taxanes in the treatment of NSCLC. Further, gemcitabme has significant radiosensitising properties, and results of continuing combined modality studies will also be of interest.

Gem&tine

No. of studies

in NSCLC

SCLC, small-cell

A. A. ADJEI

in lung cancer

Treatment

Single-agent Single-agent Combination

AND

in SCLC

Gemcitabine has not been well studied in SCLC. A 30% single-agent response rate was reported in a phase II trial in 26 previously untreated patients (160) (Table 3).

VINORELBINE Vinorelbine (3’,4’-didehydro-4-deoxy-C’-nor-vincaleucoblastine; Navelbine) is a semisynthetic vinca alkaloid that is analogous to vincristine, vinblastine, and vindesine (Figure 5). It differs from other vinca alkaloids by substitutions on the catharanthine rather than the vindoline ring of the vinca alkaloid molecule (166). Unlike other vinca alkaloids, vinorelbine acts primarily on non-axonal microtubules, with specific binding to the microtubules of the mitotic spindle (167). This is thought to be the reason for the minimal neurotoxicity observed with this agent. It has been studied in a variety of

,CWH,

CH, Vinorelbine

Figure

5

Structure

of vinorelbine.

solid tumors and is approved for clinical use in patients with advanced NSCLC in the United States.

Mechanism

of action

Microtubules are essential for mitosis. Vinorelbine binds to tubulin and inhibits mitotic microtubule formation. This leads to dissolution of mitotic spindles and metaphase arrest in dividing cells. The disruption of microtubules also results in toxicity to non-dividing cells, since microtubules are essential for other cellular processes. Besides its effect on microtubules, vinorelbine, like other vinca alkaloids, may inhibit synthesis of proteins and nucleic acids; interfere with glutathione, cyclic adenosine monophosphate (CAMP), and lipid metabolism; and inhibit calcium-calmodulin regulated CAMP phosphodiesterase. Thus, vinorelbine may exert cytotoxic effects unrelated to mitotic inhibition. In preclinical studies, vinorelbine inhibited mitotic spindle microtubles at a concentration of 2pmol/ 1. However, axonal microtubule depolymerisation occurred only at a concentration of 40pmol/l. Vincristine and vinblastine also inhibit mitotic microtubular formation at the same concentration as vinorelbine. However, they produce axonal microtubular depolymerisation at lower concentrations

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(vincristine, 5pmol/l; vinblastine, 30pmol/l) These data indicate the relative selectivity norelbine for mitotic microtubules.

CANCER

(166). of vi-

47

vinorelbine was administered before cisplatin in preclinical studies using human lung adenocarcinoma PC-12 cells (173).

Toxicity

Mechanisms

Neutropenia is the major dose-limiting toxicity of vinorelbine, occurring in 80% of patients, with a 30% risk of grade 4 neutropenia. The rate of hospitalisations for neutropenic complications is around lo%, but deaths are rare. Significant anemia or thrombocytopenia is rare with vinorelbine. The drug is fairly well tolerated overall. Although 20-25% of patients have some symptoms of peripheral neuropathy, grade 3 or 4 neuropathy is rare, occurs in fewer than 5% of patients, and is usually reversible. Other toxicities (usually mild) include fatigue, nausea, vomiting, constipation, diarrhea, alopecia, phlebitis and injection site reactions.

Preclinical studies have shown that similar to other vinca alkaloids, vinorelbine is associated with pglycoprotein-mediated drug resistance that is completely reversed by verapamil (174). Cells may also exhibit resistance because of enhanced recovery from damage sustained to microtubules and other cytoskeletal mechanisms (175).

Clinical pharmacology Vinorelbine is highly lipid-soluble, leading to rapid cellular accumulation. It is highly bound to platelets (168). The elimination of vinorelbine has been studied in both animal and human models. It is eliminated mainly by hepatic metabolism, with 5060% excretion in the feces. Urinary excretion accounts for lO-15% of drug elimination. The rest of the administered dose is thought to be persistently bound to tissues. The initial phase of elimination lasts several minutes, and the terminal elimination phase requires 3040h (166, 169). Tissue concentrations in the lung are up to 300-fold higher than in serum, in both healthy lung and tumor tissue (170). The usual dose of vinorelbine is 25-30mg/m2 given weekly. The drug has also been used in combination with cisplatin at the same dosage. As with other vinca alkaloids, dose reductions are not needed in renal failure. Although the use of vinorelbine in patients with hepatic dysfunction has not been studied, dose adjustments in the range of 50% are recommended for patients with mild hepatic dysfunction (total bilirubin, >2.0mg/dl). For patients with total bilirubin exceeding 3.0mg/dl, a 75% dose adjustment is recommended. The taxoids and vinorelbine both target microtubules but through different mechanisms. A schedule-dependent synergism was observed when vinorelbine was administered 24h before paclitaxel in both preclinical and clinical studies in lung cancer (171). Synergy also occurred with docetaxel in preclinical studies with an SCLC cell line (172). Schedule-dependent synergism was also observed when

of resistance

Clinical activity horelbine

in NSCLC

Vinorelbine has significant activity in NSCLC. In phase II trials, response rates were 29-33% when vinorelbine was used as a single agent and 33-57% when used in combination with cisplatin (Table 4). In addition, four randomised controlled trials compared vinorelbine with the combination of vinorelbine and cisplatin. A European multicenter trial randomised 612 patients with advanced NSCLC to treatment with vinorelbine (206 patients), or vinorelbine and cisplatin (206 patients), or vindesine and cisplatin (200 patients) (183). The dose of vinorelbine was 30mg/m2 weekly, cisplatin, 120mg/ m* on Days 1 and 29 and then every 6 weeks, and vindesine, 3mg/m2 weekly for 6 weeks and then every other week. The response rate with singleagent vinorelbine (14%) was lower than that with the combination of cisplatin and vinorelbine (28%). Survival was better in the cisplatin-vinorelbine arm (median survival, 40 weeks) than with vinorelbine alone (median survival, 31 weeks) (p =O.Ol). Activity and survival in the vindesine and cisplatin arm were comparable to those with single-agent vinorelbine. The response rate with single-agent vinorelbine in this study was lower than the 33% response rate in an earlier phase II study (176). The Southwest Oncology Group recently reported initial results from a phase III randomised study of cisplatin and cisplatin with vinorelbine in the treatment of advanced NSCLC (184). A total of 432 previously untreated patients were randomised to receive cisplatin, lOOmg/m*, every 4 weeks or cisplatin every 4 weeks with vinorelbine, 25mg/m2, weekly, and 394 patients were evaluable for response. The response rate was 10% with cisplatin alone and 25% with the combination of cisplatin and vinorelbine. There were 116 episodes of grade 4 granulocytopenia with the combination, but only

48

S. V. RAJKUMAR Table

4

Single-agent

phase

II activity

of vinorelbine

NSCLC,

No. of studies

No. of patients

2 :

149 30 226 32

activlty in NSCLC activity in SCLC chemotherapy (cisplatin) in NSCLC chemotherapy (carboplatin) in NSCLC non-small-cell

lung cancer;

SCLC, small-ceil

A. A. ADJEI

in lung cancer

Treatment

Single-agent Single-agent Combination Combination

AND

I

Response

rates

Ref.

(%I 29-33 27 33-57 28

176, 177 178 179-181 182

lung cancer.

three episodes with cisplatin alone. There was a statistically significant improvement in progressionfree survival (median, 2 zx 4 months; p = 0.0001) and overall survival (median, 6 ~1s7 months; p =O.OOl) favoring cisplatin plus vinorelbine. The l-year survival rate was 33% with the combination and 12% with cisplatin alone. Depierre et al. (185) compared vinorelbine (30mg/ m2 weekly) with vinorelbine (30mg/m2 weekly) and cisplatin (BOmg/m’ every 3 weeks) in a randomised controlled trial involving 231 patients. The objective response rates (16 and 43%, respectively; p =O.OOOl) and median time to progression (10 and 20 weeks; p =O.OOOl) favored the combination of vinorelbine and cisplatin. There was no improvement in median survival (vinorelbine, 32 weeks; vinorelbine plus cisplatin, 33 weeks; p = 0.48). Toxicity was greater with the addition of cisplatin, particularly nausea and vomiting, neuropathy, and renal and hematologic effects. A randomised controlled trial from Argentina compared vinorelbine (30mg/m* weekly) with vinorelbine (30mg/m* weekly for 3 weeks every 4 weeks) and cisplatin (100mg/m2 every 4 weeks) in 162 patients with NSCLC (186). Preliminary data showed no significant difference in response rates (42% in both arms) or survival (vinorelbine, 33 months; vinorelbine plus cisplatin, 41 months; p not reported). Except for the trial from Argentina, these randomised controlled trials indicated a higher response rate with the combination of vinorelbine and cisplatin than with vinorelbine alone, and two trials also showed a modest improvement in overall survival. Toxicity is greater, however, with combination therapy. It is not clear how this regimen would compare with the combinations of platinum compounds and agents such as paclitaxel, docetaxel, gemcitabine and irinotecan. A randomised trial by the Southwest Oncology Group is comparing the efficacy of vinorelbine and cisplatin with that of paclitaxel and carboplatin, and should yield important information about the relative effectiveness of these two combinations.

Mnordbine in SCLC Vinorelbine (30mg/m2 weekly) has activity in SCLC as well, with a 27% single-agent response rate observed after 6 weeks of treatment in 30 previously untreated patients (178) (Table 4). In addition, vinorelbine has modest activity in previously treated SCLC, with a 13-17% response rate noted in two studies; one conducted by the EORTC and another from Japan, involving 48 patients (187, 188).

CONCLUSIONS In the past few years, several new drugs have shown promise in the treatment of lung cancer. Several studies using combinations of these drugs with one another and with platinum compounds are underway. Agents such as docetaxel also seem to have activity in platinum-refractory disease. Several studies are also looking into the place of these agents in combination with radiation therapy, both as primary treatment and as neoadjuvant therapy.

REFERENCES 1 Parker SL, Tong T, Bolden S, Wmgo PA. Cancer statistics, CA Cancer ] Clin 1997; 47: 5-27. 2 Ihde DC. Chemotherapy of lung cancer. N Engl J Med 1992; 327: 1434-1441. 3 Strauss GM, Langer MP, Elias AD, Skarin AT, Sugarbaker DJ. Multimodality treatment of stage IIIA non-small-cell lung carcinoma: a critical review of the literature and strategies for future research. ] Clin Oncol 1992; 10: 829-838. 4 Hilaris BS, Nori D. The role of external radiation and brachytherapy in unresectable non-small cell lung cancer. Surg Chin North Am 1987; 67: 1061-1071. 5 Perez CA, Stanley K, Gnmdy G et al. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung: report by the Radiation Therapy Oncology Group. Cancer 1982; 50: 1091-1099. 6 Curran WJ Jr., Stafford PM. Lack or apparent difference in outcome between clinically stage IIL4 and BIB non-smallcell lung cancer treated with radiation therapy. J Clin Oncol 1990; 8: 409-415. 7 Perez CA, Bauer M, Edelstein S, Gillespie SW, Birch R. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 1986; 12: 539-547.

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