New Perspectives on an Old Friend: Optimizing Carboplatin for the Treatment of Solid Tumors

New Perspectives on an Old Friend: Optimizing Carboplatin for the Treatment of Solid Tumors DAVID S. ALBERTS, ROBERT T. DORR University of Arizona, Arizona Cancer Center, Tucson, Arizona, USA Key Words. Carboplatin Cisplatin Paclitaxel Etoposide Ovarian cancer Non-small cell lung cancer Small cell lung cancer Solid tumors Pharmacokinetics Pharmacodynamics ABSTRACT Background. Since its clinical introduction in 1981, carboplatin has proved a feasible alternative to cisplatin for the treatment of many solid tumors, especially ovarian cancer. Because the pharmacokinetics and, ultimately, the pharmacodynamics of carboplatin are highly dependent on the status of renal function, fixed dosing based on body surface area has led to carboplatin overdosing or, especially, underdosing. This has resulted in less than optimal treatment results compared with cisplatin in a variety of solid tumor types. Only in the past few years has the optimal dosing method for carboplatin individualizing the dose (area under the concentration-versus-time curve [AUC]) rather than conventional use of body surface area been adopted by clinical oncologists. Methods. An extensive review of the oncology literature has been performed to update both carboplatin dosing guidelines as well as its present role in solid tumor chemotherapy. Initial efforts to devise a dosing formula for carboplatin focused on reducing myelotoxicity (especially thrombocytopenia). Subsequently, a simple formula was developed to adjust the carboplatin dose according to renal function. By targeting a carboplatin AUC rather than empirically dosing according to body surface area, doses of carboplatin can be individualized to fall within the drug s therapeutic index. Results. The use of carboplatin dosing guidelines based on renal function has led to optimization of its pharmacodynamic effects both with respect to its safety profile and its ultimate impact on solid tumor response and patient survival. Since carboplatin has little neurotoxicity, it has become the platinum agent of choice in combination with paclitaxel for therapy of previously untreated ovarian cancer. Carboplatin plus etoposide and carboplatin plus paclitaxel have been studied in phase II and III trials, with the latter combination demonstrating improved activity against advanced non-small cell lung cancer. Additional trials in patients with other solid tumors have shown that carboplatin is more cost-effective and less toxic than cisplatin. Conclusions. Dosing based on renal function and a targeted serum AUC, rather than on body surface area, has resulted in the optimal utilization of carboplatin in cancer chemotherapy. Its predictable toxicity and clinical efficacy equivalent to cisplatin make carboplatin the drug of choice for selected tumor types. The Oncologist 1998;3:15-34 INTRODUCTION Since its clinical introduction in 1981, carboplatin has proved a feasible alternative to cisplatin for the treatment of many solid tumors, especially ovarian cancer, an indication that was approved by the United States FDA in the late 1980s [1, 2]. As a second-generation analog of cisplatin, carboplatin shares many structural and pharmacologic features with cisplatin, yet it has an improved toxicity profile. These characteristics have made carboplatin an ideal candidate for not only dose-intensive chemotherapy but also combination therapy with newer agents such as paclitaxel. Only recently was the optimal dosing method for carboplatin individualizing the dose (area under the concentration-versus-time curve, [AUC]) rather than conventional use of body surface area (BSA) recognized. The FDA approval within the past year of individualized dosing for carboplatin marks the beginning of a new era for this drug. Although its effectiveness in many tumors was similar to that of cisplatin, Correspondence: David S. Alberts, M.D., University of Arizona, Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, Arizona 85724, USA. Telephone: 520-626-7685; Fax: 520-626-2445; e-mail: dalberts@azcc.arizona.edu Accepted for publication November 19, 1997. AlphaMed Press 1083-7159/98/$5.00/0 The Oncologist 1998;3:15-34

16 Optimizing Carboplatin for Solid Tumors even when carboplatin was suboptimally dosed, the results of recent trials that use individualized dosing of carboplatin are just now maturing. Because of its lower toxicity and equivalent efficacy, as compared to cisplatin, carboplatin is the platinum analog of choice for selected tumor types. Clinical Pharmacology Both carboplatin and cisplatin exert their therapeutic effects primarily by forming intrastrand DNA adducts with adjacent guanine residues in tumor-cell DNA [3]. Although the platinum-containing moieties of carboplatin and cisplatin are identical (Fig. 1), it is the unique leaving groups of each that ultimately facilitate DNA binding. In the case of carboplatin, the carboxylate groups are much more stable adducts than the chloride groups of cisplatin. This decreases the chemical reactivity of carboplatin relative to cisplatin and significantly lengthens the time required for its aquation and subsequent DNA-adduct formation [4, 5]. Despite these timecourse differences, both carboplatin and cisplatin appear to induce an equivalent number of DNA cross-links, which determines the extent to which they are cytotoxic [5]. Pharmacokinetics of Carboplatin After i.v. infusion of carboplatin in the dose range 20-1,600 mg/m 2, the disposition of platinum typically is followed by measuring the free platinum the therapeutically active form of the drug present in plasma ultrafiltrate, the proteinbound platinum, and the total platinum, a composite of free and protein-bound platinum plus metabolites. After carboplatin is distributed throughout the body, total platinum concentrations found in various tissues are higher than those found in plasma, with the highest concentrations in liver, kidney, skin, and tumors [5, 6]. Carboplatin is excreted almost exclusively by the kidneys. The total body clearances of ultrafiltrable platinum and that of the parent carboplatin molecule are roughly equivalent and correlate linearly with the pretreatment glomerular filtration rate (GFR). Approximately 65%-70% of the total platinum dose is eliminated as intact carboplatin in the urine during the first 12-16 hours after administration, while the remaining 30%-35% of the dose, which is protein-bound and inactive, is eliminated slowly over the next five days [4, 7, 8]. The extent of the pharmacodynamic effects of carboplatin on the body is directly related to the amount of drug delivered to the tissues, which is determined by its plasma concentration. Because physiologic variables, such as renal function, can affect the plasma concentration of carboplatin in proportion to its total body clearance, the AUC should comprise a more accurate reflection of the actual exposure of body tissues (especially the tumor) to carboplatin than should a single empiric dose based solely on the BSA [9]. Because NH 1 NH 1 Pt O O AUC dosing is adjusted for pharmacokinetic variables within each individual, it should achieve a more standardized level of drug delivery than empiric dosing based entirely on BSA. Administration and Dosing Administration Carboplatin is easily administered in the outpatient setting because, unlike cisplatin, it does not require hydration or prophylactic diuretics. Additionally, it can be delivered in a bolus i.v. dose over as short a period as 15 min. In contrast, cisplatin, owing to its renal toxicity, must be administered much more slowly (generally at a rate of 1 mg/min) with saline and a diuretic such as the osmotic nonmetabolized sugar mannitol [10, 11]. Because cisplatin is also far more emetogenic than carboplatin, and its administration requires considerably more time, carboplatin should cost significantly less to administer [2, 12]. Although oral administration of carboplatin has been studied, the low bioavailability of the drug with this route and its untoward gastrointestinal side effects preclude oral administration. On the other hand, the response of tumors located within the peritoneal cavity, such as ovarian cancer, could potentially benefit from intraperitoneal (i.p.) administration of carboplatin. Although the theoretical advantages of enhanced carboplatin exposure after i.p. administration have been investigated [13, 14], pharmacokinetic studies revealed that despite the slower clearance of carboplatin from the peritoneal cavity than from plasma, and the resultant 10-fold O C C O Carboplatin NH 1 NH 1 Pt Cl Cl Cisplatin Figure 1. Molecular structure of carboplatin and cisplatin.

Alberts, Dorr 17 higher i.p. AUC, the benefits of i.p. administration of carboplatin were unfounded. The transit of carboplatin through extracellular space is less efficient than that of cisplatin because of its larger molecular size, which prevents penetration beyond a depth of 1-2 mm of tumor tissue [13-16]. Individualized Dosing The conventional method of dosing carboplatin by BSA is being replaced by pharmacokinetically individualized dosing based on the desired plasma concentration versus time curve (AUC). Carboplatin is considerably less toxic than cisplatin, but its dose-limiting toxicity is myelosuppression, particularly thrombocytopenia. Initial efforts by Egorin and Jodrell at the University of Maryland to devise a dosing formula for carboplatin focused exclusively on reducing the drug s myelotoxicity, since the percentage reduction in platelet count was shown to correlate linearly with the AUC [9]. Subsequently, Calvert and colleagues at the Royal Marsden in the United Kingdom developed a simple formula for adjusting the carboplatin dose according to renal function [9, 17-21]. This formula was based on the GFR, calculated using the clearance of radiolabeled chromium-edta, a test not available in the United States. This formula was based on the observation of a high correlation of measured GFR with renal clearance of carboplatin, which is its primary mode of elimination. The nonrenal contribution to carboplatin clearance was relatively constant at 25 ml/min, and thus the AUC of carboplatin varied solely as a function of renal clearance, reflected in the measured GFR values. The total carboplatin dose could then be measured in milligrams. Total dose (mg) = target AUC (mg/ml min) (GFR [ml/min] + 25) The value of 25 ml/min is a constant that used to correct for the nonrenal clearance of irreversibly tissue-bound carboplatin [17]. By targeting a carboplatin AUC, rather than empirically dosing according to BSA, doses of carboplatin can be individualized to a target AUC, which should be within the drug s therapeutic index. This is believed to fall within the range of AUCs of 5-7 in nonpretreated patients receiving single-agent carboplatin and 3-5 in heavily pretreated patients or those receiving concomitant myelosuppressive agents, although the ideal targeted AUC determination would be based on studies exploring a relationship with tumor response and toxicity [23]. Much of the work on target AUC has been done on ovarian cancer and would be different for other cancers. However, if one knows that the total dose of carboplatin is equal to the AUC [creatinine clearance 25], this equation should theoretically allow the AUC to be determined for any cancer. However, at AUC values >5-7, there may be no increase in carboplatin efficacy, despite the occurrence of greater thrombocytopenia, which is the case in ovarian cancer [23]. For example, patients who have a BSA of 1.7 m 2 and are dosed empirically might experience a wide range of AUCs (AUC 3-11.1), depending on their GFR (Table 1). However, since the Calvert formula is based on the GFR value, a specific AUC can be targeted for specific cancers. Thus, recommended target AUC values are 5 mg/ml min when carboplatin is used in combination, 6 mg/ml min when it is used as a single agent in previously treated patients, and 7 mg/ml min when it is used as a single agent in previously untreated patients because they are associated with manageable levels of hematologic toxicity [4, 17, 18, 22]. A parallel rise in hematologic toxicity with an increasing carboplatin AUC as evidenced by a reduced platelet count two weeks after carboplatin administration has been shown empirically by Calvert (Table 2A) [17]. Similarly, Canetta observed an inverse relationship between myelosuppression and GFR as the GFR decreases, the incidence of WHO grade 3-4 neutropenia and thrombocytopenia induced by carboplatin increases (Table 2B) [22]. The relationship between the carboplatin AUC during the first course of chemotherapy and the degree of myelosuppression also has been retrospectively evaluated in 450 chemotherapy-naive and 578 previously treated ovarian cancer patients who were given single-agent carboplatin [23]. There was a Table 1. Comparison of formulaic and empiric dosing as exemplified by two patients with a body surface area of 1.7 m 2 and with different glomerular filtration rates Patient 1 Patient 2 Empiric Formulaic (AUC) Empiric Formulaic (AUC) Target dose 360 mg/m 2 AUC = 5 360 mg/m 2 AUC = 6 Glomerular filtration rate (ml/min) 30 30 120 120 Dose administered (mg) 612 275 612 870 Carboplatin plasma concentration-versus-time curve (AUC) (mg/ml min) 11 5 4 6

18 Optimizing Carboplatin for Solid Tumors Table 2. Relationship between myelosuppression, glomerular filtration rate, and carboplatin AUC A. Relationship between thrombocytopenia and carboplatin AUC, two weeks after carboplatin treatment (adapted from [17]) Observed AUC Median platelet % of pretreatment (mg/ml/h) count ( 10 9 /l) platelet count 4 6 103 27 6 8 113 18 >8 51 15 B. Relationship between glomerular filtration rate and WHO grade 3-4 myelosuppression in patients receiving 400 mg/m 2 of carboplatin (adapted from [22]) Glomerular filtration Patients with Patients with rate (ml/min) neutropenia (%) thrombocytopenia (%) 120 0 3 100 119 4 11 80 99 8 11 60 79 21 25 40 59 32 30 <40 40 50 significant correlation between the carboplatin AUC and the degree of thrombocytopenia and leukopenia. Regression analysis also indicated that increases in the exposure to carboplatin to an AUC of 5 to 7 were associated with significant improvements in the objective response rate. A similar relationship between AUC and response rate was demonstrated for single-agent carboplatin in patients with germ cell tumors. In a phase I/II study, 88% of those who received an AUC above 6.5 achieved a durable complete remission compared with 20% of those who experienced a carboplatin AUC below 6.5 [24]. Although the associations between tumor response, median survival, time to progression, and AUC are not as definitive as the relationship between toxicity and AUC, the ability to preselect an AUC based on GFR confers several benefits: Avoidance of subtherapeutic dosing in patients with high renal clearance values [17]; Avoidance of overdosing in patients with impaired renal function, especially older patients with reduced bone marrow reserve [17]; Usefulness regardless of previous or concurrent therapy [25], and High association between target AUC values and manageable thrombocytopenia [4, 17, 20, 23, 26]. One question of great concern is whether the AUC for carboplatin is affected by concurrent administration of other agents. In most cases, it does not appear to be. For example, in studies combining carboplatin with cyclophosphamide [4, 25], with etoposide [9, 27], or with methotrexate and vinblastine [28], the AUC of carboplatin was identical to its single-agent AUC. However, the addition of other agents can alter the degree of myelosuppression. Leukopenia and thrombocytopenia at a given AUC of carboplatin are greater when carboplatin is used alone [29, 30]. When carboplatin is combined with paclitaxel, paclitaxel appears to exert a protective effect on platelets, and severe thrombocytopenia is reduced to levels considerably below those for single agent carboplatin at the same AUC. This positive interaction occurs without altering the pharmacokinetics of either drug. Although the mechanism of this platelet-sparing effect is unknown, it increases commensurate with the paclitaxel dose [31-38]. Measuring GFR by Creatinine Clearance The most accurate methods for determining the GFR use radioisotopes. Perhaps the most common direct measurement of GFR in the United Kingdom is obtained by i.v. injection of chromium-tagged ethylenediaminetetraacetic acid ( 51 Cr-EDTA), a chemically stable compound that is eliminated only by glomerular filtration. However, the need for a nuclear medicine facility, the expense of this technique, and the exposure of the patient to radiation limit the utility of this approach for routine practice [26]. Because creatinine is eliminated primarily through glomerular filtration, creatinine clearance (CrCl) can be determined from steady-state serum creatinine (Scr) levels and substituted for the GFR in the Calvert formula, Alternatively, the AUC can be derived from a simple dosing chart based on the Calvert formula (Table 3). Four methods have been developed to estimate CrCl. The urine-collection method, although less invasive than isotope injection, also has its drawbacks. Either a timed urine collection or a 24-h complete urine collection can be time consuming to collect, and are typically incomplete, yielding inaccurate estimates of CrCl and renal function [26]. Nevertheless, CrCl may be calculated from a 24-h total urine collection using the following equation: CrCl = Volume of urine after 24 h (ml) urine creatinine concentration (µm) [39] Serum creatinine concentration (µm) 1,440 (min) Another equation for estimating CrCl was developed by Jelliffe as a simple bedside method that does not require urine collections. It includes an adjustment for sex because the lower muscle mass in women produces less creatinine than in men. For women, a value of 90% of the predicted CrCl for men is used. Additionally, including an adjustment for BSA did not produce a major change in CrCl estimates. This implies that even though BSA is important for dosing many drugs, it is not

Alberts, Dorr 19 Table 3. Dose chart based on the Calvert formula: carboplatin dose (mg) = target AUC (GFR + 25) in mg/ml/h Creatinine clearance (ml/min) Dose for AUC = 5 a (mg) Dose for AUC = 7 b (mg) 20 225 315 30 275 385 40 325 455 50 375 525 60 425 595 70 475 665 80 525 735 90 575 805 100 625 875 110 675 945 120 725 1,015 130 775 1,085 140 825 1,155 150 875 1,225 160 925 1,295 170 975 1,365 a AUC recommended in combination with other myelosuppressive agents. b AUC recommended for single-agent therapy in previously untreated patients. the primary determinant for renally eliminated drugs [40]. The Jelliffe equation is: CrCl (ml/min/1.73 m 2 ) = 98-0.8(Age - 20) Scr Another commonly used CrCl estimation method uses age, weight, and sex. Cockcroft and Gault devised this method shortly after Jelliffe, in which the CrCl should be reduced by 15% for women [41]: CrCl = (140 - Age ) Wt (kg) 72 Scr (mg/100 ml) Chatelut et al. more recently developed a fourth method for estimating the clearance of carboplatin which mathematically integrates several patient variables into the calculation [42]: Cl carbo = 0.134 Wt + [218 Wt (1-0.00457 Age) (1-0.314 sex)]/creatinine expressed in µm (with weight in kg, age in years, and sex = 0 if male and sex = 1 if female) Scr (µm) Importantly, this method has been prospectively validated in a small patient population receiving carboplatin [42]. Several studies comparing the accuracy of these four methods of estimating CrCl have yielded equivocal results. In a comparison of the Jelliffe and the Cockcroft-Gault equations, the Cockcroft-Gault equation was found to be better suited for nonelderly patients with normal Scr values, while the Jelliffe equation was better for men with elevated Scr values (>1.5 mg/dl) [39]. The Cockcroft-Gault estimation of CrCl also compared well with the GFR determined by diethylenetriamine pentaacetic acid (DPTA) [43]. Finally, a comparison of 24-h urine collection, the Cockcroft-Gault equation, and the Chatelut equation demonstrated the latter to be both precise and unbiased [36]. In all likelihood, all four methods produce acceptable results when performed correctly, although recent studies indicate that the Chatelut equation may be the most accurate [44-48]. Single-sample assays have also been developed for determining the carboplatin AUC, primarily from studies using retrospective analyses [49-51]. Toxicity One of the driving forces behind developing cisplatin analogs was to mitigate the extensive toxicities of cisplatin while preserving its antitumor efficacy. For the treatment of many solid tumors, carboplatin has satisfied this goal. Carboplatin causes significantly less nephrotoxicity than cisplatin, eliminating the need for hydration during administration, except in patients with impaired renal function or those receiving dose-intensive carboplatin (>800 mg/m 2 ) [52-55]. Whereas renal tubular damage is the acute dose-limiting toxicity of cisplatin, the cumulative dose-limiting effect of cisplatin is peripheral (sensory) neuropathy. These peripheral sensory neuropathies manifest as hearing loss and foot and hand numbness, eventually leading to an inability to hear high frequencies or an inability to walk. This is virtually absent with carboplatin. At conventional doses (360 mg/m 2 ) carboplatin is associated with a low incidence of hearing loss, and it is considerably less ototoxic than cisplatin [5, 55-59]. Cisplatin is one of the most emetogenic chemotherapeutic agents, whereas carboplatin is considerably less emetogenic. Carboplatin-induced dose-related nausea or vomiting is also of shorter duration and is highly manageable with standard antiemetic therapy [5, 55]. This lessens the need for extensive antiemetic drug combination therapy with carboplatin. When combined with the lack of need for prophylactic hydration and diuretics, there is much greater cost-effectiveness with carboplatin. In general, carboplatin-induced emesis is completely prevented by combining a serotonin-3 receptor antagonist with a glucocorticoid such as dexamethasone. For example, a study to develop a cost-effective antiemetic regimen for carboplatin demonstrated that when low-dose granisetron (0.5 mg) was combined with dexamethasone, emesis was completely or mostly controlled in 96% of patients at a reasonable cost [60]. Hematologic toxicity is the dose-limiting toxicity of conventional carboplatin therapy, with thrombocytopenia being more severe than leukopenia or anemia. Although carboplatininduced myelosuppression appears to be reversible, its severity may be cumulative with successive cycles. Platelet nadirs usually occur between 14 and 28 days after administration, and recovery ensues 7-10 days thereafter [5, 55, 61, 62]. Because

20 Optimizing Carboplatin for Solid Tumors of the relationship between the carboplatin AUC, the degree of myelotoxicity, and the therapeutic activity of carboplatin, platelet- and neutrophil-count nadirs can be used to determine whether the dosage (or targeted AUC) of single-agent carboplatin is appropriate. The platelet count nadir should lie between 50,000/µl and 100,000/µl, and the neutrophil count nadir should lie between 500/µl and 1,000/µl after carboplatin treatment. If the nadirs are above these levels, the carboplatin dose should be escalated during subsequent cycles, whereas if the nadirs are below these levels, the carboplatin dose should be reduced by 25% [12]. When high-dose carboplatin therapy (>1,200 mg/m 2 ) is given, 90% of patients experience WHO grade 4 thrombocytopenia and neutropenia. This often delays the administration of repeated cycles and thereby reduces dose intensity [54, 55]. Because the low nonhematologic toxicity profile of carboplatin is well suited for dose-intensive therapy, numerous trials have investigated the use of natural and synthetic hematopoietic agents erythropoietin, the cytokines, amifostine, and the colony-stimulating factors to mitigate the myelosuppressive effects of carboplatin [56, 63-74]. Of these, erythropoietin, interleukin 1 alpha (IL-1α), IL-6, and amifostine have been shown to reduce the leukopenia and granulocytopenia associated with carboplatin. Except for the sulfhydryl-based cytoprotectant amifostine [75], these growth factors have little effect on the thrombocytopenia. In the randomized study of Budd et al. [75], administration of amifostine markedly reduced cumulative carboplatin-induced thrombocytopenia and preserved carboplatin dose intensity. The probable mechanism of amifostine s beneficial interaction with carboplatin involves a primary stimulation of primitive bone marrow progenitor cell growth [76, 77]. Growth factors are effective in limiting thrombocytopenia after carboplatin therapy when they are used to augment the collection of peripheral blood progenitor cells (PBPCs), and their use also may reduce the overall cost of high-dose therapy by lessening the need for blood cell support [78]. In contrast, thanks to its natural platelet-sparing ability when used in concert with carboplatin, paclitaxel significantly reduces the thrombocytopenic effects of carboplatin. For example, in a study of ovarian cancer patients, ten Bokkel Huinink and colleagues found that as the dose of carboplatin was escalated from 300 mg/m 2 to 600 mg/m 2, higher doses of paclitaxel yielded higher platelet nadirs [32]. This same effect was also found when Siddiqui and colleagues treated ovarian cancer patients with increasing doses of paclitaxel plus a fixed dose of carboplatin (AUC = 7 mg/ml min) [33]. Moreover, the administration of high-dose carboplatin plus a 3-h infusion rather than a 24-h infusion of paclitaxel may eliminate the need for concurrent G-CSF to reduce neutropenia [79, 80]. Based on phase II study results, the combination of paclitaxel plus carboplatin appears highly active in patients with advanced ovarian cancer, resulting in an overall response rate of 75% and only mild myelotoxicity [81]. CARBOPLATIN TREATMENT OF SOLID TUMORS Non-Small Cell Lung Cancer Metastatic Non-Small Cell Lung Cancer In patients with Stages IIIB (with pleural effusion) or IV (metastatic) non-small cell lung cancer (NSCLC), curative therapy is not available, and providing palliation with chemotherapy and extending survival continue to be major challenges. One reason is that in NSCLC, an improved therapeutic response has not always been accompanied by an improved outcome in this case, longer survival. Thus, the results of randomized clinical trials in this population of NSCLC patients have been difficult to interpret because the response rates are low and do not translate into longer survival [2]. An equally important consideration in patients with advanced disease is the quality of survival, since chemotherapeutic agents are not curative but their toxicity might diminish the quality of life without adding any survival advantage. Thus, the low toxicity profile of carboplatin renders it a promising treatment for patients with metastatic disease, especially when carboplatin is optimally dosed. Indeed, the benefits of single-agent carboplatin were borne out in a phase III clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG) in which 699 patients with Stage IV NSCLC were randomized to receive either single-agent carboplatin or iproplatin, followed by mitomycin/vinblastine/cisplatin (MVP) at time of disease progression, or three other cisplatin-based combination regimens, MVP, VP, or MVP alternated with cyclophosphamide/doxorubicin/methotrexate/procarbazine (CAMP) [2, 82-85]. Despite the low response rate of 9% with single-agent carboplatin treatment compared with the response rates with the combination regimens (20% with MVP, 13% with VP, and 13% with MVP/CAMP), patients treated with carboplatin had significantly longer median durations of survival (31 weeks, p = 0.008), longer times to disease progression (p = 0.01), and fewer adverse effects (p < 0.0001). Moreover, as shown in Table 4, the response rate was inversely related to the duration of survival, since the drug combinations with the highest response rates yielded the shortest mean survivals. In the carboplatin arm, crossover to MVP after disease progression did not significantly affect either survival duration or time to progression, since patients who received carboplatin without subsequent MVP had a mean survival of 29.3 weeks compared with 22.7 weeks for those who received MVP as primary treatment. Likewise, the median time to progression for the whole study population

Alberts, Dorr 21 Table 4. Median survival and response rate in NSCLC after chemotherapy in the ECOG trial EST 1583 [84] Regimen Median survival (wk) Response rate (%) MVP 23 20 VP 25 13 MVP/CAMP 25 13 Carboplatin/MVP 32 9 Iproplatin/MVP 26 6 MVP = Mitomycin/vinblastine/cisplatin; VP = vinblastine/cisplatin; CAMP = cyclophosphamide/doxorubicin/methotrexate/procarbazine; NSCLC = non-small cell lung cancer. was 23.6 weeks, compared with 29.0 weeks for patients who received carboplatin. The reason for the superior outcomes is unclear, but the lower toxicity of carboplatin may contribute to improved survival. The European Organization for Research and Treatment of Cancer (EORTC) compared the efficacy of etoposide plus carboplatin or cisplatin in a phase III trial of 239 patients with advanced-stage NSCLC [2, 83, 86-88]. Although the cisplatin regimen tended to have a higher response rate objective response rate of 16% for carboplatin/etoposide versus 27% for cisplatin/etoposide (p = 0.07) the survival durations were similar (i.e., 27 weeks versus 30, respectively) and the carboplatin/etoposide regimen was significantly less toxic. This led to fewer toxic deaths and a lower incidence and severity of leukopenia, ototoxicity, and nephrotoxicity for the carboplatin/etoposide combination. When combined with etoposide, carboplatin appeared to have activity similar to that of cisplatin in metastatic NSCLC and was better tolerated. Carboplatin plus etoposide was also studied in several phase II trials (Table 5) [71, 89-91], highlighting the question of which agent(s) may have superior activity when added to carboplatin in two-drug combinations. Various trials have explored different drug combinations [92-95]. A number of dose-escalation studies are listed in Table 5 [96-98]. For both response rate and survival, the combination of paclitaxel and carboplatin appears to be as active as any other platinum-based regimen for metastatic NSCLC, yet toxicity is manageable. Locally Advanced Unresectable NSCLC Historically, the standard of care for Stage IIIA and IIIB unresectable NSCLC has been radiotherapy, although it results in a median survival of only about 10 months. In recent years, cisplatin-based chemotherapy has been added to radiotherapy, extending the median survival by a few months [82]. The dose and fractionation schedules for radiation have also shifted from continuous or split-course therapy, which does not enhance long-term survival, to hyperfractionation, whereby a small dose of radiation is delivered continuously a few times per day up to standard cumulative dose limits [99]. Another strategy for treating nonresectable NSCLC disease is neoadjuvant therapy, in which patients are initially treated with chemotherapy (with or without radiotherapy) to stem Table 5. Carboplatin-based trials in patients with metastatic NSCLC Reference Number of patients Treatment Response rate (%) Median survival Bonomi et al. [84] 699 MVP 20 23 wk VP 13 25 wk MVP/CAMP 13 25 wk Carboplatin 9 32 wk Iproplatin 6 26 wk Sculier et al. [96] 121 Cisplatin 23 26 wk Cisplatin/carboplatin 22 28 wk Klastersky et al. [87] 228 Cisplatin/etoposide 27 30 wk Carboplatin/etoposide 16 27 wk Schiller [89] 25 Cisplatin/vinblastine/amifostine 64 17 mo Frasci et al. [71] 39 Carboplatin/oral etoposide/g-csf 38.5 * 10 mo * Hsieh et al. [91] 33 ICE 27.3 8 mo Langer et al. [93 95] 53 Paclitaxel/carboplatin/G-CSF 62 12.5 mo Belani et al. [97] 26 Paclitaxel/carboplatin/G-CSF 50 Not reported Vafai et al. [98] 44 Paclitaxel/carboplatin 61 10 NSCLC = non-small cell lung cancer; MVP = mitomycin/vinblastine/cisplatin; VP = vinblastine/cisplatin; CAMP = cyclophosphamide/doxorubicin/methotrexate/procarbazine; G-CSF = granulocyte colony-stimulating factor; ICE = ifosfamide/mesna/carboplatin/etoposide; AUC = area under the concentration-versus-time curve. * There was a 66% response rate with an AUC of 8 and a 16.5-month median survival rate with an AUC of 4 to 8.1.

22 Optimizing Carboplatin for Solid Tumors local growth and make subsequent surgical resection possible. This is followed by an intensive radiotherapy program including prophylactic central nervous system irradiation. In clinical trials, neoadjuvant therapy has reduced tumor burden sufficiently to allow surgical resection in approximately 50% of patients [82]. Like cisplatin, carboplatin is an experimental radiosensitizer and has been incorporated as such into recent radiotherapy trials. In a phase III study, 100 patients were randomized to receive either conventional radiotherapy (60 Gy in six weeks), accelerated radiotherapy (60 Gy in three weeks), conventional radiotherapy plus carboplatin (350 mg/m 2 during weeks 1 and 5 of radiotherapy), or accelerated radiotherapy plus carboplatin (350 mg/m 2 during week 1 of radiotherapy) [100]. Although the toxicity in both radiotherapy/chemotherapy arms was considerably worse than with radiotherapy alone more severe neutropenia, thrombocytopenia, and esophagitis the median overall survival duration for the study was relatively long at 17.1 months [100]. Another randomized trial was conducted in 169 patients using hyperfractionated radiotherapy with carboplatin plus etoposide [101]. Patients were randomized to receive either hyperfractionated radiation alone consisting of 64.8 Gy in hyperfractionated doses of 1.2 Gy twice daily (group 1), hyperfractionated radiation plus 100 mg carboplatin on days 1 and 2 and 100 mg etoposide on days 1-3 weekly during radiotherapy (group 2), or hyperfractionated radiation plus 200 mg carboplatin on days 1 and 2 and 100 mg etoposide on days 1-5 of weeks 1, 3, and 5 during radiotherapy (group 3). Compared with radiation alone (group 1), concomitant radiotherapy and chemotherapy (group 2) produced a significantly longer median survival of 18 months (p = 0.0027). This compares with 8 months for radiation alone (group 1) and only 13 months for simultaneous plus sequential chemotherapy with radiation (group 3). Patients in group 2 also had a slightly higher local recurrence-free survival than patients in group 1, although the concomitant treatment was somewhat more toxic than radiation therapy alone. In a phase II randomized trial, cisplatin (60 mg/m 2 ) was compared with carboplatin (300 mg/m 2 ), each in combination with etoposide (100 mg/m 2 on days 1-3) and epirubicin (50 mg/m 2 on day 1). Four courses of chemotherapy were alternated with three cycles of local irradiation (15 Gy per course, delivered in five consecutive daily fractions) [102]. Among the 53 patients, the response rates for the carboplatin (59%) and cisplatin (62%) arms were similar, but those who received carboplatin had less severe leukopenia and emesis. Thus, carboplatin alone or in combination with etoposide, when administered concurrently with radiotherapy, appears to be a promising strategy in the treatment of locally advanced unresectable NSCLC. Given that paclitaxel is more active than etoposide in NSCLC and is also an experimental radiosensitizer [103], the efficacy of paclitaxel plus carboplatin also should be evaluated in this population. In fact, several feasibility studies recently established that carboplatin plus a three-hour infusion of paclitaxel and radiotherapy is highly active in terms of response rates, although it is still too early to determine whether including carboplatin provides an added survival benefit [104-109]. Resectable NSCLC In the rare patients diagnosed with Stage I disease, surgical resection alone is curative in 60%-70% of patients, and radiation is reserved for those who do not undergo surgery; chemotherapy does not confer any advantage. For those with Stages II or IIIA NSCLC, the effectiveness of radiation is questionable because even though radiation eliminates local recurrence, it has little effect on distant recurrence or survival. On the other hand, adjuvant chemotherapy has been shown to increase disease-free survival by approximately seven months and is particularly warranted in patients who have undergone incomplete resection. Evidence of the efficacy of neoadjuvant therapy for reducing the size of the primary tumor, enhancing the resectability rate, and eliminating systemic micrometastases is more preliminary, and more trials are currently under way to test this [82, 99, 110, 111]. Few studies have evaluated the role of carboplatin in Stages I-IIIA NSCLC, but in a phase II trial, carboplatinbased neoadjuvant therapy effectively reduced tumor size, allowing surgery in more than 50% of patients whose tumors were previously only marginally resectable [112, 113]. The extremely promising results with paclitaxel plus carboplatin in advanced disease support further evaluation of this combination in both the neoadjuvant and adjuvant setting. Small Cell Lung Cancer Small-cell lung cancer (SCLC) is an aggressive disease characterized by a rapid tumor growth rate and early dissemination. When treated by surgery alone or with radiation, the two-year survival of patients with limited disease is less than 10% and the median survival is approximately 12 months [114]. The prognosis for patients with extensive disease is even more dismal, with a median survival of less than three months [114-117]. A combined modality approach that incorporates chemotherapy has stretched the survival time, although for extensive disease, survival has not been prolonged beyond six to nine months [115, 116]. Chemotherapy is the cornerstone of treatment for limited SCLC, but it is still far from ideal, since most patients relapse and die within two years of diagnosis [2, 118, 119]. Some of the newer agents, including carboplatin, when used alone or

Alberts, Dorr 23 in combination, have considerably improved outcomes in patients with limited disease [2]. Carboplatin is one of the most active single agents for SCLC, yielding objective response rates of 25%-35% [82, 118, 119]. Its high activity provided the rationale for its inclusion in combination chemotherapy regimens, and it has been studied extensively in combination with etoposide [120]. Table 6 lists various studies of carboplatin plus etoposide. Carboplatin and etoposide also form the foundation for other chemotherapeutic combinations (e.g., ifosfamide, vincristine, epirubicin) [124, 125], but modest gains in survival appear to be offset by increased morbidity and mortality [125]. Although the three- and four-drug regimens have produced responses, they have not been directly compared in the same trial [82, 126], and thus the efficacy of increasing the number of drugs is not established [127]. Approximately two-thirds of all patients with SCLC have extensive disease. Unfortunately, this group is incurable with current therapy, and, therefore, the therapeutic goal is palliation with the possibility of a modest survival benefit. Numerous studies have shown that chemotherapy, with or without radiation, can temporarily ameliorate the predominant symptoms of extensive SCLC [127]. Etoposide is one of the drugs most commonly combined with carboplatin for patients with extensive disease (Table 6) [117]. Response rates can range from 59%-88%, and the median survival varies from 4.6 to 10.4 months [128-131]. In one randomized trial that compared carboplatin with cisplatin, both in combination with etoposide, the two groups had equivalent complete responses and median survival durations, although the carboplatin-containing regimen was considerably less toxic [130]. Table 6. Carboplatin-based combination chemotherapy trials in patients with SCLC Reference Treatment (mg/m 2 ) Number of patients Response rate (%) Median survival Carboplatin versus cisplatin Evans et al. [130] Carboplatin (300)/etoposide (100) ED = 32 56 34.7 wk Kosmidis et al. [121] Carboplatin (300) or LD = 82 49 carboplatin LD = 14.1 mo cisplatin (50) days 1-2, 29 cisplatin ED = 10.4 mo plus etoposide (100) days 1-3 ED = 61 48 carboplatin and radiation 40 cisplatin Carboplatin plus etoposide Ellis et al. [128] Carboplatin (600)/ LD = 28 93 9 mo etoposide (120) days 1-3 ED = 26 81 6 mo Pfeiffer et al. [122] Carboplatin (300)/ LD = 44 89 15 mo etoposide (240 orally) days 1 3 ED = 62 53 8.5 mo and radiation Smith et al. [123] Carboplatin (300)/ LD = 28 82 9.5 mo etoposide (100) days 1 3 and radiation ED = 24 88 9.5 mo Viren et al. [129] Carboplatin (450)/ ED = 56 59 4.6 mo etoposide (100) days 1 3 3- and 4-drug regimens Gridelli et al. [126] Carboplatin (300), etoposide LD = 23 96.5 14 mo (100) days 1-3, epirubicin (50) day 1 ED = 49 83.6 10 mo Joss et al. [134] Carboplatin (80), teniposide (80), ED = 59 carb/ten 29 147 days versus cisplatin (30) days 1-3, adriamycin (40), standard 65 260 days etoposide (100) days 1-3, cyclophosphamide (1,000), methotrexate (10) days 14 and 17, vincristine (1.4) day 1, lomustine (40) Prendiville et al. [125] Carboplatin (300), etoposide LD = 73 81 16.6 mo (120) days 1-2 and (240 orally) day 3, ED = 14 overall 13.4 mo ifosfamide (5), and mesna, vincristine (1.0) midcycle, and radiation Wolff et al. [131] Ifosfamide (5,000), mesna, ED = 35 83 8.8 mo carboplatin (300), etoposide (50 orally) days 1-21 LD = limited disease; ED = extensive disease.

24 Optimizing Carboplatin for Solid Tumors In an effort to improve the median survival, three- and four-drug regimens based on carboplatin/etoposide have also been tested [132, 133]. However, the optimal balance between response, toxicity, and subjective well-being requires further study [134]. Ovarian Cancer Carboplatin is one of the key agents in first-line therapy for advanced ovarian cancer. In fact, during the last few years, two separate groups have endorsed its use for this indication. A consensus development conference on ovarian cancer held in 1994 by the National Institutes of Health confirmed the important activity of combination chemotherapy with carboplatin and cyclophosphamide, both for its effectiveness and its acceptable toxicity [135, 136]. The previous year, an international group of leading researchers on chemotherapy for ovarian cancer issued a consensus statement acknowledging that carboplatin-based combinations are the appropriate choice in patients with suboptimal Stage III and IV ovarian cancer [137]. Another group, the Advanced Ovarian Cancer Trialists Group initiated by the British Medical Research Council, which conducted a meta-analysis of 45 randomized clinical trials that included 8,139 ovarian cancer patients, came to a similar conclusion [138-140]. Carboplatin also offers cost advantages over cisplatin in the overall cost of delivering care. Because the second-generation analog carboplatin is more expensive, a comparative cost analysis study was performed on retrospective information derived from the medical records of 94 ovarian cancer patients included in a phase III clinical trial comparing carboplatin and cisplatin plus cyclophosphamide conducted by the Southwest Oncology Group (SWOG). The results revealed that in the long run, carboplatin is significantly more cost-effective than cisplatin [141]. Because of its greater toxicity, cisplatin incurred higher administration costs (e.g., hospitalization, hydration, antiemetics) and midcourse toxicity-related hospitalizations that together amounted to $2,882.40 for six cycles of chemotherapy compared with $1,074.53 for carboplatin. This $1,807.87 toxicity-related cost differential exceeds the $1,254 difference in acquisition costs (in 1988) for the two drugs $4,140 for carboplatin versus $2,886 for cisplatin such that carboplatin may cost about $550 less per patient. Some of the earlier randomized phase III trials that compared single-agent carboplatin and cisplatin in ovarian cancer are shown in Table 7 [58, 142-145]. Together they demonstrate that there is no significant difference between the two drugs in overall response rate, complete response rate, or median survival. A meta-analysis of three trials that compared carboplatin 400 mg/m 2 with cisplatin 100 mg/m 2, comprising a total of 385 patients, also demonstrated no significant difference in the effectiveness of the two agents: complete response rates of 23% for carboplatin versus 22% for cisplatin, median durations of complete response of 30 months versus 24 months, median time to progression of 14 months for both groups, and median survival times of 22 months versus 23 months [146-148]. On the other hand, the two agents had markedly different toxicity profiles (Table 8). Although myelosuppression occurred more frequently in patients treated with carboplatin, the incidence of nonhematologic toxicities peripheral neuropathy, ototoxicity, renal impairment, and emesis were considerably lower with carboplatin than with cisplatin [148]. Several phase III clinical trials in ovarian cancer have compared carboplatin and cisplatin in combination with other chemotherapeutic agents (Table 7). The SWOG and the National Cancer Institute of Canada (NCIC) conducted two pivotal trials comparing carboplatin and cisplatin plus cyclophosphamide, which together led to the general acceptance of carboplatin/cyclophosphamide as standard therapy for patients with advanced ovarian cancer [147, 148]. In the SWOG study (SWOG-8412), 291 patients with Stage III or IV disease were randomized to receive six courses of chemotherapy with cyclophosphamide (600 mg/m 2 ) plus either carboplatin (300 mg/m 2 ) or cisplatin (100 mg/m 2 ) [149-151]. In the NCIC study, which was almost identical in design, 417 patients with optimal or suboptimal advanced ovarian cancer were randomized to receive six cycles of chemotherapy with cyclophosphamide (600 mg/m 2 ) plus either carboplatin (300 mg/m 2 ) or cisplatin (75 mg/m 2 ) [152]. Both studies demonstrated that carboplatin/cyclophosphamide and cisplatin/ cyclophosphamide were equally effective with respect to median survival, overall response rate, and time to progression. Both studies also highlighted the differences in toxicity between the two regimens (Table 9). Treatment with cisplatin/cyclophosphamide generally resulted in more severe platinum-related side effects, particularly renal impairment, neuropathy, and ototoxicity. On the other hand, patients treated with carboplatin/cyclophosphamide were more likely to experience hematologic toxicity, especially thrombocytopenia, infection, and hemorrhage [151, 153]. Several other phase III trials have also compared cisplatin and carboplatin in ovarian cancer [153-156]. New chemotherapeutic strategies also have been developed that include paclitaxel, since the Gynecologic Oncology Group (GOG) showed that cisplatin/paclitaxel is significantly more effective than cisplatin/cyclophosphamide [157]. In a phase III trial conducted by the GOG (GOG-111), patients with advanced ovarian cancer who were treated with cisplatin/paclitaxel had a significantly greater complete response (54% versus 33%), longer median progression-free survival duration (18.0 months versus 12.9 months), and

Alberts, Dorr 25 Table 7. Phase III trials comparing carboplatin and cisplatin in ovarian cancer Reference Treatment (mg/m 2 ) Number of patients Response rate (%) Median survival Single-agent chemotherapy Adams et al. [142] Carboplatin (400) 40 CR 20, PR 48 >25 mo Cisplatin (100) 40 CR 15, PR 33 >18 mo Pecorelli et al. [143] Carboplatin (400) 82 CR 27, PR 31 >15 mo Mangioni et al. [144] Cisplatin (100) 81 CR 25, PR 47 >15 mo Wiltshaw et al. [58] Carboplatin (400) 40 CR 23, PR 30 16.4 mo Taylor et al. [145] Cisplatin (100) 50 CR 24, PR 40 16.4 mo Combination chemotherapy Anderson et al. [153] Carboplatin (300) 17 CR 41, PR 12 24 mo /cyclophosphamide Gurney et al. [154] Cisplatin (100) 14 CR 21, PR 57 19 mo /cyclophosphamide Iproplatin (240) 19 CR 21, PR 53 18 mo /cyclophosphamide Alberts et al. [148] Carboplatin (300) 61 CR 33, PR 33 23 mo /cyclophosphamide Hannigan et al. [149] Cisplatin (100) 62 CR 27, PR 29 17 mo /cyclophosphamide Swenerton et al. [152] Carboplatin (300) 71 CR 27, PR 32 110 wk /cyclophosphamide Cisplatin (75) 75 CR 36, PR 21 100 wk /cyclophosphamide Chiara et al. [155] Carboplatin (200) 76 CR 22, PR 43 23 mo /doxorubicin/cyclophosphamide Conte et al. [156] Cisplatin (50) 74 CR 36, PR 34 23 mo /doxorubicin/cyclophosphamide CR = Complete response (complete disappearance of all known disease); PR = partial response (50% or greater reduction of lesion mass). Table 8. Comparative toxicity of single-agent carboplatin versus cisplatin in patients with advanced ovarian cancer (adapted from [147]) Carboplatin Cisplatin % of patients with grade % of patients with grade Toxicity * 2 3 4 2 3 4 p value Hematologic Thrombocytopenia 13 7 2 0 1 0 0.001 Leukopenia 27 3 0 18 0 0 0.001 Granulocytopenia 26 8 0 15 3 0 0.001 Anemia 25 5 2 16 1 1 0.5 % of total patients % of total patients Nonhematologic Renal dysfunction (<60 ml/min creatinine clearance) 25 44 0.001 Peripheral neuropathy 1 17 0.001 Ototoxicity 2 13 0.001 Emesis (grades 2 and 3) 53 69 0.001 * Analysis of toxicity used World Health Organization criteria whenever applicable and was limited to myelosuppression, emesis, neurologic manifestations, and alterations in kidney and liver function tests in first-line chemotherapy.

26 Optimizing Carboplatin for Solid Tumors Table 9. Comparative toxicity of carboplatin/cyclophosphamide versus cisplatin/cyclophosphamide in randomized studies of patients with advanced ovarian cancer Cisplatin Carboplatin % of patients with grade % of patients with grade Toxicity 2 3 4 2 3 4 A. Southwest Oncology Group Study 8412 [150] Hematologic Thrombocytopenia 9 6 2 21 17 7 Leukopenia 24 56 10 19 66 8 Granulocytopenia 20 24 32 28 27 28 Anemia 46 3 0 30 3 0 Nonhematologic Neurotoxicity 5 1 0 3 1 0 Renal 15 1 0 2 0 0 Hearing loss 5 2 0 0 0 0 Tinnitus 6 1 0 1 0 0 B. National Cancer Institute of Canada Study [152] Hematologic Thrombocytopenia 16 6 0 13 25 57 Granulocytopenia 12 36 42 28 27 28 Anemia 26 29 0 18 42 0 Infection 0 0 0 0 2 1 Hemorrhage 0 0 0 0.5 0.5 0 Nonhematologic Neurotoxicity 15 1 0 2 0 0 Renal 2 0 0 1 0 0 longer median survival duration (37.5 months versus 24.4 months) than patients treated with cisplatin/cyclophosphamide (Table 10) [157, 158]. As a result, cisplatin/paclitaxel has replaced cisplatin/cyclophosphamide as standard therapy for advanced ovarian cancer [158-160]. Unfortunately, the neurotoxicity of combination therapy with cisplatin and paclitaxel can be unacceptably high. This was particularly evident in a recent study of paclitaxel 175 mg/m 2 (3-h infusion) plus cisplatin 75 mg/m 2, in which 16 (42%) of the 38 patients with gynecologic malignancies experienced grade 2 or higher peripheral neuropathy [161, 162]. This contrasts with the 13% incidence of grade 2 or higher peripheral neuropathy in GOG-111. As a result, studies are now under way to compare the effectiveness and toxicity of carboplatin/paclitaxel with cisplatin/paclitaxel. An initial phase I/II dose-intensification study by the GOG showed that the maximum tolerated dose (MTD) of carboplatin, when used with paclitaxel, a targeted AUC of 7.5, and the MTD of paclitaxel is 175 mg/m 2 [79, 81, 163-165]. Among the 24 study participants with measurable disease, the overall response rate was 75%, the complete response rate was 67%, and the median survival time has not yet been reached after >60 weeks [81]. Owing to its platelet-sparing effect on carboplatin (dosed to achieve an AUC of 7.5), the 3-h infusion of paclitaxel (175 Table 10. Clinical response and survival for Gynecologic Oncology Group (GOG) 111 [157] in patients with advanced ovarian cancer Paclitaxel/ Cyclophosphamide/ p value Cisplatin Cisplatin Overall response (%) 77 64 0.025 Complete response (%) 54 33 0.02 Median progression-free survival (mo) 18.0 12.9 0.0002 Median survival (mo) 37.5 24.4 0.0001 mg/m 2 ) does not require concomitant use of G-CSF [81]. This regimen is also useful in the outpatient setting because of the ease of administration of the 3-h infusion [81, 166]. As the current platinum-based regimen of choice, paclitaxel plus carboplatin holds great promise in the treatment of ovarian cancer. A phase III study now being conducted by the GOG (GOG-158) is designed to compare the effectiveness of cisplatin or carboplatin combined with paclitaxel. In an effort to minimize the toxicity of cisplatin/paclitaxel, paclitaxel is delivered over a 24-h period. Ovarian cancer patients with optimal Stage III disease are randomized to receive either paclitaxel 175 mg/m 2 (3 h) plus carboplatin (AUC = 7.5) or paclitaxel 135 mg/m 2 (24 h) plus cisplatin 75 mg/m 2. When the results of GOG-158 are mature, they

Alberts, Dorr 27 should provide a more complete picture of comparative outcomes with carboplatin/paclitaxel and cisplatin/paclitaxel. Other Solid Tumors Carboplatin has been used to treat several other solid tumors, both as a single agent and with other drugs, with varying degrees of success. Germ Cell Tumors In germ cell tumors, although carboplatin appears promising because of its low toxicity, recent data suggest that cisplatin is more effective [167]. In a randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in 598 patients with good-risk nonseminomatous germ cell tumors, combination therapy based on cisplatin was superior to that based on carboplatin [167]. Because the cure rate in men with metastatic germ cell tumors is 70%-80%, studies have focused on patients with good-risk disease those with the highest probability of a cure in a search for ways to diminish treatment toxicity without sacrificing cure rate [2]. In one large randomized trial, the effectiveness of carboplatin (500 mg/m 2 ) plus etoposide (100 mg/m 2 on days 1-5) was compared with that of cisplatin (20 mg/m 2 on days 1-5) plus etoposide in 265 patients [168, 169]. Despite equivalent complete response rates (88% for carboplatin versus 90% for cisplatin), responses were less durable in the carboplatin group, and event-free and relapsefree survival were inferior with the carboplatin combination. Although carboplatin may have been given at suboptimal doses because the AUC formula dosing was not used, cisplatin appears to be the platinum analog of choice for germ cell tumors [167]. Carboplatin also has been used as adjuvant therapy for germ cell tumors. In one study, a carboplatin AUC of 7 was administered along with radiation to 51 patients, and there were only two relapses during a five-year follow-up; both patients are currently in remission. Another 63 patients who received a single course of carboplatin more recently had no relapses during the two years of follow-up [24]. Two studies of high-dose carboplatin treatment of germ cell tumors also were recently completed. In the first study, 20 patients with relapsed germ cell tumors were given two cycles of ICE (ifosfamide 2 gm/m 2, carboplatin 400 mg/m 2, and etoposide 20 mg/kg, for three days, plus mesna) plus hematopoietic support (bone marrow or peripheral stem cells or both). After a median follow-up of 45 months, nine patients (45%) remained alive and disease-free. The regimen was well tolerated, which is particularly important for this poor-prognosis population [170]. In the second study, prognostic variables for response and survival were retrospectively determined in 310 patients with poor-prognosis germ cell tumors who were treated with high-dose chemotherapy plus hematopoietic support. Adverse prognostic factors included progressive disease before high-dose chemotherapy, mediastinal nonseminomatous primary tumor, disease refractory to conventionaldose cisplatin, and greater than 1,000 U/l of chorionic gonadotropin before high-dose chemotherapy [171]. Bladder Cancer In urothelial cancer, single-agent carboplatin produces only low response rates of approximately 15%. However, when combined with methotrexate, much higher response rates are attained (36%), toxicity is manageable, and median survival times exceed one year [172, 173]. Carboplatin at an AUC of 6 also has been combined with a 3-h infusion of paclitaxel in a phase I/II trial in patients with advanced bladder cancer [174]. The response rate was 50%, although the survival and response duration data are not yet mature. Thus, carboplatin-based combination chemotherapy especially with paclitaxel holds promise in the treatment of bladder cancer. Head and Neck Cancer Carboplatin also may have a role in treating head and neck cancer. The SWOG conducted a phase III trial comparing carboplatin/fluorouracil, cisplatin/fluorouracil, and methotrexate in the treatment of 277 patients with metastatic and recurrent head and neck cancer. The response rate for the carboplatin/fluorouracil was 21% versus 32% for cisplatin/fluorouracil and 10% for methotrexate. Nonetheless, all three regimens were equivalent with respect to median survival, which averaged five to six months [175, 176]. The concurrent use of chemotherapy and radiotherapy may improve outcomes in patients with head and neck cancer [177]. In a phase II trial in which single-agent carboplatin was administered with concurrent radiotherapy, a 66% complete remission rate and 98% overall response rate were achieved, and 53 of the 56 patients remained disease-free with a median survival of >25 months [178]. In a second phase II trial that compared single-agent carboplatin or cisplatin, each administered with radiotherapy, complete response rates and overall response rates were similar for both platinum agents, as were the estimated one- and two-year overall and disease-free survival rates. Clinical toxicities were significantly lower on the carboplatin arm. Carboplatin produced outcomes similar to those with cisplatin but with less toxicity, when combined with radiation therapy [179]. Paclitaxel also has shown activity in head and neck cancer and currently is being tested in combination with carboplatin [180]. In one phase II study, 11 patients were treated with radiotherapy plus paclitaxel (60 mg/m 2 ) and carboplatin (AUC = 2) [181]. Despite the high toxicity, 10 patients responded (91% response rate), five of whom had a complete

28 Optimizing Carboplatin for Solid Tumors response. Tolerance improved after carboplatin was reduced to AUC = 1. In another phase I dose-escalation study, the systemic exposure to carboplatin was held constant at AUC = 7.5, and a 3-h infusion of paclitaxel was increased from 150 mg/m 2 to 250 mg/m 2 in 21 patients [182]. The overall response rate was 62%, with 29% showing a complete response. Although the results are preliminary, carboplatin plus paclitaxel may prove advantageous in treating head and neck cancer. Breast Cancer Carboplatin also offers some advantages in the treatment of breast cancer. Although its use as a single agent with AUC dosing shows moderate activity in previously untreated patients, its inclusion with mitoxantrone, methotrexate, and vincristine (MIMOC) shows enhanced activity in advanced breast cancer. In a phase II trial of 51 patients with Stage IIIB and IV breast cancer, the objective response rate to the MIMOC combination was 60%, and the median time to disease progression was 12 months [183, 184]. Another active combination for advanced breast cancer is continuous infusion of carboplatin plus 5-fluorouracil and epirubicin. In a phase II study of 52 patients, the overall response rate was 81%, with a complete response rate of 17% in patients with metastatic disease and of 56% in patients with locally advanced disease [185]. Patients with metastatic breast cancer had a median survival time of 14 months, which is similar to outcomes for infusional therapy with cisplatin/fluorouracil/epirubicin [185], although carboplatin offered the advantage of reduced toxicity. Cervical and Endometrial Cancer In cervical cancer, cisplatin continues to be the primary platinum-containing analog used in treating advanced disease. However, carboplatin also has activity in endometrial cancer, producing objective response rates in 30%-35% of patients [186], and its favorable toxicity profile may make carboplatin superior to cisplatin for treating these older patients [2]. In a phase II study of 32 patients with advanced endometrial cancer conducted by the SWOG, carboplatin (400 mg/m 2 ) yielded an overall response rate of 30%, with four of the responding patients remaining alive 839+ and 987+ days after starting treatment [187]. DISCUSSION A large body of evidence suggests that carboplatin, when properly dosed, holds a key place at the forefront of first-line therapy for many solid tumors. Its role will likely be redefined in the coming years, as researchers replace BSA dosing with optimal AUC dosing. Despite the fact that results based on BSA dosing have negatively biased carboplatin performance, this drug appears equivalent in activity to cisplatin in most solid tumors and is more easily tolerated. As the results emerge from recent studies in which carboplatin is optimally dosed in combination with other active agents, such as paclitaxel, carboplatin may well prove to be more active than cisplatin in ovarian and lung cancer and at least equivalent to cisplatin in other tumor types. Germ cell tumors remain an exception and are most sensitive to cisplatin. In combination with paclitaxel, carboplatin appears to have at least an additive cytotoxic effect. Because their toxicities are complementary, they can be administered together without exacerbating their individual toxicity profiles. This is often not possible with cisplatin, which has additive dose-limiting neuropathy. In contrast, paclitaxel appears to have a protective effect on thrombocytopenia, the normally dose-limiting toxicity of carboplatin. Furthermore, this highly active combination does not require the concomitant use of growth factors when paclitaxel is administered as a 3-h infusion. Thus, carboplatin/paclitaxel will likely displace other chemotherapeutic regimens for sensitive solid tumors, based on its activity, good tolerability, and potentially lower administration costs. Indeed, the combination of AUC-dosed carboplatin and 3-h infusions of paclitaxel may well become a standard chemotherapeutic regimen once large-scale phase III studies of its activity are completed in patients with advanced cancer of the ovary or lung. Further studies of carboplatin, in combination with newly approved cytotoxic agents, must be pursued to determine the future role of carboplatin in the treatment of solid malignancies. REFERENCES 1 Ruckdeschel JC. The future role of carboplatin. Semin Oncol 1994;21(suppl 12):114-118. 2 Alberts DS. Carboplatin versus cisplatin in the chemotherapy of solid tumors pro-carboplatin. In: International Symposium on Platinum Coordinating Compounds. New York: Plenum Press, 1996. 3 Schurig JE, Rose WC, Catino JJ et al. The pharmacologic characteristics of carboplatin: preclinical experience. In: Bunn PA, Canetta R, Ozols RF et al., eds. Carboplatin (JM-8): Current Perspectives and Future Directions. Philadelphia: Saunders, 1990:3-17. 4 Calvert H, Judson I, van der Vijgh WJF. Platinum complexes in cancer medicine: pharmacokinetics and pharmacodynamics in relation to toxicity and therapeutic activity. Cancer Surv 1993;17:189-217. 5 Wagstaff AJ, Ward A, Benfield P et al. Carboplatin, a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of cancer. Drugs 1989;37:162-190.

Alberts, Dorr 29 6 Newell DR, Siddik ZH, Gumbrell LA et al. Plasma free platinum pharmacokinetics in patients treated with high dose carboplatin. Eur J Cancer 1987;23:1399-1405. 7 Gaver RC, Colombo N, Green MD et al. The disposition of carboplatin in ovarian cancer patients. Cancer Chemother Pharmacol 1988;22:263-270. 8 Oguri S, Sakakibara T, Mase H et al. Clinical pharmacokinetics of carboplatin. J Clin Pharmacol 1988;28:208-215. 9 Egorin MJ, Jodrell DI. Utility of individualized carboplatin dosing alone and in combination regimens. Semin Oncol 1992;19:132-138. 10 Rainey JM, Alberts DS. Safe, rapid administration schedule for cis-platinum-mannitol. Med Pediatr Oncol 1978;4:371-375. 11 Brock J, Alberts DS. Safe, rapid administration of cisplatin in the outpatient clinic. Cancer Treat Rep 1986;70:1409-1414. 12 Alberts DS. Clinical pharmacology of carboplatin. Semin Oncol 1990;17:6-8. 13 van der Vijgh WJF. Clinical pharmacokinetics of carboplatin. Clin Pharmacokinet 1991;21:242-261. 14 Schneider JG. Intraperitoneal chemotherapy. Obstet Gynecol Clin North Am 1994;21:195-212. 15 Markman M, Reichman B, Hakes T et al. Evidence supporting the superiority of intraperitoneal cisplatin compared to intraperitoneal carboplatin for salvage therapy of small-volume residual ovarian cancer. Gynecol Oncol 1993;50:100-104. 16 Elferink F, van der Vijgh WJF, Klein I et al. Pharmacokinetics of carboplatin after intraperitoneal administration. Cancer Chemother Pharmacol 1988;21:57-60. 17 Calvert AH, Newell DR, Gumbrell LA et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;17:1748-1756. 18 Alberts DS, Garcia DJ. Total platinum dose versus platinum dose intensification in ovarian cancer treatment. Semin Oncol 1994;21:11-15. 19 van Warmerdam LJC, Rodenhuis S, ten Bokkel Huinink WW et al. The use of the Calvert formula to determine the optimal carboplatin dosage. J Cancer Res Clin Oncol 1995;121:478-486. 20 Egorin MJ, Van Echo DA, Tipping SJ et al. Pharmacokinetics and dosage reduction of cis-diamine (1,1-cyclobutanedicarboxylato) platinum in patients with impaired renal function. Cancer Res 1984;44:5432-5438. 21 Egorin MJ, Van Echo DA, Olman EA et al. Prospective validation of a pharmacologically based dosing scheme for the cis-diamminedichloroplatinum (II) analogue diamminecyclobutane-dicarboxylatoplatinum. Cancer Res 1985;45:6502-6506. 22 Canetta R, Goodlow J, Smaldone L et al. Pharmacologic characteristics of carboplatin: clinical experience. In: Bunn PA, Canetta R, Ozols RF et al., eds. Carboplatin (JM-8): Current Perspectives and Future Directions. Philadelphia: Saunders, 1990:19-38. 23 Jodrell DI, Egorin MJ, Canetta M et al. Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 1992;10:520-528. 24 Oliver RTD, Ong J. Seventeen years experience of phase I/II studies of single agent platinum compounds as alternatives for metastatic and stage I seminoma. Proc Am Soc Clin Oncol 1996;15:244a. 25 Sorensen BT, Stromgren A, Jakobsen P et al. Dose-toxicity relationship of carboplatin in combination with cyclophosphamide in ovarian cancer patients. Cancer Chemother Pharmacol 1991;28:397-401. 26 Calvert AH. Dose optimisation of carboplatin in adults. Anticancer Res 1994;14:2273-2278. 27 Belani CP, Egorin MJ, Abrams JS et al. A novel pharmacodynamically-based approach to dose optimization of carboplatin when used in combination with etoposide. J Clin Oncol 1989;7:1896-1902. 28 Chatelut E, Chevreau C, Brunner V et al. A pharmacologically guided phase I study of carboplatin in combination with methotrexate and vinblastine in advanced urothelial cancer. Cancer Chemother Pharmacol 1995;35:391-396. 29 Reyno LM, Egorin MJ, Canetta RM et al. Impact of cyclophosphamide on the relationship between carboplatin exposure and response or toxicity when used in the treatment of advanced ovarian cancer. J Clin Oncol 1993;11:1156-1164. 30 Egorin MJ, Reyno LM, Canetta RM et al. Modeling toxicity and response in carboplatin-based combination chemotherapy. Semin Oncol 1994;21:7-19. 31 Kearns CM, Belani CP, Erkmen K et al. Pharmacokinetics of paclitaxel and carboplatin in combination. Semin Oncol 1995;22:1-4. 32 ten Bokkel Huinink WW, Veenhof CHN, Helmerhorst T et al. Paclitaxel plus carboplatin in the treatment of ovarian cancer. Semin Oncol 1995;22(suppl 6):97-100. 33 Siddiqui N, Bailey N, Memon M et al. A phase I/pharmacokinetic study of escalating paclitaxel in combination with carboplatin dosed at a fixed area under the curve in epithelial ovarian cancer. Proc Am Soc Clin Oncol 1995;14:271a. 34 Shea T, Graham M, Bernard S et al. A clinical and pharmacokinetic study of high-dose carboplatin, paclitaxel, granulocyte colony-stimulating factor, and peripheral blood stem cells in patients with unresectable or metastatic cancer. Semin Oncol 1995;22:80-85. 35 Kearns CM, Belani CP, Erkmen K et al. Reduced platelet toxicity with combination carboplatin and paclitaxel: pharmacodynamic modulation of carboplatin associated thrombocytopenia. Proc Am Soc Clin Oncol 1995;14:170a. 36 van Warmerdam LJC, Rodenhuis S, ten Bokkel Huinink WW. Evaluation of formulas using the serum creatinine level to calculate the optimal dosage of carboplatin. Cancer Chemother Pharmacol 1996;37:266-270. 37 Calvert AH, Boddy A, Bailey NP et al. Carboplatin in combination with paclitaxel in advanced ovarian cancer: dose determination and pharmacokinetic and pharmacodynamic interactions. Semin Oncol 1995;22:91-98. 38 Aisner J, Belani CP, Kearns C et al. Feasibility and pharmacokinetics of paclitaxel, carboplatin, and concurrent radiotherapy

30 Optimizing Carboplatin for Solid Tumors for regionally advanced squamous cell carcinoma of the head and neck and for regionally advanced non-small cell lung cancer. Semin Oncol 1995;22:17-21. 39 Rhodes PJ, Rhodes RS, McClelland GH et al. Evaluation of eight methods for estimating creatinine clearance in men. Clin Pharm 1987;6:399-406. 40 Jelliffe RW. Estimation of creatinine clearance when urine cannot be collected. Lancet 1971;1:975-976. 41 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41. 42 Chatelut E, Canal P, Brunner V et al. Prediction of carboplatin clearance from standard morphological and biological patient characteristics. J Natl Cancer Inst 1995;87:573-580. 43 Robinson BA, Frampton CM, Colls BM et al. Comparison of methods of assessment of renal function in patients with cancer treated with cisplatin, carboplatin or methotrexate. Aust NZ J Med 1990;20:657-662. 44 Okamoto H, Nagatomo A, Kunitoh H et al. The predictive performance of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance. Proc Am Soc Clin Oncol 1996;15:174a. 45 Barth A, Kochli OR, Kung F et al. Comparison of bedside estimates of GFR for AUC dosing of carboplatin in patients with ovarian cancer. Proc Am Soc Clin Oncol 1996;15:292a. 46 Belani CP, Kim K, Bonomi P et al. Retrospective estimation of carboplatin exposure by Calvert s and Chatelut s formulae and correlation with pharmacodynamic effects in metastatic nonsmall cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1996;15:376a. 47 Wada T, Nakamura T, Maeda Y et al. Actual carboplatin AUC had better correlation with Chatelut s formula than arranged Calvert s formula using 24-hr creatinine clearance. Proc Am Soc Clin Oncol 1996;15:475a. 48 Camp MJ, Sencer A, Fanucchi M. Comparison of Calvert versus Chatelut method for dosing carboplatin (CBP) in combination with paclitaxel. Proc Am Soc Clin Oncol 1996;15:477a. 49 Sorensen BT, Stromgren A, Jakobsen P et al. A limited sampling method for estimation of the carboplatin area under the curve. Cancer Chemother Pharmacol 1993;31:324-327. 50 van Warmerdam LJC, Rodenhuis S, van Tellingen O et al. Validation of a limited sampling model for carboplatin in a high-dose chemotherapy combination. Cancer Chemother Pharmacol 1994;35:179-181. 51 Ghazal-Aswad S, Calvert AH, Newell DR. A single-sample assay for the estimation of the area under the free carboplatin plasma concentration versus time curve. Cancer Chemother Pharmacol 1996;37:429-434. 52 Cornelison TL, Reed E. Nephrotoxicity and hydration management for cisplatin, carboplatin, and ormaplatin. Gynecol Oncol 1993;50:147-158. 53 Reed I, Jacob J. Carboplatin and renal dysfunction. Ann Intern Med 1989;110:409. 54 Gore ME, Calvert AH, Smith IE. High dose carboplatin in the treatment of lung cancer and mesothelioma: a phase I dose escalation. Eur J Cancer Clin Oncol 1987;23:1391-1397. 55 McKeage MJ. Comparative adverse effect profiles of platinum drugs. Drug Safety 1995;13:228-244. 56 Alberts DS, Noel JK. Cisplatin-associated neurotoxicity: can it be prevented? Anticancer Drugs 1995;6:369-383. 57 Roelofs RI, Hrushesky W, Rogin J et al. Peripheral sensory neuropathy and cisplatin chemotherapy. Neurology 1984;34:934-938. 58 Wiltshaw E. Ovarian trials at the Royal Marsden. Cancer Treat 1985;12(suppl 1):67-71. 59 Shea TC, Flaherty M, Elias A et al. A phase I and pharmacokinetic study of carboplatin and autologous bone marrow support. J Clin Oncol 1989;23:1391-1397. 60 Markman M, Kennedy A, Webster K et al. Control of carboplatin-induced emesis with a fixed low dose of granisetron (0.5 mg) plus dexamethasone. Gynecol Oncol 1996;60:435-437. 61 Calvert AH, Harland SJ, Newell DR et al. Early clinical trials with cis-diamine-1,1-cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol 1982;9:140-147. 62 Calvert AH, Newell DR, Gore ME. Future directions with carboplatin: can therapeutic monitoring, high-dose administration, and hematologic support with growth factors expand the spectrum compared with cisplatin? Semin Oncol 1992;19:155-163. 63 ten Bokkel Huinink WW, Dercksen MW, van Tinteren H. Further studies to ameliorate toxicity of carboplatin. Semin Oncol 1994;21:27-33. 64 de Campos E, Radford J, Steward W et al. Clinical and in vitro effects of recombinant human erythropoietin in patients receiving intensive chemotherapy for small-cell lung cancer. J Clin Oncol 1995;13:1623-1631. 65 Vadhan-Raj S, Kudelka AP, Garrison L et al. Effects of interleukin-1α on carboplatin-induced thrombocytopenia in patients with recurrent ovarian cancer. J Clin Oncol 1994;12:707-714. 66 Smith JW, Longo DL, Alvord WG et al. The effects of treatment with interleukin-1α on platelet recovery after high-dose carboplatin. N Engl J Med 1993;328:756-761. 67 D Hondt V, Humblet Y, Guillaume T et al. Thrombopoietic effects and toxicity of interleukin-6 in patients with ovarian cancer before and after chemotherapy: a multicentric placebo-controlled, randomized phase Ib study. Blood 1995;85:2347-2353. 68 Crawford J, George M. The role of hematopoietic growth factors in support of ifosfamide/carboplatin/etoposide chemotherapy. Semin Oncol 1995;22:18-22. 69 Sredni B, Albeck M, Tichler T et al. Bone marrow-sparing and prevention of alopecia by AS101 in non-small-cell lung cancer patients treated with carboplatin and etoposide. J Clin Oncol 1995;13:2342-2353. 70 Treskes M, van der Vijgh WJF. WR2721 as a modulator of cisplatin- and carboplatin-induced side effects in comparison with other chemoprotective agents: a molecular approach. Cancer Chemother Pharmacol 1993;33:93-106.

Alberts, Dorr 31 71 Frasci G, Perillo G, Comella G et al. Phase I/II study of carboplatin and oral etoposide with granulocyte-colony stimulating factor in advanced nonsmall cell lung cancer. Cancer 1995;75:1578-1585. 72 Calvert AH, Lind MJ, Ghazal-Aswad S et al. Carboplatin and granulocyte colony-stimulating factor as first-line treatment for epithelial ovarian cancer: a phase I dose-intensity escalation study. Semin Oncol 1994;21:1-6. 73 Shea TC, Mason JR, Storniolo AM et al. Sequential cycles of high-dose carboplatin administered with recombinant human granulocyte-macrophage colony-stimulating factor and repeated infusions of autologous peripheral-blood progenitor cells: a novel and effective method for delivering multiple courses of dose-intensive therapy. J Clin Oncol 1992;10:464-473. 74 Suzuki M, Ohwada M, Aida I et al. Macrophage colony-stimulating factor enhances platelet recovery following cisplatin/carboplatin chemotherapy in ovarian cancer. Gynecol Oncol 1994;54:23-26. 75 Budd GT, Bukowski RM, Adelstein D et al. Mature results of a randomized trial of carboplatin (C) and amifostine (A) vs. C alone in patients (pts) with advanced malignancies. Proc Am Soc Clin Oncol 1996;15:532a. 76 List AF, Heaton R, Glinsmann-Gibson B et al. Amifostine stimulates formation of multipotent progenitors and generates macroscopic colonies in normal and myelodysplastic bone marrow. Proc Am Soc Clin Oncol 1996;15:449a. 77 List AF, Heaton R, Glinsmann-Gibson B et al. A phase I/II clinical trial of amifostine inpatients with myelodysplastic syndrome (MDS): promotion of multilineage hematopoiesis. Proc Am Soc Clin Oncol 1996;16:7a. 78 Elias AD, Ayash L, Tepler I et al. The use of G-CSF or GM- CSF mobilized peripheral blood progenitor cells (PBPC) alone or to augment marrow as hematologic support of single or multiple cycle high-dose chemotherapy. J Hematother 1993;2:377-382. 79 Ozols RF, Kilpatrick D, O Dwyer P et al. Phase I and pharmacokinetic study of Taxol (T) and carboplatin (C) in previously untreated patients (PTS) with advanced epithelial ovarian cancer (OC): a pilot study of the Gynecologic Oncology Group. Proc Am Soc Clin Oncol 1993;12:259a. 80 Muggia FM, Vafai D, Natale R et al. Paclitaxel 3-hour infusion given alone and combined with carboplatin: preliminary results of dose-escalation trials. Semin Oncol 1995;22(suppl 9):63-66. 81 Bookman MA, McGuire WP III, Kilpatrick D et al. Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group. J Clin Oncol 1996;14:1895-1902. 82 Bunn PA. Clinical experiences with carboplatin (Paraplatin) in lung cancer. Semin Oncol 1992;19(suppl 2):1-11. 83 Comis RL. Carboplatin in the treatment of non-small cell lung cancer: a review. Oncology 1993;50(suppl 2):37-41. 84 Bonomi PD, Finkelstein DM, Ruckdeschel JC et al. Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: a study of the Eastern Cooperative Oncology Group. J Clin Oncol 1989;7:1602-1613. 85 Bonomi P. Carboplatin in non-small cell lung cancer: review of the Eastern Cooperative Oncology Group trial and comparison with other carboplatin trials. Semin Oncol 1991;18(suppl 2):2-7. 86 Klastersky J. Cisplatin and carboplatin in combination with etoposide as a treatment for non-small cell lung cancer: the experience of the EORTC Lung Cancer Working Party. Cancer Treat Rev 1988;15:33-40. 87 Klastersky J, Sculier JP, Lacroix H et al. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol 1990;8:1556-1562. 88 Bonomi P. Platinum/etoposide therapy in non-small cell lung cancer. Oncology 1992;49(suppl 1):43-50. 89 Schiller JH, Storer B, Berlin J et al. Amifostine, cisplatin, and vinblastine in metastatic non-small-cell lung cancer: a report of high response rates and prolonged survival. J Clin Oncol 1996;14:1913-1921. 90 Green MR, Kreisman H, Doll DC et al. Carboplatin in nonsmall cell lung cancer: an update on the Cancer and Leukemia Group B experience. Semin Oncol 1992;19(suppl 2):44-49. 91 Hsieh R-K, Chang AYC, Boros L et al. Phase II study of ifosfamide, carboplatin and etoposide in patients with advanced non-small cell lung cancer. Am J Clin Oncol 1994;17:509-513. 92 Bonomi P, Kim K, Chang A et al. Phase III trial comparing etoposide (E) cisplatin (C) versus Taxol (T) with cisplatin- G-CSF (G) versus Taxol-cisplatin in advanced non-small cell lung cancer. An Eastern Cooperative Oncology Group (ECOG) trial. Proc Am Soc Clin Oncol 1996;15:382a. 93 Langer CJ, Leighton JC, Comis RL et al. Paclitaxel by 24- or 1-hour infusion in combination with carboplatin in advanced non-small cell lung cancer: the Fox Chase Cancer Center experience. Semin Oncol 1995;22(suppl 9):18-29. 94 Langer CJ, Leighton JC, Comis RL et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-smallcell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol 1995;13:1860-1870. 95 Langer CJ, Leighton J, McAleer C et al. Paclitaxel and carboplatin in the treatment of advanced non-small cell lung cancer. Semin Oncol 1995;22(suppl 6):64-69. 96 Sculier JP, Klastersky J, Giner V et al. Phase II randomized trial comparing high-dose cisplatin with moderate-dose cisplatin and carboplatin in patients with advanced non-small cell lung cancer. J Clin Oncol 1994;12:353-359. 97 Belani CP, Aisner J, Hiponia D et al. Paclitaxel and carboplatin with and without filgrastim support in patients with metastatic non-small cell lung cancer. Semin Oncol 1995;22(suppl 9):7-12. 98 Vafai D, Israel V, Zaretsky S et al. Phase I/II trial of combination carboplatin and Taxol in non-small cell lung cancer. Presented at the thirty-first annual meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 20-23, 1995.

32 Optimizing Carboplatin for Solid Tumors 99 Murren JR, Buzaid AC. Chemotherapy and radiation for the treatment of non small-cell lung cancer. Clin Chest Med 1993;14:161-171. 100 Ball D, Bishop J, Smith J et al. A phase III study of accelerated radiotherapy with and without carboplatin in nonsmall cell lung cancer: an interim toxicity analysis of the first 100 patients. Int J Radiat Oncol Bio Phys 1995;31:267-272. 101 Jeremic B, Shibamoto Y, Acimovic L et al. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. J Clin Oncol 1995;13:452-458. 102 Comella P, Scoppa G, Daponte A et al. Alternated approach with local irradiation and combination chemotherapy including cisplatin or carboplatin plus epirubicin and etoposide in intermediate stage non-small cell lung cancer. Cancer 1994;74:1874-1881. 103 Liebmann J, Cook JA, Fisher J et al. In vitro studies of Taxol as a radiation sensitizer in human tumor cells. J Natl Cancer Inst 1994;86:441-446. 104 Choy H, Akerley W, Safran H et al. Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 1996;15:371a. 105 Choy H, Akerley W, Safran H et al. Paclitaxel plus carboplatin and concurrent radiation therapy for patients with locally advanced non-small cell lung cancer. Semin Oncol 1996;23 (suppl 16):117-119. 106 Belani CP, Aisner J, Hiponia D et al. Paclitaxel and carboplatin with concurrent thoracic radiotherapy for regionally advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1996;15:396a. 107 Langer C, Rosvold C, Kaplan R et al. Induction therapy with paclitaxel (Taxol) and carboplatin (CBDCA) followed by concurrent chemotherapy in unresectable locally advanced nonsmall cell lung carcinoma (NSCLC): preliminary report of FCCC 94-001. Proc Am Soc Clin Oncol 1996;15:376a. 108 Bonomi P, Siddiqui S, Lincoln S et al. Escalating paclitaxel doses combined with carboplatin/etoposide and thoracic radiotherapy as preoperative or definitive treatment for stage III non-small cell lung cancer. Semin Oncol 1996;23 (suppl 16):102-107. 109 Siddiqui S, Bonomi P, Faber L et al. Phase I-II trial of escalating doses of paclitaxel-carboplatin-etoposide and simultaneous thoracic radiation ± pulmonary resection in stage III non-small cell lung cancer. Proc Am Soc Clin Oncol 1996;15:405a. 110 Bunn PA, Kelly K. New treatment agents for advanced small cell and non-small cell lung cancer. Semin Oncol 1995;22(suppl 6):53-63. 111 Friedland DM, Comis RL. Perioperative therapy of nonsmall cell lung cancer: a review of adjuvant and neoadjuvant approaches. Semin Oncol 1995;22:571-581. 112 Deutsch M, Crawford J, Leopold K et al. Phase II study of neoadjuvant chemotherapy and radiation therapy with thoracotomy in the treatment of clinical stage IIIA non-small cell lung cancer. Cancer 1994;74:1243-1252. 113 Deutsch MA, Leopold KA, Crawford J et al. Carboplatin, etoposide, and radiotherapy, followed by surgery, for the treatment of marginally resectable non-small cell lung cancer. Cancer Treat Rev 1993;19(suppl C):53-62. 114 Rosenow EC, Carr DT. Bronchogenic carcinoma. Cancer 1979;29:233-243. 115 Raghavan D, Perez R, Creaven P et al. Carboplatin for small cell lung cancer: progress toward greater efficacy and reduced toxicity. Semin Oncol 1994;21(suppl 6):1-8. 116 Aisner J. Extensive-disease small-cell lung cancer: the thrill of victory, the agony of defeat. J Clin Oncol 1996;14:658-665. 117 Carney DN. Carboplatin/etoposide combination chemotherapy in the treatment of poor prognosis patients with small cell lung cancer. Lung Cancer 1995;12(suppl 3):S77-S83. 118 Lorigan P, Lee SL, Betticher D et al. Chemotherapy with vincristine/ifosfamide/carboplatin/etoposide in small cell lung cancer. Semin Oncol 1995;22(suppl 7):32-41. 119 Canetta R, Bragman K, Smaldone L et al. Carboplatin: current status and future prospects. Cancer Treat Rev 1988;15(suppl B):17-32. 120 Bishop JF. Carboplatin/etoposide in small cell lung cancer. Oncology 1992;49(suppl 1):11-18. 121 Kosmidis PA, Samantas E, Fountzilas G et al. Cisplatin/etoposide versus carboplatin etoposide chemotherapy and irradiation in small cell lung cancer: a randomized phase III study. Semin Oncol 1994;21(suppl 3):23-30. 122 Pfeiffer P, Sorensen P, Rose C. Is carboplatin and oral etoposide an effective and feasible regimen in patients with small cell lung cancer? Eur J Cancer 1995;31A:64-69. 123 Smith IE, Evans BD, Gore ME et al. Carboplatin (Paraplatin; JM8) and etoposide (VP-16) as first-line combination therapy for small-cell lung cancer. J Clin Oncol 1987;5:185-189. 124 Smith IE, Perren TJ, Ashley SA et al. Carboplatin, etoposide, and ifosfamide as intensive chemotherapy for small cell cancer. J Clin Oncol 1990;3:899-905. 125 Prendiville J, Lorigan P, Hicks F et al. Therapy for small cell lung cancer using carboplatin, ifosfamide, etoposide (without dose reduction), mid-cycle vincristine with thoracic and cranial irradiation. Eur J Cancer 1994;30A:2085-2090. 126 Gridelli C, Ianniello GP, Maiorino A et al. Carboplatin, epirubicin and VP-16 chemotherapy in the treatment of small cell lung cancer. Am J Clin Oncol 1994;17:160-162. 127 Greco FA, Hainsworth JD. Practical approaches to the treatment of patients with extensive stage small cell lung cancer. Semin Oncol 1994;21(suppl 7):3-6. 128 Ellis PA, Talbot DC, Priest K et al. Dose intensification of carboplatin and etoposide as first-line combination chemotherapy in small cell lung cancer. Eur J Cancer 1995;31A:1888-1889. 129 Viren M, Liippo K, Ojala A et al. Carboplatin and etoposide in extensive small cell lung cancer. Acta Oncol 1994;33:921-924.

Alberts, Dorr 33 130 Evans WK, Eisenhauer E, Hughes P et al. VP-16 and carboplatin in previously untreated patients with extensive small cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group. Br J Cancer 1988;58:464-468. 131 Wolff AC, Ettinger DS, Neuberg D et al. Phase II study of ifosfamide, carboplatin, and oral etoposide chemotherapy for extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group Pilot Study. J Clin Oncol 1995;13:1615-1622. 132 Skarlos DV, Samantas E, Kosmidis P et al. Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol 1994;5:601-607. 133 Ettinger DS. The place of ifosfamide in chemotherapy of small cell lung cancer: the Eastern Cooperative Oncology Group experience and a selected literature update. Semin Oncol 1995;22(suppl 2):23-27. 134 Joss RA, Alberto P, Hürny C et al. Quality versus quantity of life in the treatment of patients with advanced small-cell lung cancer? A randomized phase III comparison of weekly carboplatin and teniposide versus cisplatin, adriamycin, etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine. Ann Oncol 1995;6:41-48. 135 National Institutes of Health. National Institutes of Health consensus development conference statement. Ovarian cancer: screening, treatment, and follow-up. Gynecol Oncol 1994;55:S4-S14. 136 National Institutes of Health Consensus Development Panel on Ovarian Cancer. NIH consensus conference. Ovarian cancer: screening, treatment, and follow-up. JAMA 1995;273:491-497. 137 Consensus group. Advanced epithelial ovarian cancer: 1993 consensus statements. Ann Oncol 1993;4:583-588. 138 Advanced Ovarian Cancer Trialists Group. Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. Br Med J 1991;303:884-893. 139 Stewart LA, Parmar MKB, on behalf of the Advanced Ovarian Cancer Trialists Group. The results of a quantitative overview of chemotherapy in advanced ovarian cancer: what can we learn? Bull Cancer 1993;80:146-151. 140 Williams CJ, Stewart L, Parmar M et al., on behalf of the Advanced Ovarian Cancer Trialists Group. Meta-analysis of the role of platinum compounds in advanced ovarian carcinoma. Semin Oncol 1992;19(suppl 2):120-128. 141 Alberts D, Hannigan E, Canetta R et al. Cisplatin versus carboplatin in advanced ovarian cancer: an economic analysis. Pharmacy Therapeut 1994;19:692-706. 142 Adams M, Kerby IJ, Rocker I et al. on behalf of the Swiss Gynaecological Cancer Group. A comparison of the toxicity and efficacy of cisplatin and carboplatin in advanced ovarian cancer. Acta Oncol 1989;28:57-60. 143 Pecorelli S, Bolis G, Vassena L et al. Randomized comparison of cisplatin and carboplatin in advanced ovarian cancer. Proc Am Soc Clin Oncol 1988;7:136a. 144 Mangioni C, Bolis G, Pecorelli S et al. Randomized trial in advanced ovarian cancer comparing cisplatin and carboplatin. J Natl Cancer Inst 1989;81:1464-1471. 145 Taylor AE, Wiltshaw E, Gore ME et al. Long-term followup of the first randomized study of cisplatin versus carboplatin for advanced epithelial ovarian cancer. J Clin Oncol 1994;12:2066-2070. 146 Ozols RF. New developments with carboplatin in the treatment of ovarian cancer. Semin Oncol 1992;19:85-89. 147 Rozencweig M, Martin A, Beltangady M et al. Randomized trials of carboplatin versus cisplatin in advanced ovarian cancer. In: Bunn PA, Canetta R, Ozols RF et al., eds. Carboplatin (JM-8): Current Perspectives and Future Directions. Philadelphia: Saunders, 1990:175-186. 148 Alberts DS, Canetta R, Mason-Liddil N. Carboplatin in the first-line chemotherapy of ovarian cancer. Semin Oncol 1990;17(suppl 2):54-60. 149 Hannigan EV, Green S, Alberts DS et al. Results of a Southwest Oncology Group phase III trial of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide in advanced ovarian cancer. Oncology 1993;50(suppl 2):2-9. 150 Alberts DS, Green S, Hannigan EV et al. Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 1992;10:706-717. 151 Alberts DS, Dahlberg S, Green SJ et al. Analysis of patient age as an independent prognostic factor for survival in a phase III study of cisplatin-cyclophosphamide versus carboplatin cyclophosphamide in stages III (suboptimal) and IV ovarian cancer. Cancer 1993;71:618-627. 152 Swenerton K, Jeffrey J, Stuart G et al. Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1992;10:718-726. 153 Anderson H, Wagstaff J, Crowther D et al. Comparative toxicity of cisplatin, carboplatin (CBDCA) and iproplatin (CHIP) in combination with cyclophosphamide in patients with advanced epithelial ovarian cancer. Eur J Clin Oncol 1988;24:1471-1479. 154 Gurney H, Crowther D, Anderson H et al. Five year follow-up and dose delivery analysis of cisplatin, iproplatin or carboplatin in combination with cyclophosphamide in advanced ovarian carcinoma. Ann Oncol 1990;1:427-433. 155 Chiara S, Bruzzone M, Calciati A et al. A randomized study comparing two combination chemotherapy regimens containing cisplatin or carboplatin (CAC vs PAC) in advanced ovarian carcinoma. Proceedings of the Sixth Meeting of the European Society of Gynaecological Oncology, Versailles, France, April 1989. Abstract 40. 156 Conte PF, Bruzzone M, Carnino F et al. Carboplatin, doxorubicin, and cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide: a randomized trial in stage III-IV epithelial ovarian carcinoma. J Clin Oncol 1991;9:658-663. 157 McGuire WP, Hoskins WJ, Brady MF et al. Taxol and cisplatin improves outcome in advanced ovarian cancer as compared to cytoxan and cisplatin. Proc Am Soc Clin Oncol 1995;14:275a.

34 Optimizing Carboplatin for Solid Tumors 158 Thigpen T, Vance R, Puneky L et al. Chemotherapy in advanced ovarian carcinoma: current standards of care based on randomized trials. Gynecol Oncol 1994;55(suppl):S97-S107. 159 Ozols RF. Current status of chemotherapy for ovarian cancer. Semin Oncol 1995;22(suppl 12):61-66. 160 Ozols RF. Combination regimens of paclitaxel and the platinum drugs as first-line regimens for ovarian cancer. Semin Oncol 1995;22(suppl 15):1-6. 161 Markman M, Connelly B, Kennedy A et al. Cisplatin (75 mg/m 2 ) plus 3-hour infusional taxol (135 or 175 mg/m 2 ): unexpected high incidence of peripheral neuropathy. Gynecol Oncol 1996;60:98-99. 162 Connelly E, Markman M, Kennedy A et al. Paclitaxel delivered as a 3-hour infusion with cisplatin in patients with gynecologic cancers: unexpected incidence of neurotoxicity. Gynecol Oncol 1996;62:166-168. 163 Alberts DS. Carboplatin versus cisplatin in ovarian cancer. Semin Oncol 1995;22(suppl 12):88-90. 164 Ozols RF. Carboplatin and Taxol (paclitaxel) in advanced ovarian carcinoma. Ann Oncol 1994;5(suppl 6):S39-S43. 165 Ozols RF. Carboplatin and paclitaxel in ovarian cancer. Semin Oncol 1995;22(suppl 6):78-83. 166 Guastalla JP, Pujade Lauraine E, Orfeuvre H et al. Efficacy and safety of carboplatin (Cb)-paclitaxel (Px) association in pretreated advanced ovarian cancer (AOC) patients (pts). Proc Am Soc Clin Oncol 1996;15:278a. 167 Horwich A, Sleijfer DT, Fossa SD et al., and the Medical Research Council Testicular Tumour Working Party. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in goodprognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 1997;15:1844-1852. 168 Bajorin DF, Sarosdy MF, Pfister DG et al. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multi-institutional study. J Clin Oncol 1993;11:598-606. 169 Horwich A, Mason M, Dearnaley DP. Use of carboplatin in germ cell tumors of the testis. Semin Oncol 1992;19(suppl 2):72-77. 170 Margolin K, Doroshow JH, Ahn C et al. Treatment of germ cell cancer with two cycles of high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell support. J Clin Oncol 1996;14:2631-2637. 171 Beyer J, Kramar A, Mandanas R et al. High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. J Clin Oncol 1996;14:2638-2645. 172 Mottet-Auselo N, Bons-Rosset F, Costa P et al. Carboplatin and urothelial tumors. Oncology 1993;50(suppl 2):28-36. 173 Dogliotti L, Bertetto O, Berruti A et al. Combination chemotherapy with carboplatin and methotrexate in the treatment of advanced urothelial carcinoma. Am J Clin Oncol 1995;18:78-82. 174 Vaughn DJ, Malkowicz SB, Zoltick B et al. Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: a well-tolerated outpatient regimen. Proc Am Soc Clin Oncol 1996;15:240a. 175 Forastiere AA, Metch B, Schuller DE et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992;10:1245-1251. 176 Aisner J, Sinibaldi V, Eisenberger M. Carboplatin in the treatment of squamous cell head and neck cancers. Semin Oncol 1992;19(suppl 2):60-65. 177 Aisner J, Jacobs M, Sinabaldi V et al. Chemoradiotherapy for the treatment of regionally advanced head and neck cancers. Semin Oncol 1994;21(suppl 12):35-44. 178 Zamboglou N, Achterrath W, Schnabel T et al. Simultaneous radiotherapy and chemotherapy with carboplatin in inoperable squamous cell carcinoma of the head and neck: a phase II study. Cancer Invest 1992;10:349-355. 179 Gasparini G, Testolin A, Maluta S et al. Treatment of locally advanced squamous-cell carcinoma of the head and neck with concurrent radio-chemotherapy: randomized comparison of cisplatin versus carboplatin. Int J Oncol 1993;2:185-190. 180 Forastiere AA. Paclitaxel (Taxol) for the treatment of head and neck cancer. Semin Oncol 1994;21(suppl 8):49-52. 181 Chougule P, Wehbe T, Leone L et al. Concurrent Taxol, carboplatin and radiotherapy in advanced head and neck cancers: a phase II study. Proc Am Soc Clin Oncol 1996;15:317a. 182 Dunphy F, Boyd J, Varvares M et al. Phase I trial of preoperative (pre) chemotherapy using paclitaxel/paraplatin in head and neck carcinoma (HNCA). Proc Am Soc Clin Oncol 1996;15:316a. 183 O Brien MER, Talbot DC, Smith IE. Carboplatin in the treatment of advanced breast cancer: a phase II study using a pharmacokinetically guided dose schedule. J Clin Oncol 1993;11:2112-2117. 184 Bafaloukos D, Samonis G, Klinaki A et al. First-line combination chemotherapy with mitoxantrone, methotrexate, vincristine and carboplatin (MIMOC) in advanced breast cancer. Eur J Cancer 1993;6:851-853. 185 Bonnefoi H, Smith IE, O Brien MER et al. Phase II study of continuous infusional 5-fluorouracil with epirubicin and carboplatin (instead of cisplatin) in patients with metastatic/locally advanced breast cancer (infusional ECarboF): a very active and well-tolerated outpatient regimen. Br J Cancer 1996;73:391-396. 186 Alberts DS, Garcia DJ. Salvage chemotherapy in recurrent or refractory squamous cell cancer of the uterine cervix. Semin Oncol 1994;21(suppl 7):37-46. 187 Green JB, Green S, Alberts DS et al. Carboplatin therapy in advanced endometrial cancer. Obstet Gynecol 1990;75:696-700.