Gemcitabine in Combination With New Platinum Compounds: An Update

March 3, 2001

Combinations of gemcitabine (Gemzar) with cisplatin (Platinol) are among the most active new chemotherapy regimens developed for advanced non-small-cell lung cancer. Carboplatin (Paraplatin) is a platinum analog

ABSTRACT: Combinations of gemcitabine (Gemzar) with cisplatin (Platinol)are among the most active new chemotherapy regimens developed for advanced non-small-celllung cancer. Carboplatin (Paraplatin) is a platinum analog devoid of many of thenonhematologic toxicities associated with cisplatin. Although few directcomparisons have been made, when administered by area under theconcentration-time curve (AUC) dosing, carboplatin is probably equivalent tocisplatin in advanced non-small-cell lung cancer and provides an improvedtherapeutic index. Based on its favorable toxicity profile, carboplatin hassupplanted cisplatin for use in combination with paclitaxel in several differenttumor types. Initial trials combining gemcitabine and carboplatin using standarddays 1, 8, and 15 dosing of gemcitabine suggested that thrombocytopenia wasproblematic. More recently, 21-day schedules in which gemcitabine isadministered only on days 1 and 8 have demonstrated both efficacy and improvedtoxicity profiles. Here we review recent studies investigating gemcitabine pluscarboplatin and preliminary data regarding combinations of gemcitabine with thenew platinum analog oxaliplatin. [ONCOLOGY 15(Suppl 6):13-17, 2001]

Introduction

A number of randomized trialsand meta-analyses have concluded that platinum-based therapy results in improved survival, symptomcontrol, and quality of life compared to patients receiving supportive carealone. In a Cox multivariate analysis of approximately 2,300 cases of advancednon-small-cell lung cancer treated on studies of the Southwest Oncology Group(SWOG), platinum-based chemotherapy emerged as an independent predictive factorfor improved survival, along with performance status and female gender.[1] Infact, randomized cooperative group studies have failed to demonstrate thatadding another chemotherapeutic agent or agents to cisplatin (Platinol) improvessurvival compared to cisplatin alone.[2,3] However, this perspective is nowchanging.

Recently, several new chemotherapeutic agents such asgemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine(Navelbine), and irinotecan (CPT-11, Camptosar) have demonstrated considerablesingle-agent activity in non-small-cell lung cancer. In randomized trials,these new agents, in combination with platinum compounds, have demonstratedimproved response rates or survival compared to cisplatin alone or olderplatinum-based combinations. Combinations of gemcitabine and cisplatin aretheoretically attractive due to preclinical synergism related in part toinhibition of repair of platinum-induced DNA damage, and have proven to be amongthe most active in clinical studies.

Gemcitabine and Cisplatin

The most common dose and schedule has been gemcitabine deliveredon days 1, 8, and 15, with cisplatin given on either days 1, 2, or 15 of a28-day schedule. In a recent phase III trial by Sandler et al,[4] this 28-dayschedule of gemcitabine (1,000 mg/m2 on days 1, 8, and 15) plus cisplatin (100mg/m2 on day 1) was compared to cisplatin alone in patients with advanced non-small-celllung cancer.[4] Both response rate (30% vs 11%) and median survival (9 vs 6months) were increased in the combination arm. As in most studies using this28-day schedule, thrombocytopenia was dose-limiting, commonly resulting inomission of the day 15 gemcitabine dose (Table1). Grade 4 thrombocytopeniaoccurred in 28% of patients receiving the combination; 22% received platelettransfusions. Similarly, in the phase III trial of Crino et al,[5] in whichgemcitabine was delivered on days 1, 8, and 15, and cisplatin was given on day2, grade 4 thrombocytopenia was reported in 38% of patients, while 15% receivedplatelet transfusions.[5]

In contrast, the Spanish Lung Cancer Group[6] conducted a trialof a 21-day schedule delivering gemcitabine at 1,250 mg/m2 on days 1 and 8 andcisplatin at 100 mg/m2 on day 1. Grade 4 thrombocytopenia occurred in 16%, withonly 3% of patients requiring platelet transfusion.[6]

It is important to point out that regardless of incidence,thrombocytopenia associated with gemcitabine and cisplatin regimens in thesestudies rarely resulted in bleeding and was, therefore, of little clinicalsignificance. Nevertheless, this observed difference in thrombocytopenia between28- and 21-day schedules of gemcitabine/cisplatin appears to be particularlycogent when considering development of combinations of gemcitabine withcarboplatin.

Gemcitabine and Carboplatin

Although there have been few direct comparisons of cisplatin-and carboplatin (Paraplatin)-containing regimens in non-small-cell lungcancer, available literature suggests that carboplatin is equally efficacious.For example, in a European Organization for Research and Treatment of Cancer(EORTC) trial reported by Klastersky et al, etoposide plus carboplatin resultedin survival equivalent to etoposide plus cisplatin in the treatment of advancednon-small-cell lung cancer.[7]

While early studies dosed carboplatin by body surface area, morerecent trials have administered carboplatin based on formulas derived from atargeted area under the concentration-time curve (AUC), thus accounting fordifferences in renal excretion. Although carboplatin offers an improvedtherapeutic index, namely reduced nonhematologic toxicities, compared withcisplatin, additive myelotoxicity may be problematic when combining carboplatinwith other myelosuppressive chemotherapeutic agents. In initial trials combininga day 1, 8, and 15 schedule of gemcitabine with carboplatin, severethrombocytopenia was problematic, prompting some investigators to conclude thatthis regimen was not feasible.[8]

More recently, alternative dose schedules have been employed.One approach has been a 21-day schedule, with carboplatin administered on day 1and gemcitabine on days 1 and 8. The rationale is that in 28-day schedulescombining gemcitabine with either cisplatin or carboplatin, thrombocytopeniarequires that the day-15 gemcitabine dose be omitted in over 50% of courses.

A recent trial by the Spanish Lung Cancer Group reported byCarratoet al[9] is particularly instructive in optimizing the dose and schedule ofgemcitabine/platinum combinations.Patients with advanced non-small-cell lung cancer were treated withgemcitabine at 1,000 mg/m2 and carboplatin, at an AUC of 5 mg/mL/min. Insequential cohorts of patients, gemcitabine was administered either on days 1,8, and 15 of a 28-day cycle or on days 1 and 8 of a 21-day cycle. While thesetwo schedules proved to be equally efficacious, hematologic toxicity, especiallysevere thrombocytopenia, occurred much more frequently with the 28-day cycle(61% vs 17%) (Table 2). This difference in toxicity was observed despiteachieving a greater delivered dose intensity with the 21-day cycle.

Similarly, a pilot study of sequential combination chemotherapyby Edelman et al[10] at the University of California, Davis, used a 21-dayschedule with day 1 and 8 dosing of gemcitabine at 1,000 mg/m2 and carboplatinat an AUC of 5.5 for three cycles prior to sequencing to single-agentpaclitaxel. The gemcitabine/carboplatin regimen was well tolerated, with nadirthrombocytopenia occurring on day 15, a nontreatment day, and with recovery byday 21 in the vast majority of patients (Figure1).

Grade 4 thrombocytopenia was observed in 19% of patients,without significant bleeding sequelae. This level of thrombocytopenia iscomparable to that seen in the 21-day regimens of gemcitabine/cisplatin[6] andgemcitabine/carboplatin.[9] The overall response rate in the Edelman study was31% (95% confidence interval [CI] = 13%-53%) and the median survival was 10months.[10] Table 3 compares the level of grade 4 thrombocytopenia observed inseveral studies investigating gemcitabine and carboplatin combinations. Based onrelative efficacy and toxicity, new trials investigating gemcitabine/platinumcombinations employing either cisplatin or carboplatin are using 21-dayschedules with gemcitabine dosing on days 1 and 8.

Figure 2 shows the study design for a recently completedrandomized phase II Southwest Oncology Group (SWOG) study (S9806) evaluating twodifferent sequential combination chemotherapy regimens in advanced non-small-celllung cancer. If the results prove to be encouraging, S9806 will provide therationale for testing sequential vs concurrent three-drug combinations, with theobjective of determining the relative therapeutic index of each approach.

To further evaluate the day-21 gemcitabine/carboplatin regimendeveloped by Edelman et al,[10] a National Coalition Trial will directly comparethis regimen to paclitaxel/carboplatin and to the nonplatinum combination ofgemcitabine/paclitaxel (Figure 3). A proposed Cancer and Leukemia Group B(CALGB) trial will compare the sequential regimen of gemcitabine/carboplatinfollowed by weekly paclitaxel immediately to gemcitabine/carboplatin followed byweekly paclitaxel at the time of progressive disease, to the "triplet"of the three agents given concurrently (Figure4).

Gemcitabine and Oxaliplatin

Oxaliplatin is a novel platinum derivative with a1,2-diaminocyclohexane (DACH) carrier ligand, providing several therapeuticadvantages over classic platinum compounds such as cisplatin and carboplatin.Oxaliplatin appears to be more potent than cisplatin, requires fewer DNA adductsto achieve equal levels of cytotoxicity, and is relatively non-cross-resistant.[12]Oxaliplatin has demonstrated impressive clinical activity against a number oftumor types, including malignancies where cisplatin has relatively littleactivity, such as colorectal cancer.

In non-small-cell lung cancer, the initial phase II trial hasreported a 15% response rate.[13] Due to the unique synergism betweengemcitabine and platinum compounds, combinations of oxaliplatin and gemcitabineare of particular interest. Based on proposed molecular mechanisms ofinteraction, the substitution of oxaliplatin for cisplatin or carboplatin mayoptimize cytotoxicity when combined with gemcitabine. Two phase I trials of thiscombination have been reported.[14]

The California Cancer Consortium is further evaluating thiscombination with a fixed dose of oxaliplatin at 130 mg/m2 on day 1 andescalating doses of gemcitabine on days 1 and 8 of a 21-day cycle (Table4).Laboratory correlative studies performed on patient tumor tissue are designed todissect potential molecular mechanisms of interaction, and include DNA repairgenes (ERCC1 and ribonucleotide reductase), deoxycitadine deaminase, HER2/neu,apoptosis-related genes, and quantitation of oxaliplatin-DNA adducts inperipheral blood mononuclear cells. A subsequent phase II trial of thiscombination in advanced non-small-cell lung cancer is planned by the SouthwestOncology Group.

Summary

Gemcitabine/cisplatin has proven to be one of the mostefficacious new combination chemotherapy regimens available for the treatment ofnon-small-cell lung cancer. The platinum derivatives carboplatin andoxaliplatin offer potential therapeutic advantages in terms of reducedtoxicities or possible increased efficacy. Further studies of gemcitabine in combination with platinum derivatives are clearly warranted.

References:

1. Alban KS, Crowley JJ, LeBlanc M, et al: Survival determinantsin extensive-stage non-small-cell lung cancer: The Southwest Oncology Groupexperience. J Clin Oncol 9:1618-1626, 1991.

2. Gandara DR, Crowley J, Livingston RB, et al: Evaluation ofcisplatin intensity in metastatic non-small-cell lung cancer: A phase IIIstudy of the Southwest Oncology Group. J Clin Oncol 11:873-878, 1993.

3. Klastersky J, Saulier JP, Bureau G, et al: Cisplatin versuscisplatin plus etoposide in the treatment of advanced non small cell lungcancer. J Clin Oncol 7:1087-1092, 1989.

4. Sandler AB, Nemunaitis J, Denham C, et al: Phase III trial ofgemcitabine plus cisplatin versus cisplatin alone in patients with locallyadvanced or metastatic non-small-cell lung cancer. J Clin Oncol 18:122-130,2000.

5. Crino L, Scagliotti GV, Ricci S, et al: Gemcitabine andcisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-celllung cancer: A randomized phase III study of the Italian Lung Cancer Project. JClin Oncol 17:3522-3530, 1999.

6. Cardenal F, Lopez-Cabrerizo MP, Anton A, et al: Randomizedphase III study of gemcitabine-cisplatin versus etoposide-cisplatin in thetreatment of locally advanced or metastatic non-small-cell lung cancer. J ClinOncol 17:12-18, 1999.

7. Klastersky J, Sculier JP, Laccroiz H, et al: A randomizedstudy comparing cisplatin or carboplatin with etoposide in patients withadvanced non-small-cell lung cancer: European Organization for Research andTreatment of Cancer protocol 07861. J Clin Oncol 8:1556-1562, 1990.

8. Ng EW, Sandler AB, Einhorn AB, et al: A phase II study ofcarboplatin plus gemcitabine in non-small-cell lung cancer (abstract 1801).Proc Am Soc Clin Oncol 17:468a, 1998.

9. Carrato A, Alberola V, Massuti B, et al: Combination ofgemcitabine and carboplatin as first-line treatment in non-small-cell lungcancer (abstract 431P). Ann Oncol 9:89, 1998.

9a. Carrato A, García-Gómez J, Alberola V, et al: Carboplatinin combination with gemcitabine in advanced non-small-cell lung cancer.Comparison of two consecutive phase II trials using different schedules(abstract 1922). Proc Am Soc Clin Oncol 18:498a, 1999.

10. Edelman MJ, Gandara DR: Sequential chemotherapy: Rationaleand clinical trial design in advanced NSCLC. J Clin Lung Cancer 1:122-126, 1999.

11. Carmichael J, Allerheiligen S, Walling J: A phase II studyof gemcitabine and carboplatin in non-small-cell lung cancer. Semin Oncol23(suppl 10):55-59, 1996.

12. Page JD, Husein I, Saucer A, et al: Effect of thediaminocyclohexane carrier ligand on platinum adduct formation, repair, andactuality. Biochemistry 29:1016-1024, 1990.

13. Monnet I, Brienza S, Hugret F: Phase II study of oxaliplatinin poor prognosis non-small-cell lung cancer. Eur J Cancer 34(7):1124-1127,1998.

14. Mavroudis D, Kouroussis C, Kakolyris S, et al: A phase Istudy of the gemcitabine and oxaliplatin combination in patients with advancedsolid tumors (abstract 842). Proc Am Soc Clin Oncol 18:2191, 1999.

15. Martinez J, Panizo A, Alonso MA, et al: Gemcitabine pluscarboplatin in advanced non-small-cell lung cancer: A phase I trial. Proc AmSoc Clin Oncol 17:494a, 1998.