- Email: [email protected]
First Experience of Active Surveillance Before Systemic Target Therapy in Patients With Metastatic Renal Cell Carcinoma
Medical Oncology First Experience of Active Surveillance Before Systemic Target Therapy in Patients With Metastatic Renal Cell Carcinoma Nobuaki Matsubara, Hirofumi Mukai, Yoichi Naito, Kuniaki Itoh, Yoshinobu Komai, and Yasuyuki Sakai OBJECTIVE METHODS
RESULTS
CONCLUSION
To reveal the outcomes of initial active surveillance (AS), followed by deferred systemic target therapy, in a subpopulation of patients with indolent metastatic renal cell carcinoma (mRCC). We retrospectively reviewed the clinical and pathologic data of patients with mRCC, who initially were monitored by planned AS before systemic therapy because of their preference and asymptomatic or slowly progressive disease, at our institution between 2000 and 2011. The primary outcome measures were progression-free survival (PFS) and overall survival (OS). Twenty-nine patients with a metastatic lesion at start of AS were eligible for this analysis. The median age at the start of AS was 69 years. Of these patients, 65% had recurrent disease and 35% were in stage IV. All patients had undergone nephrectomy and 86% had clear-cell carcinoma. No patients were categorized into a poor risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) and Heng criteria. The median follow-up period was 35.4 months. Disease progression was observed in 72% of patients, but only 14% died during the follow-up period. The median PFS time was 26.1 months. After disease progression was observed, only 58% of these patients received treatment. The median OS had not been reached, but 12, 24, and 48 months OS rates were 96.4%, 88.7%, and 83.8%, respectively. PFS and OS of patients who underwent AS were acceptable. AS might be a reasonable approach, particularly for patients with prolonged, indolent course of the disease. Further observational studies with a larger sample size might be needed. UROLOGY 82: 118e123, 2013. 2013 Elsevier Inc.
T
he present standard treatment for patients with metastatic renal cell carcinoma (mRCC) is systemic target therapy, which includes the multitargeted tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitor, and vascular endothelial growth factor (VEGF) monoclonal antibody in combination with interferon-a (IFN-a).1-3 Systemic treatment of patients with mRCC has dramatically changed and has improved the survival outcomes with the development of target agents. There are now 5 and 7 approved target agents in Japan and the United States, respectively. These agents, commercially available in the last 5 years, are already accepted worldwide as a standard treatment for mRCC. However, it is an established fact that these treatments are administered with
This investigation was presented as a part of The 2013 Genitourinary Cancers Symposium, February 14-16, 2013, Orland, USA. Financial Disclosure: The authors declare that they have no relevant financial interests. From the Division of Oncology and Hematology, National Cancer Center Hospital East, Chiba, Japan; and Department of Urology, National Cancer Center Hospital East, Chiba, Japan Reprint requests: Nobuaki Matsubara, M.D., 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: [email protected] Submitted: December 16, 2012, accepted (with revisions): March 18, 2013
118
ª 2013 Elsevier Inc. All Rights Reserved
a noncurative intent and are toxic and expensive. We sometimes experience that patients, especially those with asymptomatic disease, refuse or abandon the systemic target therapy because of these considerations. On the other hand, the clinical course of mRCC has a wide spectrum that ranges from indolent to rapidly progressive disease.4,5 To establish a prognosis, prognostic factors for patients treated in clinical trials and retrospective population-based studies have traditionally been investigated.4,5 Therefore, clinicians can now use established risk categories, such as those of the Memorial Sloan-Kettering Cancer Center (MSKCC) or the Heng criteria, not only to predict survival but also to decide on the appropriate treatment. However, it is still difficult to predict survival in patients with mRCC.6 In daily practice, we have encountered patients who have a surprisingly indolent clinical course without receiving systemic treatment. For this subpopulation with an indolent clinical course, initial active surveillance (AS) before systemic target treatment might be a valid treatment option. AS, as an initial treatment, has been well established by randomized trials in other malignancies, such as low-grade follicular lymphoma.7 However, there is no randomized control trial in mRCC that has compared 0090-4295/13/$36.00 http://dx.doi.org/10.1016/j.urology.2013.03.035
early systemic treatment with deferred systemic treatment after disease progression. In addition, the present treatment guidelines do not mention AS or discuss when systemic target treatment should be started.1-3 Very few studies have been published on AS, and the survival outcome of AS is uncertain.8,9 Several case studies that reported the natural history of mRCC without treatment might indirectly support our suggested approach.10,11 We hypothesized that AS, followed by deferred systemic target therapy, might be a treatment option for a subpopulation of indolent mRCC. If the AS strategy were a treatment option without prognostic disadvantage, toxic and expensive systemic target therapy could be deferred for a significant period of time. AS has great potential benefits not only for patient satisfaction but also for medical economics. To test this hypothesis, we report here the clinical outcomes, such as progression-free survival (PFS) and overall survival (OS), in patients with mRCC, who initially were monitored by AS in our institution. In addition, to reveal potential factors that might predict which type of indolent mRCC would be suitable for AS, we analyzed factors that could predict PFS and OS.
MATERIALS AND METHODS
or favorable risks, who did not want to receive immediate systemic therapy but wanted to receive initial planned AS before target therapy, were evaluated and their treatment was decided in urologic oncology conference at our institution. The following was the standard AS schedule in our institution: outpatients were initially examined monthly and subsequently every 3 months for checking symptoms and signs of disease progression. Laboratory tests, including blood cell counts, renal and liver function tests, and C related protein (CRP), were routinely performed at every outpatient visit. Chest, abdominal, and pelvic computed tomography (CT) scans were performed routinely with 3 or 4 months intervals. Other radiographic tests, such as bone scans or brain magnetic resonance imaging (MRI), and extra visits to the outpatient clinic were performed as appropriate or according to individual physician discretion. Disease progression was defined according to the response evaluation criteria in solid tumors (RECIST). Patients, in whom disease progression was observed, were offered to undergo standard treatment at that time. However, whether the patients received standard treatment was at their discretion. Patients who initially refused systemic treatment after disease progression could receive standard treatment any time they wanted. If definitive disease progression was not observed, the patients continued to be under AS. Initiation of treatment with bonemodifying agents (ie denosumab or bisphosphonate) alone for bone metastasis was not considered as systemic treatment in this investigation.
Patients We retrospectively reviewed the clinical and pathologic records of patients with mRCC who were monitored by planned AS before systemic therapy from April 2000 to December 2011 at National Cancer Center Hospital East (Kashiwa, Japan). Patients with mRCC included those with stage IV and those with recurrent disease. Stage IV disease, also called metastatic disease, was defined as tumor spread beyond regional lymph nodes that could not be radically resected at the time of the initial diagnosis. Recurrent disease was defined as tumor reappearance at any site after radical nephrectomy. Metastatic lesions were diagnosed by radiographic evidence of the disease or by biopsy. However, histologic or cytologic confirmation of metastatic lesions was not essential for this investigation. Patients who received metastasectomy, regardless of complete or incomplete resection, were excluded from this investigation. Patients who had received neoadjuvant or adjuvant therapy or both, including cytokine therapy, hormonal therapy, chemotherapy, target therapy, or radiation therapy were also excluded. Patients in stage IV, whether they had undergone nephrectomy or not, were eligible for the study. Information on the parameters of age, performance status, primary renal tumor size, node metastasis status, histologic type, histologic grade, number of metastatic sites, metastatic organ site, duration from first diagnosis to recurrence, and laboratory parameters associated with MSKCC and Heng criteria, had to be available for patient enrollment. Risk classification was performed in individual patients according to MSKCC and Heng criteria.
Statistical Analysis The primary outcome measure of this investigation was to reveal the PFS and OS in patients who initially were monitored by planned AS before systemic therapy. Clinical and pathologic data for this investigation were collected retrospectively. Follow-up duration was defined as the time from nephrectomy to the last follow-up date in patients with stage IV disease, and the time from the date of diagnosis of recurrence to the last follow-up date in patients with recurrent disease. PFS period was defined as the interval from the date of nephrectomy to that of the first diagnosis of progression or the last follow-up date without progression in patients with stage IV disease, and the interval from the date of diagnosis of recurrence to that of the first diagnosis of progression or the last follow-up date without progression in patients with recurrent disease. OS period was also defined as the interval from the date of nephrectomy to death or the last follow-up date in patients with stage IV disease and the interval from the date of diagnosis of recurrence to death or the last follow-up date in patients with recurrent disease. Associations between clinical or pathologic factors and PFS or OS were analyzed using the c2 test or Fisher’s exact test, where appropriate. Survival distributions were estimated using the Kaplan-Meier method for PFS and OS. The log-rank test was used to compare survival in different strata. All statistical tests were two-sided and had a 95% confidence interval (CI), with the level of significance established at P <.05. Statistical analyses were performed using PASW 18.0 software (SPSS, IBM, Chicago, IL).
Active Surveillance Patients with mRCC who wanted to receive immediate systemic treatment were managed in accordance with their preferences. AS was not indicated in our institutional policy, so immediate systemic treatment was offered to patients in a poor-risk group according to MSKCC or Heng criteria. Patients with intermediate UROLOGY 82 (1), 2013
RESULTS Patients The study evaluated 133 patients with mRCC and 29 patients (21.8%) were initially monitored by planned AS 119
Table 1. Patient characteristics Characteristics
No. of Patients
Table 1. Continued %
Total patient number 29 100 Median age, y (range) 69.0 (43-78) Sex Male 20 69 Female 9 31 ECOG performance status 0 23 79 1 6 21 S2 0 0 Disease status Recurrence 19 65 Stage IV 10 35 Nephrectomy Done 29 100 Not done 0 0 Histology Clear-cell carcinoma 25 86 Other 3 10 Unknown 1 4 Histologic grade 1 4 14 2 20 68 3 1 4 Unknown 4 14 Number of metastatic organ sites 1 18 62 2 9 31 S3 2 7 Metastatic organ sites Lung 22 76 Distant lymph node 7 24 Bone 6 21 Pancreas 4 14 Other 3 10 CRP level before nephrectomy* <0.5 mg/dL 15 52 S0.5 mg/dL 7 24 Unknown 7 24 CRP level at surveillance* <0.5 mg/dL 24 83 S0.5 mg/dL 5 17 Hemoglobin* 12 g/dL 7 24 S12 g/dL 22 76 Albumin* 4.0 g/dL 6 20 S4.0 g/dL 21 73 Unknown 2 7 Corrected serum calcium* 10.0 mg/dL 29 100 S10.0 mg/dL 0 0 LDH level (cutoff value was 1.5 upper limit of laboratory's range) 343 IU/L 26 90 S343 IU/L 3 10 Thrombocytosis (cutoff value was more than 36 104/mL) Absence 29 100 Presence 0 0 Neutrophilia (cutoff value was more than 61%) Absence 16 55 Presence 13 45 Time from diagnosis to recurrence <1 year or stage IV 11 38 >1 year 18 62 Continued 120
Characteristics MSKCC risk category Favorable Intermediate Poor Heng risk category Favorable Intermediate Poor
No. of Patients
%
18 11 0
62 38 0
18 11 0
62 38 0
CRP, C related protein; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; MSKCC, Memorial Sloan-Kettering Cancer Center. * Cutoff value was upper limit of laboratory's range
before systemic therapy at our institution because of asymptomatic or slowly progressing disease. Baseline patient characteristics are listed in Table 1. The median age at the time of starting AS was 69.0 years (range: 4378 years), and 69% of the patients were men. Sixty-five percent of patients had recurrent disease and 35% were in stage IV. In patients with recurrent disease, the median duration from radical nephrectomy to diagnosis of recurrence was 65.9 months (range: 11.2-141.3 months), and only one patient had a duration of less than 1 year. All of the patients had undergone nephrectomy and had a good general condition, with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 at the time of starting AS. Almost all patients (86%) had clear cell histology and 82% had histologic grade (HG) 1 or 2. The major involved organ sites were found most frequently in the lung (76%), followed by distant lymph nodes (24%) and bone (21%). In 62% of patients, the disease had involved only one organ site at the time of starting AS. The median maximum unidimensional diameter of metastatic lesion at the time of AS was 3.5 cm (range: 1.5-8.0 cm). Abnormal laboratory parameters related to anemia, CRP, lactate dehydrogenase (LDH), and calcium were observed during AS in 24%, 17%, 10%, and 0% of patients, respectively. A total of 62% and 38% of patients were categorized into favorable and intermediate-risk groups, respectively, according to the MSKCC and Heng criteria. None of the patients enrolled in this investigation was categorized into a poor-risk group. The pathologic or cytologic confirmation of metastasis was performed by biopsy from the involved organ in 18 patients (62%). Outcome and Treatment Procedure The median follow-up period was 35.3 months (range: 7.4-174.5 months). Table 2 shows the detail of clinical outcome and treatment delivered. Disease progression was observed in 21 patients (72%) during follow-up. Figure 1 shows that the PFS curve and the median PFS time was 26.1 months. Treatment was delivered to only 12 patients, after disease progression was observed. UROLOGY 82 (1), 2013
Figure 1. Progression-free survival curve.
Figure 2. Overall survival curve.
The residual 9 patients did not receive treatment because of their refusal, despite the recommendation of treatment by the physician. None of the patients who did not observe disease progression received any treatment during the follow-up period. The following are
UROLOGY 82 (1), 2013
the details of the initial treatment procedure after disease progression: systemic therapy with sunitinib in 6 patients, radiation therapy in 3 patients, surgery in 2 patients, and systemic therapy with sorafenib in 1 patient. All patients who initially had received local
121
Table 2. Clinical outcome at median follow-up and treatment delivered n ¼ 29
No. of Patients
%
Median follow-up, mo (range) 35.3 (7.4-174.5) Progression Observed 21 72 Not observed 8 28 Treatment delivered Yes 12 41 No 17 59 Initial treatment procedure after progression (n ¼ 12) Systemic treatment 7 58 Sunitinib 6 Sorafenib 1 Radiation 3 25 Operation 2 17 Survival status Alive 25 86 Dead 4 14
treatment such as radiation therapy and surgery received subsequent systemic therapy with sunitinib. Among the 12 patients who received subsequent systemic target therapy, partial response was observed in 4 patients, stable disease in 5 patients, and progressive disease in 3 patients. Twenty-five patients (86%) were alive and only 4 patients (14%) died during the follow-up period. All 4 patients died because of mRCC. Figure 2 shows the OS curve and the median OS has not been reached yet. However, the 12, 24, and 48 months of OS rates were 96.4%, 88.7%, and 83.8%, respectively. Predictive Factors for PFS or OS Seven prognostic parameters, which were selected based on previous studies4,5 and our clinical experience, were analyzed for association with PFS and OS. In PFS, none of the parameters was identified as being significantly associated with a favorable PFS as shown in Supplementary Table 1. However, in OS, only disease status (stage IV or recurrent disease) was identified as being significantly associated with OS as shown in Supplementary Table 1. Supplementary Figure 1 shows the OS curves according to disease status (stage IV or recurrent disease). A statistically significant difference was observed between the two groups of the OS curve (log-rank P ¼ .006).
DISCUSSION To the best of our knowledge, the present report contains the largest analyzed sample size of patients with mRCC who initially were monitored by AS. The primary outcome measures of this investigation were to reveal the clinical outcomes, such as recurrence-free survival (RFS) and OS, which were surprisingly favorable. The outcomes of AS for mRCC have been evaluated previously in a few studies.8,9 However, the results of those were substantially different from ours. For example, a small retrospective 122
study from Singapore reported the outcomes of 15 patients with mRCC, who underwent cytoreductive nephrectomy followed by AS.8 The median time to progression and the median OS were 2.0 months and 25.0 months, respectively. Another retrospective study from the United Kingdom reported the outcomes of 64 patients who underwent a planned period of observation before the initiation of systemic treatment with sunitinib or IFN-a.9 The median time from diagnosis of metastasis to beginning of treatment was 14.7 months, and the median OS was 35.0 months. There are several possible explanations for this difference in outcome between our study and the other studies. First, the difference in treatment procedures among the studies might have an effect. We assumed that the survival outcome is more favorable in patients who initially were treated using target therapy than in those treated using cytokine therapy. The clinical outcome from our investigation is the most favorable of the three studies. Thus, 100%, 65%, and 0% of the enrolled patients received target therapy as the initial systemic treatment in our study, the UK study, and the Singapore study, respectively. Second, the disease status, stage IV or recurrent disease, might also affect the outcomes. We also assume that the prognosis for patients with stage IV is worse than that for those with recurrence. The clinical outcome from our investigation was more favorable than that from the Singapore study. Thus, 35% and 100% of the enrolled patients in our study and the Singapore study, respectively, were in stage IV at the time of starting AS. In addition, according to our present investigation, the 2-year OS rate was significantly shorter in patients with stage IV disease than in those with recurrent disease. On the basis of these observations, we suggest that the AS strategy might not be suitable for patients with stage IV disease and that systemic target therapy should be started immediately in these patients. However, these limited retrospective data are not enough to definitely exclude patients with initial stage IV disease from AS. Further investigation is needed. Lead-time bias might be present and also affect the clinical outcomes. Generally in Japan, including our institution, patients who have undergone radical nephrectomy receive strict periodical work-ups that include CT scan of the chest, abdominal, and pelvic areas every 6 months or more frequently. This intensive workup might be associated with the early detection of recurrence. However, the present treatment guidelines from Western countries, such as those of National Comprehensive Cancer Network (NCCN), mention that CT scan should be obtained 4 to 6 months after surgery and then as clinically indicated. This difference in surveillance frequency might have caused a lead-time bias, and thus becomes a major reason for the different outcomes of AS. In addition, there might be many minor reasons for the different outcome, such as baseline characteristics, follow-up duration, and after initial treatment UROLOGY 82 (1), 2013
procedures. Therefore, we cannot directly compare these results. We expect to validate outcomes in a retrospective study with a larger sample size or in a prospective observational study. The present investigation could reveal clinical outcomes with AS but could not identify the exact subpopulation and factors that could predict and identify the patients suitable for initial AS deferred target therapy, except for disease status. However, we identified several predictive factors that were not statistically significant but showed a tendency to indicate who might be suitable for AS, such as sex, metastatic site, laboratory test abnormalities, and CRP elevation. However, these factors are well known as prognostic factors for mRCC.12,13 It is assumed that a subpopulation suitable for AS might be the same as a subpopulation of patients with super indolent mRCC. Additionally, in the present investigation, we did not test for other potential prognostic factors, including immunological14 and molecular markers.15 Therefore, further investigations are needed to reveal the subpopulation that is suitable for AS and the predictive prognostic factors. There are several potential limitations in the present study, such as small size, retrospective study, patient selection bias, and lack of histologic or cytologic confirmation of recurrence or metastasis in all patients. Thus, 62%, 38%, and 0% of AS patients were categorized into favorable, intermediate, and poor-risk groups, respectively, according to MSKCC criteria. On the other hand, during study period, 13%, 56%, and 31% of non-AS patients were categorized into favorable, intermediate, and poor-risk groups, respectively according to the MSKCC criteria. The difference in patient proportion of risk category between AS and non-AS was statistically significant in our institution (P <.001). Histologic or cytologic confirmation should be performed for patients with recurrent disease, especially for those who have had a long disease-free interval. However, the AS strategy might still be attractive with respect to patient satisfaction and medical economics. To reveal and clarify these benefits definitely, further prospective studies would be needed and also evaluation of quality of life data, cost-effectiveness, and medical economics.
CONCLUSIONS We treated 29 patients with mRCC using initial AS, followed by deferred systemic target therapy. PFS and OS of patients who underwent AS were acceptable. For these indolent subpopulations, AS might be a reasonable approach, and toxic and expensive systemic target therapy might be deferred for a significant period of time. However, some of the bias was contained in this study.
UROLOGY 82 (1), 2013
Further observational studies with a larger sample size might be needed to identify the exact subpopulation and predictive factors for AS. Acknowledgment. This investigation was presented as a part of The 2013 Genitourinary Cancers Symposium, February 14-16, 2013, Orland, USA. References 1. Escudier B, Kataja V. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010; 21(suppl 5):v137-v139. 2. Ljungberg B, Cowan NC, Hanbury DC, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010;58:398-406. 3. Motzer RJ, Agarwal N, Beard C, et al. NCCN clinical practice guidelines in oncology: kidney cancer. J Natl Compr Canc Netw. 2009;7:618-630. 4. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289-296. 5. Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27: 5794-5799. 6. Powles T, Hutson TE. Difficulty in predicting survival in metastatic renal cancer. Lancet Oncol. 2012;13:859-860. 7. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003;362:516-522. 8. Wong AS, Chong KT, Heng CT, et al. Debulking nephrectomy followed by a “watch and wait” approach in metastatic renal cell carcinoma. Urol Oncol. 2009;27:149-154. 9. Fisher R, Pender A, Thillai K, et al. Observation as a treatment strategy for advanced renal cell carcinoma—a call for prospective validation. Front Oncol. 2012;2:1-2; Article 155. 10. Ozono S, Miyao N, Igarashi T, et al. Tumor doubling time of renal cell carcinoma measured by CT: collaboration of Japanese Society of Renal Cancer. Jpn J Clin Oncol. 2004;34:82-85. 11. Kai F, Takayama T, Ito T, et al. Natural history of renal cell carcinoma: a case with 18 years follow-up. Clin Exp Nephrol. 2011; 15:312-315. 12. Naito S, Yamamoto N, Takayama T, et al. Prognosis of Japanese metastatic renal cell carcinoma patients in the cytokine era: a cooperative group report of 1463 patients. Eur Urol. 2010;57: 317-325. 13. Atzpodien J, Royston P, Wandert T, et al. Metastatic renal carcinoma comprehensive prognostic system. Br J Cancer. 2003;88: 348-353. 14. Donskov F, von der Maase H. Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J Clin Oncol. 2006;24:1997-2005. 15. Rini BI. Current status and future directions of molecular markers in renal cell carcinoma. Curr Opin Urol. 2006;16:332-336.
APPENDIX SUPPLEMENTARY
DATA
Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.urology. 2013.03.035.
123
RESULTS
CONCLUSION
To reveal the outcomes of initial active surveillance (AS), followed by deferred systemic target therapy, in a subpopulation of patients with indolent metastatic renal cell carcinoma (mRCC). We retrospectively reviewed the clinical and pathologic data of patients with mRCC, who initially were monitored by planned AS before systemic therapy because of their preference and asymptomatic or slowly progressive disease, at our institution between 2000 and 2011. The primary outcome measures were progression-free survival (PFS) and overall survival (OS). Twenty-nine patients with a metastatic lesion at start of AS were eligible for this analysis. The median age at the start of AS was 69 years. Of these patients, 65% had recurrent disease and 35% were in stage IV. All patients had undergone nephrectomy and 86% had clear-cell carcinoma. No patients were categorized into a poor risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) and Heng criteria. The median follow-up period was 35.4 months. Disease progression was observed in 72% of patients, but only 14% died during the follow-up period. The median PFS time was 26.1 months. After disease progression was observed, only 58% of these patients received treatment. The median OS had not been reached, but 12, 24, and 48 months OS rates were 96.4%, 88.7%, and 83.8%, respectively. PFS and OS of patients who underwent AS were acceptable. AS might be a reasonable approach, particularly for patients with prolonged, indolent course of the disease. Further observational studies with a larger sample size might be needed. UROLOGY 82: 118e123, 2013. 2013 Elsevier Inc.
T
he present standard treatment for patients with metastatic renal cell carcinoma (mRCC) is systemic target therapy, which includes the multitargeted tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitor, and vascular endothelial growth factor (VEGF) monoclonal antibody in combination with interferon-a (IFN-a).1-3 Systemic treatment of patients with mRCC has dramatically changed and has improved the survival outcomes with the development of target agents. There are now 5 and 7 approved target agents in Japan and the United States, respectively. These agents, commercially available in the last 5 years, are already accepted worldwide as a standard treatment for mRCC. However, it is an established fact that these treatments are administered with
This investigation was presented as a part of The 2013 Genitourinary Cancers Symposium, February 14-16, 2013, Orland, USA. Financial Disclosure: The authors declare that they have no relevant financial interests. From the Division of Oncology and Hematology, National Cancer Center Hospital East, Chiba, Japan; and Department of Urology, National Cancer Center Hospital East, Chiba, Japan Reprint requests: Nobuaki Matsubara, M.D., 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: [email protected] Submitted: December 16, 2012, accepted (with revisions): March 18, 2013
118
ª 2013 Elsevier Inc. All Rights Reserved
a noncurative intent and are toxic and expensive. We sometimes experience that patients, especially those with asymptomatic disease, refuse or abandon the systemic target therapy because of these considerations. On the other hand, the clinical course of mRCC has a wide spectrum that ranges from indolent to rapidly progressive disease.4,5 To establish a prognosis, prognostic factors for patients treated in clinical trials and retrospective population-based studies have traditionally been investigated.4,5 Therefore, clinicians can now use established risk categories, such as those of the Memorial Sloan-Kettering Cancer Center (MSKCC) or the Heng criteria, not only to predict survival but also to decide on the appropriate treatment. However, it is still difficult to predict survival in patients with mRCC.6 In daily practice, we have encountered patients who have a surprisingly indolent clinical course without receiving systemic treatment. For this subpopulation with an indolent clinical course, initial active surveillance (AS) before systemic target treatment might be a valid treatment option. AS, as an initial treatment, has been well established by randomized trials in other malignancies, such as low-grade follicular lymphoma.7 However, there is no randomized control trial in mRCC that has compared 0090-4295/13/$36.00 http://dx.doi.org/10.1016/j.urology.2013.03.035
early systemic treatment with deferred systemic treatment after disease progression. In addition, the present treatment guidelines do not mention AS or discuss when systemic target treatment should be started.1-3 Very few studies have been published on AS, and the survival outcome of AS is uncertain.8,9 Several case studies that reported the natural history of mRCC without treatment might indirectly support our suggested approach.10,11 We hypothesized that AS, followed by deferred systemic target therapy, might be a treatment option for a subpopulation of indolent mRCC. If the AS strategy were a treatment option without prognostic disadvantage, toxic and expensive systemic target therapy could be deferred for a significant period of time. AS has great potential benefits not only for patient satisfaction but also for medical economics. To test this hypothesis, we report here the clinical outcomes, such as progression-free survival (PFS) and overall survival (OS), in patients with mRCC, who initially were monitored by AS in our institution. In addition, to reveal potential factors that might predict which type of indolent mRCC would be suitable for AS, we analyzed factors that could predict PFS and OS.
MATERIALS AND METHODS
or favorable risks, who did not want to receive immediate systemic therapy but wanted to receive initial planned AS before target therapy, were evaluated and their treatment was decided in urologic oncology conference at our institution. The following was the standard AS schedule in our institution: outpatients were initially examined monthly and subsequently every 3 months for checking symptoms and signs of disease progression. Laboratory tests, including blood cell counts, renal and liver function tests, and C related protein (CRP), were routinely performed at every outpatient visit. Chest, abdominal, and pelvic computed tomography (CT) scans were performed routinely with 3 or 4 months intervals. Other radiographic tests, such as bone scans or brain magnetic resonance imaging (MRI), and extra visits to the outpatient clinic were performed as appropriate or according to individual physician discretion. Disease progression was defined according to the response evaluation criteria in solid tumors (RECIST). Patients, in whom disease progression was observed, were offered to undergo standard treatment at that time. However, whether the patients received standard treatment was at their discretion. Patients who initially refused systemic treatment after disease progression could receive standard treatment any time they wanted. If definitive disease progression was not observed, the patients continued to be under AS. Initiation of treatment with bonemodifying agents (ie denosumab or bisphosphonate) alone for bone metastasis was not considered as systemic treatment in this investigation.
Patients We retrospectively reviewed the clinical and pathologic records of patients with mRCC who were monitored by planned AS before systemic therapy from April 2000 to December 2011 at National Cancer Center Hospital East (Kashiwa, Japan). Patients with mRCC included those with stage IV and those with recurrent disease. Stage IV disease, also called metastatic disease, was defined as tumor spread beyond regional lymph nodes that could not be radically resected at the time of the initial diagnosis. Recurrent disease was defined as tumor reappearance at any site after radical nephrectomy. Metastatic lesions were diagnosed by radiographic evidence of the disease or by biopsy. However, histologic or cytologic confirmation of metastatic lesions was not essential for this investigation. Patients who received metastasectomy, regardless of complete or incomplete resection, were excluded from this investigation. Patients who had received neoadjuvant or adjuvant therapy or both, including cytokine therapy, hormonal therapy, chemotherapy, target therapy, or radiation therapy were also excluded. Patients in stage IV, whether they had undergone nephrectomy or not, were eligible for the study. Information on the parameters of age, performance status, primary renal tumor size, node metastasis status, histologic type, histologic grade, number of metastatic sites, metastatic organ site, duration from first diagnosis to recurrence, and laboratory parameters associated with MSKCC and Heng criteria, had to be available for patient enrollment. Risk classification was performed in individual patients according to MSKCC and Heng criteria.
Statistical Analysis The primary outcome measure of this investigation was to reveal the PFS and OS in patients who initially were monitored by planned AS before systemic therapy. Clinical and pathologic data for this investigation were collected retrospectively. Follow-up duration was defined as the time from nephrectomy to the last follow-up date in patients with stage IV disease, and the time from the date of diagnosis of recurrence to the last follow-up date in patients with recurrent disease. PFS period was defined as the interval from the date of nephrectomy to that of the first diagnosis of progression or the last follow-up date without progression in patients with stage IV disease, and the interval from the date of diagnosis of recurrence to that of the first diagnosis of progression or the last follow-up date without progression in patients with recurrent disease. OS period was also defined as the interval from the date of nephrectomy to death or the last follow-up date in patients with stage IV disease and the interval from the date of diagnosis of recurrence to death or the last follow-up date in patients with recurrent disease. Associations between clinical or pathologic factors and PFS or OS were analyzed using the c2 test or Fisher’s exact test, where appropriate. Survival distributions were estimated using the Kaplan-Meier method for PFS and OS. The log-rank test was used to compare survival in different strata. All statistical tests were two-sided and had a 95% confidence interval (CI), with the level of significance established at P <.05. Statistical analyses were performed using PASW 18.0 software (SPSS, IBM, Chicago, IL).
Active Surveillance Patients with mRCC who wanted to receive immediate systemic treatment were managed in accordance with their preferences. AS was not indicated in our institutional policy, so immediate systemic treatment was offered to patients in a poor-risk group according to MSKCC or Heng criteria. Patients with intermediate UROLOGY 82 (1), 2013
RESULTS Patients The study evaluated 133 patients with mRCC and 29 patients (21.8%) were initially monitored by planned AS 119
Table 1. Patient characteristics Characteristics
No. of Patients
Table 1. Continued %
Total patient number 29 100 Median age, y (range) 69.0 (43-78) Sex Male 20 69 Female 9 31 ECOG performance status 0 23 79 1 6 21 S2 0 0 Disease status Recurrence 19 65 Stage IV 10 35 Nephrectomy Done 29 100 Not done 0 0 Histology Clear-cell carcinoma 25 86 Other 3 10 Unknown 1 4 Histologic grade 1 4 14 2 20 68 3 1 4 Unknown 4 14 Number of metastatic organ sites 1 18 62 2 9 31 S3 2 7 Metastatic organ sites Lung 22 76 Distant lymph node 7 24 Bone 6 21 Pancreas 4 14 Other 3 10 CRP level before nephrectomy* <0.5 mg/dL 15 52 S0.5 mg/dL 7 24 Unknown 7 24 CRP level at surveillance* <0.5 mg/dL 24 83 S0.5 mg/dL 5 17 Hemoglobin* 12 g/dL 7 24 S12 g/dL 22 76 Albumin* 4.0 g/dL 6 20 S4.0 g/dL 21 73 Unknown 2 7 Corrected serum calcium* 10.0 mg/dL 29 100 S10.0 mg/dL 0 0 LDH level (cutoff value was 1.5 upper limit of laboratory's range) 343 IU/L 26 90 S343 IU/L 3 10 Thrombocytosis (cutoff value was more than 36 104/mL) Absence 29 100 Presence 0 0 Neutrophilia (cutoff value was more than 61%) Absence 16 55 Presence 13 45 Time from diagnosis to recurrence <1 year or stage IV 11 38 >1 year 18 62 Continued 120
Characteristics MSKCC risk category Favorable Intermediate Poor Heng risk category Favorable Intermediate Poor
No. of Patients
%
18 11 0
62 38 0
18 11 0
62 38 0
CRP, C related protein; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; MSKCC, Memorial Sloan-Kettering Cancer Center. * Cutoff value was upper limit of laboratory's range
before systemic therapy at our institution because of asymptomatic or slowly progressing disease. Baseline patient characteristics are listed in Table 1. The median age at the time of starting AS was 69.0 years (range: 4378 years), and 69% of the patients were men. Sixty-five percent of patients had recurrent disease and 35% were in stage IV. In patients with recurrent disease, the median duration from radical nephrectomy to diagnosis of recurrence was 65.9 months (range: 11.2-141.3 months), and only one patient had a duration of less than 1 year. All of the patients had undergone nephrectomy and had a good general condition, with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 at the time of starting AS. Almost all patients (86%) had clear cell histology and 82% had histologic grade (HG) 1 or 2. The major involved organ sites were found most frequently in the lung (76%), followed by distant lymph nodes (24%) and bone (21%). In 62% of patients, the disease had involved only one organ site at the time of starting AS. The median maximum unidimensional diameter of metastatic lesion at the time of AS was 3.5 cm (range: 1.5-8.0 cm). Abnormal laboratory parameters related to anemia, CRP, lactate dehydrogenase (LDH), and calcium were observed during AS in 24%, 17%, 10%, and 0% of patients, respectively. A total of 62% and 38% of patients were categorized into favorable and intermediate-risk groups, respectively, according to the MSKCC and Heng criteria. None of the patients enrolled in this investigation was categorized into a poor-risk group. The pathologic or cytologic confirmation of metastasis was performed by biopsy from the involved organ in 18 patients (62%). Outcome and Treatment Procedure The median follow-up period was 35.3 months (range: 7.4-174.5 months). Table 2 shows the detail of clinical outcome and treatment delivered. Disease progression was observed in 21 patients (72%) during follow-up. Figure 1 shows that the PFS curve and the median PFS time was 26.1 months. Treatment was delivered to only 12 patients, after disease progression was observed. UROLOGY 82 (1), 2013
Figure 1. Progression-free survival curve.
Figure 2. Overall survival curve.
The residual 9 patients did not receive treatment because of their refusal, despite the recommendation of treatment by the physician. None of the patients who did not observe disease progression received any treatment during the follow-up period. The following are
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the details of the initial treatment procedure after disease progression: systemic therapy with sunitinib in 6 patients, radiation therapy in 3 patients, surgery in 2 patients, and systemic therapy with sorafenib in 1 patient. All patients who initially had received local
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Table 2. Clinical outcome at median follow-up and treatment delivered n ¼ 29
No. of Patients
%
Median follow-up, mo (range) 35.3 (7.4-174.5) Progression Observed 21 72 Not observed 8 28 Treatment delivered Yes 12 41 No 17 59 Initial treatment procedure after progression (n ¼ 12) Systemic treatment 7 58 Sunitinib 6 Sorafenib 1 Radiation 3 25 Operation 2 17 Survival status Alive 25 86 Dead 4 14
treatment such as radiation therapy and surgery received subsequent systemic therapy with sunitinib. Among the 12 patients who received subsequent systemic target therapy, partial response was observed in 4 patients, stable disease in 5 patients, and progressive disease in 3 patients. Twenty-five patients (86%) were alive and only 4 patients (14%) died during the follow-up period. All 4 patients died because of mRCC. Figure 2 shows the OS curve and the median OS has not been reached yet. However, the 12, 24, and 48 months of OS rates were 96.4%, 88.7%, and 83.8%, respectively. Predictive Factors for PFS or OS Seven prognostic parameters, which were selected based on previous studies4,5 and our clinical experience, were analyzed for association with PFS and OS. In PFS, none of the parameters was identified as being significantly associated with a favorable PFS as shown in Supplementary Table 1. However, in OS, only disease status (stage IV or recurrent disease) was identified as being significantly associated with OS as shown in Supplementary Table 1. Supplementary Figure 1 shows the OS curves according to disease status (stage IV or recurrent disease). A statistically significant difference was observed between the two groups of the OS curve (log-rank P ¼ .006).
DISCUSSION To the best of our knowledge, the present report contains the largest analyzed sample size of patients with mRCC who initially were monitored by AS. The primary outcome measures of this investigation were to reveal the clinical outcomes, such as recurrence-free survival (RFS) and OS, which were surprisingly favorable. The outcomes of AS for mRCC have been evaluated previously in a few studies.8,9 However, the results of those were substantially different from ours. For example, a small retrospective 122
study from Singapore reported the outcomes of 15 patients with mRCC, who underwent cytoreductive nephrectomy followed by AS.8 The median time to progression and the median OS were 2.0 months and 25.0 months, respectively. Another retrospective study from the United Kingdom reported the outcomes of 64 patients who underwent a planned period of observation before the initiation of systemic treatment with sunitinib or IFN-a.9 The median time from diagnosis of metastasis to beginning of treatment was 14.7 months, and the median OS was 35.0 months. There are several possible explanations for this difference in outcome between our study and the other studies. First, the difference in treatment procedures among the studies might have an effect. We assumed that the survival outcome is more favorable in patients who initially were treated using target therapy than in those treated using cytokine therapy. The clinical outcome from our investigation is the most favorable of the three studies. Thus, 100%, 65%, and 0% of the enrolled patients received target therapy as the initial systemic treatment in our study, the UK study, and the Singapore study, respectively. Second, the disease status, stage IV or recurrent disease, might also affect the outcomes. We also assume that the prognosis for patients with stage IV is worse than that for those with recurrence. The clinical outcome from our investigation was more favorable than that from the Singapore study. Thus, 35% and 100% of the enrolled patients in our study and the Singapore study, respectively, were in stage IV at the time of starting AS. In addition, according to our present investigation, the 2-year OS rate was significantly shorter in patients with stage IV disease than in those with recurrent disease. On the basis of these observations, we suggest that the AS strategy might not be suitable for patients with stage IV disease and that systemic target therapy should be started immediately in these patients. However, these limited retrospective data are not enough to definitely exclude patients with initial stage IV disease from AS. Further investigation is needed. Lead-time bias might be present and also affect the clinical outcomes. Generally in Japan, including our institution, patients who have undergone radical nephrectomy receive strict periodical work-ups that include CT scan of the chest, abdominal, and pelvic areas every 6 months or more frequently. This intensive workup might be associated with the early detection of recurrence. However, the present treatment guidelines from Western countries, such as those of National Comprehensive Cancer Network (NCCN), mention that CT scan should be obtained 4 to 6 months after surgery and then as clinically indicated. This difference in surveillance frequency might have caused a lead-time bias, and thus becomes a major reason for the different outcomes of AS. In addition, there might be many minor reasons for the different outcome, such as baseline characteristics, follow-up duration, and after initial treatment UROLOGY 82 (1), 2013
procedures. Therefore, we cannot directly compare these results. We expect to validate outcomes in a retrospective study with a larger sample size or in a prospective observational study. The present investigation could reveal clinical outcomes with AS but could not identify the exact subpopulation and factors that could predict and identify the patients suitable for initial AS deferred target therapy, except for disease status. However, we identified several predictive factors that were not statistically significant but showed a tendency to indicate who might be suitable for AS, such as sex, metastatic site, laboratory test abnormalities, and CRP elevation. However, these factors are well known as prognostic factors for mRCC.12,13 It is assumed that a subpopulation suitable for AS might be the same as a subpopulation of patients with super indolent mRCC. Additionally, in the present investigation, we did not test for other potential prognostic factors, including immunological14 and molecular markers.15 Therefore, further investigations are needed to reveal the subpopulation that is suitable for AS and the predictive prognostic factors. There are several potential limitations in the present study, such as small size, retrospective study, patient selection bias, and lack of histologic or cytologic confirmation of recurrence or metastasis in all patients. Thus, 62%, 38%, and 0% of AS patients were categorized into favorable, intermediate, and poor-risk groups, respectively, according to MSKCC criteria. On the other hand, during study period, 13%, 56%, and 31% of non-AS patients were categorized into favorable, intermediate, and poor-risk groups, respectively according to the MSKCC criteria. The difference in patient proportion of risk category between AS and non-AS was statistically significant in our institution (P <.001). Histologic or cytologic confirmation should be performed for patients with recurrent disease, especially for those who have had a long disease-free interval. However, the AS strategy might still be attractive with respect to patient satisfaction and medical economics. To reveal and clarify these benefits definitely, further prospective studies would be needed and also evaluation of quality of life data, cost-effectiveness, and medical economics.
CONCLUSIONS We treated 29 patients with mRCC using initial AS, followed by deferred systemic target therapy. PFS and OS of patients who underwent AS were acceptable. For these indolent subpopulations, AS might be a reasonable approach, and toxic and expensive systemic target therapy might be deferred for a significant period of time. However, some of the bias was contained in this study.
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Further observational studies with a larger sample size might be needed to identify the exact subpopulation and predictive factors for AS. Acknowledgment. This investigation was presented as a part of The 2013 Genitourinary Cancers Symposium, February 14-16, 2013, Orland, USA. References 1. Escudier B, Kataja V. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010; 21(suppl 5):v137-v139. 2. Ljungberg B, Cowan NC, Hanbury DC, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010;58:398-406. 3. Motzer RJ, Agarwal N, Beard C, et al. NCCN clinical practice guidelines in oncology: kidney cancer. J Natl Compr Canc Netw. 2009;7:618-630. 4. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289-296. 5. Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27: 5794-5799. 6. Powles T, Hutson TE. Difficulty in predicting survival in metastatic renal cancer. Lancet Oncol. 2012;13:859-860. 7. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003;362:516-522. 8. Wong AS, Chong KT, Heng CT, et al. Debulking nephrectomy followed by a “watch and wait” approach in metastatic renal cell carcinoma. Urol Oncol. 2009;27:149-154. 9. Fisher R, Pender A, Thillai K, et al. Observation as a treatment strategy for advanced renal cell carcinoma—a call for prospective validation. Front Oncol. 2012;2:1-2; Article 155. 10. Ozono S, Miyao N, Igarashi T, et al. Tumor doubling time of renal cell carcinoma measured by CT: collaboration of Japanese Society of Renal Cancer. Jpn J Clin Oncol. 2004;34:82-85. 11. Kai F, Takayama T, Ito T, et al. Natural history of renal cell carcinoma: a case with 18 years follow-up. Clin Exp Nephrol. 2011; 15:312-315. 12. Naito S, Yamamoto N, Takayama T, et al. Prognosis of Japanese metastatic renal cell carcinoma patients in the cytokine era: a cooperative group report of 1463 patients. Eur Urol. 2010;57: 317-325. 13. Atzpodien J, Royston P, Wandert T, et al. Metastatic renal carcinoma comprehensive prognostic system. Br J Cancer. 2003;88: 348-353. 14. Donskov F, von der Maase H. Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J Clin Oncol. 2006;24:1997-2005. 15. Rini BI. Current status and future directions of molecular markers in renal cell carcinoma. Curr Opin Urol. 2006;16:332-336.
APPENDIX SUPPLEMENTARY
DATA
Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.urology. 2013.03.035.
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