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Treatment of Advanced Non-Small-Cell Lung Cancer in Special Populations

Treatment of Advanced Non-Small-Cell Lung Cancer in Special Populations

Lilenbaum's paper highlighting recent controversies in the management of advanced non- small-cell lung cancer (NSCLC) in the elderly and in vulnerable performance status (PS) populations is both timely and relevant. A recent Surveillance, Epidemiology and End Results (SEER) analysis suggests that nearly 50% of all patients diagnosed with NSCLC are 70 years of age or older. Non-small-cell lung cancer generally peaks in incidence in the elderly, and the population of the United States is continually aging, with nearly 20% expected to be over age 65 by the year 2030.[1] Older Patients in Clinical Trials
Historically, older patients have been underrepresented in clinical trials. There are several putative explanations for this observation[2]:
(1) Therapeutic nihilisim that imbues many practitioners as well as their patients, and that limits the expectations of older individuals;
(2) Lack of financial, social, or logistic support for trial participation;
(3) Increased incidence of functional dependency and comorbidities, which increase with age and may compromise eligibility for therapy;
(4) Outdated eligibility criteria that explicitly exclude older individuals from trial participation-even those with intact PS;
(5) Societal pressure, particularly common in European countries with nationalized health care, where resources are greatly constrained;
(6) Lack of niche trials designed specifically for the elderly. The landmark trials of Gridelli et al (Elderly Lung Cancer Vinorelbine Italian Study [ELVIS] and Multicenter Italian Lung Cancer in the Elderly Study [MILES]) have essentially defined the state of the art for this population. In addition to yielding improved survival and quality of life, vinorelbine (Navelbine) in the ELVIS trial[ 3] resulted in only a 10% incidence of grade 3/4 toxicity. Of those enrolled, 24% also had a compromised performance status (Eastern Cooperative Oncology Group [ECOG] PS 2); among the 19 patients with a compromised PS randomized to best supportive care in the ELVIS trial, the median survival was only 8 weeks, compared to 26 weeks for PS 2 patients randomized to vinorelbine, despite the absence of objective responses in this cohort. SICOG Trial
Multiple investigators in phase II studies have demonstrated the feasibility of single-agent gemcitabine (Gemzar) in the elderly population. Frasci and colleagues,[4] who conducted the Southern Italy Cooperative Oncology Group (SICOG) trial, demonstrated a median survival time of 29 weeks for the combination of gemcitabine and vinorelbine vs only 18 weeks for single-agent vinorelbine, and commensurate 1-year survival rates of 30% and 13%, respectively. In addition, outcome was highly contingent on baseline PS and Charlson comorbidity score.[4] Patients with PS 2 had a median survival of only 4.4 months, compared to 6 months for those with PS 0/1. Those with two or more comorbidities had a median survival of 3.7 months and a much greater likelihood of discontinuing therapy early compared to the Charlson 1 group, for whom the median survival was 4.8 months, and the Charlson 0 group, for whom the median survival was 6.5 months. MILES Trial
The track record of the single-agent control arm in the SICOG trial is somewhat disturbing.[4] Median survival in this group proved no better than that in the best supportive care arm in the prior ELVIS trial.[3] In this regard, the MILES trial is potentially more credible.[5] The SICOG trial accrued just over 150 patients, whereas the MILES effort accrued nearly 700 individuals. As discussed by Dr. Lilenbaum, in contrast to the SICOG effort, the MILES effort failed to show a survival benefit for the combination of gemcitabine and vinorelbine vs the constituent single agents. Unlike most North American trials in advanced NSCLC, a higher proportion of patients- in this case, 31%-had stage IIIB disease. In addition, the plurality (49%) had squamous cell histology. Nearly 50% had three or more comorbidities. The distribution of comorbidities was well balanced between each arm. The combination arm showed significantly more neutropenia, diarrhea, fatigue, vesicant reactions, cardiac toxicity, and constipation compared to the gemcitabine single-agent arm and significantly more myelosuppression compared to single-agent vinorelbine. PS 2 patients had no overt increase in toxicity, but sustained a clear reduction in survival: 1-year survival rates among PS 2 patients were 18% to 23%, compared to 30% to 43% for PS 0/1 patients. Those with higher baseline quality of life had far better survival compared to those with intermediate or inferior scores. Those with a baseline quality-of-life assessment of > 67% had a median survival of 53 weeks, compared to only 20 weeks for those with a baseline assessment of < 42%. By the same token, those with an intermediate or better baseline Instrumental Activities of Daily Living (IADL) score had improved survival compared to those with poorer scores. Retrospective Analyses
Based on these results, Gridelli and colleagues consider a nonplatinum single agent the standard of comparison in the treatment of elderly individuals with advanced NSCLC. Many investigators, however, dispute this notion, citing-as Dr. Lilenbaum has highlighted-several important retrospective analyses in which platinumbased therapy proved feasible in the elderly. In addition to the studies the author enumerates, Belani and colleagues have reviewed outcome in older patients enrolled in TAX 326, a randomized phase III effort evaluating docetaxel in combination with either cisplatin or carboplatin (Paraplatin) vs a reference regimen of vinorelbine/ cisplatin.[6] Of 1,218 patients enrolled, 410 were 65 years of age or older. Elderly individuals enrolled in the docetaxel/cisplatin arm had a median survival of 12.6 months compared to only 9.9 months for those in the vinorelbine/cisplatin arm. The respective 1- and 2-year survival rates were 52% and 24% for docetaxel/cisplatin vs 41% and 17% for vinorelbine/ cisplatin. This difference was statistically significant, with a hazard ratio of 1.34 (confidence interval [CI] = 1.011-1.776). There was no significant difference in outcome between elderly individuals enrolled in the docetaxel/carboplatin vs vinorelbine/ cisplatin arm. The elderly, however, experienced more toxicity-in particular, a higher incidence of grade 3/4 asthenia, infection, and pulmonary toxicity-and in the cisplatin arms, more diarrhea and sensory neurotoxicity. In a landmark phase III trial evaluating a truncated course of paclitaxel/ carboplatin (four cycles) vs indefinite administration until disease progression, Hensing et al analyzed outcome segregated by age.[7] The elderly experienced more fatigue, but no other exacerbation of toxicity compared to the younger cohorts. Median survival and 1- and 2-year survival rates were no different (Table 1). Despite the absence of significant differences in therapeutic outcome, older patients were much less likely to complete treatment as planned (16% vs 32%, P = .02) and were much more likely to stop treatment either because of toxicity or general reservations. Additional Data
In another randomized phase II trial evaluating various applications of weekly paclitaxel in combination with either weekly or monthly carboplatin, the least toxic arm (carboplatin at an area under the concentration-time curve [AUC] of 6 every 4 weeks and paclitaxel at 100 mg/m2 on days 1, 8, and 15 every 4 weeks) had the best therapeutic index, with response rates as well as median and 1-year survival rates equaling, if not exceeding, the more toxic approaches.[8] Among the 44 elderly individuals enrolled in this arm, there was a somewhat higher incidence of grade 4 neutropenia, but no other significant differences in toxicity compared to younger enrollees. Median survival time for those ≥ 70 years old was 49 weeks, with 1- and 2-year survival rates of 50% and 23% respectively-no different from the results observed in patients under age 70 (median survival time of 48 weeks, 1-year survival of 46%, 2-year survival of 11%). Few data exist for patients over age 80. Although patients between the ages of 70 and 80 who are fit generally do as well as, or nearly as well as, their younger counterparts (albeit with more toxicity, particularly myelosuppression), those over age 80 may fare worse. In a nested analysis of ECOG 1594, with more than 1,200 patients enrolled, only 9 were age 80 or older.[9] In this group, there were no responses. Only one individual was able to tolerate more than three cycles of therapy. Progressionfree survival was only 2.2 months, compared to 3.7 months for patients aged 70 to 79, and median survival was 4.2 vs 8.2 months in the cohort of 70- to 79-year-olds. Elderly NSCLC Patients:
Conclusions
Although the elderly are more likely to be frail and vulnerable compared to younger patients, those who are fit seem to do as well as their younger counterparts. While level 1, evidence-based data show a clear benefit for nonplatinum monotherapy (ie, vinorelbine) vs best supportive care in elderly PS 0-2 NSCLC patients, no consistent superiority has been shown for nonplatinum doublets. Comorbidities appear to be predictive of outcome. Retrospective analyses of platinum-based combinations have demonstrated similar outcomes for fit elderly and younger cohorts with respect to response rate, time to progression, median survival, and 1- and 2-year survival rates, although these benefits are vitiated by increased toxicity. Decisions regarding therapy in the elderly hinge on multiple factors, including the toxicity profile of the agent(s) under consideration, performance status, pharmacokinetics, comorbidities, organ function, and social support. Patients between the ages of 70 and 80 and those over age 80 may constitute two functionally distinct cohorts. In this regard, special consideration must be given to comorbidity, functional status (ie, IADL) as well as the mental state (psychological and cognitive) of elderly individuals with advanced NSCLC. Logistics also play a key role, as does baseline nutrition of potential study participants. Several outstanding issues remain. To date, there has been no elderlyspecific, phase III trial comparing a single agent to the identical single agent in combination with platinum. In North America, at least, a more comprehensive analysis of comorbidities and their influence on toxicity, treatment tolerance, quality of life, and survival is needed. We also need to expand our data set on NSCLC patients 80 years of age or older-a rapidly expanding cohort of patients, for whom very little information exists. Finally, in the context of clinical trials, we should at least consider nested pharmacokinetic analyses. PS 2 NSCLC
Using the database of multiple ECOG studies through the early 1990s, Mike Jiroutec, a statistician formerly associated with ECOG, conducted a recursive partitioning analysis of prognostic factors in NSCLC.[10] These trials evaluated single agents as well as platinumbased combinations. The three most important prognostic factors included performance status, gender, and appetite (and by inference, weight loss). A woman with an intact appetite and excellent performance status (PS 0) could expect a median survival of over 12 months, whereas the same woman with a compromised status (PS 2) and diminished appetite had a median survival of only 2.3 months. This represents a greater than fivefold difference in therapeutic expectations, based purely on clinical factors that are readily identifiable within the first 20 seconds of a new patient evaluation. To date, there are no therapeutic combinations that can bridge this gap. These differences speak to the intrinsic biology of the tumor as well as the intrinsic biology and physiologic function of the patient. Dr. Lilenbaum has ably reviewed outcome for PS 2 individuals enrolled in North-American trials. Outside the United States, trends are identical. In a phase III trial, Alberola et al compared cisplatin/gemcitabine to the triplet, cisplatin/gemcitabine/vinorelbine, as well as to sequential nonplatinum doublets (gemcitabine/vinorelbine-> ifosfamide (Ifex)/vinorelbine).[11] PS 2 individuals had a median survival of only 4.8 months, compared to 9.11 months in PS 0/1 individuals. Van Meerbeeck et al initiated a phase III trial comparing cisplatin combinations with either paclitaxel or gemcitabine vs the nonplatinum doublet (paclitaxel/gemcitabine).[12] Median survival in the PS 2 cohort was only 3.3 months, compared to 8.6 months in the PS 0/1 cohort. A nearly identical trend was observed by Kosimidis in a phase III trial evaluating carboplatin (AUC 6) in combination with paclitaxel at either a low dose (175 mg/m2) or high dose (225 mg/m2).[13] Median survival in the PS 2 cohort was 3.8 months vs 11.25 months in the PS 0/1 cohort. Improved Median Survival
Compared to these historic series, median survival in ECOG 1599[14]- a randomized phase II trial of cisplatin at 60 mg/m2 every 3 weeks and gemcitabine at 1 g/m2 every 3 weeks or carboplatin (AUC 6) and paclitaxel at 200 mg/m2 every 3 weeks-was somewhat better: 6.8 months for the cisplatin/gemcitabine arm and 6.1 months for the carboplatin/paclitaxel arm. That said, these improvements in median survival did not necessarily translate to improved 1-year survival rates (25% and 19%, respectively). This trial has the distinction of being one of the first specifically restricted to PS 2 individuals. In addition, it has reinforced the notion that combination therapy is, at the very least, feasible in vulnerable patients- an observation previously cited by Lilenbaum et al in a subanalysis of PS 2 individuals enrolled in CALGB 9730.[15] Although Lilenbaum's subanalysis was performed in the context of a much larger prospective randomized phase III trial, the observations are provocative.[15] The median survival of PS 2 individuals receiving combination paclitaxel/carboplatin was double that observed for those receiving single-agent paclitaxel (4.7 vs 2.4 months); and there was a commensurate increase in 1-year survival rates (18% vs 10%, log rank P = .0123). There were no 2-year survivors among the PS 2 individuals receiving singleagent paclitaxel, whereas the 2-year survival rate was nearly 10% in the PS 2 cohort receiving combination therapy. Neurotoxicity remains a major sequela of treatment in patients receiving every-3-week paclitaxel. Belani and others have looked at weekly therapy with paclitaxel in this setting.[8] In a randomized phase II effort, paclitaxel at 100 mg/m2 on days 1, 8, and 15 every 4 weeks in combination with carboplatin at AUC 6 had the best therapeutic index compared to other iterations of this combination. Median survival among PS 2 individuals in that arm was 26 weeks, and the 1- year survival rate was 28%.[8] Recently Completed Efforts:
ASCO 2004
A number of recently completed trials have also proven revealing. Kosimidis et al evaluated gemcitabine, either as a single agent or in combination with carboplatin administered every other week.[16] Median survival in the combination arm was 6.7 months, compared to 4.8 months for single-agent gemcitabine therapy (P = .49). However, the combination resulted in significantly more myelosuppression and no incremental improvement in subjective clinical response. On the other hand, single-agent studies evaluating either docetaxel alone or sequential vinorelbine followed by docetaxel have yielded somewhat poorer results. In a phase II trial reported by Hesketh et al, among 44 patients with a compromised status (PS 2), the response rate was only 10%, median survival only 4 months, and 1-year survival rate 14%, compared to 21%, 9 months, and 40% for a contemporaneous good performance status, elderly cohort.[17] In a randomized phase II trial, Lilenbaum et al evaluated docetaxel at 75 mg/m2 every 3 weeks, or 30 mg/m2 on days 1, 8 and 15 every 4 weeks.[18] Here again, median survival time was rather poor, ie, 2.4 months for the PS 2 cohort. CT-2103 (Xyotax) is a polyglutamated version of paclitaxel, with much lower likelihood of plasma esterase degradation, and far better tumor cell penetration and intracellular retention.[19-21] Phase I and II studies have demonstrated the feasibility of this agent, both alone and in combination with carboplatin.[21-23] Two separate phase III trials in the PS 2 cohort have been mounted: Selective Targeting for Efficacy in Lung cancer Lower Adverse Reactions (STELLAR) 3 compares standard paclitaxel and carboplatin to combination CT-2103 (210 mg/m2) and carboplatin (AUC 6). Both regimens are administered at 3-week intervals. This study completed accrual in the fall of 2003, with over 400 patients enrolled. STELLAR 4 compares single- agent CT-2103 to either gemcitabine or vinorelbine. This study has also completed accrual (n = 460+). The results of each effort should be available in the first quarter of 2005. PS 2 NSCLC Patients:
Conclusions
Patients designated as PS 2 represent a sizable percentage of the individuals evaluated in our clinical practices. Heretofore, they have been largely excluded from clinical research, but over the past 5 years, renewed interest has focused on this group. Emerging data suggest that chemotherapy can improve diseaserelated symptoms and may prolong survival compared to best supportive care. Combination regimens may have the greatest impact on PS 2 patients, but toxicity is clearly exacerbated, and overall, prognosis remains poor. Studies need to differentiate patients who are PS 2 on the basis of comorbidity (and are, therefore, less likely to benefit from cytotoxic therapy) from those who have rapidly expanding disease burden and who may be more likely to benefit. Patients designated as PS 2 represent a sizable percentage of the individuals evaluated in our clinical practices. Heretofore, they have been largely excluded from clinical research, but over the past 5 years, renewed interest has focused on this group. Emerging data suggest that chemotherapy can improve diseaserelated symptoms and may prolong survival compared to best supportive care. Combination regimens may have the greatest impact on PS 2 patients, but toxicity is clearly exacerbated, and overall, prognosis remains poor. Studies need to differentiate patients who are PS 2 on the basis of comorbidity (and are, therefore, less likely to benefit from cytotoxic therapy) from those who have rapidly expanding disease burden and who may be more likely to benefit.

Disclosures

Dr. Langer receives grant/research support from, is a scientific advisor for, and is a member of the speaker’s bureau for Bristol Myers Squibb, Pharmacia, Lilly, Schering-Plough Research Institute, Aventis, Amgen, Cell Therapeutics Inc, OrthoBiotech, Celgene, Vertex, Genentech, AstraZeneca, Pfizer, Active Biothech Medimmune, ImClone, Intrabiotics, GlaxoSmithKline, Pharmacyclics, Novartis, and Sanofi-Synthelabo Novartis.

References

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