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Originally published as JCO Early Release 10.1200/JCO.2008.16.2545 on December 1 2008 © 2009 American Society of Clinical Oncology. Tumor Cavitation: Impact on Objective Response Evaluation in Trials of Angiogenesis Inhibitors in Non–Small-Cell Lung Cancer
From the Cancer Research UK Clinical Centre, University of Southampton, Southampton, United Kingdom; and National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada Corresponding author: Simon J. Crabb, PhD, Cancer Research UK Clinical Centre, Somers Cancer Research Bldg (MP824), Southampton General Hospital, Tremona Rd, Southampton, SO16 6YD, United Kingdom; e-mail: S.J.Crabb{at}soton.ac.uk
Purpose We have observed cavitation of lesions in clinical trials of an angiogenesis inhibitor combined with chemotherapy for non–small-cell lung cancer (NSCLC). We hypothesized that cavitation might alter response assessment in such clinical trials. Patients and Methods We performed a retrospective radiologic review of patients with NSCLC enrolled onto three National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trials of platinum-based chemotherapy with or without a small-molecule angiogenesis inhibitor (vascular endothelial growth factor receptor inhibitor [VEGFRI]). Response was assessed both by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines and a novel alternate method in which the longest diameter of any cavity was subtracted from the overall longest diameter of that lesion to measure target lesions. Rates of cavitation were documented. Results Marked cavitation of pulmonary lesions was seen in 24% of 33 patients treated with VEGFRI combined with platinum-based chemotherapy but in none of 18 patients treated with platinum-based chemotherapy alone. Use of the alternate method for response assessment resulted in an alteration of response assessment, time to best response, duration of response, and time of disease progression in a minority of patients compared with RECIST. Conclusion Cavitation of target and nontarget lesions is common in NSCLC patients treated with VEGFRIs and platinum-based chemotherapy. Impact on response and time to event outcomes occurred but seems to be less common. Response assessment might be improved by incorporating cavitation into volume assessment for target lesions, potentially altering outcomes of key efficacy parameters in clinical trials. This should be prospectively assessed in clinical trials of angiogenesis inhibitors.
Lung cancer is the most common cause of cancer death in developed nations. In the United States, an estimated 213,000 new cases are projected for 2007.1 The most common form, non–small cell lung cancer (NSCLC), presents commonly as incurable locally advanced or metastatic disease. In such patients, treatment with cisplatin- or carboplatin-based doublet chemotherapy results in median survival times of 8 to 10 months.2-4 Recent investigation to improve treatment for NSCLC has focused on targeted therapies, including angiogenesis inhibitors. Angiogenesis is a critical component for growth and metastatic spread of tumors.5 Mediators of angiogenesis include vascular endothelial growth factor (VEGF), which is overexpressed in many human malignancies including NSCLC. VEGF expression, measured either in tumor specimens or serum, has been linked to poor survival outcomes and response to therapy.6-10 A randomized phase III trial of the addition of bevacizumab, a monoclonal antibody to VEGF, to carboplatin and paclitaxel chemotherapy for recurrent or advanced NSCLC improved median survival from 10.3 to 12.3 months.11 Results from a second study comparing bevacizumab with placebo in patients receiving cisplatin and gemcitabine indicated improved progression-free survival and response rate in the bevacizumab arm.12 Several other antiangiogenesis agents that target the VEGF receptor tyrosine kinase pathway are undergoing assessment in clinical trials for NSCLC including vandetanib, sorafenib, sunitinib, axitinib, AMG 706, and cediranib.13 The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) recently completed two phase I clinical trials in patients with NSCLC of cediranib, an orally bioavailable multitargeted tyrosine kinase inhibitor, in combination with platinum-based chemotherapy, which potently inhibits VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor β; and c-kit.14-19 We observed cases of cavitation, most notably in pulmonary lesions, that were associated with response to treatment. We hypothesized that incorporating an assessment of cavitation when measuring target lesions might more accurately reflect changes in tumor volume. Furthermore, this might be associated with alteration in efficacy outcomes, such as response rate, response duration, and time to progressive disease (PD), compared with conventional methods for response assessment such as Response Evaluation Criteria in Solid Tumors (RECIST).20 Therefore, we conducted a post hoc radiologic review and analysis to investigate rates of tumor cavitation in the two NCC CTG studies and the potential for impact on response assessment.
Clinical Trial Details We identified patients for retrospective radiologic review from three clinical trials performed by the NCIC CTG. IND171 and IND175 were phase I clinical trials including patients with NSCLC.15,16 Patients were enrolled from three cancer centers in Ontario between 2005 and 2007. Inclusion criteria for both trials were the same and have been previously documented.16 Pathologic type and tumor location were not exclusion criteria. Patients were excluded for hemoptysis of more than 5 mL in the preceding 3 months, centrally located cavitating primary lesions, or prior combination chemotherapy for advanced disease. In IND171, patients received paclitaxel 200 mg/m2 and carboplatin at an area under the curve of 6 mg/mL/min every 21 days. In IND175, patients received gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1 every 21 days. In both trials, the dose of cediranib escalated from 30 mg to 45 mg and commenced as continuous dosing from day 2 of cycle 1. Patients from the same three centers who were randomly assigned to the placebo arm of the NCIC CTG BR18 study were used as historical controls. This was a phase II/III randomized comparison of carboplatin and paclitaxel, using the same dosing regimen as IND171, combined with placebo or the matrix metalloproteinase inhibitor BMS-275291 in patients with advanced NSCLC of any histology.21 BR18 recruited patients between April 2000 and May 2002. In each study, imaging of known or suspected disease occurred after every other treatment cycle with response assessed by RECIST.20
Patient Selection
Radiologic Review
Fifty-three patients were included in these analyses. Of these, all 20 patients enrolled onto IND171 and 13 of 15 patients enrolled onto IND175 had undergone at least one response assessment after baseline and were assessable for response and cavitation (two patients had no follow-up imaging after entry onto IND175). In addition, from the three cancer centers involved in this analysis, 36 patients were randomly assigned to the placebo arm of BR18. None had cavitation noted on local institution radiology reports. Films remained available for 18 patients who were included in this analysis. Patient clinical and treatment details are listed in Table 1. Baseline characteristics and median number of chemotherapy cycles delivered were similar across each trial. For BR18 patients, baseline characteristics and best response were broadly similar to the original overall trial cohort.21
After formal radiologic review, more patients in the two VEGF receptor inhibitor (VEGFRI) trials were found to have cavitation in lesions after treatment (Table 2). Marked cavitation in pulmonary lesions occurred in five (25%) of 20 patients in IND171 and three (23%) of 13 patients in IND175 after receiving chemotherapy and cediranib. An example is shown in Figure 1B (patient 18). In contrast, none of the 18 patients reviewed in the chemotherapy-alone arm of BR18 developed marked pulmonary cavitation after treatment. One patient from IND171 was found on pretreatment imaging to have a 7-mm cavitation in a pulmonary lesion with longest overall diameter of 46 mm. This patient achieved a partial response (PR) by RECIST and our alternate response method, as the overall largest diameter decreased and the cavity enlarged, until PD occurred at cycle 14 with the appearance of new lesions. No other patient in any of the three studies had baseline cavitation. One patient from IND171 (patient 1) had target lesions confined to the adrenal glands (in addition to pleural effusions, ascites, and bony metastases). Both underwent marked cavitation. All other patients had pulmonary target lesions, and all other cavitation was seen in pulmonary lesions.
Of note, patients in whom marked cavitation was noted included patients with RECIST best responses of PR, stable disease (SD), and PD. In six of the eight patients found to have marked cavitation, cavitation occurred by the first imaging assessment after two treatment cycles. Minor pulmonary cavitation occurred in four additional patients (one patient in IND171, one patient in IND175, and two patients in BR18). We next addressed the degree to which assessment of best response by RECIST might have been altered by our exploratory alternate method for response assessment. Patients from BR18 are not included because no marked pulmonary cavitation was noted on radiology review. Results are listed in Table 3, with details for individual patients in Table 4. Table 5 includes target lesion measurements for selected patients in whom response assessment and duration would change by using the alternate method.
Of the 20 patients in IND171, one RECIST nonresponding patient (patient 18) would have achieved a designation of confirmed PR by our alternate method with a 74% decrease by cycle 2 in combined measurements compared with a designation of SD with a 25% decrease by cycle 8 by RECIST. An additional patient (patient 16) had an unconfirmed PR by the alternate method with a 53% decrease in measurements compared with an 18% decrease by RECIST. However, this patient discontinued therapy at cycle 3 because of a pulmonary embolism and grade 3 fatigue and was not assessed further, resulting in best response of SD using either method. Patient 1 had two cavitating target lesions that, at the first response assessment, met criteria for PD by RECIST (20% increase in summed measurements) but PR using the alternate method (93% decrease). However, new hepatic lesions were detected at this point, leading to a best response of PD by either method. In IND175, no changes in best response assessment occurred. We also evaluated whether duration of response or time to response changed with our alternate assessment method. For patient 8, PR was declared at cycle 2 after 6 weeks by our alternate method (70% decrease in summed measurements) with PD 30 weeks later at cycle 12 (increase of 205% of the smallest documented measurements; Table 5). Filling in of one of the two target lesions (both of which cavitated) was the cause for the designation of PD by the alternate method at this stage despite that the sum of the overall diameters did not increase. However, using RECIST, PR was first seen after 30 weeks at cycle 10 (41% decrease), and PD was noted 15 weeks later at cycle 15 (when new lesions were documented). Similar discrepancies occurred for patient 18 in whom use of the alternate criteria led to a best response of PR after 6 weeks at cycle 2 with PD after 18 weeks at cycle 8, again with filling in of the solitary target lesion without increase in the overall diameter. With RECIST, the response assessment was SD until cycle 9 (when treatment was discontinued). Finally, we addressed whether treatment duration would change by using the alternate response assessment. Patient 8 would have discontinued treatment at cycle 12 with PD by our alternate method. Instead, a PR was maintained by RECIST for a further 9 weeks until PD was declared. Similarly, patient 18 met alternate criteria for PD by cycle 8, with her combined lesion measurement increasing to 165% of its minimum assessment as a result of filling in of target lesion cavitation. In contrast, RECIST indicated continuing SD up to her final imaging at cycle 9. Although according to protocol, the patient could have continued therapy, the investigator decided to discontinue treatment because the single target lesion, which had undergone marked cavitation, was filling in despite the fact that the overall largest diameter still met criteria for SD.
As with other malignancies, treatment strategies for NSCLC are evolving toward investigation and potentially routine use of targeted agents, including inhibitors of angiogenesis. Incorporation of such treatment heralds challenges relating to radically different mechanisms of action compared with conventional cytotoxic agents. These mechanistic differences may also alter patterns of therapeutic benefit and the most appropriate means for its assessment. In trials of VEGFRI, we and others have noted that responding lesions frequently exhibit marked central cavitation. Here, we sought to describe our experience in two phase I clinical trials and investigate the effects of cavitation on response assessment. Our data indicate that marked pulmonary cavitation occurred in 24% of patients. Although we acknowledge the retrospective nature of our analyses and the limitations in patient numbers, these data suggest that angiogenesis inhibition induces a common rate of marked cavitation that is distinct from the results seen with chemotherapy alone. It has been postulated that this occurs through central necrosis of lesions after inhibition of angiogenesis. Further investigation of the pathophysiologic processes producing such lesions (for example, through the use of metabolic imaging such as positron emission tomography) and more descriptive radiologic studies are warranted to understand this phenomenon. Cavitation is likely to represent a class effect of inhibitors of angiogenesis because it has been reported with both antibodies against VEGF and VEGF receptor tyrosine kinase inhibitors.22-24 Marom et al23 described a retrospective single-institution experience of 124 patients treated with various angiogenesis inhibitors in which 14% of patients developed cavitation. Cavitation was correlated with squamous histology but not other characteristics studied (ie, tumor location, imaging characteristics, progression-free survival, and overall survival). Impact on tumor response assessment was not assessed. A potential link between clinically relevant pulmonary hemorrhage and cavitation has been raised by studies of bevacizumab and warrants further investigation.24 We did not find any clear link between pulmonary hemorrhage and tumor cavitation (data not shown), although small patient numbers preclude definitive conclusions from being drawn. In this report, we have described the application of an alternate, modified assessment method that may more clearly capture the change in volume of tumor tissue after development of a central cavity. We hypothesized that tumor response assessment would change if one took into account loss of tumor volume as a result of cavitation because this is not captured by measurement of the sum of the longest diameter of target lesions, which is central to the methodology established by RECIST.20 We have shown that, in some patients, RECIST does not seem to describe adequately change in tumor tissue volume if cavitation is present. Our alternate method was able to describe decreases in tumor volume of target lesions that respond by undergoing cavitation. Some of the potential differences in outcome between RECIST and our alternate method for response assessment are represented in a diagram in Figure 1C. This depicts a lesion undergoing PR if cavitation is incorporated into assessment, regardless of whether the overall diameter decreases, remains stable, or increases. Central filling in of a cavity also allows for a declaration of disease progression if cavitation is included in the assessment of the lesion without an increase in overall diameter. The most appropriate method to measure volume of tumor tissue, or approximations to volume such as RECIST or our alternate method, remains to be defined. Advances in the technical aspects of tumor volume assessment are likely to allow for greater sophistication. Computer-aided diagnosis software represents a range of diagnostic tools that allow for automation and assistance of the detection and volumetry of lesions. This raises the potential to rapidly, accurately, and reproducibly determine tumor volume and incorporate the effect of cavitation into assessment of treatment response.25 Prospective evaluation of such approaches will be required. Although best response remains an important end point in phase II studies, the potential for inconsistencies in the duration of response and time to progression is perhaps more concerning, particularly in randomized phase II trials. Reassuringly, there were only two patients in whom the date of progression would have changed because, in other patients, the presence of new lesions, rather than an increase in size of target lesions, drove the designation of progression. With regard to the duration of treatment exposure, we found one example where a patient would have discontinued treatment 9 weeks earlier based on the incorporation of cavitation into assessment. In another patient, the investigator discontinued therapy in the absence of PD by RECIST 3 weeks after our alternate method would have mandated it. Thus, clinicians might already be tempted to make pragmatic decisions regarding therapy if, for example, a lesion clearly seems to undergo filling in of a central cavity, indicating that PD not reflected by RECIST may be occurring. Guidance in such scenarios would be of value. Lesions that are cavitated and then become solid on the next assessment likely represent true biologic progression when noted with this class of agent, although in other tumor types, shrinkage and fibrosis may follow cavitation and may not be indicative of progression. Given preclinical data suggesting that VEGFRIs result in central necrosis with a viable rim of tumor tissue that later grows in and fills the cavity, we believe that it is biologically plausible and likely that our observations are indicative of tumor progression. This is further supported by our observation that progression in other lesions or the appearance of new lesions is often contemporaneous. However, pathologic data to support this hypothesis in humans are lacking. Functional imaging (positron emission tomography) would be one method to assess this in future studies. Our study has some limitations. Analysis was retrospective and included a limited number of patients. Our comparison with patients from BR18, who were treated with chemotherapy alone, can only be viewed as an exploratory analysis, and patients were not enrolled contemporaneously. Others have addressed alternatives or revisions to RECIST in specific disease types such as mesothelioma and GI stromal tumors.26-28 Other features of target lesions, such as eccentricity (the degree of divergence from a perfect sphere), have also been shown to affect response outcomes if incorporated into methodology such as RECIST.29 To our knowledge, this report is the first to investigate volumetric assessment of target lesions in the face of cavitation compared with RECIST. RECIST is currently under review with revised guidelines due in 2008.30 In conclusion, cavitation may be an angiogenesis inhibitor class effect, and evaluation of response and subsequent progression in the presence of cavitation may be problematic. These findings have important implications for the continued evaluation of these agents in clinical trials. Further investigation is indicated, particularly regarding the effect of cavitation on response designation and duration and survival outcomes, in large phase III trials of chemotherapy with or without angiogenesis inhibition. We plan to undertake such an analysis in a current NCIC CTG phase II/III randomized comparison of platinum-based chemotherapy with either cediranib or placebo in advanced NSCLC.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Scott A. Laurie, AstraZeneca (C) Stock Ownership: Lesley Seymour, AstraZeneca Honoraria: Peter M. Ellis, AstraZeneca; Natasha B. Leighl, AstraZeneca Research Funding: Lesley Seymour, AstraZeneca, Bristol-Myers Squibb Co; Scott A. Laurie, AstraZeneca Expert Testimony: None Other Remuneration: None
Conception and design: Simon J. Crabb, Peter M. Ellis, Andrew Arnold, Glenwood Goss, Frances A. Shepherd, Lesley Seymour, Scott A. Laurie Financial support: Lesley Seymour Administrative support: Natasha B. Leighl, Lesley Seymour Provision of study materials or patients: Peter M. Ellis, Andrew Arnold, Glenwood Goss, Natasha B. Leighl, Frances A. Shepherd, Scott A. Laurie Collection and assembly of data: Simon J. Crabb, Demetris Patsios, Eric Sauerbrei, Peter M. Ellis, Andrew Arnold, Glenwood Goss, Natasha B. Leighl, Jean Powers, Lesley Seymour, Scott A. Laurie Data analysis and interpretation: Simon J. Crabb, Jean Powers, Lesley Seymour, Scott A. Laurie Manuscript writing: Simon J. Crabb, Eric Sauerbrei, Peter M. Ellis, Andrew Arnold, Glenwood Goss, Frances A. Shepherd, Jean Powers, Lesley Seymour, Scott A. Laurie Final approval of manuscript: Simon J. Crabb, Demetris Patsios, Eric Sauerbrei, Peter M. Ellis, Andrew Arnold, Glenwood Goss, Natasha B. Leighl, Frances A. Shepherd, Lesley Seymour, Scott A. Laurie
published online ahead of print at www.jco.org on December 1, 2008 Supported by the Canadian Cancer Society. Presented in part at the 12th World Conference on Lung Cancer, September 2-6, 2007, Seoul, South Korea. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
