Introduction

Encouraging results of several Phase III studies presented at the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO 2002) held May 18-21, 2002 in Orlando, Florida suggest that the current standard of care for advanced non-small cell lung cancer (NSCLC) should be platinum-based combination chemotherapy.^1-4

Although many community physicians believe that chemotherapy does not offer benefits to patients with advanced NSCLC, numerous studies have determined that chemotherapy improves survival and symptoms in advanced NSCLC.⁵

Studies presented at ASCO 2002 suggest that quality of life (QOL) is measurable and that newer combinations of chemotherapeutic agents can improve QOL.^6,7 Thus, oncologists should consider the individual patient profile when selecting a chemotherapy regimen. Factors to consider are patient age, Performance Status, comorbidities, and patient preference (is extending life a priority or avoiding toxicity a priority?). Newer chemotherapeutic agents offer efficacious and well-tolerated alternative chemotherapy options for patients who cannot tolerate platinum-based chemotherapy. One such combination chemotherapy is gemcitabine (Gemzar, Eli Lilly) and vinorelbine (Navelbine, GlaxoSmithKline), as reported in a Phase III study showing improved QOL with this combination.¹

Combination chemotherapy using two drugs was deemed the standard for patients with advanced NSCLC by Paul A. Bunn, Jr., MD, newly installed President of ASCO 2002. Dr. Bunn discussed an important Cancer and Leukemia Group B (CALGB) study presented at a Plenary Session⁴, which demonstrated the superiority of platinum-based combination chemotherapy over single-agent paclitaxel chemotherapy, even for a subset analysis of elderly patients and patients with a poor Performance Status (PS) of 2 (PS2).

Dr. Bunn told listeners that numerous studies over the past decade have clearly established that chemotherapy provides a treatment advantage compared to best supportive care for patients with advanced NSCLC. He said that studies presented at this year's ASCO 2002 meeting show that two drugs are better than one, even if one of those drugs is a newer chemotherapeutic agent.

"Studies at this meeting show that three drugs are no better than two," he said. "Two-drug combination chemotherapy improves survival and QOL in advanced NSCLC in patients of all ages. Results in the CALGB study suggest that PS2 patients should be included in clinical trials."

He told listeners that single-agent chemotherapy as second-line therapy improves quality of life (QOL) and survival and that combination chemotherapy should be studied in the second-line setting.

Although there is no cure yet for lung cancer, "we are near the top of the mountain. Please offer your patients a clinical trial to help us reach the summit," he told the audience.

The study Dr. Bunn discussed (CALGB 9730) involved a comparison between paclitaxel and carboplatin versus paclitaxel alone in Stage IIIb/IV NSCLC and clearly answered the question, "Is it worth it to have chemotherapy?" according to lead author Rogerio C. Lilenbaum, MD, Director of the Thoracic Oncology Program, The Mount Sinai Cancer Center, Miami Beach, Florida.

CALGB 9730 showed that combination chemotherapy increased response rates compared to single-agent chemotherapy, and improved failure-free survival in advanced NSCLC compared to single-agent chemotherapy. Overall survival at 1 year was not statistically different (37% vs. 33%, respectively; log rank test p=0.2022, Wilcoxon test p=0.0125). "Toxicity is somewhat greater with combination chemotherapy," noted Dr. Lilenbaum, "but the clinical implications of toxicity associated with combination chemotherapy are modest."

The study included 584 patients (158 patients were over 70 years of age). The same results were found in a preplanned analysis of elderly patients and those with PS2--that is, the superiority of combination chemotherapy over single-agent chemotherapy. Among the elderly group, 35% of patients were alive at 1 year on the combination chemotherapy treatment arm vs. 31% of patients treated with single-agent chemotherapy.

"In the context of overall poor outcome for patients with PS2, combination chemotherapy was superior in this subset of patients," Dr. Lilenbaum said. Further, no detrimental impact on QOL was found with combination chemotherapy and no significant differences emerged in health resource utilization between the two treatment arms of the CALGB 9730 trial, suggesting that combination chemotherapy is no more costly overall than single-agent chemotherapy.

"Patients with advanced NSCLC and good PS should be treated with a platinum-based doublet. This should be the template upon which new [chemotherapy] strategies are based. Elderly patients can be treated similarly," Dr. Lilenbaum advised the audience. Patients who cannot tolerate platinum-based therapy can be offered a doublet containing newer agents, he added. This includes the frail elderly, poor PS patients, and those with comorbidities.

Gemcitabine/Vinorelbine Offers Improved QOL Compared With Platinum-Based Chemotherapy

A Phase III study demonstrated improved QOL with gemcitabine and vinorelbine combination chemotherapy for patients with Stage IIIB or IV NSCLC in terms of physical function, emotional function, role function, and global QOL on days 1 and 8 when chemotherapy was given.¹ The positive impact on QOL by gemcitabine and vinorelbine was observed in the context of slightly shorter progression-free survival and overall survival with this combination, explained Cesare Gridelli, MD, Division of Medical Oncology, SG Moscato Hospital, Naples, Italy.

"Gemcitabine and vinorelbine could be offered to patients who are particularly concerned about toxicity or who cannot tolerate a platinum-based regimen," Dr. Gridelli told listeners.

The study randomized 503 patients with advanced NSCLC to receive one of three treatment arms in a 2:1:1 ratio: cisplatin 80 mg/m² day 1 plus vinorelbine 30 mg/m² days 1 and 8; or cisplatin 80 mg/m² day 1 plus gemcitabine 1200 mg/m² days 1 and 8; or gemcitabine 1000 mg/m² days 1 and 8 plus vinorelbine 25 mg/m² days 1 and 8. Patients included in the trial were under age 70 and had received no prior chemotherapy. Patient demographics included median age 62 years, 87% PS 0-1, 80% were Stage IV, 80% were male, and 43% had adenocarcinoma.

Significantly more grade 3/4 leukopenia and neutropenia, and significantly more vomiting (p < 0.0001), alopecia (p = 0.006), and ototoxicity (p = 0.03) was observed in platinum-treated patients than in the gemcitabine and vinorelbine treatment arm.

Median progression-free survival favored the cisplatin-based treatment arms: 22 weeks vs. 17 weeks (1-sided p = 0.005, Hazard Rate (HR) 1.29, 90% Confidence Interval (CI) 1.10-1.52). At one year, 37% of those treated with platinum-based chemotherapy were alive compared with 31% who received gemcitabine and vinorelbine combination chemotherapy.

During the discussion period following Dr. Gridelli's presentation, Jeffrey Crawford, MD, Duke University Medical Center, Durham, North Carolina said that this study shows that a non-platinum-containing doublet offers greater benefits in QOL compared with a cisplatin-containing chemotherapy. "Newer chemotherapy agents offer better QOL and less toxicity. These are important considerations in our patients, and we should consider them when making treatment decisions," Dr. Crawford emphasized. For most patients, he continued, "a platinum and a new agent appears to be the best paradigm," but in patients who cannot tolerate this therapy or who do not want to suffer toxicity, combinations such as gemcitabine and vinorelbine are appropriate.

QOL in the Elderly

A substudy of the MILES (Multicenter Italian Lung Cancer in the Elderly Study) trial, reported by Francesco Perrone, MD on behalf of the MILES investigators, Napoli, Italy found that baseline self-assessed QOL using the EORTC C30 global QOL score (items 29-30) has significant predictive ability of survival of elderly patients with advanced NSCLC.⁶ However, baseline assessment of activities of daily living (ADL) did not have predictive ability, and instrumental activities of daily living (IADL) had borderline predictive ability.

The MILES study, the largest study ever performed in elderly NSCLC patients, showed that single-agent vinorelbine was preferable to combination chemotherapy in elderly patients (age ≥ 70 years) who had 2 or more comorbidities with advanced NSCLC.⁸ Single-agent chemotherapy with either vinorelbine or gemcitabine was compared to non-platinum based combination chemotherapy. One year overall survival ranged from 41% on the vinorelbine treatment arm to 26% and 31% on the gemcitabine and non-platinum-based combination treatment arms, respectively. Thus, combination chemotherapy did not improve survival in these patients versus single-agent treatment.

Dr. Perrone said that results of the MILES trial suggest that elderly patients are able to tolerate chemotherapy well in general, and that there was no advantage for a doublet chemotherapy regimen over single-agent chemotherapy. The QOL substudy utilized overall survival as the end point. Analysis was performed by adding baseline values of ADL, IADL, and QOL singly or combined to a multivariable Cox model that included sex, age, PS, and number of comorbidities of patients, as well as tumor characteristics (histology, stage, number of metastatic sites), size of the institution and type of chemotherapy as adjusting covariates. Relevant data were obtained in 566 of the 698 patients (81%) enrolled in the MILES trial.

References

1. Gridelli C, Shepherd F, Perrone F, et al. Gemvin III: A Phase III Study of Gemcitabine Plus Vinorelbine (GV) Compared to Cisplatin Plus Vinorelbine or Gemcitabine Chemotherapy (PCT) for Stage IIIb or IV Non-Small Cell Lung Cancer (NSCLC): An Italo-Canadian Study. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 1165.
2. Sederholm C. Gemcitabine (G) Compared with Gemcitabine Plus Carboplatin (GC) in Advanced Non-Small Cell Lung Cancer (NSCLC): A Phase III Study by the Swedish Lung Cancer Study Group (SLUSG). 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 1162.
3. Georgoulias V, Ardavanis A, Agelidou M, et al. Preliminary Analysis of a Multicenter Phase III Trial Comparing Docetaxel (D) versus Docetaxel/Cisplatin (DC) in Patients with Inoperable Advanced and Metastatic Non-Small Cell Lung Cancer (NSCLC). 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 1163.
4. Lilenbaum RC, Herndon J, List M, et al. Single-Agent (SA) versus Combination Chemotherapy (CC) in Advanced Non-Small Cell Lung Cancer (NSCLC): A CALGB Randomized Trial of Efficacy, Quality of Life (QOL), and Cost-Effectiveness. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 2.
5. [no authors listed] Chemotherapy in Non-Small Cell Lung Cancer: A Meta-Analysis Using Updated Data on Individual Patients from 52 Randomized Clinical Trials. BMJ 1995;311:899-909.
6. Perrone F, Gridelli C, Cigolari S, et al. Baseline Assessment of Quality of Life (QOL) is a Strong Prognostic Factor for Survival of Elderly Patients with Advanced Non-Small Cell Lung Cancer (NSCLC). A Secondary Analysis of the MILES Study. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 1346.
7. Ohashi Y, Matsumoto T, Nishiwaki Y, et al. Favorable QOL-Profile of Docetaxel (D) + Cisplatin (P) Compared to Vindesine (V) + P and Its Influence on Survival in Stage IV Non-Small Cell Lung Cancer (NSCLC) Patients. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 1497.
8. Gridelli C, Perrone F, Cigolari S, et al. The MILES (Multicenter Italian Lung Cancer in the Elderly Study) Phase III Trial: Gemcitabine + Vinorelbine vs. Vinorelbine and vs. Gemcitabine in Elderly Advanced NSCLC Patients. 37th Annual Meeting of the American Society of Clinical Oncology 2001;20 Abstract 1230.