ONCOLOGY. Vol. 17 No. 7

The Benefits of Achieving Stable Disease in Advanced Lung Cancer

By KAREN KELLY, MD
Associate Professor of Medicine
Division of Medical Oncology
University of Colorado
Health Sciences Center
Denver, Colorado | July 1, 2003

The cytostatic, molecular-targeted therapies becoming available for lung cancer and other human solid tumors are more likely to result in stable disease than to produce tumor regression. In the setting of advanced lung cancer, stable disease provides significant benefit to the patient. However, in the context of clinical trials, stable disease is vaguely defined, difficult to measure, and may represent a heterogeneous patient population. The inclusion of alternative trial end points such as symptom improvement and biologic activity may help to identify patients who have achieved clinically relevant stable disease. The epidermal growth factor receptor–tyrosine kinase inhibitor gefitinib (Iressa) has been shown to produce partial responses and stable disease in patients with advanced lung cancer who have previously received treatment with standard chemotherapies. In the monotherapy trials of gefitinib, stable disease was correlated with improvements in diseaserelated symptoms and quality of life—the most meaningful end points for the patient with advanced lung cancer. Thus, with the introduction of new molecular-targeted agents, stable disease with clinical benefit should become an important goal of anticancer therapy.

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.[3] 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 counterparts. 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 agents. Stable Disease 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,[7] stable disease is not widely considered an indication of therapeutic efficacy in clinical trials.[8] The reasons for this discrepancy may lie with the difficulties in evaluating stable disease in clinical trials. Criteria
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).[9] As a result, the stable disease category in clinical trials actually represents a wide spectrum, making it difficult to evaluate the potential benefits.[7] Some studies have suggested that patients with stable disease are not a homogeneous population.[8] One example is a study that investigated stable disease in patients with advanced colorectal cancer who had been treated with carboplatin(Drug information on carboplatin) (Paraplatin), fluorouracil(Drug information on 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).[8] Furthermore, patients with stable disease and clinical benefit showed significantly improved survival compared with patients with progressive disease (P = .0000051).[8] 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.[7] 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(Drug information on ifosfamide) [Ifex], carboplatin, and etoposide(Drug information on etoposide) followed by twice-daily radiation up to 45 Gy with simultaneous administration of carboplatin and vindesine(Drug information on vindesine)).[11] 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.

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).[13] 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.[14]
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 evaluation of stable disease is likely to differ depending on the natural history of the tumor type. For example, a more extended follow-up period may be required for a tumor with a longer average time to progression such as breast cancer compared with NSCLC. The benefits of a particular drug may only be seen in a subpopulation of patients at a later time (ie, the "tail" of the curve). This approach of longer follow-up is in contrast to the relatively straightforward assessment of tumor progression or objective response on radiologic scan. However, in NSCLC even objective responses are often short-lived, with progressive disease developing at 6 months.[16] In summary, different clinical trial end points in addition to tumor response may be necessary to fully illustrate treatment benefit, particularly in patients classified as having stable disease.[8] Therapy for NSCLC: New Options, New Outcomes Cytotoxic chemotherapy is the current standard of care for patients with advanced NSCLC. Recommended first-line chemotherapy is a platinumbased regimen.[17,18] In several large randomized studies comparing various chemotherapy combinations, investigators found no significant differences in efficacy between any of the platinum doublets.[3,19] Objective response rates ranged from 17% to 28%, median survival ranged from 7.4 to 8 months, and 1-year overall survival rates ranged from 31% to 38%. Docetaxel(Drug information on docetaxel) (Taxotere) is considered the standard of care for second-line treatment of patients who fail to respond to, cannot tolerate, or relapse after platinum-based therapy, based on results from two large randomized trials.[20,21] Importantly, the results from the phase III trial comparing docetaxel to best supportive care demonstrated a clinical benefit for docetaxel. Quality of life favored the treatment arm, with significant differences in pain and fatigue (P = .006 and P = .06, respectively). Given that overall response rates ranged from approximately 7% to 11%, and 33% to 44% of patients had stable disease,[ 20,21] we can speculate that the clinical benefit observed with docetaxel was highest in the stable disease population. Beyond second-line therapy with docetaxel, there is no clear standard of treatment for patients with NSCLC, and tumors increasingly show resistance and lack of response.[22] The data suggest that the relative inaccessibility and nonlogarithmic growth of advanced solid tumors as well as the nonspecific cytotoxicity of standard chemotherapies may inherently limit the effectiveness of treatment.[4] Targeting the Epidermal Growth Factor Receptor
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[25] 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(Drug information on adenosine) triphosphate binding site of the receptor.[23] 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.[4] 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.[34] 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.[4] Basing treatment evaluation on tumor response rate alone may lead to the dismissal of potentially beneficial therapies.[34] 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.[35] 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(Drug information on 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.[47] 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.[52] In IDEAL-1, tumor response rates were 18% and 19%, respectively, in the two dose groups.[53] 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.[52] 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.

FIONA H. BLACKHALL, MD, PhD and FRANCES A. SHEPHERD, MD, FRCP
TIEN HOANG, MD and JOAN H. SCHILLER, MD

Dr. Kelly has research grants from, has acted as a consultant to, and has received honoraria from AstraZeneca.

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Breast Breast (HER2+) Breast (Triple-Negative) CML Colorectal Gastrointestinal GIST Genitourinary Gynecologic Head & Neck	Hematology Kidney (Renal Cell) Leukemia Lung Lymphoma Melanoma Multiple Myeloma Ovarian Prostate Sarcoma
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The Benefits of Achieving Stable Disease in Advanced Lung Cancer

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