Platinum compounds remain the cornerstone of chemotherapy for
advanced nonsmall-cell lung cancer (NSCLC). A number of
randomized trials and meta-analyses have concluded that
platinum-based therapy results in improved survival, symptom control,
and quality of life compared to supportive care alone.[1-3] In a Cox
multivariate analysis of approximately 2,300 cases of advanced NSCLC
treated in studies conducted by the Southwest Oncology Group (SWOG),
platinum-based chemotherapy was found to be an independent predictive
factor for improved survival, along with performance status and
More recently, studies of several new chemotherapeutic agents, such
as gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere),
vinorelbine (Navelbine), and irinotecan (Camptosar), have
demonstrated better single-agent activity in NSCLC than that observed
with platinum compounds or other chemotherapeutic agents previously
available. Phase II trials of these new agents in combination with
cisplatin (Platinol) or carboplatin (Paraplatin) have subsequently
reported impressive response and survival data. In randomized
phase III trials, these combinations have yielded improved response
rates and/or survival compared to cis-platin alone or older
platinum-based combinations.[7-10] As a result, these studies have
changed what is regarded as the optimal therapy for advanced-stage
At present, none of these new regimens has proven to be superior,
leaving several alternative therapeutic options for the treatment of
advanced NSCLC. A number of issues remain unresolved for each of
these regimens (Table 1).
The nucleotide analog, gemcitabine, is one of the most promising of
the new chemotherapeutic agents. In addition to reproducible
single-agent activity with response rates of approximately 20% in
several phase II trials, two randomized studies have demonstrated
that single-agent gemcitabine produces survival equivalent to that
achieved with combinations of cisplatin and etoposide.[11,12]
However, gemcitabine has proven to be most efficacious against NSCLC
when administered in combination with cisplatin.[8,13,14]
Combinations of gemcitabine and cisplatin are attractive
theoretically because of the observed preclinical synergism, possibly
related to reduced repair of platinum-induced DNA damage, a
recognized mechanism of platinum resistance. The most common
dosing schedule employed has been gemcitabine delivered on days 1, 8,
and 15, with cisplatin delivered on either day 1, 2, or 15. Although
the toxicity of these combinations has varied somewhat depending on
the day cisplatin is administered, thrombocytopenia has typically
Carboplatin appears to be equally efficacious to cisplatin in the
treatment of advanced NSCLC. In a randomized trial by the European
Organization for Research and Treatment of Cancer (EORTC), the
combination of carbo-platin/etoposide produced activity equivalent to
that of cisplatin/etoposide. When single-agent carboplatin was
compared with several cisplatin-containing combinations in a phase
III Eastern Cooperative Oncology Group (ECOG) trial, carboplatin
produced the longest survival time, despite a response rate of only
In these early studies, carboplatin administration was calculated
according to body surface area (mg/m²). Because carboplatin is
highly excreted renally, dosing by body-surface area resulted in
relative underdosing in patients with normal renal function, and
overdosing in those with impaired renal function. More recently,
clinical trials have delivered carboplatin at a target area under the
curve (AUC) according to the Calvert formula (dose in mg = AUC
[glomerular filtration rate + 25]), resulting in more appropriate
dosing of this agent.
Carboplatin provides an improved therapeutic index compared to
cisplatin, especially in terms of reduced nonhematologic toxicities.
However, added hematologic toxicity may be problematic when combining
carboplatin with other myelosuppressive chemotherapeutic agents.
One of the earliest trials to evaluate the combination of gemcitabine
and carboplatin in NSCLC was conducted by Carmichael and
colleagues. This phase I trial was designed to determine the
maximum-tolerated dose (MTD) of carboplatin when administered prior
to gemcitabine 1,000 mg/m² on days 1, 8, and 15 of a 28-day
cycle. The MTD of carboplatin was an AUC of 5.2 mg/mL × min, as
calculated by the Calvert formula. Myelosuppression was
dose-limiting, with grade 3-4 neutropenia occurring in 58% of cycles
and grade 3-4 thrombocytopenia in 35% of cycles. The reverse sequence
of drug administration produced similar results.
Subsequently, Ng et al from Indiana University treated seven
chemotherapy-naive patients with advanced NSCLC with a 28-day
schedule of gemcitabine (1,000 mg/m² weekly for 3 weeks)
followed by carboplatin (AUC = 5). Grade 4 thrombocytopenia was
observed in three of five patients evaluable for toxicity. There were
no clinical sequelae reported. Nevertheless, these investigators
concluded that thrombocytopenia precluded further development of this
gemcitabine and carboplatin combination.
Alternative dosing schedules of gemcitabine and carboplatin are now
being investigated with encouraging results. One approach has been
the development of a 21-day schedule, with carboplatin administered
on day 1 and gemcitabine on days 1 and 8, similar to the
gemcitabine-cisplatin regimen used by Cardenal et al. The
rationale is that grade 4 thrombocytopenia is common with 28-day
schedules combining gemcitabine with cisplatin, necessitating
omission of the day 15 gemcitabine dose in over 50% of courses.
In studies of the 28-day schedule conducted by Sandler and
Crino, grade 4 thrombocytopenia was observed in 28% and 38% of
patients, and 22% and 15% of patients received platelet transfusions,
respectively. However, with the 21-day schedule reported by
Cardenal, grade 4 platelet toxicity occurred in only 16% of
cases, and only 3% required platelet transfusion (Table
2). These data support further study of similar dose schedules
of gemictabine/carboplatin combinations.
In a trial by Carrato et al, patients with advanced NSCLC were
treated with carboplatin at an AUC of 5 and gemcitabine (1,000
mg/m²) administered either on day 1, 8, and 15 of a 28-day
cycle, or day 1 and 8 of a 21-day cycle. While these regimens proved
to be equally efficacious, hematologic toxicity, especially severe
thrombocytopenia, occurred much more frequently with the 28-day cycle
(51% vs 17%) (Table 3). This
difference in toxicity was observed despite a greater delivered dose
intensity with the 21-day cycle.
Similarly, a pilot study of sequential combination chemotherapy by
Edelman et al at the University of California Davis Cancer Center
used a 21-day schedule with gemcitabine at 1,000 mg/m²
administered on days 1 and 8 and carboplatin administered at an AUC
of 5.5 for three cycles prior to sequencing to single-agent
paclitaxel. This gemcitabine/carboplatin regimen was well
tolerated in the majority of patients, with nadir thrombocytopenia
occurring on day 15 (a nontreatment day), and recovery by day 21 (Figure
1). Grade 4 thrombocytopenia was observed in 19% of patients,
without significant bleeding sequelae.
This level of thrombocytopenia is less than that seen with 28-day
regimens of gemcitabine/cisplatin or gemcitabine/carboplatin, and
comparable to that seenwith 21-day gemcitabine/cisplatin regimens
such as that by Cardenal et al (Table
4). The overall response rate was 31% (confidence interval
[CI], 13%53%), and the median survival was 10 months.
Subsequently, this regimen of sequential gemcitabine-carboplatin
followed by paclitaxel has been investigated as one arm of SWOG
randomized phase II trial evaluating the concept of sequential
combination chemotherapy (Figure 2).
If encouraging results are obtained, this SWOG trial (S9806) would
provide the basis for testing sequential vs concurrent three-drug
combinations, with the object of determining which approach provides
the greatest therapeutic index in the palliative management of
These studies demonstrate the feasibility and tolerability of
combining gemcitabine and carboplatin using alternative dosing
schedules. To further evaluate this combination, a National Coalition
phase III trial is in development that will compare the University of
California Davis Cancer Center regimen of gemcitabine/carboplatin to
two other new combinations: paclitaxel/carboplatin and the
nonplatinum regimen of gemcitabine/paclitaxel (Figure
Based on the therapeutic ratio of efficacy to toxicity, it is likely
that additional new studies investigating gemcitabine/platinum
combinations, which employ either cisplatin or carboplatin, will use
a 21-day schedule. Gemcitabine will be administered on day 1 and 8,
or other alternative dose-schedules will be designed to avoid
In summary, gemcitabine/cisplatin has proven to be one of the most
effective new combination chemotherapy regimens available for the
treatment of NSCLC. The platinum derivative carboplatin offers
potential therapeutic advantages in terms of reduced toxicity and
efficacy equal to cisplatin. Further studies of gemcitabine in
combination with carboplatin are clearly warranted.
1. NonSmall-Cell Lung Cancer Collaborative Group: Chemotherapy
in nonsmall-cell lung cancer: A meta-analysis using updated
data on individual patients from 52 randomized clinical trials. Br
Med J 311:899-909, 1995.
2. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong
survival in patients with advanced nonsmall-cell lung cancer:
Report of a Canadian Multicenter Randomized Trial. J Clin Oncol
3. Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin,
ifosfamide, and cisplatin in unresectable nonsmall-cell lung
cancer: Effects on survival and quality of life. J Clin Oncol
4. Albain KS, Crowley JJ, LeBlanc M, et al: Survival determinants in
extensive-stage nonsmall-cell lung cancer: The Southwest
Oncology Group experience. J Clin Oncol 9:1618-1626, 1991.
5. Edelman MJ, Gandara DR: Promising new agents in the treatment of
non-small cell lung cancer. Cancer Chemother Pharmacol 37:385-393, 1996.
6. Perez EA, Edelman MJ: Curent status of new chemotherapeutic agents
in nonsmall-cell lung cancer. J Clin Oncol 1:3-6, 1997.
7. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized trial
comparing cisplatin with cisplatin plus vinorelbine in the treatment
of advanced nonsmall-cell lung cancer: A Southwest Oncology
Group study. J Clin Oncol 16:2459-2465, 1998.
8. Sandler AB, Nemunaitis J, Denham C, et al: Phase III trial of
gemcitabine plus cisplatin vs cisplatin alone in patients with
locally advanced or metastatic nonsmall-cell lung cancer. J
Clin Oncol 18(1):122, 2000.
9. Gandara DR, Edelman MJ, Lara PA, et al: Current status and novel
therapeutic approaches in advanced nonsmall-cell lung cancer.
ASCO Education Book 362-369, 1999.
10. Bonomi P, Kim K, Fairclough D, et al: Comparison of survival and
quality of life in advanced nonsmall-cell lung cancer patients
treated with two dose levels of paclitaxel combined with cisplatin vs
etoposide with cisplatin: Results of an Eastern Cooperative Oncology
Group trial. J Clin Oncol 18(3):623-631, 2000.
11. Perng RP, Chen YM, Ming-Liu J, et al: Gemcitabine vs the
combination of cisplatin and etoposide in patients with inoperable
nonsmall-cell lung cancer in a phase II randomized study. J
Clin Oncol 15(5):2097-3102, 1997.
12. Manegold C, Bergman B, Chemaissani A, et al: Single-agent
gemcitabine vs cisplatin/etoposide: Early results of a randomized
phase II study in locally advanced or metastatic nonsmall-cell
lung cancer. Ann Oncol 8(6): 525-529, 1997.
13. Einhorn LH: Phase II trial of gemcitabine plus cisplatin in
nonsmall-cell lung cancer: A Hoosier Oncology Group study.
Semin Oncol 24(3 suppl 8):S8-24 S8-26, 1997.
14. Crino L, Scagliotti GV, Ricci S, et al: Gemcitabine and cisplatin
vs mitomycin, ifosfamide, and cisplatin in advanced
nonsmall-cell lung cancer: A randomized phase III study of the
Italian Lung Cancer Project. J Clin Oncol 17(11):3522-3530, 1999.
15. Peters GJ, Bergman AM, Ruiz van Haperen VS, et al: Interaction
between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol
22(4 suppl 11):72-79, 1995.
16. Klastersky J, Sculier JP, Laccroiz H, et al: A randomized study
comparing cisplatin or carboplatin with etoposide in patients with
advanced nonsmall-cell lung cancer: European Organization for
Research and treatment of Cancer, Protocol 07861. J Clin Oncol
17. Bonomi PD, Finkelstein DM, Ruckdeschel JC, et al: Combination
chemotherapy versus single agents followed by combination
chemotherapy in stage IV nonsmall-cell lung cancer. J Natl
Cancer Inst 91:66-72, 1999.
18. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage:
Prospective evaluation of a simple formula based on renal function. J
Clin Oncol 7:1748-1756, 1989.
19. Carmichael J, Allerheiligen S, Walling J: A phase I study of
gemcitabine and carboplatin in nonsmall-cell lung cancer. Semin
Oncol 23(5 suppl 10):55-59, 1996.
20. Ng EW, Sandler AB, Einhorn LH: A phase II study of carboplatin
plus gemcitabine in nonsmall-cell lung cancer (NSCLC)
(abstract). Proc Am Soc Clin Oncol 17:468a, 1998.
21. Cardenal F, Lopez-Cabrerizo MP, Anton A, et al: Randomized phase
III study of gemcita-
bine/cisplatin vs etoposide-cisplatin in the treatment of locally
advanced or metastatic nonsmall-cell lung cancer. J Clin Oncol
22. Carrato A, Garcia-Gomez J, Alberola V, et al: Carboplatin in
combination with gemcitabine in advanced nonsmall-cell lung
cancer: Comparison of trials using different schedules (abstract
1922). Proc Soc Am Clin Oncol 18:498a, 1999.
23. Edelman MJ, Gandara DR: Sequential chemotherapy: Rationale and
clinical trial design in advanced NSCLC. Clinical Lung Cancer
24. Day RS: Treatment sequencing, asymmetry, and uncertainty:
Protocol strategies for combination chemotherapy. Cancer Res