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Risk of residual cancer after complete response following first-line chemotherapy in men with metastatic non-seminomatous germ cell tumor and IGCCCG intermediate/poor prognosis: a multi-institutional retrospective cohort study

Open AccessPublished:January 19, 2023DOI:https://doi.org/10.1016/j.ejca.2022.12.032

      Highlights

      • >95% long-term survival if intermediate/poor risk metastatic NSGCT and remission.
      • Most men with intermediate/poor IGCCCG have residual cancer in the retroperitoneum.
      • 6% of those men managed with surveillance relapse in the retroperitoneum only.

      Abstract

      Introduction

      Current guidelines recommend surveillance in metastatic non-seminomatous-germ-cell-tumour (NSGCT) patients treated with first-line-chemotherapy and complete clinical response (normalization of serum tumour markers and residual masses <1 cm). However, this recommendation is based on series including patients with good prognosis according to International-Germ-Cell-Cancer-Cooperative-Group-prognostic-group (IGCCCG-PG). The aim of this study was to analyse the proportion of residual teratoma and survival among patients with intermediate/poor IGCCCG-PG and complete clinical response after first-line-chemotherapy.

      Material & Methods

      This is a retrospective study of men with intermediate/poor IGCCCG-PG who had a complete clinical response after first-line-chemotherapy. Patients were either followed by surveillance or treated with post-chemotherapy-retroperitoneal-lymph-node-dissection (pcRPLND).

      Results

      Between 2009–2018, 143 men with intermediate (n = 83) or poor (n = 60) IGCCCG-PG were treated at 11 international centres. Among 33 patients treated with pcRPLND, the specimen showed teratoma and viable cancer in 16 (48%) and 4 (12%). During a median 7-year follow-up, 20/110 (18%) patients managed with surveillance relapsed, of whom 7 (6%) had a retroperitoneal-only relapse, vs 2/33 patients managed with pcRPLND relapsed. No difference was observed regarding overall survival (OS) among men treated with pcRPLND or surveillance (5-year OS, 93% and 89%, p-value=0.35). The median time-to-recurrence among men on surveillance was 1.3 years (range: 0.3–9.1), and the most common sites of relapses included retroperitoneum (11%), chest (5%), and bones (4%).

      Conclusions

      While most men with intermediate/poor IGCCCG-PG harbour teratoma/cancer in the retroperitoneum despite a complete response to first-line-chemotherapy, only 6% managed with surveillance relapsed in the retroperitoneum. There was no significant difference in OS between the two groups.

      Keywords

      Introduction

      Around 30% of all men with non-seminomatous germ cell tumours (NSGCT) present with metastases at initial diagnosis [
      • DeSantis C.E.
      • Lin C.C.
      • Mariotto A.B.
      • et al.
      Cancer treatment and survivorship statistics.
      ]. An additional 15–30% of patients who initially present with localised disease will develop metastatic disease recurrence during follow-up [
      • Chung P.
      • Daugaard G.
      • Tyldesley S.
      • et al.
      Evaluation of a prognostic model for risk of relapse in stage I seminoma surveillance.
      ,
      • Daugaard G.
      • Gundgaard M.G.
      • Mortensen M.S.
      • et al.
      Surveillance for stage I nonseminoma testicular cancer: outcomes and long-term follow-up in a population-based cohort.
      ]. Of patients with metastatic disease who are treated with first-line chemotherapy, 60% respond favourably (i.e., normalization of serum tumour markers with radiographic residuals), and up to 30% achieve a complete clinical response (i.e., normalization of serum tumour markers and residual masses <1 cm) [
      • Nichols C.R.
      • Catalano P.J.
      • Crawford E.D.
      • Vogelzang N.J.
      • Einhorn L.H.
      • Loehrer P.J.
      Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study.
      ]. For patients who achieve a complete clinical response, current guidelines [5 6] recommend ongoing surveillance based on data from four retrospective cohort studies that reported recurrences in 41 of 540 patients (8%) [
      • Nason G.J.
      • Jewett M.A.S.
      • Bostrom P.J.
      • et al.
      Long-term Surveillance of Patients with Complete Response Following Chemotherapy for Metastatic Nonseminomatous Germ Cell Tumor.
      ,
      • Ravi P.
      • Gray K.P.
      • O'Donnell E.K.
      • Sweeney C.J.
      A meta-analysis of patient outcomes with subcentimeter disease after chemotherapy for metastatic non-seminomatous germ cell tumor.
      ,
      • Kollmannsberger C.
      • Daneshmand S.
      • So A.
      • et al.
      Management of disseminated nonseminomatous germ cell tumors with risk-based chemotherapy followed by response-guided postchemotherapy surgery.
      ,
      • Ehrlich Y.
      • Brames M.J.
      • Beck S.D.
      • Foster R.S.
      • Einhorn L.H.
      Long-term follow-up of cisplatin combination chemotherapy in patients with disseminated nonseminomatous germ cell tumors: is a postchemotherapy retroperitoneal lymph node dissection needed after complete remission?.
      ]. Two-thirds of relapses were observed in the retroperitoneum, and most patients were successfully treated using post-chemotherapy retroperitoneal lymph node dissection (pcRPLND) and/or further chemotherapy.
      However, most patients in the retrospective cohort studies had a good International Germ Cell Cancer Cooperative Group prognostic group (IGCCCG-PG). Data extracted from these studies and stratified by IGCCCG-PG indicate that limited data are available for men with intermediate or poor IGCCCG-PG, but recurrence is described in up to 23% of such patients. This risk of recurrence is aligned with the findings of smaller surgical studies that found teratoma and/or viable cancer in the retroperitoneum in about 34% of patients [11 12]; half of all recurrences in these studies occurred after two years [7 9 10], which suggests that there is a considerable risk for late relapse and poor outcomes.
      The aim of this study is to provide additional data regarding the proportion of residual cancer in the retroperitoneum at time of pcRPLND and the risk of relapse during surveillance. The study examines these factors among patients with intermediate or poor IGCCCG-PG who had a complete clinical response after first-line chemotherapy within a multicentre cohort study.

      Material & Methods

      This retrospective multicentre cohort study collected data from male patients with metastatic testicular NSGCT and intermediate or poor IGCCCG-PG who had been treated with platinum-based first-line chemotherapy between 1990–2018 and had at least two years of follow-up since receiving first-line chemotherapy. Patients who had a complete clinical response after first-line chemotherapy - defined as residual masses <1 cm in the largest axial dimension and normalized serum tumour markers - were included. All patients included in the study had either been followed through surveillance or treated with post-chemotherapy RPLND. The decision to perform immediate pcRPLND or follow the patient was based on individual case-by-case discussions with each patient. Patients with bilateral testis cancer, those undergoing primary RPLND before chemotherapy, and patients without retroperitoneal lymphadenopathy prior to chemotherapy were excluded from the study.
      Patient characteristics, including pathological and survival outcomes, were extracted from electronic health records. Baseline variables included age, IGCCCG prognostic group, serum tumour markers, retroperitoneal lymph node size before pcRPLND, primary tumour staging, and type and cycles of first-line chemotherapy. Pathological variables included the presence of viable carcinoma, teratoma, and malignant transformation in the pcRPLND specimen. Oncological variables included time of relapse, serum tumour markers, description of metastases, and treatment at relapse. Follow-up was based on clinical notes and radiological reports.
      Recurrence-free survival (RFS) was defined as the time from start date of chemotherapy until one of the following: progression according to imaging (axial short axis of mass > 1 cm) or a rising level of tumour markers upper to the normal limit, confirmed by a second measurement. Survival status was retrieved from medical charts or death certificates. Patients were censured at date of last follow-up or date of death. Log-rank tests and Kaplan-Meier methods were used to estimate RFS, cancer-specific survival (CSS) and overall survival (OS) probability stratified by intermediate or poor IGCCCG-PG and by use of pcRPLND or surveillance.
      Cox proportional hazards regression was used to identify risk factors for relapse. Subgroup analyses were performed for patients followed by surveillance only or after pcRPLND. For patients after pcRPLND, univariable and multivariable binary regression models were used to identify predictors for cancer in the pcRPLND specimen (i.e., viable/teratoma versus necrosis, teratoma only, viable cancer only). Statistical analysis was performed using R version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria).

      Results

      After excluding 27 patients with follow-up of less than two years and 1 patient younger than 18 years old, 143 men from 11 institutions in six countries were included in the study sample (see Supplementary Figure 1, Table 1).
      Table 1Patient characteristics stratified by management strategy including RPLND or surveillance.
      OverallSurveillanceRPLND
      Number of patients14311033
       National Cancer Institute, Bratislava1111-
       Dana-Farber Cancer Institute, Boston101
       Institute Gustave Roussy, Villejuif Cedex743
       University Hospital Cologne, Cologne1313-
       N.N. Blokhin Cancer Research Center, Moscow29281
       University of Southern California, Los Angeles22-
       Mayo Clinic, Scottsdale1-1
       Indiana University of Medicine, Indianapolis3737-
       IRCCS Istituto Nazionale dei Tumori271512
       University of Chicago Medical Center, Chicago10-10
       University of Texas Southwestern, Texas5-5
      Age28 (IQR 23-33)31 (IQR 24-36)25 (IQR 21-32)
      Intermediate IGCCCG-PG83/143 (58%)66/110 (60%)17/33 (52%)
      Poor IGCCCG-PG60/143 (42%)44/110 (40%)16/33 (48%)
      Mean AFP value before chemotherapy (μg/l)4272 (±16641)4209 (±19085)4413 (±9265)
      Mean β-HCG value before chemotherapy (U/l)31098 (±92465)29963 (±95160)33976 (±86855)
      Mean LDH value before chemotherapy (U/l)859 (±968)807 (±786)1028 (±1424)
      Largest diameter of retroperitoneal mass before chemotherapy (mm)34 (IQR 20-50)30 (IQR 20-50)38 (IQR 26-68)
      Other metastases sites before chemotherapy
       Chest55 (38%)43 (39%)12 (36%)
       Mediastinum20 (14%)14 (13%)6 (18%)
       Liver16 (11%)11 (10%)5 (15%)
       Neck lymph node9 (6%)6 (5%)3 (9%)
       Bones4 (3%)2 (2%)2 (6%)
       Inguinal lymph node2 (1%)1 (<1%)1 (3%)
       Duodenum1 (<1%)1 (<1%)-
       Spleen1 (<1%)-1 (3%)
      Type of platin-based first-line chemotherapy
       BEP99 (69%)72 (66%)27 (82%)
       VIP12 (8%)11 (10%)1 (3%)
       BEP + EP10 (7%)9 (8%)1 (3%)
       EP8 (6%)7 (6%)1 (3%)
       Others14 (10%)11 (10%)3 (9%)
      First-line-chemotherapy cycles
       < 48 (6%)6 (5%)2 (6%)
       = 4127 (88%)98 (90%)29 (88%)
       > 48 (6%)6 (5%)2 (6%)
      Teratoma at RPLND histology16 (48%)-16 (48%)
      Vital cancer at RPLND histology4 (12%)-4 (12%)
      Number of patients with relapse22 (15%)20 (18%)2 (6.1%)
      Relapse sites
       Retroperitoneum12 (8%)12 (11%)-
       Chest6 (4%)5 (5%)1 (3%)
       Bones4 (3%)3 (3%)1 (3%)
       Mediastinum2 (1%)2 (2%)-
       Liver2 (1%)2 (2%)-
       Brain2 (1%)2 (2%)-
       Contralateral testis1 (<1%)1 (<1%)-
      Outcomes
       Relapse21 (15%)19 (18%)2 (6%)
      Alive at last follow-up after relapse9 (6%)8 (7%)1 (3%)
      Dead due to disease progression12 (9%)11 (10%)1 (3%)
       No relapse121 (85%)90 (82%)31 (94%)
      Alive at last follow-up118 (83%)88 (80%)30 (91%)
      Dead for other reasons3 (2%)2 (2%)1 (3%)
      RPLND= Retroperitoneal lymph node dissection; IGCCCG-PG= International Germ Cell Cancer Cooperative Group prognostic group; AFP= Alpha-Fetoprotein; β-HCG= Beta-Human chorionic gonadotropin; LDH= Lactate dehydrogenase; BEP= Bleomycin, Etoposide, Cisplatin; VIP= Cisplatin, Etoposide, Ifosfamide; EP= Etoposide, Cisplatin.
      Surveillance was selected for 110 men, whereas 33 were treated with pcRPLND. Post-chemotherapy pcRPLND was performed in half or most male patients in Chicago, Texas, and Milano, whereas the other study sites showed a preference for surveillance. The median diameter of the retroperitoneal mass was 34 mm (IQR: 20–50 mm) before chemotherapy. Aside from the retroperitoneum, metastases were found in the chest for 55 of 143 patients (38%), in the mediastinum for 20 of 143 patients (14%), and in the liver for 16 of 143 patients (11%).
      Of the 33 men undergoing pcRPLND, residual tumor was observed in 19 (58%), including teratoma in 16 of the 33 patients (48%) and viable cancer in 4 of the 33 patients (12%). No patient received additive chemotherapy in case of residual viable cancer. In binary regression, a larger diameter of the retroperitoneal lymph node metastases (according to the computerized tomography scan and as a continous variable) before chemotherapy was associated with a heightened chance of residual teratoma (OR: 1.04, 95% CI: 1.01–1.08, p-value = 0.013) and a lowered chance of residual viable cancer (OR: 0.92, 95% CI: 0.78–1.00, p-value = 0.038) in the pcRPLND specimen (see Supplementary Table 1).
      During a median 7-year follow-up for the entire group (IQR: 4 – 10), 22/143 (15%) patients relapsed after a median of 6.6 years (IQR: 3.8–9.7) of follow-up for those who relapsed. Among patients who had surveillance only, 20/110 (18%) relapses were observed after a median of 1.3 years (IQR: 0.8–2.7; range 0.3–9.1). Sites of recurrence during surveillance included the retroperitoneum (12 of 20 patients), chest (5 of 20 patients), bones (3 of 20 patients), mediastinum (2 of 20 patients), liver (2 of 20 patients), brain (2 of 20 patients), and contralateral testis (1 of 20 patients). Elevated serum tumour markers (STM) at relapse were observed in 6 of 20 patients (30%). Retroperitoneal-only relapse was observed in 7/110 (6%) patients.
      Among patients with immediate pcRPLND, relapse was observed in 2/33 (6%) patients, one with viable cancer and teratoma histology in the pcRPLND specimen and one with teratoma only; both relapses occurred 2 years after pcRPLND, 1 patient relapsed with bone and 1 with pulmonary metastases.
      Of the 22 patients who experienced a relapse, salvage chemotherapy was used for treatment in 19, metastasectomy in 6, and radiotherapy in 3 patients. Salvage chemotherapy regimens consisted of high-dose chemotherapy for 6 patients, cisplatin, etoposide, and ifosfamide (VIP) for 4, paclitaxel, ifosfamide, and cisplatin (TIP) for 2 and other different regimens for 7. The metastasectomies consisted of 3 pcRPLND, 1 brain mass excision, 1 lobectomy plus brain surgery, 1 mediastinal lymph node removal. In those seven with retroperitoneal-only relapse, salvage options consisted of pcRPLND in 1, pcRPLND plus additive chemotherapy in 2, and chemotherapy in 4.
      No difference was observed between men managed with immediate pcRPLND or surveillance regarding RFS (5-year RFS: 93% versus 84%, p-value = 0.12), CSS (5-year CSS: 93% versus 89%, p-value = 0.47), or OS (5-year OS: 97% versus 92%, p-value = 0.35; see Figure 1). In a multivariable Cox-regression adjusted for pcRPLND or surveillance-only, a larger measured diameter of the retroperitoneal lymph node metastases before chemotherapy according to the computerized tomography scan as a continous variable was associated with an increased risk of recurrence (HR: 1.02, 95% CI: 1.00–1.03, p-value = 0.02) but not OS or CSS (see Table 2).
      Figure 1
      Figure 1Kaplan Meier estimates of recurrence free survival (a), overall survival (b) and cancer specific survival (c) among patients stratified by surveillance or post-chemotherapy retroperitoneal lymph node dissection; IGCCCG-PG= International Germ Cell Cancer Cooperative Group prognostic group; AFP= Alpha-Fetoprotein; β-HCG= Beta-Human chorionic gonadotropin; LDH= Lactate dehydrogenase; BEP= Bleomycin, Etoposide, Cisplatin; VIP= Cisplatin, Etoposide, Ifosfamide; EP= Etoposide, Cisplatin.
      Table 2Multivariable Cox regression analysis of predictors for RFS, OS, CSS.


      Variables
      RFSOSCSS
      HR (95% CI)p-valueHR (95% CI)p-valueHR (95% CI)p-value
      Diameter of largest retroperitoneal lymph node1.02 (1.00-1.03)0.021.01 (0.99-1.03)0.31.02 (1.00-1.04)0.10
      Surveillance versus RPLND0.29 (0.04-2.29)0.20.50 (0.06-4.29)0.50.00> 0.9
      HR= Hazard ratio; CI= Confidence interval; RFS= Recurrence-free survival; OS= Overall survival; CSS= Cancer specific survival; RPLND= Retroperitoneal lymph node dissection.

      Discussion

      Among male patients with intermediate or poor IGCCCGP-PG who had a complete clinical response after first-line chemotherapy, the post-chemotherapy pcRPLND specimen showed germ cell residuals in most pcRPLND specimens. Patients undergoing immediate pcRPLND had an OS of 97% at 5 years, compared to an 92% OS among men on surveillance (p-value= 0.47).
      Numerous surgical series of men with good IGCCCG-PG, non-measurable serum tumour markers, and retroperitoneal residuals less than 10 mm [
      • Karellas M.
      • Carver B.S.
      • Stasi J.
      • Motzer R.J.
      • Bosl G.J.
      • Sheinfeld J.
      830: Clinical Outcome Following Post-Chemotherapy Retroperitoneal Lymph Node Dissection for Men with CII Non-Seminomatous Germ Cell Tumors and a Radiographically Normal Retroperitoneum.
      ,
      • Fossa S.D.
      • Qvist H.
      • Stenwig A.E.
      • Lien H.H.
      • Ous S.
      • Giercksky K.E.
      Is postchemotherapy retroperitoneal surgery necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses?.
      ,
      • Oldenburg J.
      • Alfsen G.C.
      • Lien H.H.
      • Aass N.
      • Waehre H.
      • Fossa S.D.
      Postchemotherapy retroperitoneal surgery remains necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses.
      ,
      • Schmelz H.U.
      • et al.
      Pfister DJ BJ WC
      Pathohistologic findings in patients with nonseminomatous germ cell tumors (NSGCT) who undergo postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for small tumors.
      ] or less than 15mm [
      • Toner G.C.
      • Panicek D.M.
      • Heelan R.T.
      • et al.
      Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection.
      ] have found teratoma or viable cancer in 20–39% and 3–14% of patients, respectively, in the pcRPLND specimen (see Table 3). These findings suggest that about 23–53% of patients should relapse during follow-up, contrasted with actually only 10% of patients relapsing in the surveillance cohort with the longest follow-up [
      • Ehrlich Y.
      • Brames M.J.
      • Beck S.D.
      • Foster R.S.
      • Einhorn L.H.
      Long-term follow-up of Cisplatin combination chemotherapy in patients with disseminated nonseminomatous germ cell tumors: is a postchemotherapy retroperitoneal lymph node dissection needed after complete remission?.
      ] (see Table 4). Three potential explanations as to why some patients do not develop a relapse despite suspected unresected post-chemotherapy teratoma or viable malignant tumour include: 1) insufficient follow-up length with as yet undiscovered late relapses, 2) the selection of cases undergoing immediate pcRPLND in this study presenting a confounding variable that inflates the risk of teratoma or viable residuals, and 3) most pcRPLND teratoma or viable residuals will gradually disappear even though their morphologic appearance seems viable.
      Table 3Immediate post-chemotherapy retroperitoneal lymph node dissection series following primary chemotherapy for metastatic testis cancer.
      IGCCCG-PGNumber of patientsPost-CHT residual sizepc-RPLND specimen histology (necrosis)pc-RPLND specimen histology (teratoma)pc-RPLND specimen histology (vital cancer)All relapsesRP only relapseRelapse-free rateDisease related deaths
      Toner [
      • Toner G.C.
      • Panicek D.M.
      • Heelan R.T.
      • et al.
      Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection.
      ]
      122≤ 15mm57 (47%)48 (39%)17 (14%)NANANA
       GoodNA
       IntermediateNA
       PoorNA
      Fossa [
      • Fossa S.D.
      • Qvist H.
      • Stenwig A.E.
      • Lien H.H.
      • Ous S.
      • Giercksky K.E.
      Is postchemotherapy retroperitoneal surgery necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses?.
      ]
      49≤ 10mm35 (72%)11 (22%)3 (6%)NANANA
       Good38 (77 %)
       Intermediate7 (14 %)
       Poor4 (9 %)
      Steyerberg [
      • Steyerberg E.W.
      • Marshall P.B.
      • Keizer H.J.
      • Habbema J.D.
      Resection of small, residual retroperitoneal masses after chemotherapy for nonseminomatous testicular cancer: a decision analysis.
      ]
      199≤ 10mm141 (71%)48 (24%)10 (5%)NANANA
       GoodNA
       IntermediateNA
       PoorNA
      Oldenburg [
      • Oldenburg J.
      • Alfsen G.C.
      • Lien H.H.
      • Aass N.
      • Waehre H.
      • Fossa S.D.
      Postchemotherapy retroperitoneal surgery remains necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses.
      ]
      54
      Only patients with residual disease < 10 mm were extracted.
      ≤ 10 mm38 (71%)11 (20%)5 (9%)NANANA
       Good41 (76%)
       Intermediate8 (14%)
       Poor5 (10%)
      Steiner [
      • Steiner H.A.T.
      • Gozzi C.
      • et al.
      High rate of retroperitoneal teratoma despite complete remission after chemotherapy for metastatic nonseminomatous germ cell tumor.
      ]
      81NA57 (70%)24 (30%)02 (2%)098% during 7 years median follow-up0
       GoodNA
       IntermediateNA
       PoorNA
      Pfister [
      • Schmelz H.U.
      • et al.
      Pfister DJ BJ WC
      Pathohistologic findings in patients with nonseminomatous germ cell tumors (NSGCT) who undergo postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for small tumors.
      ]
      27≤ 10mm18 (67%)6 (22%)3 (11%)NANANA
      GoodNA
      IntermediateNA
      PoorNA
      Karellas [
      • Karellas M.
      • Carver B.S.
      • Stasi J.
      • Motzer R.J.
      • Bosl G.J.
      • Sheinfeld J.
      830: Clinical Outcome Following Post-Chemotherapy Retroperitoneal Lymph Node Dissection for Men with CII Non-Seminomatous Germ Cell Tumors and a Radiographically Normal Retroperitoneum.
      ]
      147≤ 10mm108 (73%)34 (23%)5 (3%)NA5-year RFS 97%NA
       Good144 (98%)
       Intermediate3 (2%)
       Poor
      Antonelli (current series)33≤ 10mm14 (42%)16 (48%)4 (12%)2 (6%)05-years RFS 93%1 (3%)
       Good0
       Intermediate17 (52%)6 (35%)8 (47%)3 (18%)005-years RFS 100%0
       Poor16 (48%)8 (50%)8 (50%)1 (6%)2 (13%)05-years RFS 87%1 (6%)
      IGCCCG-PG= International Germ Cell Cancer Cooperative Group prognostic group; CHT= Chemotherapy; pc-RPLND= Post chemotherapy-Retroperitoneal lymph node dissection; RFS= Recurrence-free survival.
      a Only patients with residual disease < 10 mm were extracted.
      Table 4Surveillance series following primary chemotherapy for metastatic testis cancer.
      IGCCCG-PGNumber of patientsPost-CHT residual sizeAll relapsesRP only relapsePatients treated with salvage RPLNDSalvage RPLND specimen histology (necrosis)Salvage RPLND specimen histology (teratoma)Salvage RPLND specimen histology (vital cancer)Relapse-free rateDisease related deathsSuccessful salvage treatmentDisease related deaths with RP relapses
      Ehrlich [
      • Ehrlich Y.
      • Brames M.J.
      • Beck S.D.
      • Foster R.S.
      • Einhorn L.H.
      Long-term follow-up of Cisplatin combination chemotherapy in patients with disseminated nonseminomatous germ cell tumors: is a postchemotherapy retroperitoneal lymph node dissection needed after complete remission?.
      ]
      141≤ 10mm12 (9%)5 (4%)4 (3%)0Mostly (not specified)15 years RFS 90%4 (3%)8/12 (67%)

      (RPLND success 100% in patients with RP relapse)
      2 (1%)

      (treated with salvage CHT)
       Good108 (77%)4 (4%)15 years RFS 95%1 (1%)
       Intermediate13 (9%)1 (3%)15 years RFS 73%3 (23%)
       Poor20 (14%)0
      Ravi
      Patients from the Ravi et al and King et al papers are included in the current series.
      [
      • Ravi P.
      • Gray K.P.
      • O'Donnell E.K.
      • Sweeney C.J.
      A meta-analysis of patient outcomes with subcentimeter disease after chemotherapy for metastatic non-seminomatous germ cell tumor.
      ]
      47≤ 10mm3 (6%)1 (2%)2 (4%)94% during 5.4 years median follow-up0
       Good37 (79%)
       Intermediate7 (15%)1 (14%)
       Poor3 (6%)
      Nason [
      • Nason G.J.
      • Jewett M.A.S.
      • Bostrom P.J.
      • et al.
      Long-term Surveillance of Patients with Complete Response Following Chemotherapy for Metastatic Nonseminomatous Germ Cell Tumor.
      ]
      191≤ 10mm16 (8%)9 (5%)11 (6%)1 (<1%)6 (3%)4 (2%)92% during 6.8 years median follow-up4 (2%)12/16 (75%)

      (RPLND success 100% in patients with RP relapse)
      3 (2%)
       Good149 (78%)12 (8%)7 (5%)9 (6%)1 (<1%)5 (3%)3 (3%)2 (1%)10/12 (83%)2 (1%)

      (1 treated with CHT and neck surgery, 1 no treatment)
       Intermediate34 (18%)1 (3%)000001 (3%)0/12 (0%)0
       Poor8 (4%)3 (38%)2 (25%)2 (25%)01 (13%)1 (13%)1 (13%)2/3 (67%)1 (13%)

      (CHT +RT)
      Kalkiashvili [
      • Kakiashvili D.A.-C.L.
      • Moore M.
      • et al.
      Post-chemotherapy retroperitoneal lymph node dissection for testicular germ cell tumors: Is surgery indicated in all and is bilateral template necessary? Princess Margaret Hospital experience.
      ]
      106≤ 10mm00100% during 7 years median follow-up0
       GoodNA
       IntermediateNA
       PoorNA
      Kollmannsberger [
      • Kollmannsberger C.
      • Daneshmand S.
      • So A.
      • et al.
      Management of disseminated nonseminomatous germ cell tumors with risk-based chemotherapy followed by response-guided postchemotherapy surgery.
      ]
      161≤ 10mm10 (6%)9 (6%)9 (6%)9 (6%)94% during 3.3 years median follow-up0
       Good151 (94%)10 (7%)9 (6%)9 (6%)9 (6%)
       Intermediate5 (3%)0000
       Poor5 (3%)0000
      King
      Patients from the Ravi et al and King et al papers are included in the current series.
      [
      • King J.M.
      • Althouse S.
      • Cary C.
      • et al.
      Surveillance after Complete Response to First-Line Chemotherapy in Patients with Metastatic Nonseminomatous Germ Cell Tumor.
      ]
      367≤ 10mm34 (9%)16 (4%)22 (6%)2-years RFS 91%; 4-years RFS 90%10 (3%)24/34 (71%)

      (RPLND success 91% in patients with RP relapse)
      3 (<1%)
       Good316 (86%)2-years RFS 92%; 4-years RFS 91%6 (2%)2 (<1%)

      (1 treated with RPLND + CHT, 1 with CHT only)
       Intermediate22 (6%)2-years RFS 90%; 4-years RFS 85%2 (9%)1 (5%)

      (treated with RPLND + CHT)
       Poor29 (8%)2-years RFS 87%; 4-years RFS 87%2 (7%)0
      Cotner [
      • Cotner C.E.
      • Hilton S.
      • Mamtani R.
      • Guzzo T.
      • Vaughn D.J.
      Surveillance of postchemotherapy subcentimeter residual retroperitoneal mass in metastatic nonseminomatous germ cell tumor: Does how you measure matter?.
      ]
      39≤ 10mm2 (5%)02 (5%)2 (5%)005-years RFS 94.7%0
       GoodNA
       IntermediateNA
       PoorNA
      Antonelli (current series)110≤ 10mm20 (18%)7 (6%)3 (3%)02 (2%)3 (3%)5-years RFS 84%11 (10%)9/20 (45%)

      (RPLND success 33% in patients with RP relapse)
      6 (5%)
       Good0
       Intermediate66 (60%)10 (15%)4 (6%)3 (5%)02 (3%)3 (4%)5-years RFS 87%5 (8%)5/10 (50%)

      (RPLND success 33% in patients with RP relapse)
      4 (6%)

      (2 treated with CHT + RPLND, 2 treated with CHT only)
       Poor44 (40%)10 (23%)3 (7%)00005-years RFS 79%6 (14%)4/10 (40%)2 (5%)

      (treated with CHT)
      IGCCCG-PG= International Germ Cell Cancer Cooperative Group prognostic group; CHT= Chemotherapy; RPLND= Retroperitoneal lymph node dissection; RFS= Recurrence-free survival; RT= Radiotherapy.
      a Patients from the Ravi et al and King et al papers are included in the current series.
      The benefits of immediate post-chemotherapy pcRPLND may include accurately staging and identifying men with intermediate IGCCCG-PG who may benefit from additive chemotherapy as suggested in a previous study by Fizazi et al. [
      • Fizazi K.
      • Tjulandin S.
      • Salvioni R.
      • et al.
      Viable malignant cells after primary chemotherapy for disseminated nonseminomatous germ cell tumors: prognostic factors and role of postsurgery chemotherapy--results from an international study group.
      ]. In addition, surgical removal of teratoma may decrease the risk of late relapse, which most commonly occurs in the retroperitoneum [
      • Ronnen E.A.
      • Kondagunta G.V.
      • Bacik J.
      • et al.
      Incidence of late-relapse germ cell tumor and outcome to salvage chemotherapy.
      ,
      • O'Shaughnessy M.J.
      • Feldman D.R.
      • Carver B.S.
      • Sheinfeld J.
      Late Relapse of Testicular Germ Cell Tumors.
      ]; and the risk of malignant transformation [
      • Ronnen E.A.
      • Kondagunta G.V.
      • Bacik J.
      • et al.
      Incidence of late-relapse germ cell tumor and outcome to salvage chemotherapy.
      ,
      • Sharma A.
      • Alifrangis C.
      • Milic M.
      • et al.
      Somatic Transformation in Metastatic Testicular Germ Cell Tumours - A Different Disease Entity.
      ]. In contrast, surveillance may prevent morbidity from immediate pcRPLND, observed in 20–30% of patients [
      • Subramanian V.S.
      • Nguyen C.T.
      • Stephenson A.J.
      • Klein E.A.
      Complications of open primary and post-chemotherapy retroperitoneal lymph node dissection for testicular cancer.
      ,
      • Baniel J.
      • Foster R.S.
      • Rowland R.G.
      • Bihrle R.
      • Donohue J.P.
      Complications of post-chemotherapy retroperitoneal lymph node dissection.
      ]. Because 60% had tumor in the pcRPLND specimen, overtreatment may affect >40% of patients with intermediate or poor IGCCCG-PG.
      Our figures differ from previous studies, which argued for or against immediate pcRPLND based on data from men with mainly good IGCCCG-PG. In previous series, residual cancer has been observed in only 3–39% of patients with good IGCCCG-PG and clinically complete response; thus, pcRPLND is unnecessary in 61–97% of such patients. In addition, salvage RPLND was found to cure 91–100% of all male patients with relapse during surveillance. Similarly, the present study found no significant survival differences between men treated with pcRPLND or surveillance. However, this finding does not confirm the equivalence of both options, because the limited sample size, follow-up or unmeasured confounding variables could have influenced the results in either direction.
      In addition, based on the histopathological results of men undergoing pcRPLND, a considerable proportion of patients may be considered at risk of relapse. Salvage options were only successful in 33% of patients with intermediate or poor IGCCCG-PG, which raises the question of whether a surveillance only but with follow-up for at least 10 years with cross-sectional imaging can safely be recommended. Testis cancer patients are generally difficult to follow because many are geographically mobile. For this and other reasons, this patient population has a high risk of non-adherence to follow-up protocols, which leads to a high proportion of relapse detection in advanced cancer stages. Thus, patients who relapse may require intense treatment, which can lead to treatment-related toxicity or impaired oncological outcomes [
      • Endo T.
      • Kawai K.
      • Kamba T.
      • et al.
      Risk factors for loss to follow-up during active surveillance of patients with Stage I seminoma.
      ,
      • Gyawali B.
      • Griffiths R.
      • Robinson A.G.
      • McInnes M.D.F.
      • Bedard P.L.
      • Booth C.M.
      Use of imaging for active surveillance in testicular cancer: Is real-world practice concordant with guidelines?.
      ,
      • Lehnich A.T.
      • Rusner C.
      • Chodick G.
      • Katz R.
      • Sella T.
      • Stang A.
      Actual frequency of imaging during follow-up of testicular cancer in Israel-a comparison with the guidelines.
      ,
      • Rusner C.
      • Stang A.
      • Dieckmann K.P.
      • Friedel H.
      Frequency of computed tomography examinations in the follow-up care of testicular cancer patients - an evaluation of patterns of care in Germany.
      ].
      If pcRPLND is chosen, the next question is whether a full bilateral or modified template should be performed. Historically, bilateral pcRPLND has led to anejaculation in nearly all patients. Based on anatomical mapping studies of retroperitoneal metastases, several surgical templates have been developed for male patients with clinical stage 1 disease to avoid potential damage to the contralateral efferent sympathetic chain, which should result in preservation of antegrade ejaculation [
      • Large M.C.
      • Sheinfeld J.
      • Eggener S.E.
      Retroperitoneal lymph node dissection: reassessment of modified templates.
      ,
      • Heidenreich A.
      • Pfister D.
      • Witthuhn R.
      • Thuer D.
      • Albers P.
      Postchemotherapy retroperitoneal lymph node dissection in advanced testicular cancer: radical or modified template resection.
      ]. The templates used in surgeries for stage 1 disease have rarely been examined in studies with long-term follow-up [
      • Cho J.S.
      • Kaimakliotis H.Z.
      • Cary C.
      • Masterson T.A.
      • Beck S.
      • Foster R.
      Modified retroperitoneal lymph node dissection for post-chemotherapy residual tumour: a long-term update.
      ]. For men with complete treatment response and intermediate or poor IGCCCG-PG, no precise and sufficiently large anatomical mapping studies have described templates that are supported by long-term follow-up data.
      This study has several limitations. First, complete treatment response among intermediate or poor IGCCCG-PG patients is rare, which limited the size of the study cohort and the number events. Second, the follow-up in this study might be too short to draw conclusions about the risk of late relapse. Third, no central review of imaging was performed. Fourth, retrospective data collection is subject to selection and reporting bias, missing data, heterogeneity in practice patterns, and other potentially unmeasured confounders. For example, the template used for pcRPLND or the reason to perform a pcRPLND were missing. In addition, we did not collect the histopathology of the orchiectomy specimen and it was therefore not possible to analyse the data by the presence or absence of teratoma in the orchiectomy specimen. However, as it is unlikely that a randomized controlled trial could be performed in this very rare disease setting; the present study findings offer the best available data to guide treatment decisions.

      Conclusions

      In conclusion, this study indicates that patients with intermediate or poor risk metastatic NSGCT who achieve a complete remission in the retroperitoneum have a >95% long term survival whether managed by immediate post-chemotherapy pcRPLND or surveillance. While a majority of men with intermediate or poor IGCCCG-PG harbour teratoma or cancer in the retroperitoneum despite a complete clinical response to first-line chemotherapy, 6% managed with surveillance relapse in the RP only. Surveillance can be recommended to male patients who will comply with the recommended follow-up protocol including serial cross-sectional imaging of the retroperitoneum.

      Statements and declarations

      The Authors have no conflicts of interest to declare.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Statement on the welfare of animals

      This article does not contain any studies/experiments with human participants or animals performed by any of the authors.

      Statement of human rights

      All person gave their informed consent to use their data (deidentified) for this retrospective study.

      Author contribution

      Luca Antonelli: Data curation, Formal analysis, Investigation, Methodology, Visualization, Roles/Writing - original draft, Christian D. Fankhauser: Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Roles/Writing - original draft.
      Davide ardizzone: Data curation, Praful Ravi: Writing - review & editing, Christopher Sweeney: Writing - review & editing, Aditya Bagrodia: Writing - review & editing, Michal Mego: Writing - review & editing, Antoin Douglawi: Writing - review & editing, Sia Daneshmand: Writing - review & editing, Nicola Nicolai: Writing - review & editing, Sebastiano Nazzani: Writing - review & editing, Patrizia Giannatempo: Writing - review & editing, Andrea Franza: Writing - review & editing, Axel Heidenreich: Writing - review & editing, Pia Paffenholz: Writing - review & editing, Ragheed Saoud: Writing - review & editing, Scott Eggener: Writing - review & editing, Matthew Ho: Writing - review & editing, Nathaniel Oswald: Writing - review & editing, Kathleen Olson: Writing - review & editing, Alexey Tryakin: Writing - review & editing, Mikhail Fedyanin: Writing - review & editing, Natacha Naoun: Writing - review & editing, Christophe Javaud: Writing - review & editing, Karim Fizazi: Writing - review & editing, Clint Cary: Writing - review & editing, Jennifer M. King: Writing - review & editing, Nabil Adra: Writing - review & editing, Nobody: Funding acquisition, Project administration,Resources, Software, Supervision.

      Uncited References

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      Declaration of interests

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Appendix A. Supplementary data

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