- Email: [email protected]
Non–Guideline-concordant Treatment of Testicular Cancer Is Associated With Reduced Relapse-free Survival
Original Study
NoneGuideline-concordant Treatment of Testicular Cancer Is Associated With Reduced Relapse-free Survival Pia Paffenholz,1 Isabel Maria Heidegger,2 Kathrin Kuhr,3 Sven Heiko Loosen,4 David Pfister,1 Axel Heidenreich1 Abstract The treatment of testicular cancer (TC) requires a multimodal approach. We retrospectively evaluated the diagnostic work-up, treatment, and outcomes of 131 patients with respect to the European Association of Urology guidelines. Of 131 patients, 18% had received noneguideline-concordant treatment, with undertreatment having a negative effect on relapse-free survival. Thus, implementation of guidelines is needed to decrease the mortality of TC. Introduction: The management of testicular cancer (TC) requires a complex multimodal therapeutic approach. Despite the availability of regularly updated guidelines, noneguideline-concordant treatment of TC still occurs. The purpose of the present study was to evaluate the compliance patterns in diagnosis and therapy and their potential effects on patient outcomes with respect to the guidelines of the European Association of Urology. Patients and Methods: We performed a retrospective analysis of 131 patients diagnosed with TC who had been referred to our department from September 2015 to October 2016. Patient characteristics were compared with European Association of Urology guideline recommendations. Results: Of the 131 primary treated patients, 23 (18%) had received a noneguidelineconcordant treatment. The most common error was undertreatment (n ¼ 12; 52%), mainly due to missing chemotherapy cycles. Overtreatment occurred in 30% of patients (n ¼ 7); however, inappropriate treatment (n ¼ 2; 9%) and misdiagnosis (n ¼ 2; 9%) were rarely observed. In salvage therapy, noneguideline concordant treatment was observed less frequently compared to patients receiving primary therapy (12% vs. 18%). Of the 131 patients, 35 developed a relapse, 23 of whom were treated correctly and 6 of whom were undertreated. Undertreatment of patients resulted in significantly reduced relapse-free survival compared with guideline-concordant management in primary treated patients (P ¼ .005). Conclusion: Despite the standardization of treatment by interdisciplinary guidelines, its integration into daily practice remains limited. Undertreatment of TC patients is associated with significantly reduced relapse-free survival and should thus be avoided. Clinical Genitourinary Cancer, Vol. -, No. -, 1-7 ª 2017 Elsevier Inc. All rights reserved. Keywords: EAU, Germ cell tumor, Guidelines, TC, Treatment failure
Introduction Management of testicular cancer (TC), the most common cancer in young men, requires a complex multimodal therapeutic 1 Department of Urology, Uro-Oncology, Robot Assisted and Reconstructive Urologic Surgery, University Hospital Cologne, Cologne, Germany 2 Department of Urology, Medical University Innsbruck, Innsbruck, Austria 3 Institute of Medical Statistics, Informatics and Epidemiology, University Hospital Cologne, Cologne, Germany 4 Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
Submitted: Jul 20, 2017; Revised: Aug 29, 2017; Accepted: Aug 31, 2017 Address for correspondence: Axel Heidenreich, MD, PhD, Department of Urology, Uro-Oncology, Robot Assisted and Reconstructive Urologic Surgery, University Hospital Cologne, Kerpener Straße 62, Cologne 50937, Germany E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2017.08.018
approach.1,2 Depending on the patients’ clinical status, which is defined by the presence and localization of metastases and tumor marker profiles, the potential treatment options include surveillance, chemotherapy, radiotherapy, and surgery. For standardized management of TC, different national and international guidelines on TC are available and regularly updated, including the widely used European Association of Urology (EAU) guidelines for TC treatment.1,3 A recently reported study suggested that integration of interdisciplinary guidelines significantly reduced therapeutic mistakes from 28% to 8% in a tertiary referral center, leading to decreased patient mortality.4 Despite the available guidelines, the translation of the recommended treatment into clinical practice has remained inadequate among institutions, which could affect patient outcomes.5,6
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Association of NoneGuideline Treatment of TC and RFS The German second-opinion network, which aims to improve the quality of care for TC patients by providing advice to requesting urologists, reported a discrepancy between the first and second opinions in 39.5% of cases.7 Moreover, a recently reported study revealed noneguideline-directed care for 30% of patients with TC in the United States. In that study, noneguideline-concordant treatment was most frequently caused by inappropriate imaging studies and overtreatment, leading to delayed definitive therapy, greater morbidity, and greater rates of relapse.8 In Europe, only limited data on guideline conformity for treatment of TC, especially with respect to patient outcomes, is available. In the present study, we performed a retrospective investigation of frequently occurring mistakes in the diagnosis of and therapy for TC in consideration of the current EAU guidelines. We hypothesized that noneguideline-concordant treatment of TC might still be a major problem in various TC-treating institutions and might have a negative effect on patient outcomes.
Patients and Methods Study Population In our study, we retrospectively analyzed the TC database at the University Hospital of Cologne as an observational cohort study. We identified 147 patients with a diagnosis of TC (International Classification of Disease, 10 revision, code C62) who had been referred to our department from September 2015 to October 2016. Patients with benign testicular tumors, nonegerm cell tumors, or testicular masses from nontesticular primary tumors were excluded from the present study (n ¼ 15). Patients with insufficient medical records were also excluded (n ¼ 1), for a total of 131 patients enrolled in the present study. We collected data on age, histologic findings, clinical stage, and International Germ Cell Cancer Collaborative Group risk classification. Moreover, the treatment type, treatment duration, and follow-up analysis results were included. Disease recurrence was defined as in- or outfield lymph node metastases and distant metastases. Survival data were not available for 5 of the analyzed patients. The year of diagnosis is listed in Supplemental Table 1 (available in the online version), and the patient characteristics are listed in Table 1. The local ethics committee approved the present study, which complied with the Declaration of Helsinki.
Definition of Guideline Concordance
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The patients’ treatment was compared with the current EAU guidelines for TC.1 The EAU guidelines for TC were initially published in 2001 and have been regularly updated, including major changes in the diagnosis and treatment of germ cell tumors.3 Noneguideline-concordant treatment was defined as treatment that was not in line with the EAU guidelines. It was further subdivided into overtreatment, undertreatment, inappropriate treatment, and misdiagnosis, similar to the categories used in a recent study.8 Modified treatment, defined as a planned modification of guideline-concordant treatment because of chemotherapy side effects or thrombosis, another simultaneous tumor burden or an atypical histologic type, was classified as correct treatment. The members of the TC working group of our department manually reviewed the data from all the patients included in the present study using the following standardized
Clinical Genitourinary Cancer Month 2017
Table 1 Patient Characteristics of Study Population (n [ 131) Characteristic
n (%)
Age (y) Median IQR
35 28-49
Age distribution <20 y
4 (3)
20-30 y
42 (34)
31-40 y
32 (26)
40-50 y
20 (16)
>50 y
25 (21)
Histologic type Nonseminoma
74 (57)
Seminoma
47 (37)
Extragonadal
4 (3)
Bilateral
4 (3)
Clinical stage 1
55 (43)
2
52 (40)
3
22 (17)
IGCCCG risk classification Good
103 (80)
Intermediate
15 (12)
Poor
10 (8)
Treatment Surveillance/follow-up Orchiectomy Chemotherapy
25 (19) 5 (4) 44 (33)
RT
4 (3)
RPLND
0 (0)
Chemotherapy plus RPLND
48 (37)
Chemotherapy plus RT
1 (1)
Chemotherapy plus RPLND plus RT
4 (3)
RPLND field Unilateral modified
19 (53)
Bilateral
17 (47)
Chemotherapy cycles (n) Median IQR
3 3-4
Follow-up (mo) Median IQR
9 4-22
Relapse until follow-up end No
91 (72)
Yes
35 (28)
Relapse treatment
classification and subclassification in accordance with the EAU guidelines (see Tables 2 and 3). Overtreatment was defined as unintended and/or too intense treatment, including unnecessary high dosages of chemotherapy or radiotherapy, the performance
Pia Paffenholz et al Results
Table 1 Continued Characteristic Chemotherapy
Patient Characteristics n (%) 15 (50)
RPLND
5 (17)
Chemotherapy plus RPLND
6 (20)
Chemotherapy plus RT
4 (13)
Time point of mismanagement Low-volume center before referral Our high-volume institution
24 (83) 5 (17)
Data presented as median and IQR for continuous variables and n (%) for categorical variables. Abbreviations: IGCCCG ¼ International Germ Cell Cancer Collaborative Group; IQR ¼ interquartile range; RPLND ¼ retroperitoneal lymph node dissection (in accordance with the Heidenreich criteria,9 patients with low-volume retroperitoneal disease [< 5 cm] limited to the primary landing zone of the tumor underwent with unilateral modified RPLND; all other patients underwent bilateral dissection); RT ¼ radiotherapy.
of unnecessary computed tomography scans and unnecessarily biopsied metastases. Undertreatment was defined as a patient unintentionally not receiving the recommended number of chemotherapy cycles or the full regimen or the guidelineconcordant surgery such as retroperitoneal lymph node dissection after chemotherapy. Inappropriate treatment was defined as a patient unintentionally receiving treatment that did not conform to the guidelines and could not be categorized as overor undertreatment. Misdiagnosis was, in all cases, due to incorrect pathology interpretation of frozen section analyses during the initial surgery of the testis. The intraoperative benign histology report was reclassified as malignant germ cell tumor in the final analysis, implying a second operation with testicular ablation. For a better comparison of the data, the data from the primary treated patients and the salvage treated patients were analyzed separately. However, primary treatment was evaluated for all the patients. Mismanagement was observed in either primary or salvage treatment; thus, each patient was counted only once with respect to the mismanagement rate. The patients were also subdivided into 2 groups according to whether the noneguideline-concordant care had occurred at an outside, low-volume hospital before referral to our institution or at our high-volume institution.
Statistical Analysis Statistical analyses were performed using SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, NY). Continuous variables are presented as the median and interquartile range (25th to 75th percentile) and categorical variables as numbers and percentages. Pairwise comparisons were performed using the MannWhitney U test for continuous variables and Pearson’s c2 test for categorical variables. Relapse-free survival was estimated using the Kaplan-Maier method and compared between guidelineconcordant management and undertreatment for primary treatment using the log-rank test. All reported P values are 2-sided, and 2P values < .05 were considered statistically significant. Because the analyses were regarded as explorative, we did not adjust for multiple testing.
To evaluate whether noneguideline-concordant treatment predominantly occurs in certain subgroups of patients, we first compared the patient characteristics between guideline-concordant and noneguideline-concordant treatment (Table 2). No significant differences were found between guideline-concordant and noneguideline-concordant treatment with respect to patient age, disease stage, International Germ Cell Cancer Collaborative Group risk classification, and the different treatment options during the total disease course. In addition, the relapse rates, retroperitoneal lymph node dissection (RPLND) field, number of chemotherapy cycles, and follow-up period did not differ significantly between the 2 groups (Table 2). We found that 83% (n ¼ 24 of 29) of none guideline-concordant care had occurred at an outside, low-volume hospital before referral to our institution and 17% (n ¼ 5 of 29) had occurred at our high-volume institution (Table 1). Furthermore, 71% (n ¼ 32 of 51) of patients receiving salvage therapy had been treated at a high-volume center and 29% (n ¼ 13 of 51) at a low-volume center. Noneguideline-concordant treatment for salvage therapy occurred only at low-volume centers (P ¼ .001; Supplemental Table 2; available in the online version).
Subcategories of NoneGuideline-concordant Treatment We next investigated the different subtypes of noneguidelineconcordant treatment in our cohort of patients (Table 3). Of the 131 primary treated patients, 23 (18%) had received noneguideline-concordant treatment, with undertreatment being the most common type of noncompliance (n ¼ 12; 52%; Table 3). Overtreatment occurred in 30% (n ¼ 7), although inappropriate treatment (n ¼ 2; 9%) and misdiagnosis (n ¼ 2; 9%) were rarely seen (Table 3). Of the patients receiving salvage treatment, none guideline-concordant therapy was observed less frequently (n ¼ 6; 12%), with undertreatment being again the most common medical error (n ¼ 4; 66%; Table 3). The subgroup analyses revealed that missing or only partially given chemotherapy cycles (58.3%) were the most common reasons for undertreatment in the primary treated patients. This included unintentional administration of 2 instead of 3 cycles of BEP (bleomycin, etoposide, and cisplatin) chemotherapy as the initial treatment option for stage III (5 patients); 2 cycles, instead of 3 cycles, of TIP (paclitaxel [Taxol], ifosfamide, cisplatin) chemotherapy as the salvage treatment option (1 patient); or 1 cycle of BEP chemotherapy as the initial treatment option for stage IS (1 patient). The second most common undertreatment was surveillance for patients with clinical stage IS (33.3%), defined as persistently elevated serum tumor marker levels after orchiectomy as an indicator of subclinical metastatic disease. The third most common undertreatment was observation for patients with retroperitoneal lymph nodes > 1 cm in nonseminoma patients or > 3 cm in seminoma patients (8.3%; Table 3). Overtreatment also occurred frequently in the primary treated patients (30%). Of those, 29% of patients experienced unnecessary biopsies of potentially metastatic lesions in the retroperitoneum or inappropriate imaging studies (eg, staging computed tomography scans after 2 cycles of chemotherapy). Of all the overtreated
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Association of NoneGuideline Treatment of TC and RFS Table 2 Patient Characteristics Stratified by Guideline-concordant and NoneGuideline-concordant Treatment (n [ 131) Characteristic
Guideline-concordant Management (n [ 108)
Mismanagement (n [ 23)
36
33
27-48
28.25-50
Age (y) Median IQR
.824
Histologic type
.137
Nonseminoma
56 (53)
18 (78)
Seminoma
42 (39)
5 (22)
Extragonadal
4 (4)
0 (0)
Bilateral
4 (4)
0 (0)
1
44 (41)
11 (52)
2
46 (42)
6 (29)
3
18 (17)
4 (19)
Good
86 (82)
17 (74)
Intermediate
11 (10)
4 (17)
8 (8)
2 (9)
Clinical stage
.478
IGCCCG risk classification
Poor
.623
Treatment Surveillance/follow-up Orchiectomy Chemotherapy
.366 22 (20)
3 (13)
4 (4)
1 (4)
35 (32)
9 (40)
RT
4 (4)
0 (0)
RPLND
0 (0)
0 (0)
40 (37)
8 (35)
Chemotherapy plus RPLND Chemotherapy plus RT
0 (0)
1 (4)
Chemotherapy plus RPLND plus RT
3 (3)
1 (4)
Unilateral modified
13 (45)
6 (86)
Bilateral
16 (55)
1 (14)
RPLND field
.052
Chemotherapy cycles (n) Median IQR
.357 3
4
3-4
3-4
9
11
4-18.5
1.75-61.25
11 (52%)
4 (45%)
Follow-up (mo) Median IQR
.952
Relapse treatment Chemotherapy
P Value
.265
RPLND
2 (10%)
3 (33%)
Chemotherapy plus RPLND
4 (19%)
2 (22%)
Chemotherapy plus RT
4 (19%)
0
Data presented as median and IQR for continuous variables and n (%) for categorical variables. Abbreviations: IGCCCG ¼ International Germ Cell Cancer Collaborative Group; IQR ¼ interquartile range; RPLND ¼ retroperitoneal lymph node dissection (in accordance with the Heidenreich criteria,9 patients with low-volume retroperitoneal disease [< 5 cm] limited to the primary landing zone of the tumor underwent with unilateral modified RPLND; all other patients underwent bilateral dissection); RT ¼ radiotherapy.
4
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patients, 14% received an inappropriate dosage of radiotherapy, unnecessary radiotherapy, or an inappropriate number of chemotherapy cycles (6 cycles of BEP chemotherapy as the initial treatment option for stage III, poor prognosis disease; Table 3). Inappropriate treatment was given to 9% of all primary treated patients and was because of the wrong chemotherapy regimens in
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67% of all cases, with one patient been treated with PEI (cisplatin, etoposide, ifosfamide) chemotherapy as primary treatment or VeIP (vinblastine sulfate [Velban], ifosfamide, cisplatin) chemotherapy as salvage treatment. One patient underwent RPLND for a markerpositive relapse tumor (a-fetoprotein, 1607 U/mL) in a nondesperation setting (33%; Table 3).
Pia Paffenholz et al Table 3 Mismanagement Characteristics for Whole Study Population (n [ 29 of 131), Primary Treatment Patients (n [ 23 of 131), and Salvage Therapy Patients (n [ 6 of 51) Mismanagement Type Total Undertreatment Missing ChT cycles/ChT regimen partly given
Total
Primary Treatment
Salvage Therapy
29/131 (22)
23/131 (18)
6/51 (12)
16 (55) 8 (50)
12 (52) 7 (58.3)
4 (66) 1 (25)
Surveillance in stage IS
4 (25)
4 (33.3)
0 (0)
Observation of post-ChT RPLN
4 (25)
1 (8.3)
3 (75)
Overtreatment
8 (28)
7 (30)
1 (17)
Unnecessary biopsies
3 (37.5)
2 (29)
1 (100)
Inappropriate imaging studies
2 (25)
2 (29)
0 (0)
Inappropriate dosage of RT
1 (12.5)
1 (14)
0 (0)
Unnecessary RT
1 (12.5)
1 (14)
0 (0)
Inappropriate ChT cycles
1 (12.5)
1 (14)
0 (0)
Inappropriate treatment
3 (10)
2 (9)
1 (17)
Wrong ChT regimen
2 (67)
1 (50)
1 (100)
RPLND at marker-positive relapse tumor
1 (33)
1 (50)
0 (0)
Misdiagnosis Incorrect pathology interpretation
2 (7)
2 (9)
0 (0)
2 (100)
2 (100)
0 (0)
Data presented as n (%); patients receiving salvage treatment were also included in the cohort of primary treated patients. Abbreviations: ChT ¼ chemotherapy; RPLN ¼ retroperitoneal lymph node; RPLND ¼ RPLN dissection.
A misdiagnosis occurred in 9% of all noneguideline-concordant primary treated patients, and in all cases was based on incorrect pathology reports of the frozen section analyses during initial surgery of the testis (Table 3).
Analysis of Relapse-free Survival We next analyzed the influence of noneguideline-concordant treatment with respect to relapse-free survival of primary treated patients. The median follow-up period was 9 months (interquartile range, 4-22 months; Table 1). In all primary treated patients, 35 patients developed a relapse, 23 of whom had been treated correctly and 6 had been undertreated. Kaplan-Meier estimates revealed that undertreatment led to significantly reduced relapse-free survival compared with guideline-concordant management in primary treated patients (P ¼ .005; Figure 1).
Discussion Treatment of TC requires a standardized, evidence-based, and guideline-adapted approach to achieve or maintain a high cure rate of almost 95%.1 However, in our study, we identified noneguideline-concordant treatment in 18% of all primary treated TC patients. In addition, undertreatment, which was the most common mistake, was associated with reduced relapse-free survival. In 2006, a study of the benefits of guideline implementation was performed at a tertiary referral center and found that the implementation of interdisciplinary guidelines led to significantly reduced therapeutic mistakes (28% vs. 8%) and was associated with a decreased mortality.3 However, guideline incompliance regarding the treatment of TC in different institutions is still frequently observed and seems to have been constant for decades.5,7,8 Therefore, the German second-opinion network analyzed the treatment of TC in Germany regarding the effect of second opinions on the
quality of treatment. Its first survey from 2010 revealed a discrepancy between the first and second opinions in 32.3% of all analyzed 642 cases.5 The second survey, with 926 cases, showed an even greater discrepancy of 39.5% between the first and second opinions.7 These analyses clearly showed that no improvement had occurred in guideline-directed care of TC in Germany from 2010 to 2014. Another recently reported study revealed noneguidelinedirected care of TC in 30% of patients treated in the United States.8 Moreover, a previous study revealed noneguideline-directed care in 50% of TC patients treated with salvage chemotherapy.10 In accordance with these studies, our analysis showed that, despite their universal availability, the implementation of guidelines into daily clinical practice is still limited, because nonadherence to the current EAU guidelines on TC was present in 18% of all primary treated patients. Nevertheless, this proportion could have been underestimated because many patients have been diagnosed with testicular cancer in 2016, resulting in a relatively short median follow-up period for our study. Compared with previous studies, patients with stage III disease or a poor prognosis did not show a greater incidence of noneguideline-concordant treatment compared with patients without metastases in our cohort of patients.5,7,8 Nevertheless, the threshold to enter into a dialogue with other urologists or seek advice at the German second-opinion network should be rather low, especially in complex cases. In line with the findings from the German second-opinion network from 2014, we found that the most common treatment mistake was undertreatment (52%).7 In 58% of patients, it resulted from missing chemotherapy cycles or only partially given chemotherapy regimens, which were also the most common reasons for undertreatment in the US study.8 In our study, overtreatment of patients occurred in only 30% of cases compared with the rate in 2 other studies, with overtreatment reported as the most common
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Association of NoneGuideline Treatment of TC and RFS Figure 1 Kaplan-Meier Estimates for Relapse-free Survival Showing Comparison Between Guideline-concordant Treatment and Undertreatment in Primary Treated Patients
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treatment error.5,8 Misdiagnosis because of an incorrect pathology interpretation of frozen section analysis during the initial surgery of the testis was observed in 9% of all cases in our study. Even greater rates of incorrect pathology reports were found in a previous study comparing initial and referral histopathology reports, revealing that the pathology reports were altered after central review for 27.7% of the cases.11 In that study, misread pathology reports strongly affected the treatment (6.5%) and prognosis (9%) of patients, emphasizing the importance of reference pathology.11 The previously cited US study described undertreatment as the strongest predictor of disease relapse.8 In accordance with that finding, our analysis revealed significantly reduced relapse-free survival in undertreated patients compared with patients who had received a guideline-concordant therapy. These data suggest that undertreatment should be avoided because the management of recurring disease requires a more intensive therapeutic approach, which could lead to more side effects and greater psychological and socioeconomic burden.1,12,13 Although overtreatment did not show any relevant effects on the oncologic outcome in our study, it might nevertheless lead to increased long-term toxicity and secondary malignancies.1
Clinical Genitourinary Cancer Month 2017
However, the reasons for the high frequency of guideline incompliance are unknown. A potential reason might be that most urologists believe the treatment of TC is easy to understand. Furthermore, the referral of patients to a high-volume center might suggest inexperience or might have a negative effect on the physician’s reputation. Accordingly, a recently reported study revealed that most RPLNDs in the United States are performed by lowvolume surgeons, despite the importance of the surgical quality for patient outcomes.14 Furthermore, it was shown that treatment of TC patients at tertiary referral centers leads to significantly improved survival, especially for advance disease stages.4 That finding was supported by our study, in which 83% of noneguideline-concordant care of all patients occurred at an outside, low-volume hospital before referral to our institution. Mismanagement of salvage therapy was only seen in low-volume centers. Thus, centralization is recommended for the management of intermediate- and poor-risk disease and for complex procedures such as post-chemotherapy RPLND or salvage chemotherapy.10,15 Additional reasons for noneguideline-directed care could be a misinterpretation of the guidelines or the patients’ characteristics.5 Therefore, the inclusion of TC patients into clinical studies or the
Pia Paffenholz et al involvement of second-opinion centers might be helpful to further increase guideline adherence.5,16 Moreover, incentives for guideline-based therapy from health care providers, medical insurance companies, or organizations such as the EAU might further help to overcome the problem of noneguideline-concordant treatment. Our study had some limitations. First, the retrospective design of our study could have led to limited accuracy. Second, our study was performed in a tertiary referral center, which could have led to a referral bias, making the true population-based incidence of none guideline-concordant treatment difficult to assess. Furthermore, we did not adjust for multiple testing, because the analyses were regarded as explorative. Additionally, an increased number of patients, especially those receiving salvage therapy and those included in the analysis of relapse-free survival might enable further subgroup analyses. Thus, we are planning a multicenter study of a larger patient collective to further expand the findings of the present study.
We found that 18% of all patients received noneguideline-
concordant treatment; undertreatment represented the most common treatment failure, leading to reduced relapse-free survival. Thus, even in 2017, many TC patients did not receive the optimal therapy; therefore, the stringent implementation of the current guidelines represents a key factor in the treatment of patients with TC to further improve the outcomes of these patients. We believe that centralization of TC management should be discussed and implemented.
Disclosure The authors declare that they have no competing interests.
Supplemental Data Supplemental tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.clgc.2017.08.018.
Conclusion Even in 2017, many patients with TC will not receive the optimal therapy. Despite the standardization of treatment by interdisciplinary guidelines, its integration into daily practice is still limited. Therefore, the stringent implementation of the current guidelines represents a key factor in the treatment of patients with TC to further improve the outcomes of those patients. Thus, a centralization of TC management should be discussed.
Clinical Practice Points The management of TC requires a complex, multimodal thera-
peutic approach. the availability of regularly updated guidelines, noneguideline-concordant treatment of TC still persists. Limited data on the guideline conformity of treatment of TC have been reported. One study revealed noneguideline-directed care of TC in 30% of patients treated in the United States, with noneguidelineconcordant treatment mostly frequently caused by inappropriate imaging studies and overtreatment, leading to delayed definitive therapy and greater morbidity and relapse rates. The German second-opinion network, analyzing the treatment of TC in Germany with respect to the effect of second opinions on the quality of treatment, reported a discrepancy between the first and second opinion in 39.5% of cases. Moreover, a previous study revealed noneguideline-directed care in 50% of TC patients who had undergone salvage chemotherapy. In our study, we retrospectively evaluated the diagnostic workup, treatment, and its outcome of 131 patients with respect to the EAU guidelines.
Despite
References 1. Albers P, Albrecht W, Algaba F, et al. Guidelines on testicular cancer: 2015 update. Eur Urol 2015; 68:1054-68. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017; 67:7-30. 3. Laguna MP, Pizzocaro G, Klepp O, et al. EAU guidelines on testicular cancer. Eur Urol 2001; 40:102-10. 4. Schrader AJ, Ohlmann C-H, Rossmanith S, Hofmann R, Heidenreich A. Impact of evidence-based interdisciplinary guidelines on testis cancer management. Cancer 2006; 106:313-9. 5. Schrader M, Weissbach L, Hartmann M, et al. Burden or relief: do second-opinion centers influence the quality of care delivered to patients with testicular germ cell cancer? Eur Urol 2010; 57:867-72. 6. Raine R, Sanderson C, Black N. Developing clinical guidelines: a challenge to current methods. BMJ 2005; 331:631-3. 7. Zengerling F, Hartmann M, Heidenreich A, et al. German second-opinion network for testicular cancer: sealing the leaky pipe between evidence and clinical practice. Oncol Rep 2014; 31:2477-81. 8. Wymer KM, Pearce SM, Harris KT, Pierorazio PM, Daneshmand S, Eggener SE. Adherence to National Comprehensive Cancer Network Guidelines for testicular cancer. J Urol 2016; 197:684-9. 9. Heidenreich A, Pfister D, Witthuhn R, Thüer D, Albers P. Postchemotherapy retroperitoneal lymph node dissection in advanced testicular cancer: radical or modified template resection. Eur Urol 2009; 55:217-26. 10. Thibault C, Fizazi K, Barrios D, et al. Compliance with guidelines and correlation with outcome in patients with advanced germ-cell tumours. Eur J Cancer 2014; 50: 1284-90. 11. Purshouse K, Watson RA, Church DN, et al. Value of supraregional multidisciplinary review for the contemporary management of testicular tumors. Clin Genitourin Cancer 2017; 15:152-6. 12. Smith AB, Butow P, Olver I, et al. The prevalence, severity, and correlates of psychological distress and impaired health-related quality of life following treatment for testicular cancer: a survivorship study. J Cancer Surviv 2016; 10:223-33. 13. Vehling S, Mehnert A, Hartmann M, Oing C, Bokemeyer C, Oechsle K. Anxiety and depression in long-term testicular germ cell tumor survivors. Gen Hosp Psychiatry 2016; 38:21-5. 14. Flum AS, Bachrach L, Jovanovic BD, Helenowski IB, Flury SC, Meeks JJ. Patterns of performance of retroperitoneal lymph node dissections by American urologists: most retroperitoneal lymph node dissections in the United States are performed by low-volume surgeons. Urology 2014; 84:1325-8. 15. Heidenreich A, Haidl F, Paffenholz P, Pape C, Neumann U, Pfister D. Surgical management of complex residual masses following systemic chemotherapy for metastatic testicular germ cell tumours. Ann Oncol 2016; 28:362-7. 16. Schrader M, Hartmann M, Krege S, Heidenreich A, Miller K, Weißbach L. Testikuläre keimzelltumoren. Urologe 2009; 48:393-8.
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Association of NoneGuideline Treatment of TC and RFS Supplemental Table 1 Year of Diagnosis of Study Population (n [ 127) Year of Diagnosis
n (%)
2016 2015 2010-2014 2005-2009 2000-2004 Before 2000
49 40 28 5 3 2
(39) (31) (22) (4) (2) (2)
Supplemental Table 2 Comparison of Mismanagement Between Low-volume and High-volume Centers for Salvage Therapy (n [ 51)a Treatment Location Low-volume center before referral High-volume center; our institution Data presented as n (%). a 2P ¼ .001 for difference between low-volume and high-volume centers.
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Guideline-concordant Management (n [ 45)
Mismanagement (n [ 6)
13 (29) 32 (71)
6 (100) 0 (0)
NoneGuideline-concordant Treatment of Testicular Cancer Is Associated With Reduced Relapse-free Survival Pia Paffenholz,1 Isabel Maria Heidegger,2 Kathrin Kuhr,3 Sven Heiko Loosen,4 David Pfister,1 Axel Heidenreich1 Abstract The treatment of testicular cancer (TC) requires a multimodal approach. We retrospectively evaluated the diagnostic work-up, treatment, and outcomes of 131 patients with respect to the European Association of Urology guidelines. Of 131 patients, 18% had received noneguideline-concordant treatment, with undertreatment having a negative effect on relapse-free survival. Thus, implementation of guidelines is needed to decrease the mortality of TC. Introduction: The management of testicular cancer (TC) requires a complex multimodal therapeutic approach. Despite the availability of regularly updated guidelines, noneguideline-concordant treatment of TC still occurs. The purpose of the present study was to evaluate the compliance patterns in diagnosis and therapy and their potential effects on patient outcomes with respect to the guidelines of the European Association of Urology. Patients and Methods: We performed a retrospective analysis of 131 patients diagnosed with TC who had been referred to our department from September 2015 to October 2016. Patient characteristics were compared with European Association of Urology guideline recommendations. Results: Of the 131 primary treated patients, 23 (18%) had received a noneguidelineconcordant treatment. The most common error was undertreatment (n ¼ 12; 52%), mainly due to missing chemotherapy cycles. Overtreatment occurred in 30% of patients (n ¼ 7); however, inappropriate treatment (n ¼ 2; 9%) and misdiagnosis (n ¼ 2; 9%) were rarely observed. In salvage therapy, noneguideline concordant treatment was observed less frequently compared to patients receiving primary therapy (12% vs. 18%). Of the 131 patients, 35 developed a relapse, 23 of whom were treated correctly and 6 of whom were undertreated. Undertreatment of patients resulted in significantly reduced relapse-free survival compared with guideline-concordant management in primary treated patients (P ¼ .005). Conclusion: Despite the standardization of treatment by interdisciplinary guidelines, its integration into daily practice remains limited. Undertreatment of TC patients is associated with significantly reduced relapse-free survival and should thus be avoided. Clinical Genitourinary Cancer, Vol. -, No. -, 1-7 ª 2017 Elsevier Inc. All rights reserved. Keywords: EAU, Germ cell tumor, Guidelines, TC, Treatment failure
Introduction Management of testicular cancer (TC), the most common cancer in young men, requires a complex multimodal therapeutic 1 Department of Urology, Uro-Oncology, Robot Assisted and Reconstructive Urologic Surgery, University Hospital Cologne, Cologne, Germany 2 Department of Urology, Medical University Innsbruck, Innsbruck, Austria 3 Institute of Medical Statistics, Informatics and Epidemiology, University Hospital Cologne, Cologne, Germany 4 Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
Submitted: Jul 20, 2017; Revised: Aug 29, 2017; Accepted: Aug 31, 2017 Address for correspondence: Axel Heidenreich, MD, PhD, Department of Urology, Uro-Oncology, Robot Assisted and Reconstructive Urologic Surgery, University Hospital Cologne, Kerpener Straße 62, Cologne 50937, Germany E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2017.08.018
approach.1,2 Depending on the patients’ clinical status, which is defined by the presence and localization of metastases and tumor marker profiles, the potential treatment options include surveillance, chemotherapy, radiotherapy, and surgery. For standardized management of TC, different national and international guidelines on TC are available and regularly updated, including the widely used European Association of Urology (EAU) guidelines for TC treatment.1,3 A recently reported study suggested that integration of interdisciplinary guidelines significantly reduced therapeutic mistakes from 28% to 8% in a tertiary referral center, leading to decreased patient mortality.4 Despite the available guidelines, the translation of the recommended treatment into clinical practice has remained inadequate among institutions, which could affect patient outcomes.5,6
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Association of NoneGuideline Treatment of TC and RFS The German second-opinion network, which aims to improve the quality of care for TC patients by providing advice to requesting urologists, reported a discrepancy between the first and second opinions in 39.5% of cases.7 Moreover, a recently reported study revealed noneguideline-directed care for 30% of patients with TC in the United States. In that study, noneguideline-concordant treatment was most frequently caused by inappropriate imaging studies and overtreatment, leading to delayed definitive therapy, greater morbidity, and greater rates of relapse.8 In Europe, only limited data on guideline conformity for treatment of TC, especially with respect to patient outcomes, is available. In the present study, we performed a retrospective investigation of frequently occurring mistakes in the diagnosis of and therapy for TC in consideration of the current EAU guidelines. We hypothesized that noneguideline-concordant treatment of TC might still be a major problem in various TC-treating institutions and might have a negative effect on patient outcomes.
Patients and Methods Study Population In our study, we retrospectively analyzed the TC database at the University Hospital of Cologne as an observational cohort study. We identified 147 patients with a diagnosis of TC (International Classification of Disease, 10 revision, code C62) who had been referred to our department from September 2015 to October 2016. Patients with benign testicular tumors, nonegerm cell tumors, or testicular masses from nontesticular primary tumors were excluded from the present study (n ¼ 15). Patients with insufficient medical records were also excluded (n ¼ 1), for a total of 131 patients enrolled in the present study. We collected data on age, histologic findings, clinical stage, and International Germ Cell Cancer Collaborative Group risk classification. Moreover, the treatment type, treatment duration, and follow-up analysis results were included. Disease recurrence was defined as in- or outfield lymph node metastases and distant metastases. Survival data were not available for 5 of the analyzed patients. The year of diagnosis is listed in Supplemental Table 1 (available in the online version), and the patient characteristics are listed in Table 1. The local ethics committee approved the present study, which complied with the Declaration of Helsinki.
Definition of Guideline Concordance
2
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The patients’ treatment was compared with the current EAU guidelines for TC.1 The EAU guidelines for TC were initially published in 2001 and have been regularly updated, including major changes in the diagnosis and treatment of germ cell tumors.3 Noneguideline-concordant treatment was defined as treatment that was not in line with the EAU guidelines. It was further subdivided into overtreatment, undertreatment, inappropriate treatment, and misdiagnosis, similar to the categories used in a recent study.8 Modified treatment, defined as a planned modification of guideline-concordant treatment because of chemotherapy side effects or thrombosis, another simultaneous tumor burden or an atypical histologic type, was classified as correct treatment. The members of the TC working group of our department manually reviewed the data from all the patients included in the present study using the following standardized
Clinical Genitourinary Cancer Month 2017
Table 1 Patient Characteristics of Study Population (n [ 131) Characteristic
n (%)
Age (y) Median IQR
35 28-49
Age distribution <20 y
4 (3)
20-30 y
42 (34)
31-40 y
32 (26)
40-50 y
20 (16)
>50 y
25 (21)
Histologic type Nonseminoma
74 (57)
Seminoma
47 (37)
Extragonadal
4 (3)
Bilateral
4 (3)
Clinical stage 1
55 (43)
2
52 (40)
3
22 (17)
IGCCCG risk classification Good
103 (80)
Intermediate
15 (12)
Poor
10 (8)
Treatment Surveillance/follow-up Orchiectomy Chemotherapy
25 (19) 5 (4) 44 (33)
RT
4 (3)
RPLND
0 (0)
Chemotherapy plus RPLND
48 (37)
Chemotherapy plus RT
1 (1)
Chemotherapy plus RPLND plus RT
4 (3)
RPLND field Unilateral modified
19 (53)
Bilateral
17 (47)
Chemotherapy cycles (n) Median IQR
3 3-4
Follow-up (mo) Median IQR
9 4-22
Relapse until follow-up end No
91 (72)
Yes
35 (28)
Relapse treatment
classification and subclassification in accordance with the EAU guidelines (see Tables 2 and 3). Overtreatment was defined as unintended and/or too intense treatment, including unnecessary high dosages of chemotherapy or radiotherapy, the performance
Pia Paffenholz et al Results
Table 1 Continued Characteristic Chemotherapy
Patient Characteristics n (%) 15 (50)
RPLND
5 (17)
Chemotherapy plus RPLND
6 (20)
Chemotherapy plus RT
4 (13)
Time point of mismanagement Low-volume center before referral Our high-volume institution
24 (83) 5 (17)
Data presented as median and IQR for continuous variables and n (%) for categorical variables. Abbreviations: IGCCCG ¼ International Germ Cell Cancer Collaborative Group; IQR ¼ interquartile range; RPLND ¼ retroperitoneal lymph node dissection (in accordance with the Heidenreich criteria,9 patients with low-volume retroperitoneal disease [< 5 cm] limited to the primary landing zone of the tumor underwent with unilateral modified RPLND; all other patients underwent bilateral dissection); RT ¼ radiotherapy.
of unnecessary computed tomography scans and unnecessarily biopsied metastases. Undertreatment was defined as a patient unintentionally not receiving the recommended number of chemotherapy cycles or the full regimen or the guidelineconcordant surgery such as retroperitoneal lymph node dissection after chemotherapy. Inappropriate treatment was defined as a patient unintentionally receiving treatment that did not conform to the guidelines and could not be categorized as overor undertreatment. Misdiagnosis was, in all cases, due to incorrect pathology interpretation of frozen section analyses during the initial surgery of the testis. The intraoperative benign histology report was reclassified as malignant germ cell tumor in the final analysis, implying a second operation with testicular ablation. For a better comparison of the data, the data from the primary treated patients and the salvage treated patients were analyzed separately. However, primary treatment was evaluated for all the patients. Mismanagement was observed in either primary or salvage treatment; thus, each patient was counted only once with respect to the mismanagement rate. The patients were also subdivided into 2 groups according to whether the noneguideline-concordant care had occurred at an outside, low-volume hospital before referral to our institution or at our high-volume institution.
Statistical Analysis Statistical analyses were performed using SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, NY). Continuous variables are presented as the median and interquartile range (25th to 75th percentile) and categorical variables as numbers and percentages. Pairwise comparisons were performed using the MannWhitney U test for continuous variables and Pearson’s c2 test for categorical variables. Relapse-free survival was estimated using the Kaplan-Maier method and compared between guidelineconcordant management and undertreatment for primary treatment using the log-rank test. All reported P values are 2-sided, and 2P values < .05 were considered statistically significant. Because the analyses were regarded as explorative, we did not adjust for multiple testing.
To evaluate whether noneguideline-concordant treatment predominantly occurs in certain subgroups of patients, we first compared the patient characteristics between guideline-concordant and noneguideline-concordant treatment (Table 2). No significant differences were found between guideline-concordant and noneguideline-concordant treatment with respect to patient age, disease stage, International Germ Cell Cancer Collaborative Group risk classification, and the different treatment options during the total disease course. In addition, the relapse rates, retroperitoneal lymph node dissection (RPLND) field, number of chemotherapy cycles, and follow-up period did not differ significantly between the 2 groups (Table 2). We found that 83% (n ¼ 24 of 29) of none guideline-concordant care had occurred at an outside, low-volume hospital before referral to our institution and 17% (n ¼ 5 of 29) had occurred at our high-volume institution (Table 1). Furthermore, 71% (n ¼ 32 of 51) of patients receiving salvage therapy had been treated at a high-volume center and 29% (n ¼ 13 of 51) at a low-volume center. Noneguideline-concordant treatment for salvage therapy occurred only at low-volume centers (P ¼ .001; Supplemental Table 2; available in the online version).
Subcategories of NoneGuideline-concordant Treatment We next investigated the different subtypes of noneguidelineconcordant treatment in our cohort of patients (Table 3). Of the 131 primary treated patients, 23 (18%) had received noneguideline-concordant treatment, with undertreatment being the most common type of noncompliance (n ¼ 12; 52%; Table 3). Overtreatment occurred in 30% (n ¼ 7), although inappropriate treatment (n ¼ 2; 9%) and misdiagnosis (n ¼ 2; 9%) were rarely seen (Table 3). Of the patients receiving salvage treatment, none guideline-concordant therapy was observed less frequently (n ¼ 6; 12%), with undertreatment being again the most common medical error (n ¼ 4; 66%; Table 3). The subgroup analyses revealed that missing or only partially given chemotherapy cycles (58.3%) were the most common reasons for undertreatment in the primary treated patients. This included unintentional administration of 2 instead of 3 cycles of BEP (bleomycin, etoposide, and cisplatin) chemotherapy as the initial treatment option for stage III (5 patients); 2 cycles, instead of 3 cycles, of TIP (paclitaxel [Taxol], ifosfamide, cisplatin) chemotherapy as the salvage treatment option (1 patient); or 1 cycle of BEP chemotherapy as the initial treatment option for stage IS (1 patient). The second most common undertreatment was surveillance for patients with clinical stage IS (33.3%), defined as persistently elevated serum tumor marker levels after orchiectomy as an indicator of subclinical metastatic disease. The third most common undertreatment was observation for patients with retroperitoneal lymph nodes > 1 cm in nonseminoma patients or > 3 cm in seminoma patients (8.3%; Table 3). Overtreatment also occurred frequently in the primary treated patients (30%). Of those, 29% of patients experienced unnecessary biopsies of potentially metastatic lesions in the retroperitoneum or inappropriate imaging studies (eg, staging computed tomography scans after 2 cycles of chemotherapy). Of all the overtreated
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Association of NoneGuideline Treatment of TC and RFS Table 2 Patient Characteristics Stratified by Guideline-concordant and NoneGuideline-concordant Treatment (n [ 131) Characteristic
Guideline-concordant Management (n [ 108)
Mismanagement (n [ 23)
36
33
27-48
28.25-50
Age (y) Median IQR
.824
Histologic type
.137
Nonseminoma
56 (53)
18 (78)
Seminoma
42 (39)
5 (22)
Extragonadal
4 (4)
0 (0)
Bilateral
4 (4)
0 (0)
1
44 (41)
11 (52)
2
46 (42)
6 (29)
3
18 (17)
4 (19)
Good
86 (82)
17 (74)
Intermediate
11 (10)
4 (17)
8 (8)
2 (9)
Clinical stage
.478
IGCCCG risk classification
Poor
.623
Treatment Surveillance/follow-up Orchiectomy Chemotherapy
.366 22 (20)
3 (13)
4 (4)
1 (4)
35 (32)
9 (40)
RT
4 (4)
0 (0)
RPLND
0 (0)
0 (0)
40 (37)
8 (35)
Chemotherapy plus RPLND Chemotherapy plus RT
0 (0)
1 (4)
Chemotherapy plus RPLND plus RT
3 (3)
1 (4)
Unilateral modified
13 (45)
6 (86)
Bilateral
16 (55)
1 (14)
RPLND field
.052
Chemotherapy cycles (n) Median IQR
.357 3
4
3-4
3-4
9
11
4-18.5
1.75-61.25
11 (52%)
4 (45%)
Follow-up (mo) Median IQR
.952
Relapse treatment Chemotherapy
P Value
.265
RPLND
2 (10%)
3 (33%)
Chemotherapy plus RPLND
4 (19%)
2 (22%)
Chemotherapy plus RT
4 (19%)
0
Data presented as median and IQR for continuous variables and n (%) for categorical variables. Abbreviations: IGCCCG ¼ International Germ Cell Cancer Collaborative Group; IQR ¼ interquartile range; RPLND ¼ retroperitoneal lymph node dissection (in accordance with the Heidenreich criteria,9 patients with low-volume retroperitoneal disease [< 5 cm] limited to the primary landing zone of the tumor underwent with unilateral modified RPLND; all other patients underwent bilateral dissection); RT ¼ radiotherapy.
4
-
patients, 14% received an inappropriate dosage of radiotherapy, unnecessary radiotherapy, or an inappropriate number of chemotherapy cycles (6 cycles of BEP chemotherapy as the initial treatment option for stage III, poor prognosis disease; Table 3). Inappropriate treatment was given to 9% of all primary treated patients and was because of the wrong chemotherapy regimens in
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67% of all cases, with one patient been treated with PEI (cisplatin, etoposide, ifosfamide) chemotherapy as primary treatment or VeIP (vinblastine sulfate [Velban], ifosfamide, cisplatin) chemotherapy as salvage treatment. One patient underwent RPLND for a markerpositive relapse tumor (a-fetoprotein, 1607 U/mL) in a nondesperation setting (33%; Table 3).
Pia Paffenholz et al Table 3 Mismanagement Characteristics for Whole Study Population (n [ 29 of 131), Primary Treatment Patients (n [ 23 of 131), and Salvage Therapy Patients (n [ 6 of 51) Mismanagement Type Total Undertreatment Missing ChT cycles/ChT regimen partly given
Total
Primary Treatment
Salvage Therapy
29/131 (22)
23/131 (18)
6/51 (12)
16 (55) 8 (50)
12 (52) 7 (58.3)
4 (66) 1 (25)
Surveillance in stage IS
4 (25)
4 (33.3)
0 (0)
Observation of post-ChT RPLN
4 (25)
1 (8.3)
3 (75)
Overtreatment
8 (28)
7 (30)
1 (17)
Unnecessary biopsies
3 (37.5)
2 (29)
1 (100)
Inappropriate imaging studies
2 (25)
2 (29)
0 (0)
Inappropriate dosage of RT
1 (12.5)
1 (14)
0 (0)
Unnecessary RT
1 (12.5)
1 (14)
0 (0)
Inappropriate ChT cycles
1 (12.5)
1 (14)
0 (0)
Inappropriate treatment
3 (10)
2 (9)
1 (17)
Wrong ChT regimen
2 (67)
1 (50)
1 (100)
RPLND at marker-positive relapse tumor
1 (33)
1 (50)
0 (0)
Misdiagnosis Incorrect pathology interpretation
2 (7)
2 (9)
0 (0)
2 (100)
2 (100)
0 (0)
Data presented as n (%); patients receiving salvage treatment were also included in the cohort of primary treated patients. Abbreviations: ChT ¼ chemotherapy; RPLN ¼ retroperitoneal lymph node; RPLND ¼ RPLN dissection.
A misdiagnosis occurred in 9% of all noneguideline-concordant primary treated patients, and in all cases was based on incorrect pathology reports of the frozen section analyses during initial surgery of the testis (Table 3).
Analysis of Relapse-free Survival We next analyzed the influence of noneguideline-concordant treatment with respect to relapse-free survival of primary treated patients. The median follow-up period was 9 months (interquartile range, 4-22 months; Table 1). In all primary treated patients, 35 patients developed a relapse, 23 of whom had been treated correctly and 6 had been undertreated. Kaplan-Meier estimates revealed that undertreatment led to significantly reduced relapse-free survival compared with guideline-concordant management in primary treated patients (P ¼ .005; Figure 1).
Discussion Treatment of TC requires a standardized, evidence-based, and guideline-adapted approach to achieve or maintain a high cure rate of almost 95%.1 However, in our study, we identified noneguideline-concordant treatment in 18% of all primary treated TC patients. In addition, undertreatment, which was the most common mistake, was associated with reduced relapse-free survival. In 2006, a study of the benefits of guideline implementation was performed at a tertiary referral center and found that the implementation of interdisciplinary guidelines led to significantly reduced therapeutic mistakes (28% vs. 8%) and was associated with a decreased mortality.3 However, guideline incompliance regarding the treatment of TC in different institutions is still frequently observed and seems to have been constant for decades.5,7,8 Therefore, the German second-opinion network analyzed the treatment of TC in Germany regarding the effect of second opinions on the
quality of treatment. Its first survey from 2010 revealed a discrepancy between the first and second opinions in 32.3% of all analyzed 642 cases.5 The second survey, with 926 cases, showed an even greater discrepancy of 39.5% between the first and second opinions.7 These analyses clearly showed that no improvement had occurred in guideline-directed care of TC in Germany from 2010 to 2014. Another recently reported study revealed noneguidelinedirected care of TC in 30% of patients treated in the United States.8 Moreover, a previous study revealed noneguideline-directed care in 50% of TC patients treated with salvage chemotherapy.10 In accordance with these studies, our analysis showed that, despite their universal availability, the implementation of guidelines into daily clinical practice is still limited, because nonadherence to the current EAU guidelines on TC was present in 18% of all primary treated patients. Nevertheless, this proportion could have been underestimated because many patients have been diagnosed with testicular cancer in 2016, resulting in a relatively short median follow-up period for our study. Compared with previous studies, patients with stage III disease or a poor prognosis did not show a greater incidence of noneguideline-concordant treatment compared with patients without metastases in our cohort of patients.5,7,8 Nevertheless, the threshold to enter into a dialogue with other urologists or seek advice at the German second-opinion network should be rather low, especially in complex cases. In line with the findings from the German second-opinion network from 2014, we found that the most common treatment mistake was undertreatment (52%).7 In 58% of patients, it resulted from missing chemotherapy cycles or only partially given chemotherapy regimens, which were also the most common reasons for undertreatment in the US study.8 In our study, overtreatment of patients occurred in only 30% of cases compared with the rate in 2 other studies, with overtreatment reported as the most common
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Association of NoneGuideline Treatment of TC and RFS Figure 1 Kaplan-Meier Estimates for Relapse-free Survival Showing Comparison Between Guideline-concordant Treatment and Undertreatment in Primary Treated Patients
6
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treatment error.5,8 Misdiagnosis because of an incorrect pathology interpretation of frozen section analysis during the initial surgery of the testis was observed in 9% of all cases in our study. Even greater rates of incorrect pathology reports were found in a previous study comparing initial and referral histopathology reports, revealing that the pathology reports were altered after central review for 27.7% of the cases.11 In that study, misread pathology reports strongly affected the treatment (6.5%) and prognosis (9%) of patients, emphasizing the importance of reference pathology.11 The previously cited US study described undertreatment as the strongest predictor of disease relapse.8 In accordance with that finding, our analysis revealed significantly reduced relapse-free survival in undertreated patients compared with patients who had received a guideline-concordant therapy. These data suggest that undertreatment should be avoided because the management of recurring disease requires a more intensive therapeutic approach, which could lead to more side effects and greater psychological and socioeconomic burden.1,12,13 Although overtreatment did not show any relevant effects on the oncologic outcome in our study, it might nevertheless lead to increased long-term toxicity and secondary malignancies.1
Clinical Genitourinary Cancer Month 2017
However, the reasons for the high frequency of guideline incompliance are unknown. A potential reason might be that most urologists believe the treatment of TC is easy to understand. Furthermore, the referral of patients to a high-volume center might suggest inexperience or might have a negative effect on the physician’s reputation. Accordingly, a recently reported study revealed that most RPLNDs in the United States are performed by lowvolume surgeons, despite the importance of the surgical quality for patient outcomes.14 Furthermore, it was shown that treatment of TC patients at tertiary referral centers leads to significantly improved survival, especially for advance disease stages.4 That finding was supported by our study, in which 83% of noneguideline-concordant care of all patients occurred at an outside, low-volume hospital before referral to our institution. Mismanagement of salvage therapy was only seen in low-volume centers. Thus, centralization is recommended for the management of intermediate- and poor-risk disease and for complex procedures such as post-chemotherapy RPLND or salvage chemotherapy.10,15 Additional reasons for noneguideline-directed care could be a misinterpretation of the guidelines or the patients’ characteristics.5 Therefore, the inclusion of TC patients into clinical studies or the
Pia Paffenholz et al involvement of second-opinion centers might be helpful to further increase guideline adherence.5,16 Moreover, incentives for guideline-based therapy from health care providers, medical insurance companies, or organizations such as the EAU might further help to overcome the problem of noneguideline-concordant treatment. Our study had some limitations. First, the retrospective design of our study could have led to limited accuracy. Second, our study was performed in a tertiary referral center, which could have led to a referral bias, making the true population-based incidence of none guideline-concordant treatment difficult to assess. Furthermore, we did not adjust for multiple testing, because the analyses were regarded as explorative. Additionally, an increased number of patients, especially those receiving salvage therapy and those included in the analysis of relapse-free survival might enable further subgroup analyses. Thus, we are planning a multicenter study of a larger patient collective to further expand the findings of the present study.
We found that 18% of all patients received noneguideline-
concordant treatment; undertreatment represented the most common treatment failure, leading to reduced relapse-free survival. Thus, even in 2017, many TC patients did not receive the optimal therapy; therefore, the stringent implementation of the current guidelines represents a key factor in the treatment of patients with TC to further improve the outcomes of these patients. We believe that centralization of TC management should be discussed and implemented.
Disclosure The authors declare that they have no competing interests.
Supplemental Data Supplemental tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.clgc.2017.08.018.
Conclusion Even in 2017, many patients with TC will not receive the optimal therapy. Despite the standardization of treatment by interdisciplinary guidelines, its integration into daily practice is still limited. Therefore, the stringent implementation of the current guidelines represents a key factor in the treatment of patients with TC to further improve the outcomes of those patients. Thus, a centralization of TC management should be discussed.
Clinical Practice Points The management of TC requires a complex, multimodal thera-
peutic approach. the availability of regularly updated guidelines, noneguideline-concordant treatment of TC still persists. Limited data on the guideline conformity of treatment of TC have been reported. One study revealed noneguideline-directed care of TC in 30% of patients treated in the United States, with noneguidelineconcordant treatment mostly frequently caused by inappropriate imaging studies and overtreatment, leading to delayed definitive therapy and greater morbidity and relapse rates. The German second-opinion network, analyzing the treatment of TC in Germany with respect to the effect of second opinions on the quality of treatment, reported a discrepancy between the first and second opinion in 39.5% of cases. Moreover, a previous study revealed noneguideline-directed care in 50% of TC patients who had undergone salvage chemotherapy. In our study, we retrospectively evaluated the diagnostic workup, treatment, and its outcome of 131 patients with respect to the EAU guidelines.
Despite
References 1. Albers P, Albrecht W, Algaba F, et al. Guidelines on testicular cancer: 2015 update. Eur Urol 2015; 68:1054-68. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017; 67:7-30. 3. Laguna MP, Pizzocaro G, Klepp O, et al. EAU guidelines on testicular cancer. Eur Urol 2001; 40:102-10. 4. Schrader AJ, Ohlmann C-H, Rossmanith S, Hofmann R, Heidenreich A. Impact of evidence-based interdisciplinary guidelines on testis cancer management. Cancer 2006; 106:313-9. 5. Schrader M, Weissbach L, Hartmann M, et al. Burden or relief: do second-opinion centers influence the quality of care delivered to patients with testicular germ cell cancer? Eur Urol 2010; 57:867-72. 6. Raine R, Sanderson C, Black N. Developing clinical guidelines: a challenge to current methods. BMJ 2005; 331:631-3. 7. Zengerling F, Hartmann M, Heidenreich A, et al. German second-opinion network for testicular cancer: sealing the leaky pipe between evidence and clinical practice. Oncol Rep 2014; 31:2477-81. 8. Wymer KM, Pearce SM, Harris KT, Pierorazio PM, Daneshmand S, Eggener SE. Adherence to National Comprehensive Cancer Network Guidelines for testicular cancer. J Urol 2016; 197:684-9. 9. Heidenreich A, Pfister D, Witthuhn R, Thüer D, Albers P. Postchemotherapy retroperitoneal lymph node dissection in advanced testicular cancer: radical or modified template resection. Eur Urol 2009; 55:217-26. 10. Thibault C, Fizazi K, Barrios D, et al. Compliance with guidelines and correlation with outcome in patients with advanced germ-cell tumours. Eur J Cancer 2014; 50: 1284-90. 11. Purshouse K, Watson RA, Church DN, et al. Value of supraregional multidisciplinary review for the contemporary management of testicular tumors. Clin Genitourin Cancer 2017; 15:152-6. 12. Smith AB, Butow P, Olver I, et al. The prevalence, severity, and correlates of psychological distress and impaired health-related quality of life following treatment for testicular cancer: a survivorship study. J Cancer Surviv 2016; 10:223-33. 13. Vehling S, Mehnert A, Hartmann M, Oing C, Bokemeyer C, Oechsle K. Anxiety and depression in long-term testicular germ cell tumor survivors. Gen Hosp Psychiatry 2016; 38:21-5. 14. Flum AS, Bachrach L, Jovanovic BD, Helenowski IB, Flury SC, Meeks JJ. Patterns of performance of retroperitoneal lymph node dissections by American urologists: most retroperitoneal lymph node dissections in the United States are performed by low-volume surgeons. Urology 2014; 84:1325-8. 15. Heidenreich A, Haidl F, Paffenholz P, Pape C, Neumann U, Pfister D. Surgical management of complex residual masses following systemic chemotherapy for metastatic testicular germ cell tumours. Ann Oncol 2016; 28:362-7. 16. Schrader M, Hartmann M, Krege S, Heidenreich A, Miller K, Weißbach L. Testikuläre keimzelltumoren. Urologe 2009; 48:393-8.
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Association of NoneGuideline Treatment of TC and RFS Supplemental Table 1 Year of Diagnosis of Study Population (n [ 127) Year of Diagnosis
n (%)
2016 2015 2010-2014 2005-2009 2000-2004 Before 2000
49 40 28 5 3 2
(39) (31) (22) (4) (2) (2)
Supplemental Table 2 Comparison of Mismanagement Between Low-volume and High-volume Centers for Salvage Therapy (n [ 51)a Treatment Location Low-volume center before referral High-volume center; our institution Data presented as n (%). a 2P ¼ .001 for difference between low-volume and high-volume centers.
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Guideline-concordant Management (n [ 45)
Mismanagement (n [ 6)
13 (29) 32 (71)
6 (100) 0 (0)