Original Article Outcomes of Men With HIV and Germ Cell Cancer: Results From an International Collaborative Study 1 Marcus Ulrich Hentrich, MD ; Mark Bower, MD2; Gedske Daugaard, DMSc3; Annette Dieing, MD4; Markus Bickel, MD5; Massimiliano Berretta, MD6,7; Florian Lesmeister, MD1; Vindi Jurinovic, PhD8; Albrecht Stoehr, MD9; Julia Heinzelbecker, MD10; Ivanka Krznaric, MD11; Klaus-­Peter Dieckmann, MD12; Andrea Necchi, MD 13 ; 14 15 16 17 Pablo Maroto Rey, MD ; Jürgen Kurt Rockstroh, MD ; Margarida Brito, MD ; David Pfister, MD ; and Christian Hoffmann, MD18,19 BACKGROUND: Previous studies have shown that men with HIV and germ cell cancer (HIV-­GCC) have inferior overall survival (OS) in comparison with their HIV-­negative counterparts. However, little information is available on treatments and outcomes of HIV-­GCC in the era of combination antiretroviral therapy (cART). METHODS: This study examined men living with HIV who were 18 years old or older and had a diagnosis of histologically proven germ cell cancer (GCC). The primary outcomes were OS and progression-­free survival (PFS). RESULTS: Data for 89 men with a total of 92 HIV-­GCCs (2 synchronous GCCs and 1 metachronous bilateral GCC) were analyzed; among them were 64 seminomas (70%) and 28 nonseminomas (30%). The median age was 36 years, the median CD4 T-­cell count at GCC diag- nosis was 420 cells/µL, and 77% of the patients on cART had an HIV RNA load < 500 copies/mL. Stage I disease was found in 44 of 79 gonadal GCCs (56%). Among 45 cases with primary disseminated GCC, 78%, 18%, and 4% were assigned to the good-­, intermediate-­, and poor-­prognosis groups, respectively, of the International Germ Cell Cancer Collaborative Group. Relapses occurred in 14 patients. Overall, 12 of 89 patients (13%) died. The causes of death were refractory GCC (n = 5), an AIDS-­defining illness (n = 3), and other causes (n = 4). After a median follow-­up of 6.5 years, the 5-­and 10-­year PFS rates were 81% and 73%, respectively, and the 5-­and 10-­year OS rates were 91% and 85%, respectively. CONCLUSIONS: The 5-­and 10-­year PFS and OS rates of men with HIV-­GCC were similar to those reported for men with HIV-­negative GCC. Patients with HIV-­GCC should be managed identically to HIV-­negative patients. Cancer 2022;128:260-268. © 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-­commercial and no modifications or adaptations are made. LAY SUMMARY: • Men living with HIV are at increased risk for germ cell cancer (GCC). • Previous studies have shown that the survival of men with HIV-­associated germ cell cancer (HIV-­GCC) is poorer than the survival of their HIV-­negative counterparts. • This study examined the characteristics, treatments, and outcomes of 89 men with HIV-­GCC in the era of effective combination antiret- roviral therapies. • The long-­term outcomes of men with HIV-­GCC were similar to those reported for men with HIV-­negative GCC. • Patients with HIV-­GCC should be managed identically to HIV-­negative patients. KEYWORDS: AIDS, germ cell cancer, HIV, HIV-­related germ cell cancer, nonseminoma, seminoma. INTRODUCTION Testicular germ cell cancer (GCC) is the most common cancer diagnosis in men aged 15 to 35 years, and the incidence has risen in recent decades.1 Today, a cure is achievable in approximately 95% of all patients and in 80% of those who have metastatic disease. The incidence of GCC is slightly elevated in men living with HIV. The standardized incidence ratios for HIV-­associated germ cell cancer (HIV-­GCC) range from 0.7 to 3.1.2-­4 Notably, the risk of GCC appears to be unrelated to the CD4+ T-­cell count and the duration of HIV/AIDS.2,5 Corresponding Author: Marcus Ulrich Hentrich, MD, Department of Hematology and Oncology, Red Cross Hospital, University of Munich, Nymphenburger Strasse 163, 80634 Munich, Germany (marcus.hentrich@swmbrk.de). 1 Department of Hematology and Oncology, Red Cross Hospital, University of Munich, Munich, Germany; 2 National Centre for HIV Malignancy, Chelsea and Westminster Hospital, London, United Kingdom; 3 Department of Oncology, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark; 4 Department of Hematology and Oncology, Vivantes Klinikum am Urban, Berlin, Germany; 5 Infektiologikum, Frankfurt, Germany; 6 National Cancer Institute, Aviano, Italy; 7 Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 8 Institute of Biometrics and Epidemiology, Ludwig Maximilian University of Munich, Munich, Germany; 9 Institute for Interdisciplinary Medicine, Hamburg, Germany; 10 Department of Urology and Pediatric Urology, Saarland University Medical Center and Saarland University, Homburg, Germany; 11 Practice of Infectious Diseases, Berlin, Germany; 12 Department of Urology, Asklepios Klinik Altona, Hamburg, Germany; 13 IRCCS San Raffaele Hospital and Scientific Institute, Vita-­Salute San Raffaele University, Milan, Italy; 14 Department of Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 15 Department of Medicine I, University Hospital Bonn, Bonn, Germany; 16 Instituto Português de Oncologia Francisco Gentil, Lisbon, Portugal; 17 Department of Urology, University Hospital Cologne, Cologne, Germany; 18 ICH Study Center, Hamburg, Germany; 19 University Hospital of Schleswig Holstein, Kiel, Germany Additional supporting information may be found in the online version of this article. DOI: 10.1002/cncr.33928, Received: June 6, 2021; Revised: August 8, 2021; Accepted: August 9, 2021, Published online September 30, 2021 in Wiley Online Library ­(wileyonlinelibrary.com) 260 Cancer   January 15, 2022 10970142, 2022, 2, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.33928 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Outcome of HIV-­Related Germ Cell Cancer/Hentrich et al Before the introduction of effective combination The GCC stage was reported according to the antiretroviral therapy (cART), the survival of men with International Union Against Cancer classification.12 HIV-­GCC was poorer than that of their HIV-­negative For allocation into risk categories, the prognostic counterparts.6-­9 This was mainly due to infectious com- classification of the International Germ Cell Cancer plications and to the lower dose intensity of the che- Collaborative Group (IGCCCG) was used.13 The HIV motherapy applied.8,9 A matched case-­ control study infection status was classified according to the 1993 comparing HIV-­ infected and HIV-­ uninfected men Centers for Disease Control and Prevention (CDC) with GCC showed that men with HIV-­GCC had simi- criteria.14 lar cancer-­free survival but inferior overall survival (OS) in comparison with their HIV-­negative counterparts.10 Definitions of Response However, very little information is available on the out- Complete response: The complete disappearance of all comes of HIV-­GCC since the introduction of cART.11 clinical, radiographic, and biochemical evidence of dis- The objective of this multi-­institutional study was ease (normal α-­fetoprotein and human chorionic go- to analyze the characteristics, treatments, and outcomes nadotropin) for a minimum of 4 weeks. of HIV-­GCC in the cART era. No evidence of disease: The complete disappearance of all biochemical evidence of disease with complete sur- gical resection of all residual radiographic masses that, MATERIALS AND METHODS if pathologically positive for malignant residual GCC, Centers collaborating within the Global Germ Cell show margins microscopically free of disease. Patients Cancer Collaborative Group and within the German must be free of disease for a minimum of 4 weeks. Testicular Cancer Study Group and institutions special- Partial response with negative tumor markers (PRm–­): izing in HIV/AIDS were contacted to share their data The complete disappearance of all biochemical evidence for men with HIV-­GCC. Detailed information was of disease in patients without a surgical procedure for collected anonymously via structured questionnaires. a residual radiographic mass. There is no biochemical The following items were included: patient character- recurrence or progression of radiographic masses for a istics regarding both HIV/AIDS and GCC, treatment minimum of 4 weeks. of HIV infection, primary and any further treatment Stable disease: Patients who do not have a response suffi- of GCC, responses to antineoplastic treatments, course cient to qualify as PRm–­or a complete response but do of the CD4+ T-­cell count and HIV viral load during not meet criteria for progressive disease. and after cancer treatment, treatment of relapse, and Progressive disease: Rising tumor markers above the limit outcomes. Data were anonymized locally, transferred, of normal over a period of 3 weeks or an increase in the and entered into a database at the Red Cross Hospital tumor volume unless this is caused by a mature tera- in Munich, Germany. toma that is completely resectable. The study was approved by the ethics committee of Relapse: Recurrent GCC after a complete response, no Ludwig Maximilian University (Munich, Germany) and evidence of disease, or PRm–­. by each participating institution. The study was performed in accordance with the Declaration of Helsinki. Toxicity Statistics was rated according to the Common Toxicity Criteria. The primary outcomes were OS and progression-­free survival (PFS). Secondary outcomes included GCC-­ Eligibility and Staging free survival, characteristics of GCC and HIV infec- The inclusion criteria for the study were as follows: male tion, treatment, and causes of death. Associations sex; being 18 years old or older; histology-­confirmed GCC; between categorical characteristics were assessed with primary GCC diagnosis after January 1, 1996; and proven the χ2 test. The Mann-­Whitney U test was used to com- infection with HIV (enzyme-­linked immunosorbent assay pare continuous variables between the 2 groups. PFS and Western blotting) at the time of the GCC diagnosis. was calculated from the date of diagnosis to the time of Patients were excluded if their HIV infection was progression, relapse, or death. OS was measured from diagnosed more than 2 months after the diagnosis of the date of diagnosis to the last follow-­up or to death GCC. A simultaneous diagnosis of both GCC and HIV from any cause. Cancer-­ free survival was calculated infection was assumed if an HIV infection was diagnosed from the date of diagnosis to the last follow-­up or death within the 2 months after the diagnosis of GCC. by GCC. Censoring was performed at the date of last Cancer   January 15, 2022 261 10970142, 2022, 2, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.33928 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article WĂƟĞŶƚƐ ;ŶсϵϭͿ WĂƟĞŶƚƐ ĞdžĐůƵĚĞĚ͗ ' ĚŝĂŐŶŽƐŝƐ х Ϯ ŵŽŶƚŚƐ ƉƌŝŽƌ ƚŽ ,/s ĚŝĂŐŶŽƐŝƐ ;ŶсϭͿ hŶŬŽǁŶ ĚĂƚĞ ŽĨ ,/s ĚŝĂŐŶŽƐŝƐ ;ŶсϭͿ WĂƟĞŶƚƐ ;ŶсϴϵͿ ^ƚĂŐĞ / ;ŶсϰϰͿ WƌŝŵĂƌLJ ĚŝƐƐĞŵŝŶĂƚĞĚ ĚŝƐĞĂƐĞ ;ŶсϰϱͿ 'ŽŽĚ ;ŶсϯϱͿ /ŶƚĞƌŵĞĚŝĂƚĞ ;ŶсϴͿ WŽŽƌ ;ŶсϮͿ EŽ ZĞůĂƉƐĞ ZĞůĂƉƐĞ EŽ ZĞůĂƉƐĞ WͬZĞůĂƉƐĞ EŽ ZĞůĂƉƐĞ ZĞůĂƉƐĞ WͬZĞůĂƉƐĞ ;ŶсϯϴͿ ;ŶсϲͿ ;ŶсϮϴͿ ;ŶсϳͿ ;ŶсϳͿ ;ŶсϭͿ ;ŶсϮͿ ĞĂƚŚ ĞĂƚŚ ĞĂƚŚ ĞĂƚŚ ĞĂƚŚ ĞĂƚŚ ĞĂƚŚ ĞĂƚŚ ůŝǀĞ ůŝǀĞ ůŝǀĞ ůŝǀĞ ůŝǀĞ ŽƚŚĞƌ ' ŽƚŚĞƌ ŽƚŚĞƌ ' ŽƚŚĞƌ ŽƚŚĞƌ ' ;ŶсϯϲͿ ;ŶсϯͿ ;ŶсϮϳͿ ;ŶсϲͿ ;ŶсϱͿ ;ŶсϮͿ ;ŶсϮͿ ;ŶсϭͿ ;ŶсϭͿ ;ŶсϭͿ ;ŶсϮͿ ;ŶсϭͿ ;ŶсϮͿ Figure 1. Patient flow diagram. GCC indicates germ cell cancer; PD, progressive disease. contact. The probability of PFS, OS, and disease-­free extragonadal GCC. Stage I disease was found in 44 of 79 survival (DFS) was determined by the Kaplan-­Meier gonadal GCCs (56%). Among the 46 cases with primary method, and differences between subgroups of patients disseminated GCC, 78%, 17%, and 4% were assigned to were assessed with the log-­rank test. Univariable Cox the IGCCCG good-­, intermediate-­, and poor-­prognosis proportional hazards models were used to explore the groups, respectively. The median time from the first pos- prognostic value of each covariable. Statistical analy- itive HIV test to the GCC diagnosis was 5 years (range, ses, including descriptive statistics such as frequencies, 0-­29 years), the median CD4+ T-­cell count at GCC diag- means, medians, ranges, interquartile ranges, minima, nosis was 420 cells/µL (range, 3-­1503 cells/µL), and 83% and maxima, were performed with R statistical software of the patients were on cART. Patient characteristics are (version 3.5.2). All P values were 2-­sided. P values of outlined in Table 1. .05 or less were considered statistically significant. Treatment RESULTS All of the 44 stage I cases underwent orchiectomy, with Patient Population 22 (50%) being followed by active surveillance and 11 Data for 91 patients from 23 institutions and 6 countries (25%) receiving adjuvant chemotherapy or radiotherapy were registered. Two patients were excluded because the (Supporting Table 1). Among 45 patients, there were 46 time of the HIV diagnosis was unknown (n = 1) or the stage II/III GCCs (1 metachronous bilateral case was diagnosis of GCC was made more than 2 months before included); 39 (85%) received cisplatin-­ based chemo- the HIV diagnosis (n = 1). Thus, 89 patients were in- therapy, 6 (13%) received radiotherapy for stage IIA/B cluded in the study. A patient flow diagram is provided seminoma, and 1 patient with stage IIA nonseminoma in Figure 1. underwent primary retroperitoneal lymph node dissec- Two patients had a synchronous GCC, and 1 had tion (RPLND). The types and numbers of cycles of pri- a metachronous bilateral GCC; this resulted in a total mary chemotherapy are shown in Table 2. of 92 HIV-­GCCs diagnosed from January 1996 to July A dose reduction of the first-­line chemotherapy was 2018. There were 64 seminomas (70%) and 28 nonsem- necessary in 3 of 39 patients (8%) because of myelotoxic- inomas (30%). Ten of the 89 cases (11%) were primary ity (n = 2) or both myelotoxicity and cholangitis (n = 1). 262 Cancer   January 15, 2022 10970142, 2022, 2, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.33928 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Outcome of HIV-­Related Germ Cell Cancer/Hentrich et al TABLE 1. Patient Characteristics (n = 89) TABLE 2. Primary Chemotherapy for Advanced-­ Stage Germ Cell Cancer (n = 39) Characteristic No. % Prognostic Group Seminoma Nonseminoma Age at GCC diagnosis, median (range), y 36 (22-­52) GCC Good 22 7 Unilateral 86 17 (3× PEB) 5 (3× PEB) Bilateral synchronous 2 3 (4× PEB) 1 (4× VIP) Bilateral metachronous 1 1 (2× PEB)a 1 (4× TIP)b S 64 70 1 (1× PEB → RT at 36 Gy)c NS 28 30 Intermediate 2 6 Gonadal 79 89 2 (4× PEB) 6 (4× PEB) Extragonadal 10 11 Poor 0 2 Retroperitoneal 7 70 1 (4× PEB) Mediastinal 3 30 1 (3× POMB/ACE) ECOG performance status (n = 74) 0 50 68 Abbreviations: PEB, cisplatin, etoposide, and bleomycin; POMB/ACE, cispl- 1 22 30 atin, vincristine, methotrexate, bleomycin, actinomycin, cyclophosphamide, 2 1 1 and etoposide; RT, radiotherapy; TIP, paclitaxel, ifosfamide, and cisplatin; VIP, 3 1 1 etoposide, ifosfamide, and cisplatin. UICC stage I 44 49 a Termination after 2× PEB because of neutropenic sepsis and complete S 32 73 remission. NS 12 27 b Case of metachronous bilateral nonseminoma. Mediastinal 3 c Switch to radiotherapy because of neutropenic sepsis after 1 cycle of PEB. S 2 NS 1 IGCCCG prognostic group (n = 46)a The administration of chemotherapy was delayed in 4 Goodb 36 78 of 39 patients (10%) because of myelotoxicity with or S 28 78 without neutropenic infections (n = 3) or bleomycin-­ NS 8 22 Intermediatec 8 17 associated dyspnea (n = 1). Furthermore, chemotherapy S 2 25 was terminated early in 3 patients (8%) because of neu- NS 6 75 Poor 2 4 tropenic sepsis after 1 or 2 cycles of cisplatin, etoposide, AFP in metastatic NS by IGCCCG prognostic group, and bleomycin (PEB) in good-­prognosis seminoma (n = median (range), ng/mL Good 124 (0-­337) 2) or because of neutropenic fever and deterioration in Intermediate 45 (7.5-­1159) the general state of a patient with primary mediastinal Poor 13387 (7-­26767) β-­HCG in metastatic NS by IGCCCG prognostic nonseminoma (PMNS) after 3 cycles of cisplatin, vincris- group, median (range), IU/L tine, methotrexate, bleomycin, actinomycin, cyclophos- Good 46 (5.4-­363) phamide, and etoposide (POMB/ACE) chemotherapy. Intermediate 598 (1-­1278) Poor 750 (154-­1347) Residual tumor resection after first-­line chemother- LDH in metastatic NS by IGCCCG prognostic apy was performed in 11 of 39 patients (28%; 7 non- group, median (range), U/L Good 227 (0-­250) seminomas and 4 seminomas). Nine of those patients Intermediate 1056 (570-­3297) underwent RPLND, 1 underwent both RPLND and re- Poor 1074 (1010-­1138) CDC (n = 69) section of lung metastases, and the patient with PMNS A 43 62 underwent resection of the mediastinal mass and lung B 13 19 C 13 19 metastases. Histopathological examinations revealed ne- Absolute CD4 T cells, median (range), /µL 420 (3-­1503) crosis in 8 cases (73%) and both necrosis and teratoma in Prior or current cART (n = 80) 66 83 2 cases (18%). A viable tumor was found in the patient HIV RNA < 50 copies/mL (n = 67) 38 57 HIV RNA < 500 copies/mL (n = 67) 39 58 with PMNS (9%). HIV RNA < 500 copies/mL + cART (n = 51) 39 76 Years from first positive HIV test to GCC diagnosis, 5.0 (0-­29) Antiretroviral Therapy and CD4 T-­Cell Counts median (range) Data on cART were available for 80 patients. After orchi- Abbreviations: AFP, α-­fetoprotein; β-­HCG, β-­human chorionic gonadotropin; ectomy, 67 patients (84%) were on cART, and the regi- cART, combination antiretroviral therapy; CDC, Centers for Disease Control and Prevention; ECOG, Eastern Cooperative Oncology Group; GCC, germ men was modified in 14 of 32 cases (44%) at the start of cell cancer; IGCCCG, International Germ Cell Cancer Collaborative Group; chemotherapy. The HIV viral load was below 500 copies/ LDH, lactate dehydrogenase; NS, nonseminoma; S, seminoma; UICC, Union for International Cancer Control. mL in 39 of 51 patients (76%) on cART for whom data a b A case of metachronous bilateral GCC was counted twice. on HIV RNA were available (Table 1). The CD4+ T-­cell count was well documented for 27 Including 5 cases of primary retroperitoneal S. c Including 1 case of primary retroperitoneal NS and 1 case of retroperito- neal S. patients under chemotherapy and for 14 patients under Cancer   January 15, 2022 263 10970142, 2022, 2, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.33928 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article radiotherapy. There was no significant difference in the After a median follow-­up of 6.5 years (range, 0.3-­ median CD4+ T-­cell counts before chemotherapy (me- 20.9 years), the 5-­and 10-­year PFS rates were 81% (95% dian, 454 cells/µL; range, 150-­1270 cells/µL) and thereaf- confidence interval [CI], 0.730-­0.899) and 73% (95% ter (median, 441 cells/µL; range, 168-­903 cells/µL). CD4 CI, 0.622-­0.854), respectively (Fig. 2A). The OS rates T cells increased in 18 patients (67%), 16 of whom were of the entire cohort at 5 and 10 years were 91% (95% on cART, and they declined in 9 (33%), 4 of whom were CI, 0.850-­0.977) and 85% (95% CI, 0.760-­0.957), re- on cART. spectively (Fig. 2B), and the 5-­and 10-­year DFS rates Under radiotherapy, CD4+ T cells decreased from were 95% (95% CI, 0.903-­0.999) and 95% (95% CI, 480 cells/µL (range, 3-­1503 cells/µL) to 223 cells/µL 0.903-­0.999), respectively, without significant differences (range, 15-­578 cells/µL). among the good-­ , intermediate-­, and poor-­ prognosis groups (Fig. 2C). Disease Control and Survival According to a univariate analysis, patients with The response to primary treatment was evaluated in 45 of seminoma had a significantly lower risk for progression or the 46 patients with advanced-­stage GCC. The remission death than those with nonseminoma (hazard ratio [HR], status remained undetermined in 1 patient who died of a 0.38; 95% CI, 0.15-­0.94; P = .023), and chemother- traffic accident shortly after the end of chemotherapy. A apy dose reductions resulted in significantly shorter PFS complete response, PRm–­, stable disease, and progressive (HR, 4.03; 95% CI, 1.03-­14.70; P = .045; Supporting disease were noted in 39 (87%), 3 (7%), 1 (2%), and 2 Table 2). A performance status higher than 1 (HR, 12.91; (4%), respectively. 95% CI, 1.43-­117.00; P = .023) and IGCCCG poor risk Relapses or primary refractory disease occurred in 15 (HR, 21.20; 95% CI, 1.58-­285.32; P = .021) were sig- patients (Table 3). There were 6 relapses from stage I and 9 nificantly associated with inferior OS, whereas other vari- from primary disseminated GCC, which corresponded to ables such as CDC stage, CD4+ T-­cell counts, age, and relapse rates of 32% (14 of 44) and 20% (9 of 46), respec- chemotherapy dose reductions had no significant impact tively. The median time from the GCC diagnosis to relapse on OS. A multivariate analysis was not performed because in patients without early progression was 10 months (range, of an insufficient number of events. 3-­107 months). There were no significant differences in the CD4+ T-­cell counts at GCC diagnosis and at the end of pri- mary treatment between patients with and without relapse DISCUSSION (420 vs 429 cells/µL and 370 vs 409 cells/µL, respectively). There are some important findings from this large co- Among the 6 patients who relapsed from stage I GCC, 5 hort study of men with HIV-­GCC. First, long-­term received chemotherapy, and 1 underwent radiotherapy for outcomes of HIV-­GCC no longer appear to be related retroperitoneal relapse of seminoma. Salvage chemotherapy to HIV infection. The 91% OS rate at 5 years is mark- was given to 8 of 9 patients who relapsed from primary edly better than the previously reported 2-­year OS rates disseminated GCC (Table 3). Notably, 3 patients who un- of 81% and 62%.9,10 Notably, both previous studies derwent high-­dose chemotherapy and autologous stem cell were much smaller and included patients mostly from transplantation as second salvage chemotherapy did not ex- the pre-­cART era, and each reported a 20% death rate perience any unexpected toxicity. from HIV/AIDS. By contrast, only 3 of 89 patients Treatment resulted in ongoing complete remission (3%) died of HIV-­related causes in the current study. in 4 cases, whereas 2 patients experienced further relapses Effective cART with a preserved or reconstituted im- or progressive disease and died of GCC. After salvage che- mune system at the GCC diagnosis and thereafter may motherapy in patients with primary disseminated GCC, have greatly contributed to the better outcomes in our 6 patients remained in ongoing complete remission, and study. In fact, the median CD4+ T-­cell count at the di- 2 experienced refractory GCC (Table 3). agnosis of GCC was 420 cells/µL in the current study In the entire cohort, 12 patients (13%) died (vs 261, 325, and 315 cells/µL in previous studies7,9,11), (Table 4). The causes of death were refractory GCC and it remained stable even during chemotherapy; this (n = 5 [including a patient with late relapse at 8.9 years]), indicated the effectiveness of cART. This is noteworthy an AIDS-­defining illness (n = 3), and sepsis 12.8 and 8.9 in light of the marked decline in the CD4+ T-­cell count years after the diagnosis of GCC (n = 2). Another patient during chemotherapy reported in previous studies of died of rectal cancer as a second primary malignancy 10 HIV-­GCC8,9,11 as well as HIV-­ associated malignant years after the GCC diagnosis (Table 4). lymphoma.15-­17 264 Cancer   January 15, 2022 Cancer   TABLE 3. Characteristics and Outcomes of Patients With Progressive Disease or Relapse TTR, IGCCCG at January 15, 2022 No. Pathology Stage/IGCCCG Primary Treatment Response mo Relapse Treatment Result Outcome 1 S I AS —­ 49 Good RT at 30 Gy CR Death from sepsis 2 S I RT —­ 9 Good 3× PEB + RPLNDa CR, 3 further Death from GCC Various regimens, including HD-­CE relapses 3 NS I AS —­ 6 Good 3× PEB + surgery CR Alive without evidence of disease 4 NS I AS —­ 5 Good 4× PEB CR Alive without evidence of disease 5 NS I AS —­ 107 Poor 2× PEB, 5× TIP PD Death from GCC 6 S I AS —­ 17 Good 4× PEB + surgery CR Alive without evidence of disease 7 NS IIA RPLND NED 5 —­ 1× PEB, 2× VIP CR Alive without evidence of disease Good 8 S IIA RT CR 29 —­ 4× PEB + RT mediastinum CR Alive without evidence of disease Good 9 S IIB 3× PEB CR 11 —­ 4× VIP, 3× HD-­CE CR Alive without evidence of disease Good 10 S IIC 4× PEB PD 0 —­ 4× TIP, 2× HD-­CE CR Alive without evidence of disease Good 11 S IIC 3× PEB PD 0 —­ 2× TIP PD Death from GCC Good 12 S IIIB 3× PEB NED 13 —­ 1× TIP, 3× VIP CR Alive without evidence of disease Good 13 NS IIIB 4× PEB PRm–­ 8 —­ 3× TIP CR Death from cryptococcosis Intermediate 14 NS IIIC 4× PEB PRm–­ 0 —­ 4× Carbo + surgery PD Death from GCC Poor 15 NS Mediastinal 3× POMB/ACE + SD 3 —­ None PD Death from GCC Poor surgery Abbreviations: AS, active surveillance; Carbo, carboplatin; CR, complete remission; GCC, germ cell cancer; HD-­CE, high-­dose carboplatin/etoposide; IGCCCG, International Germ Cell Cancer Collaborative Group; NED, no evidence of disease; NS, nonseminoma; PD, progressive disease; PEB, cisplatin, etoposide, and bleomycin; POMB/ACE, cisplatin, vincristine, methotrexate, bleomycin, actinomycin, cyclophosphamide, and etoposide; PRm–­, partial response with negative tumor markers; RPLND, retroperitoneal lymph node dissection; RT, radiotherapy; S, seminoma; SD, stable disease; TIP, paclitaxel, ifosfamide, and cisplatin; TTR, time to relapse; VIP, etoposide, ifosfamide, and cisplatin. a NS at relapse. 265 Outcome of HIV-­Related Germ Cell Cancer/Hentrich et al 10970142, 2022, 2, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.33928 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 10970142, 2022, 2, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.33928 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article TABLE 4. Deceased Patients No Pathology UICC IGCCCG Primary Treatment Relapse/Progression Cause of Death Time, ya 1 S I —­ AS Yes Sepsis from cholangi- 12.8 tis, liver failure 2 S I —­ RT Yes GCC 3.2 3 NS I —­ AS Yes GCC 10.2b 4 S IIC Good 3× PEB Yes GCC 0.7 5 NS IIIB Intermediate 4× PEB Yes Cryptococcosis 4.9 6 NS IIIC Poor 4× PEB Yes GCC 1.1 7 NS Mediastinal Poor 3× POMB/ACE + surgery Yes GCC 0.6 8 S/NSc IIB Good 3× PEB No Traffic accident 0.3 9 NS IIIB Intermediate 4× PEB + surgery No AIDSd 9.1 10 NS IIIB Intermediate 4× PEB + surgery No Rectal cancer 10.0 11 S I —­ AS No Pneumonia/sepsis 8.9 12 S I —­ AS No Kaposi sarcoma 0.6 Abbreviations: AS, active surveillance; GCC, germ cell cancer; IGCCCG, International Germ Cell Cancer Collaborative Group; NS, nonseminoma; PEB, cisplatin, etoposide, and bleomycin; POMB/ACE, cisplatin, vincristine, methotrexate, bleomycin, actinomycin, cyclophosphamide, and etoposide; RT, radiotherapy (30 Gy); S, seminoma; UICC, Union for International Cancer Control. Patients with relapse/progression are arranged downward in the same order used in Table 3. a From GCC diagnosis. b Late relapse at 8.9 years. c Synchronous bilateral GCC. d Not further specified. A 1.00 B C 1.00 III 1.00 IIII II III II IIIII IIIIII I III II I IIIIII I IIIIIIIII IIII I III II IIIII IIIIII I II III I II I IIIIII I IIIIIIIII I III III I II II II IIII I I I II I II IIIII IIIII I I I II I IIIIII I IIIIIIIII III III I II 0.75 I II IIII I I I II I 0.75 I I 0.75 I III III I II I II IIII I I I II I Survival probability Survival probability Survival probability 0.50 0.50 0.50 0.25 0.25 0.25 0.00 0.00 0.00 0 5 10 15 20 0 5 10 15 20 0 5 10 15 20 PFS in years OS in years CFS in years Subjects: 89 52 23 9 1 Subjects: 89 55 25 9 1 Subjects: 89 55 25 9 1 Figure 2. (A) Progression-­free survival (PFS), (B) overall survival (OS), and (C) cancer-­free survival (CFS). The only available comparative study investigating planned schedule of chemotherapy delivery was not re- the impact of cART on the outcomes of HIV-­GCC com- spected in 42% of the patients.9 However, unexpected pared 22 patients diagnosed with GCC before the intro- severe toxicity during chemotherapy was also observed duction of cART in 1996 with 13 diagnosed after this in the current study, with 2 patients with stage IIA/B date.10 The 5-­year actuarial survival was 88% for patients seminoma experiencing severe sepsis during the first in the cART era, which was slightly below the 91% 5-­year and second cycles of PEB. As a result, chemotherapy OS rate reported in the current study. However, the cur- was terminated early after 2 cycles in the first patient rent study is much larger and thus provides more reliable and was switched to radiotherapy after 1 cycle in the data on the beneficial effects of cART in HIV-­GCC. second patient, with both patients remaining disease-­ Second, the antineoplastic treatments adminis- free at the last follow-­up. tered largely represent the standard of care.18,19 The 7% Third, the 95% DFS rates at 5 and 10 years and the dose reduction rate and the 10% rate of delay in the 5-­year OS rate of 91% were in line with the 5-­year relative administration of first-­line chemotherapy compare fa- survival rates of 94% and 89% reported for HIV-­negative vorably with data from a previous study in which the men with testis cancer in Europe diagnosed from 1995 to 266 Cancer   January 15, 2022 10970142, 2022, 2, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.33928 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Outcome of HIV-­Related Germ Cell Cancer/Hentrich et al 1999 and from 2000 to 2007, respectively.20,21 However, number of patients in each group. However, the updated the 5-­year OS rate seems slightly below survival rates re- IGCCCG classification should also be applied to men ported in a population-­based study from Denmark, in with HIV-­GCC in the future. which the 5-­year probability for nonseminomatous GCC Nonseminomatous pathology and chemother- with a good prognosis was 95%.22 apy dose reductions were associated with inferior PFS Two of the 44 patients with stage I GCC (4.5%) but not OS, and this indicated that patients underwent died of recurrent disease; this number is slightly higher effective salvage therapy. Furthermore, a poor perfor- than that reported for HIV-­negative patients, although mance status and IGCCCG poor risk predicted inferior this may merely be due to small patient numbers.23-­26 In survival, whereas HIV characteristics such as the CDC light of the decrease in CD4+ T cells during radiother- stage, CD4+ T-­cell counts, and HIV viral load did not. apy, which was also observed in previous studies,8,10 active This again emphasizes that the prognosis of HIV-­GCC surveillance appears to be the best approach for stage I is mainly determined by the GCC stage and risk category seminoma. On the other hand, for stage I nonseminoma, rather than HIV-­related immunosuppression. either active surveillance or a risk-­adapted approach with The retrospective, uncontrolled design is a limita- 1 cycle of adjuvant PEB for high-­ risk patients seems tion of the current study. However, because of the relative appropriate.18,19 rarity of HIV-­GCC, a large prospective study is unlikely The proportions of patients assigned to the to be conclusive. IGCCCG good-­ prognosis group (78%) and the In conclusion, the 5-­and 10-­year PFS and OS rates IGCCCG intermediate-­prognosis group (17%) were sim- of men with HIV-­GCC are similar to those reported for ilar to recent data from 2 cohort studies in HIV-­negative HIV-­ negative GCC. Patients with HIV-­ GCC should GCC, in which 69% and 78% had good-­risk GCC and remain on cART and be managed identically to HIV-­ 19% and 17% had intermediate-­risk GCC.27,28 The low negative patients. proportion of poor-­risk patients observed in the current study (4% vs 19% and 9% in HIV-­negative GCC, respec- FUNDING SUPPORT tively) might be explained by the continuous health care No specific funding was disclosed. monitoring of men living with HIV/AIDS, which pre- vents them from being diagnosed with late-­stage GCC. CONFLICT OF INTEREST DISCLOSURES Response rates to both primary and salvage chemo- Marcus Ulrich Hentrich has served on advisory boards for Amgen, Janssen, BMS, Sanofi, AbbVie, Hexal, and Jazz Pharmaceuticals; has served on speaker therapy were in the expected range, and this emphasizes bureaus for Amgen, Janssen, Sanofi, Takeda, and BMS; and has received that men with HIV-­GCC should be treated identically to travel grants from Amgen, Janssen, Takeda, Celgene, and Sanofi. Mark Bower reports lecture honoraria from EUSA, ViiV, Merck, and Gilead. Gedske HIV-­negative patients.2,5 Daugaard has served on boards for Astellas, Bayer, Bristol, Janssen, and Sanofi. The IGCCCG classification was recently re-­ Albrecht Stoehr has served on advisory boards for ViiV, MSD, Gilead, and AbbVie and has received travel grants from AbbVie, Janssen, and Gilead. Julia evaluated in a database from a large international con- Heinzelbecker has served on the speaker bureau for Roche and has received sortium.29,30 Survival probabilities were shown to have travel grants from Ipsen, Pfizer, and Bayer. Klaus-­Peter Dieckmann declares an ownership interest in and has served on advisory boards for miRdetect significantly improved in both seminoma and nonsemi- GmbH. Andrea Necchi declares that an immediate family member is em- noma. Another important finding was that the original ployed by and holds ownership interests in Bayer; he has served as an consult- ant for Immunomedics, MSD, Roche, Bayer, AstraZeneca, Clovis Oncology, IGCCCG classification still distinguished 2 and 3 prog- Janssen, Incyte, Seattle Genetics/Astellas, BMS, Rainer Therapeutics, nostic groups among patients with metastatic seminoma GlaxoSmithKline, and Ferring; he has received travel grants from Roche, and nonseminoma, respectively. However, in seminoma, MSD, AstraZeneca, Janssen, and Rainer Therapeutics; he has received hono- raria from Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, and lactate dehydrogenase at a cutoff 2.5 times the upper limit BMS; and he has received research funding from MSD, AstraZeneca, and of normal was identified as a new adverse prognostic vari- Ipsen. Pablo Maroto Rey has served as a consultant for Bayer, Ipsen, Janssen, Astellas Oncology, BMS, Novartis, Pfizer, and Roche; has received research able among otherwise good-­prognosis patients,29 whereas funding from Bayer and Roche; and has received travel grants from Ipsen, a new cutoff of lactate dehydrogenase at 2.5 times the Janssen, and Pfizer. Jürgen Kurt Rockstroh has received honoraria from Gilead, Janssen, Merck, and ViiV Healthcare. Margarida Brito reports par- upper limit of normal, increasing age, and the presence ticipation on boards for Roche and Novartis. Christian Hoffmann has served of lung metastases were identified as additional adverse as a consultant for EUSA Pharma, Gilead, Hexal, Hormosan, Janssen, ViiV Healthcare, and MSD Brazil; has served on speaker bureaus for EUSA prognostic markers in metastatic nonseminoma.30 With Pharma, Gilead, Hexal, Hormosan, Janssen, ViiV Healthcare, and MSD respect to our cohort of men with HIV-­GCC, differences Brazil; has received research funding from EUSA Pharma, Gilead, Janssen, ViiV Healthcare, and MSD Brazil; and has received travel grants from EUSA in survival between groups were not calculated on the Pharma, Gilead, Hexal, Hormosan, Janssen, ViiV Healthcare, and MSD basis of the IGCCCG update criteria because of the low Brazil. The other authors made no disclosures. Cancer   January 15, 2022 267 10970142, 2022, 2, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.33928 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article AUTHOR CONTRIBUTIONS 13. International Germ Cell Cancer Collaborative Group. International Marcus Ulrich Hentrich: Design and conception of the study, essential Germ Cell Consensus Classification: a prognostic factor–­based staging study material and patients, collection and assembly of the data, analysis system for metastatic germ cell cancer. J Clin Oncol. 1997;15:594-­603. of the data, and drafting of the manuscript. Mark Bower: Essential study 14. US Centers for Disease Control and Prevention. 1993 revised classifi- material and patients. Gedske Daugaard: Essential study material and cation system for HIV infection and expanded surveillance case defi- patients. Annette Dieing: Essential study material and patients. Markus nition for AIDS among adolescents and adults. MMWR Recomm Rep. Bickel: Essential study material and patients. Massimiliano Berretta: 1992;41:1-­19. Essential study material and patients. Florian Lesmeister: Design and con- 15. Spina M, Jaeger U, Sparano JA, et al. Rituximab plus infusional ception of the study, essential study material and patients, collection and cyclophosphamide, doxorubicin, and etoposide in HIV-­ associated assembly of the data, analysis of the data, and statistical analysis. Vindi non-­Hodgkin lymphoma: pooled results from 3 phase 2 trials. Blood. Jurinovic: Analysis of the data and statistical analysis. Albrecht Stoehr: 2005;105:1891-­1897. Essential study material and patients. Julia Heinzelbecker: Essential study 16. Bower M, Stebbing J, Tuthill M, et al. Immunologic recovery in sur- material and patients. Ivanka Krznaric: Essential study material and pa- vivors following chemotherapy for AIDS-­related non-­Hodgkin lym- tients. Klaus-­Peter Dieckmann: Essential study material and patients. phoma. Blood. 2008;111:3986-­3990. Andrea Necchi: Essential study material and patients. Pablo Maroto Rey: 17. Hentrich M, Berger M, Wyen C, et al. Stage-­adapted treatment of Essential study material and patients. Jürgen Kurt Rockstroh: Essential HIV-­associated Hodgkin lymphoma: results of a prospective multi- study material and patients. Margarida Brito: Essential study material and center study. J Clin Oncol. 2012;30:4117-­4123. patients. David Pfister: Essential study material and patients. Christian 18. Beyer J, Albers P, Altena R, et al. Maintaining success, reducing treat- Hoffmann: Design and conception of the study, essential study material ment burden, focussing on survivorship: highlights from the Third and patients, and analysis of the data. All the authors have interpreted, criti- European Consensus Conference on Diagnosis and Treatment of Germ cally appraised, and given final approval of the manuscript. Cell Cancer. Ann Oncol. 2013;24:878-­888. 19. 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