The Benefits of Achieving Stable Disease in Advanced Lung Cancer
The Benefits of Achieving Stable Disease in Advanced Lung Cancer
The majority of patients diagnosed
with non-small-cell lung
cancer (NSCLC) present with
advanced, inoperable disease. Advanced
NSCLC is associated with
poor survival and debilitating symptoms
such as cough, hemoptysis, dyspnea,
chest pain, fatigue, and weight
loss.[1,2] Cytotoxic chemotherapies
are offered to patients with advanced
NSCLC who have a good performance
status. This treatment approach has
resulted in modest improvements in
median and 1-year survival for patients
with advanced NSCLC, compared
with best supportive care.
Given the limited survival times
associated with current treatment, the
most important goals of therapy are
palliation of symptoms and improved
quality of life. Clearly, new treatment
strategies are needed. The moleculartargeted
agents are attractive because
of their milder toxicity profile and
promising efficacy. Many of these
agents are primarily cytostatic in action,
and thus more likely to produce
stable disease than their cytotoxic
In advanced NSCLC, prolonged
stable disease could represent a meaningful
benefit, especially if associated
with improvement in symptoms
and enhanced quality of life. However,
assessing stable disease in clinical
trials can be a challenge. The inclusion
of new end points and outcomes
in cancer clinical trials could help to
more clearly define and evaluate stable
disease, and to fully assess the
benefits of both standard chemotherapies
and the new molecular-targeted
True stable disease entails the longterm
inhibition of further tumor
growth and metastasis. In addition to
greater time to progression, disease
stabilization may be associated with
control of metastasis, symptom relief,
improved performance status, enhanced
quality of life, and, ultimately,
with the opportunity for prolonged
survival (Table 1). However, even a
reduction in the rate of tumor growth
without complete stasis may provide
benefit to patients.[4-6] Although
many clinicians recognize the potential
value of stabilizing disease in a
variety of solid tumors, stable disease
is not widely considered an indication
of therapeutic efficacy in
clinical trials. The reasons for this
discrepancy may lie with the difficulties
in evaluating stable disease in clinical
The definition of stable disease is problematic. The current Response Evaluation Criteria in Solid Tumors (RECIST) define stable disease as not meeting the criteria for partial response or progressive disease-in other words, anything from a less than 30% decrease to a less than 20% increase in tumor size (based on longest diameter). As a result, the stable disease category in clinical trials actually represents a wide spectrum, making it difficult to evaluate the potential benefits. Some studies have suggested that patients with stable disease are not a homogeneous population. One example is a study that investigated stable disease in patients with advanced colorectal cancer who had been treated with carboplatin (Paraplatin), fluorouracil, and leucovorin. After treatment, 48 of 97 evaluable patients were categorized as having stable disease and were further stratified into two groups: those who showed clinical benefit and continued chemotherapy until eight cycles or disease progression (n = 22), and those who did not show clinical benefit and stopped chemotherapy after four cycles (n = 26; 7 were asymptomatic). Determination of clinical benefit included assessments of pain, performance status, weight, and temperature. Survival was not significantly different between patients with an objective response and patients with stable disease and clinical benefit (P = .24), but there was a significant difference in survival between responders and patients with stable disease without clinical benefit (P = .0004). Furthermore, patients with stable disease and clinical benefit showed significantly improved survival compared with patients with progressive disease (P = .0000051). Therefore, in this study, inclusion of the clinical benefit end point was required to accurately evaluate and predict which patients were benefiting from treatment. Assessment Accuracy
Another difficulty in evaluating stable disease concerns the accuracy of the method for assessing tumor response. True stable disease is not the equivalent of no change based on radiologic evaluation. Several investigators have found that clinical restaging based on radiologic evaluation does not always accurately reflect what is happening at the cellular level in the tumor. It can be difficult to distinguish between vital tumor tissue and necrotic or scar tissue.[10,11]
- Regression Grade-One study evaluated the prognostic value of tumor regression in resection specimens from 40 patients with locally advanced NSCLC who had received neoadjuvant chemoradiation therapy (two cycles of ifosfamide [Ifex], carboplatin, and etoposide followed by twice-daily radiation up to 45 Gy with simultaneous administration of carboplatin and vindesine). The specimens were evaluated morphologically for therapy-induced changes and graded as follows: grade I, no therapy-induced regression; grade IIa, regression with at least 10% of vital tissue remaining; grade IIb, regression with less than 10% of vital tumor tissue remaining; and grade III, complete tumor regression. Regression grade was significantly (P = .02) correlated with survival in this study (regression grades I/IIa: median survival 14 months, 3-year survival 9%; regression grades IIb/III: median survival 36 months, 3-year survival 52%), whereas presurgical clinical response was not significantly associated with tumor regression. More than half of the tumors that were clinically staged as showing no change exhibited pronounced morphologic regression with less than 10% of vital tumor tissue remaining.
- Response Rate/Survival Benefit- Radiologic response does not always accurately reflect a survival benefit.[ 12] In a review of two phase III trials comparing seven different combination chemotherapy regimens in patients with good performance status and metastatic NSCLC (n = 893), investigators found that the treatment regimen with the highest response rate (mitomycin/vinblastine/platinum) had significantly fewer 1-year survivors (12%) than any other regimen (P = .003). Similar rates of survival between patients with either stable disease or partial responses suggest that the benefit may be due to prevention of early disease progression rather than tumor regression.
- Follow-up Requirements-Evaluating stable disease in clinical trials may require lengthy posttreatment follow-up periods. Many solid tumors exhibit periods of slower growth or even growth cessation during their natural course. Therefore, the length of the follow-up period must be sufficient to demonstrate that true stable disease has been achieved. Most investigators indicate that a minimum of 3 months is required, but 6 months is preferred.[15,16]
The new targeted agents provide another treatment option for patients with advanced NSCLC. These agents target the molecular differences between malignant and normal cells, and several focus on the increased activity of the epidermal growth factor receptor (EGFR)-tyrosine kinase (TK) observed in lung cancer and other common solid tumors.[23-26] In normal cells, the activity of EGFR-TK is restricted and tightly regulated. In cancer, however, the activity of EGFRTK is increased through a variety of mechanisms, including overexpression of the receptor or its ligands, altered interactions with other cellsurface or intracellular molecules, or constitutively activating mutations of the receptor itself. Increased EGFR-TK activity is transforming in vitro and is associated with a variety of processes involved in tumor progression, including proliferation, metastasis, angiogenesis, and decreased apoptosis.[ 24,27,28] Increased levels of EGFR are observed in the majority of common solid human tumors, including 81% to 93% of NSCLC.[29,30] Activity of EGFR-TK is, therefore, a highly promising target for the treatment of patients with such cancers. Several novel molecular agents can be used to inhibit the autophosphorylation (and, hence, the activity) of EGFR-TK by competitively blocking the intracellular adenosine triphosphate binding site of the receptor. Inhibition of EGFR-TK activity is not necessarily lethal to tumor cells; therefore, the effect of these new agents may be cytostatic as well as cytotoxic. EGFR-TK inhibitors may promote tumor cell apoptosis and may also reduce angiogenesis, thereby indirectly inhibiting tumor growth.[24,28,31-33] Novel Clinical Trial End Points and Outcomes
Evaluating the clinical efficacy and benefits of targeted cancer therapies may require novel approaches to the design of clinical trial end points and outcomes.[4,12,34] With cytotoxic chemotherapy regimens, the goal of therapy is to maximize tumor response without exceeding the maximum tolerated dose. Phase I trials of such agents aim to establish the maximum tolerated dose, and phase II/III trials use objective tumor response as the primary efficacy outcome. For targeted therapies, toxicity is expected to be milder, and clinical efficacy may be observed at doses considerably below the maximum tolerated dose. In terms of efficacy, tumor shrinkage may not be a realistic end point. Complete assessment of clinical efficacy should include multiple parameters: assessment of objective response, including complete and partial response; stable and progressive disease; evaluation of overall, median, and progression-free survival; and changes in symptoms and quality of life. Basing treatment evaluation on tumor response rate alone may lead to the dismissal of potentially beneficial therapies. Furthermore, improvements in symptoms and quality of life are the most important end points in the palliative treatment setting and may provide clues about the benefits of stable disease. Patients with advanced NSCLC regard symptom improvement and quality of life as priorities. In one study, only 22% of patients surveyed (18/81) would choose chemotherapy for a survival advantage of 3 months, whereas 68% (55/81) would choose chemotherapy for improved symptoms even without additional survival benefits. The new molecular-targeted agents may offer a range of clinical benefits, including stable disease, symptom relief, and improved quality of life. Achieving Stable Disease in Third-Line Therapy: Gefitinib In preclinical studies, the EGFR-TK inhibitor gefitinib (Iressa) showed activity against a wide range of common solid tumor types. Gefitinib was found to inhibit EGFR-TK activity and to block downstream events, such as proliferation, invasion, and angiogenesis, as well as to promote apoptosis.[31,32,36-42] In phase I clinical trials of gefitinib, therapeutic efficacy was observed at doses well below the maximum tolerated dose of 600 to 1,000 mg/d.[43-45] Objective tumor responses were documented in 10% of patients with NSCLC (n = 100). Patients with NSCLC also experienced disease stabilization (13%), and there were anecdotal reports of symptom improvement.[43-46] In skin biopsies from these patients (n = 65), gefitinib treatment was associated with a decrease in proliferation, an increase in apoptosis, and an upregulation of markers of differentiation. These results support the further investigation of gefitinib for the treatment of advanced NSCLC and illustrate the need for alternative treatment end points, such as stable disease, symptom improvement, and biologic markers. IDEAL-1 and IDEAL-2
The Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 trials were large, randomized phase II trials designed to evaluate disease response, safety, and improvements in symptoms and quality of life in patients with advanced NSCLC treated with gefitinib at 250 or 500 mg/d.[48,49] IDEAL-2 was a US-based trial including 216 patients who had previously received two or more chemotherapy regimens that contained platinum and docetaxel given concurrently or separately. IDEAL-1 was conducted outside the United States and included 210 patients treated with one or more previous chemotherapy regimens containing a platinum agent.
- Assessing Improvements in Symptoms and Quality of Life-Improvement in NSCLC-related symptoms was a primary end point in IDEAL-2 and a secondary end point in IDEAL-1. Symptom improvement was assessed using the Lung Cancer Scale (LCS), a 7-item subscale of the Functional Assessment of Cancer Therapy-Lung (FACT-L). Quality of life was a secondary end point in both trials and was assessed with the FACT-L. The FACT-L and LCS are validated tools for use in clinical trials.[50,51] On both assessments, higher scores indicate improvement. Patients in IDEAL-2 were required to be symptomatic at baseline, as indicated by a score of 24 points or less on the LCS (a score of 28 is asymptomatic). Although patients in IDEAL- 1 were not required to be symptomatic at trial entry, 140 patients in this trial were evaluable for symptom improvement as determined by a baseline LCS score of 24 or less. The symptom improvement rate was prospectively defined as an increase of 2 or more points in LCS score that lasted for at least 4 weeks, and the rate of improvement in quality of life was defined as an increase of at least 6 points in FACT-L score (136 points = best quality of life) that lasted for at least 4 weeks. In IDEAL-2, objective tumor response rates were 12% and 9%, respectively, in the 250 and 500 mg/d groups. In IDEAL-1, tumor response rates were 18% and 19%, respectively, in the two dose groups. In both trials, a considerable percentage of patients achieved stable disease- 31% and 27%, respectively, in the 250 and 500 mg/d groups in IDEAL-2, and 36% and 32%, respectively, in IDEAL-1.[52,53] Therefore, patients with stable disease made up a substantial proportion of the total number of patients whose disease was under control during these trials (Figure 1).[52,53] As shown in Table 2,[54,55] stable disease was associated with a range of clinical benefits, including improvement in NSCLC-related symptoms and enhanced quality of life, in IDEAL-1 and IDEAL-2.[56,57] The percentage of patients with stable disease who experienced symptom improvement was 70% and 40% in IDEAL-1 and 81% and 61% in IDEAL-2, in the 250 and 500 mg/d groups, respectively. Among patients with stable disease, the percentage who experienced enhanced quality of life was 40% and 32% in IDEAL-1 and 61% and 45% in IDEAL-2, in the 250 and 500 mg/d groups, respectively.[ 54,55] In IDEAL-2, patients who achieved stable disease (n = 62) experienced greater median overall survival (9.4 months) compared with patients whose disease progressed (n = 94, 5.2 months). Median overall survival for patients with an objective response (n = 22) in IDEAL-2 had not yet been reached at the time of reporting. The inclusion of additional end points such as improvements in symptoms and quality of life in these trials allows for a more in-depth evaluation of the relevance of stable disease. The positive association between stable disease and outcomes such as improvements in symptoms and quality of life indicates that many patients in these trials derived clinical benefit from stable disease achieved through treatment with gefitinib. Although conclusions about achieving stable disease with gefitinib therapy await further follow-up, these results suggest that gefitinib may actually reduce or inhibit tumor growth to a clinically relevant degree. Conclusions Stable disease offers many potential benefits to patients with advanced NSCLC. Radiographic tumor response should no longer be considered the only measurement of tumor status in clinical trials. Although improved survival remains the most important goal of therapy, stable disease is increasingly recognized as valuable and represents a positive therapeutic outcome for patients with advanced NSCLC. There are problems associated with evaluating stable disease in clinical trials; however, many of these problems may be addressed by the inclusion of new end points in trials. For example, outcomes that address clinical benefits such as improvement in symptoms or enhanced quality of life may help to distinguish which patients with stable disease are truly benefiting from a given treatment and which may have progressive disease, requiring alternative treatment. In the future, assays to determine biologic efficacy of targeted therapy may provide additional information to guide us in understanding the complex category of stable disease.
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