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Originally published as JCO Early Release 10.1200/JCO.2008.20.6524 on July 13 2009

Journal of Clinical Oncology, Vol 27, No 23 (August 10), 2009: pp. 3737-3741
© 2009 American Society of Clinical Oncology.

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Genitourinary Cancer

Risk of Bilateral Renal Cell Cancer

Fredrik Wiklund, Steinar Tretli, Toni K. Choueiri, Sabina Signoretti, Katja Fall, Hans-Olov Adami

From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Cancer Registry of Norway, Oslo, Norway; Dana-Farber Cancer Institute and Dana-Farber/Harvard Cancer Center; and Department of Epidemiology, Harvard School of Public Health, Boston, MA.

Corresponding author: Hans-Olov Adami, MD, PhD, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115; e-mail: adami{at}hsph.harvard.edu.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose The risk of developing bilateral kidney cancer has not been adequately defined in any large, population-based study with long-term follow-up to our knowledge.

Patients and Methods We estimated the risk of metachronous bilateral renal cell cancer in patients diagnosed with unilateral kidney cancer, as recorded in the nationwide cancer registries of Norway and Sweden. Altogether 28,642 patients were followed for an average of 4.4 years. The standardized incidence ratio—the ratio of the observed number of bilateral cancers to the number expected on the basis of the incidence in the Norwegian and Swedish population at large—was used as a measure of relative risk. We used multivariate Poisson regression to separate the effects of the explanatory variables.

Results A synchronous bilateral renal cell cancer was reported in 86 patients. A total of 112 metachronous bilateral cancers were recorded during 126,493 person-years of follow-up compared with 35.8 expected, yielding an overall relative risk (RR) of 3.1 (95% CI, 2.6 to 3.8) and a cumulative incidence of 0.8% after 20 or more years of follow-up. In the multivariate analyses, risk increased monotonically with younger age at first diagnosis (P for trend < .001); compared with patients who were 60 years or older, those younger than 40 years were at a 17-fold higher risk (RR = 17.4; 95% CI, 10.1 to 29.8). We also found a modest but statistically significant decreasing trend with increasing duration of follow-up.

Conclusion The risk of metachronous bilateral renal cell cancer is drastically higher among patients first affected at a young age, suggesting a subset of early onset renal cell cancer with a strong genetic component.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Paired organs have one feature in common; they can be affected by exactly the same carcinogenic influences, both genetic and environmental. A few exceptions might apply, such as in patients with prior exposure to unilateral radiation after unilateral breast cancer. Although an excess risk of cancer in the bilateral organ after a first unilateral disease is well documented for the breast,1,2 eye,3 and the testis,4 little is known about other paired organs such as the lung, ovary, and kidney.

Understanding the risk of bilateral kidney cancer is particularly relevant because the function of this organ is vital, and removal of the remaining kidney as a result of bilateral cancer may require life-long hemodialysis. Hence if patients at high risk of developing bilateral metachronous kidney cancer could be identified early, a longer and more intensive follow-up schedule would be undertaken, with the advantage of an earlier cancer identification. Although several risk factors for renal cell cancer are well documented,5 data on the incidence of metachronous bilateral renal cell cancer are sparse. To the best of our knowledge, the risk has been quantified in only one previous study.6 To this end, we used the high-quality, nationwide Cancer Registries in Norway and Sweden to examine the occurrence of bilateral kidney cancer. Because of the low incidence of renal pelvis cancer compared with renal cell carcinoma, we restricted our analyses to the latter entity.


    PATIENTS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Cancer Registries
We used data from the nationwide cancer registries in Norway and Sweden. Established in 1951, the Norwegian Cancer Registry is considered to be close to complete from 1953. The reporting has been compulsory after a directive from the Ministry of Health and Social Affairs in 1951. The information comes from clinical and histopathologic notifications as well as from death certificates. The registration process and data quality have been described in detail previously.7 The Swedish Cancer Registry was established in 1958. Mandatory reporting of all malignant diseases diagnosed by both clinicians and pathologists has resulted in an essentially complete register.8

For every notified cancer, both registries have a record of the individually unique national registration number, International Classification of Diseases code, and the date of diagnosis. Information on stage of disease and treatment is included in the Norwegian but not in the Swedish Cancer Register. However, neither registry records information on histologic subtype, multifocality, or local recurrence. Separate coding for uni- and bilateral kidney cancer was implemented in the Norwegian Cancer Registry from 1956. In Sweden, instructions for notification of a second primary kidney cancer were unspecific before 1983. New instructions issued in 1983 explicitly request a separate notification for each incident tumor interpreted as a new primary. Consultations with the Cancer Registry indicate that the new policy had been fully implemented in the mid 1980s. Thus to ensure accurate identification of bilateral kidney cancer, we restricted the ascertainment period within the Swedish data to start in 1985.

Study Cohort and Follow-Up
We retrieved from both registries all first recorded renal cell cancers (ICD7 code 180.0) for the period 1956 to 2005 in Norway and the period 1985 to 2005 in Sweden.

Altogether 17,863 individuals in Norway and 17,895 individuals in Sweden for a total of 35,758 were identified. We excluded 3,531 individuals in Norway and 3,585 individuals in Sweden who were diagnosed with cancer before their first renal cancer, died within 1 month of diagnosis, or were 85 years or older at diagnosis. Altogether, 14,332 cases from Norway and 14,310 from Sweden were eligible for analyses.

The national registration numbers, linked to the nationwide registries of migration and cause of death, gave us information on dates of immigration and death. Through such linkages, all patients in the cohort were observed from the date of their first renal cell cancer until the date of immigration, death, or diagnosis of bilateral kidney cancer or until December 31, 2005, whichever occurred first.

Statistical Analysis
Concurring with other investigators,9 bilateral cancers diagnosed within 6 months of the first primary were categorized as synchronous and cancers diagnosed at least 6 months after the first primary were categorized as metachronous. The incidence of bilateral cancer was calculated with accumulated person-years at risk in subjects who had unilateral kidney cancer in the denominator. The person-time at risk started 6 months after the date of the first diagnosis of renal cell cancer and continued until the diagnosis of bilateral kidney cancer or the diagnosis of any other malignant disease, censoring as a result of immigration, death, or end of follow-up. The expected number of renal cell cancers was calculated based on the incidence of first renal cell cancer in the Norwegian and Swedish population at large, adjusted for sex and age (in 5-year group) for each calendar year of observation. The standardized incidence ratio—the ratio of observed to the expected number of cancers—was used as a measure of relative risk. The 95% CIs for the standardized incidence ratio were calculated on the assumption that the observations conformed to a Poisson distribution.

To separate the effects of the explanatory variables (age at diagnosis, follow-up time, sex, and country) we created a multivariate model assuming a multiplicative effect on the standardized incidence ratio for each variable. The number of observed cases was assumed to conform to Poison distribution, and the model was assessed with maximum-likelihood methods and generalized linear analysis. Group data were categorized as in Table 1. The deviance was used in testing the effects of individual variables in addition to direct inference based on parameter estimates and SEs. The degree of absolute fit of the model was measured with Pearson {chi}2 statistic.


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Table 1. Relative Effects on the Standardized Incidence Ratios in the Univariate and Multivariate Analyses According to Selected Variables

 
We used the cmprsk Package, for the R programming language, developed by Gray (Gray RJ, cmprsk Package; Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA; http://biowww.dfci.harvard.edu/~gray) to estimate cumulative incidence of bilateral kidney cancer. CI for the cumulative incidence was constructed assuming a normal distribution and applying a log-transformation. All data preparation and analysis were done with the R programming language, version 2.6.1 (R Foundation for Statistical Computing, Vienna, Austria).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Descriptive Data
A total of 28,642 patients with a first renal cell cancer were included in our analyses and observed for a total of 126,493 person-years. Approximately the same number of patients were studied from Norway and Sweden. Reflecting the higher incidence rates of renal cell cancer in men than in women,5 approximately 60% of the cases were men. The average age at first diagnosis was approximately 65 years, and the average follow-up time was 4.4 years (Table 2).


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Table 2. Descriptive Data on the Cohorts of Patients With Unilateral and Bilateral Renal Cell Cancer in Norway (1956 to 2005) and Sweden (1985 to 2005)

 
A synchronous bilateral renal cell cancer (diagnosed concomitantly or within 6 months of the first cancer) was reported in 86 cases, corresponding to one of 333 patients with newly diagnosed renal cell cancer (Table 2). Of these bilateral cancers, approximately 75% had the same date of diagnosis as the bilateral cancer. Of those classified as having a metachronous bilateral cancer, only eight were diagnosed in the time interval 6 to 12 months after first primary diagnosis.

Univariate Analyses
Among the 28,556 patients with a first renal cell cancer (without synchronous bilateral cancer and alive 6 months after diagnosis of first renal cell cancer), bilateral cancer developed in a total of 112 patients (0.4%) compared with 35.8 expected, yielding a relative risk of 3.1 (95% CI, 2.6 to 3.8). Table 3 shows the relative risks according to sex, duration of follow-up, and age at diagnosis of the first cancer. Two striking findings emerged from these univariate analyses. First, the excess risk of metachronous cancer differed by sex in Sweden, but not in Norway. Although the excess risk was five-fold in women, no significant excess risk was found in men. As a corollary, the overall excess risk was lower in Sweden than in Norway.


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Table 3. RR With 95% CIs for Metachronous Bilateral Renal Cell Cancer Among Patients With a First Primary Renal Cell Cancer by Sex, Duration of Follow-Up, and Age at Diagnosis of First Primary Cancer

 
The second and most striking finding was the steep increase in relative risk for younger age at first diagnosis of renal cell cancer. Compared with the general population, the risk was increased 90% among those aged 60 years or older, and approximately 1800% in patients younger than 40 years (Table 3). The apparent lack of trend with duration of follow-up might be confounded by age; younger patients—with higher relative risk—are gradually over-represented during longer follow-up as a result of more competing forces of death among older adult patients.

The cumulative incidence of bilateral renal cell cancer is shown in Figure 1. After 20 years of follow-up, the cumulative incidence among all patients was 0.8% (95% CI, 0.7% to 1.0%). In agreement with results shown in Table 3, analysis stratified for country revealed higher incidence of bilateral renal cell cancer in Norway (cumulative incidence = 0.9%, 95% CI, 0.7% to 1.2%) than in Sweden (cumulative incidence = 0.5%; 95% CI, 0.4% to 0.7%; data not shown). Figure 2 illustrates the difference in cumulative incidence between patients who were younger than 40 years and 60 years or older when their first renal cell cancer was diagnosed. Among patients in the oldest age group, cumulative incidence leveled at 0.5% after approximately 12 years with no further increase. In contrast, cumulative incidence increased steeply among younger patients, reaching approximately 1.5% within 10 years.


Figure 1
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Fig 1. Nelson-Aalen estimates of cumulative incidence of metachronous renal cell cancer with 95% log-transformed CIs.

 


Figure 2
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Fig 2. Nelson-Aalen estimate of cumulative incidence of metachronous renal cell cancer by time since first primary cancer stratified by age at diagnosis of primary renal cell cancer.

 
Multivariate Analyses
After controlling for the influence of other explanatory variables, the relative risk for bilateral renal cell cancer was not significantly lower in Sweden than in Norway, but was significantly higher among women than among men (Table 1). After multivariate adjustment, the relative risk of all patients in the study diminished with longer follow-up with a highly significant trend (P = .006). The most notable effect was an increasing relative risk associated with younger age at first diagnosis. This effect became even stronger when we controlled for the influence of other variables in the multivariate model. The relative risk increased monotonically and was 17-fold higher in patients who were younger than 40 years at first diagnosis compared with those who were 60 years or older (P for trend < .0001). The Pearson {chi}2 statistic for the multivariate model was 333.6 with 324 df, which indicates a good fit.

In addition to the main-effects model in Table 1, we tested for (multiplicative) interaction between country of residence and sex on the risk of bilateral cancer by including an interaction term in the multivariate model. A significant interaction (P = .0003) was observed between men and women restricted to the Swedish population.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
In this large population-based study, our most salient and novel finding was that the risk of bilateral renal cell cancer depends profoundly on age at first diagnosis. After adjustment for the influence of follow-up time, sex, and country, patients first diagnosed before age 40 years were at a 17-fold higher risk compared with patients first diagnosed at the age of 60 years or older. Synchronous bilateral cancer was indeed a rare event, notwithstanding the fact that both kidneys are thoroughly examined as part of diagnostic work-up before treatment. Further, the overall excess risk of a bilateral metachronous cancer was increased approximately three-fold based on the expected numbers of cases of any first kidney cancer. Because these numbers are obtained from the general population with bilateral organs, the expected numbers could arguably be reduced by half among patients who have only one kidney at risk of an incident cancer. With this approach, all relative risks shown in Table 3 should be doubled. Although the conservative approach we used reflects the patients' risk of developing a new primary kidney cancer compared with the general population, the alternative approach, yielding higher risk estimates, may provide information that is biologically more relevant.

Few large studies such as ours attempted to understand the risk of developing a metachronous bilateral renal cell cancer. In the 1973 to 1997 Surveillance, Epidemiology, and End Results database in the United States,6 metachronous renal cell cancer developed subsequently in 155 (0.4%) of 40,049 patients with follow-up. Given that the number of person-years of follow-up was approximately 30% larger in the United States study (166,059) compared with ours (Table 2), the expected number of metachronous bilateral cancers was surprisingly low (10.8). As a corollary, the overall relative risk was substantially higher (relative risk, 14.4; 95% CI, 12.2 to 16.8) than the three-fold excess risk we found (Table 3). The reason for this discrepancy is unclear. In the United States study, the relative risk of metachronous bilateral renal cell cancer remained stable during long-term follow-up in univariate analyses, similar to our finding (Table 3). Age at first diagnosis was not considered, nor were any multivariate analyses performed.6

Another recent large study evaluated risk factors and relevance of the primary-free interval in 120 patients with bilateral renal cell carcinoma treated at 12 international academic centers that included more than 10,000 patients with a primary renal cell carcinoma.9 With a median follow-up of 6.9 years, young age was found to be an independent risk factor for bilateral renal cell carcinoma. Patients with metachronous renal cell cancer were significantly younger at first diagnosis (age 53.5 years v 59.9 years; P < .001). Age at first presentation was strongly associated with the risk of a second renal cell cancer, with 4% decrease in risk with every 1-year increase in age.9 Because these data come from a hospital-based series from tertiary care centers, there is a potential for overestimation of the true incidence and risks as a result of referral bias or underestimation as a result of short follow-up.

Strengths of our study include its large size, extended follow-up period, and population-based design. The main potential limitation is that some synchronous and metachronous bilateral cancers may not have been completely notified to the cancer registries. The magnitude of such potential under-reporting is in practice impossible to assess because it would require scrutiny of hospital records from all members of the study cohort. Although under-reporting would entail a conservative estimate of the overall excess risk, it is unlikely to affect our main finding, the trend with age at first diagnosis. Additional studies are needed to clarify whether the unexpected higher excess risk of bilateral cancer among women than among men in our study is due to chance or reflects a real biologic phenomenon.

A further limitation of our study is the lack of detailed histopathologic information of renal cell cancer in the cancer registries. It is unclear whether occasionally bilateral cancer is a manifestation of metastatic disease originating in the first primary. Criteria for a second primary rather than metastasis are not established, although some authors advocate that a second primary metachronous renal cell cancer could be assumed when there is only one tumor in each kidney, the basic histology is the same, and each tumor shows at least partial encapsulation.10 However, because the mortality from disseminated renal cell cancer takes place predominantly during the first few years of follow-up,11 we would expect the excess risk to vanish quickly over follow-up time. We found, however, no evidence for this (Table 1).

It is generally recognized that renal cell cancer is not a single disease but consists of different types of tumors. Clear-cell carcinoma, the most frequent form of renal cancer, accounts for 70% to 80% of cases. Additional renal cell cancer subtypes include papillary (15%) and chromophobe (5%) carcinomas.12 Importantly, distinct genetic events seem to underlie the development of the different tumors subtypes, which also have different clinical courses and respond differently to treatment.13,14 Although the majority of kidney cancers are sporadic (ie, noninherited), several hereditary forms have been identified.5 Important insights into the biology of renal cell cancer have been gained from studies of inherited cancer syndromes, which include von Hippel Lindau (VHL), hereditary papillary renal carcinoma, Birt Hogg Dubé, and hereditary leiomyomatosis renal cell carcinoma.14

Of note, hereditary renal cancers are often multiple and bilateral and occur at younger age than sporadic tumors. Klatte et al9 recently reported that among patients with bilateral kidney cancer, familial renal cell carcinoma was found in 14.3% of cases and VHL disease was found in 4.3% of cases. In this study, both VHL disease and a family history of renal cell carcinoma were identified as independent risk factors for bilateral kidney cancer. Future efforts will be directed at confirming these findings in our population-based cohort and at identifying additional risk factors, especially for the nonhereditary, apparently sporadic form of bilateral renal cancer. Genetic analysis might be helpful to distinguish between a new renal cell cancer and metastasis. For example, Weaver et al15 noted that bilateral renal cell cancer was associated with more frequent loss of a sex chromosome and a gain of chromosomes 3 and 7, whereas unilateral tumors were often associated with a loss of chromosome 3 material.

In conclusion, using the Norwegian and Swedish cancer registries, the risk of a second metachronous renal cell carcinoma was found to be considerably higher among patients first affected at a young age, suggesting a subset of patients with early-onset kidney cancer with a possible strong genetic predisposition. Our findings may guide the counseling and management of patients with unilateral renal cell cancer. The reassuringly low excess and absolute risk of a contralateral cancer among older patients provides little support for extensive monitoring of the unaffected kidney. In younger patients, however, further histopathologic and genetic studies might identify a subgroup that deserves extensive monitoring because they are at high risk of developing a contralateral cancer. Our study clearly indicates that additional work needs to be performed to provide optimal clinical management for younger patients with renal cell cancer.


    AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
The author(s) indicated no potential conflicts of interest.


    AUTHOR CONTRIBUTIONS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Conception and design: Fredrik Wiklund, Steinar Tretli, Hans-Olov Adami

Collection and assembly of data: Fredrik Wiklund, Steinar Tretli

Data analysis and interpretation: Fredrik Wiklund, Steinar Tretli, Toni K. Choueiri, Sabina Signoretti, Hans-Olov Adami

Manuscript writing: Steinar Tretli, Toni K. Choueiri, Sabina Signoretti, Katja Fall, Hans-Olov Adami

Final approval of manuscript: Fredrik Wiklund, Steinar Tretli, Toni K. Choueiri, Sabina Signoretti, Katja Fall, Hans-Olov Adami


    NOTES
 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
1. Chen Y, Thompson W, Semenciw R, et al: Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev 8:855–861, 1999.[Abstract/Free Full Text]

2. Hartman M, Czene K, Reilly M, et al: Incidence and prognosis of synchronous and metachronous bilateral breast cancer. J Clin Oncol 25:4210–4216, 2007.[Abstract/Free Full Text]

3. Abramson DH, Frank CM, Susman M 3rd, et al: Presenting signs of retinoblastoma. J Pediatr 132:505–508, 1998.[CrossRef][Medline]

4. Hentrich M, Weber N, Bergsdorf T, et al: Management and outcome of bilateral testicular germ cell tumors: Twenty-five year experience in Munich. Acta Oncol 44:529–536, 2005.[CrossRef][Medline]

5. Cho E, Lindblad P, Adami H-O. Kidney cancer. HO Adami, D Hunter, and D Trichopoulos. Textbook of Cancer Epidemiology, ed 2 New York, NY: Oxford University Press, 2008. p.597–616.

6. Rabbani F, Herr HW, Almahmeed T, et al: Temporal change in risk of metachronous contralateral renal cell carcinoma: Influence of tumor characteristics and demographic factors. J Clin Oncol 20:2370–2375, 2002.[Abstract/Free Full Text]

7. Cancer Registry of Norway. Cancer in Norway: A special issue—Data quality at the cancer Registry of Norway. http://www.kreftregisteret.no.

8. Mattsson B, Wallgren A: Completeness of the Swedish Cancer Register: Non-notified cancer cases recorded on death certificates in 1978. Acta Radiol Oncol 23:305–313, 1984.[Medline]

9. Klatte T, Patard JJ, Wunderlich H, et al: Metachronous bilateral renal cell carcinoma: Risk assessment, prognosis and relevance of the primary-free interval. J Urol 177:2081–2086, 2007 discussion 2086-2087.[CrossRef][Medline]

10. Farrow GM. Diseases of the kidney. WM Murphy, Urological Pathology, ed 2 Philadelphia, PA: WB Saunders, 1997. p.464–470.

11. Choueiri TK, Rini B, Garcia JA, et al: Prognostic factors associated with long-term survival in previously untreated metastatic renal cell carcinoma. Ann Oncol 18:249–255, 2007.[Abstract/Free Full Text]

12. Lopez-Beltran A, Scarpelli M, Montironi R, et al: 2004 WHO classification of the renal tumors of the adults. Eur Urol 49:798–805, 2006.[CrossRef][Medline]

13. Cohen HT, McGovern FJ: Renal cell carcinoma. N Engl J Med 353:2477–2490, 2005.[CrossRef][Medline]

14. Linehan WM, Pinto PA, Srinivasan R, et al: Identification of the genes for kidney cancer: Opportunity for disease-specific targeted therapeutics. Clin Cancer Res 13:671s–679s, 2007.[Abstract/Free Full Text]

15. Weaver DJ, Michalski K, Miles JH: Cytogenetics of bilateral renal cell carcinoma. J Urol 142:697–700, 1989.[Medline]

Submitted October 21, 2008; accepted March 16, 2009.


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J. Clin. Oncol., August 10, 2009; 27(23): 3731 - 3733.
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