ABSTRACT
Introduction
Patients with relapsed/refractory (R/R) testicular germ cell tumor (GCT) progressing after salvage chemotherapy only have palliative therapeutic options. Real‐world data on this population are needed.
Methods
Adult men with testicular GCT receiving palliative chemotherapy in the United States were identified in the Komodo Research Database (01/2016–03/2023; index date = date of palliative chemotherapy initiation). Treatment patterns were analyzed for patients with continuous health plan enrollment from diagnosis to index date. Clinical outcomes (time to real‐world progression [TTrwP] and real‐world overall survival [rwOS]) were assessed among patients with prior salvage chemotherapy using the Kaplan–Meier method.
Results
In the treatment pattern analysis (N = 51; median age 32 years), median (interquartile range) time from diagnosis to first‐line treatment was 0.9 (0.5–2.1) months, and to palliative chemotherapy was 12.5 (9.0–16.8) months. Index palliative chemotherapy regimens included gemcitabine‐oxaliplatin (37.3%), oral etoposide (15.7%), and gemcitabine‐oxaliplatin‐paclitaxel (15.7%). Prior to palliative chemotherapy, 33 patients (64.7%) received salvage chemotherapy. In the clinical outcome analysis (N = 80; median age: 33 years), 49 (61.3%) patients were exposed to high‐dose chemotherapy (HDCT; ±conventional‐dose chemotherapy [CDCT]) and 31 (38.8%) only to CDCT. Overall median (95% confidence interval [CI]) TTrwP was 3.8 (2.6–4.7) months, 3.5 (2.3–4.7) months after HDCT±CDCT, and 4.0 (1.7–6.6) months after only CDCT, and median (95% CI) rwOS was 7.7 (6.3–9.6) months, 6.4 (5.6–9.6) months, and 9.3 (7.5–22.0) months, respectively.
Conclusions
Real‐world data captured heterogeneous treatment patterns and poor outcomes for patients with R/R testicular GCT receiving palliative chemotherapy, highlighting the need for novel therapies.
Keywords: chemotherapy, palliative care, salvage therapy, testicular neoplasms, treatment outcome, treatment pattern
1. Introduction
Testicular germ cell tumors (GCT) are the most common form of solid malignancy among males aged 15–35 [1, 2]. With effective multimodality therapy, testicular GCT accounts for fewer than 500 deaths annually in the United States (US) [3, 4]. Due in part to high cure rates, treatment for testicular GCT has remained largely unchanged for several decades, consisting of first‐line cisplatin‐based chemotherapy, mainly a combination of bleomycin, etoposide, and cisplatin (BEP) [1]. However, up to 25% of patients relapse following first‐line chemotherapy [5], and those with multiple relapses who exhaust curative treatment options face substantially worse prognoses [6, 7, 8, 9, 10, 11, 12, 13, 14].
For patients who progress after first‐line chemotherapy, salvage chemotherapy remains the standard of care treatment approach [1]. Despite being potentially curative, salvage chemotherapy achieves complete remission in only 30%–60% of patients [15, 16, 17]. Salvage options consist of conventional‐dose chemotherapy (CDCT) or high‐dose chemotherapy (HDCT) with autologous stem cell transplant (ASCT) [1, 18, 19]. Patients who relapse following initial salvage CDCT are recommended to receive third‐line treatment with HDCT. However, there is currently no consensus on the optimal salvage therapy approach, largely due to limited definitive comparative data directly evaluating CDCT vs. HDCT [1, 20]. The ongoing randomized phase III TIGER trial (NCT02375204), designed to compare CDCT and HDCT as initial salvage chemotherapy in patients with testicular GCT, may provide critical evidence for defining future standard of care recommendations in this setting [21].
Patients who progress after salvage HDCT, as well as those who progress after salvage CDCT but are not candidates for HDCT, are referred to as having relapsed/refractory (R/R) testicular GCT. Management of patients with R/R testicular GCT remains a significant challenge. In select cases, participation in a clinical trial or salvage surgery, in which surgically resectable tumors are completely removed, may be an option and has been shown to offer potential long‐term survival [16]. However, treatment options for these patients are largely limited to palliative therapy, often involving single‐agent or combination regimens of paclitaxel, gemcitabine, and oxaliplatin, or oral etoposide [22]. Clinical trial data suggest limited long‐term survival benefits with these agents [6, 7, 8, 9, 10, 11, 12, 13, 14].
A recent European registry study from the Global Germ Cell Collaborative Group G3 found poor outcomes among patients with R/R testicular GCT initiating palliative chemotherapy, with a median progression‐free survival (PFS) of only 3 months and a median overall survival (OS) of 9 months [23]. Despite the clinical significance of this patient population, real‐world evidence within the US is sparse, and further research is needed to guide clinical decision‐making and to optimize patient care. To address this gap, the current study used real‐world US data to describe the treatment journeys and clinical outcomes of patients with testicular GCT receiving palliative chemotherapy in the setting of being refractory to or relapsing after salvage chemotherapy.
2. Methods
2.1. Data Source
This study used data from the Komodo Research Database (KRD+; January 2016–March 2023). KRD+ is a comprehensive healthcare claims data source covering roughly 30% of the US insured population for commercial, Medicare, and Medicaid beneficiaries. KRD+ contains medical, laboratory, and pharmaceutical encounters, integrating closed claims directly from over 150 payers, representing approximately 170 million covered lives, as well as additional open claims from multiple processors.
This study involved the secondary use of data that were de‐identified in compliance with the Health Insurance Portability and Accountability Act and was therefore considered exempt.
2.2. Study Design and Objectives
A retrospective study was conducted among patients with testicular GCT receiving palliative chemotherapy in the US with two objectives: Objective 1 was to describe treatment patterns prior to the initiation of palliative chemotherapy, and Objective 2 was to describe clinical outcomes (i.e., time to real‐world progression [TTrwP] and real‐world OS [rwOS]) from the initiation of palliative chemotherapy among patients with prior salvage chemotherapy.
The index date was defined as the date of initiation of the first observed palliative chemotherapy regimen. For Objective 1, treatment patterns were assessed during the period spanning from the first observed testicular cancer (TC) diagnosis to the index date. For Objective 2, TTrwP and rwOS were assessed during the period spanning from the index date to the earlier of the end of health plan coverage, the end of data availability, or death (Figure S1).
2.3. Patient Selection
The study population included adult males with testicular GCT who received chemotherapy and progressed to palliative chemotherapy meeting the following criteria: (1) diagnosis of TC (International Classification of Diseases, Tenth Revision, Clinical Modification [ICD‐10‐CM] code: C62.x) on ≥ 2 instances ≥ 30 days apart; (2) aged ≥ 18 years as of the first observed TC diagnosis; (3) ≥ 1 testicular GCT‐related chemotherapy regimen following the first observed TC diagnosis; and (4) ≥ 1 testicular GCT‐related palliative chemotherapy regimen following the first observed TC diagnosis.
Of note, a TC diagnosis was used to proxy a testicular GCT diagnosis given the lack of a specific ICD‐10‐CM code for testicular GCT; testicular GCT accounts for 95% of all testicular tumors [1], and therefore relying on a general TC diagnosis would be expected to largely capture the testicular GCT population. The testicular GCT‐related chemotherapy regimen was defined as agents included in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) as chemotherapy regimen options for testicular GCT, as well as those deemed relevant by a clinical expert (Table S1). To confirm the regimens were testicular GCT‐related, patients were required to have ≥ 1 TC diagnosis code but no other primary malignancy diagnosis codes (Table S2) during the 30‐day period before regimen initiation. Similarly, the testicular GCT‐related palliative chemotherapy regimen was defined as agents included in the NCCN Guidelines as third‐line chemotherapy regimen options for testicular GCT [22], as well as those deemed relevant by a clinical expert (Table S1), that were not followed by a first‐line or salvage chemotherapy regimen (defined below).
In addition, for Objective 1, patients were required to meet ≥ 1 of the following criteria to create a sufficient washout period to account for left‐censoring in claims data and increase confidence that patients' treatment patterns from their first line of therapy could be comprehensively described: (1) health plan coverage from ≥ 12 months prior to the first observed TC diagnosis spanning until the initiation of palliative chemotherapy; or (2) health plan coverage from the first observed TC diagnosis until the initiation of palliative chemotherapy and receipt of a first‐line testicular GCT‐related chemotherapy regimen following the first observed TC diagnosis but prior to the initiation of palliative chemotherapy.
For Objective 2, patients were required to have ≥ 1 testicular GCT‐related salvage chemotherapy regimen prior to the initiation of palliative chemotherapy, defined as agents included in the NCCN Guidelines as second‐line chemotherapy regimen options for testicular GCT (i.e., salvage CDCT and HDCT regimens [22]; Table S1). Proxies were used to account for missing salvage chemotherapy agents in medical claims; specifically, inpatient stays with antineoplastic chemotherapy administrations, ASCT, and clinical trial participation were considered proxies for salvage CDCT, salvage HDCT, and general salvage chemotherapy, respectively (Table S3). Patients included in Objective 2 were also required to have an index date ≥ 12 months prior to the end of data availability to allow for a minimum of 12 months of potential follow‐up for clinical outcome observation.
2.4. Study Outcomes
2.4.1. Objective 1
Treatment patterns, including treatment sequence, regimens used, and duration of first‐line chemotherapy, salvage chemotherapy, and palliative chemotherapy, were described from the first observed TC diagnosis to the initiation of the first observed palliative chemotherapy regimen (i.e., index date).
2.4.2. Objective 2
TTrwP and rwOS were assessed among patients with prior salvage chemotherapy overall and stratified by prior exposure to HDCT with or without CDCT (HDCT±CDCT), or CDCT only. Due to the lack of direct clinical measures in claims data, progression and survival outcomes were assessed using proxies based on observed claims and were identified using an algorithm derived from prior literature [24] that was further adapted in this study specifically for testicular GCT.
TTrwP was defined as the time from the initiation of palliative chemotherapy (i.e., index date) to the earliest observed real‐world progression (rwP) event among (1) radiation after the first cycle of the index palliative chemotherapy regimen (i.e., radiation procedure observed ≥ 28 days after the index date); (2) treatment discontinuation prior to death (i.e., absence of the index palliative chemotherapy regimen for ≥ 45 days after the last day of supply and death or admission to hospice observed within 180 days of the discontinuation date); (3) treatment addition/switch (i.e., an addition of an agent to the index palliative chemotherapy regimen or a switch in the index palliative chemotherapy regimen); (4) admission to hospice; or (5) death (Table S4). If no progression event was observed, the patient's follow‐up time was censored at the end of data availability.
RwOS was defined as the time from the initiation of palliative chemotherapy (i.e., index date) to the following death events: (1) the date of patient death; (2) the last date of claims activity following the last hospice claim; or (3) the last date of claims activity with no subsequent open claims activity for ≥ 3 months prior to end of data availability (Table S4). If no death event was observed, the patient's follow‐up time was censored at the end of data availability.
2.5. Statistical Analysis
Patient characteristics and treatment patterns were summarized descriptively using medians and interquartile ranges (IQRs) for continuous variables, and frequencies and proportions for categorical variables. Prior treatment sequences, collapsed at the therapy line‐level (i.e., first line, CDCT, HDCT), were summarized with the index palliative chemotherapy regimen as the anchoring point and graphically represented as a Sankey diagram. TTrwP and rwOS, along with the 95% confidence intervals (CIs), were estimated using Kaplan–Meier analyses. All analyses were descriptive; no statistical comparisons were conducted.
3. Results
3.1. Objective 1
3.1.1. Patient Characteristics
Of the 57,508 adult male patients with a TC diagnosis, 248 (4.3%) received palliative chemotherapy, among whom 51 (20.6%) met the criteria for the treatment pattern analysis for Objective 1 (Figure S2). The patient characteristics are presented in Table 1. Of the 51 patients, the median age on the index date was 32 years; 18 patients (35.3%) were White (non‐Hispanic), 8 (15.7%) were Hispanic or Latino, 3 (5.9%) were Black or African American, and 1 (2.0%) was Asian or Pacific Islander. Most patients had commercial (31 [60.8%]) or Medicaid (14 [27.5%]) insurance. At the time of palliative chemotherapy initiation, common metastatic sites included lung (41.2%), bone (33.3%), lymph nodes (31.4%), and brain (19.6%).
TABLE 1.
Patient characteristics.
| Characteristics a | Objective 1 (treatment patterns) N = 51 | Objective 2 (clinical outcomes) N = 80 |
|---|---|---|
| Demographic characteristics | ||
| Age, median (IQR) years | 32 (25–42) | 33 (26–43) |
| 18–24, n (%) | 12 (23.5) | 14 (17.5) |
| 25–44, n (%) | 30 (58.8) | 52 (65.0) |
| ≥ 45, n (%) | 9 (17.6) | 14 (17.5) |
| Ethnicity, n (%) | ||
| White (non‐Hispanic) | 18 (35.3) | 31 (38.8) |
| Hispanic or Latino | 8 (15.7) | 12 (15.0) |
| Black or African American | 3 (5.9) | 3 (3.8) |
| Asian or Pacific Islander | 1 (2.0) | 3 (3.8) |
| Other | 4 (7.8) | 7 (8.8) |
| Unknown | 17 (33.3) | 24 (30.0) |
| Region of residence, n (%) | ||
| South | 22 (43.1) | 28 (35.0) |
| West | 13 (25.5) | 22 (27.5) |
| North | 8 (15.7) | 17 (21.3) |
| East | 7 (13.7) | 10 (12.5) |
| Unknown | 1 (2.0) | 3 (3.8) |
| Type of insurance, n (%) | ||
| Commercial | 31 (60.8) | 41 (51.3) |
| Medicaid | 14 (27.5) | 34 (42.5) |
| Medicare | 2 (3.9) | 2 (2.5) |
| Unknown | 4 (7.8) | 3 (3.8) |
| Year of index date, n (%) | ||
| 2016–2019 | 19 (37.3) | 41 (51.3) |
| 2020–2023 | 32 (62.7) | 39 (48.7) |
| Clinical characteristics | ||
| Metastatic sites, n (%) b | 39 (76.5) | 63 (78.8) |
| Lung | 21 (41.2) | 28 (35.0) |
| Bone | 17 (33.3) | 26 (32.5) |
| Lymph nodes | 16 (31.4) | 25 (31.3) |
| Brain | 10 (19.6) | 21 (26.3) |
| Liver | 3 (5.9) | 7 (8.8) |
Abbreviations: ICD‐10: International Classification of Diseases, Tenth Revision; IQR, Interquartile range.
Patient characteristics were reported as of the index date, defined as the initiation date of the first observed palliative chemotherapy regimen that was not followed at any point by a salvage chemotherapy regimen.
Metastatic sites were identified using recorded ICD‐10 codes. However, they may be underreported, as once a metastatic diagnosis is established, clinicians may not consistently document all metastatic sites in claims data.
3.1.2. Treatment Patterns
The treatment pattern analysis results are presented in Table 2, and the treatment sequence is graphically depicted in Figure 1. Among the 51 patients with a median follow‐up of 19.9 months (IQR: 15.6–28.8 months) after diagnosis, 46 (90.2%) had ≥ 1 first‐line chemotherapy regimen, most commonly BEP (60.9%) and etoposide‐cisplatin (EP; 21.7%). The median time from first observed TC diagnosis to first observed chemotherapy regimen was 0.9 months (IQR: 0.5–2.1 months).
TABLE 2.
Palliative chemotherapy and prior chemotherapy exposure.
| Objective 1 (treatment patterns) N = 51 | |
|---|---|
| Key time periods, median (IQR) months | |
| Time from the TC diagnosis to initiation of testicular GCT‐related chemotherapy | 0.9 (0.5–2.1) |
| Time from TC diagnosis to initiation of first palliative chemotherapy regimen (i.e., index date) a | 12.5 (9.0–16.8) |
| Duration of index palliative chemotherapy regimen b | 2.1 (1.2–3.4) |
| Index palliative chemotherapy regimen c , n (%) | |
| Gemcitabine‐oxaliplatin | 19 (37.3) |
| Etoposide oral | 8 (15.7) |
| Gemcitabine‐oxaliplatin‐paclitaxel | 8 (15.7) |
| Gemcitabine‐paclitaxel | 6 (11.8) |
| Other single‐agent or a combination of palliative agents | 10 (19.6) |
| Testicular GCT‐related chemotherapy regimens prior to index, n (%) | |
| ≥ 1 first‐line chemotherapy c | 46 (90.2) |
| BEP | 28 (60.9) |
| EP | 10 (21.7) |
| VIP | 4 (8.7) |
| Other combinations of first‐line chemotherapy agents | 5 (10.9) |
| ≥ 1 salvage chemotherapy | 33 (64.7) |
| HDCT and CDCT | 8 (24.2) |
| HDCT only | 15 (45.5) |
| CDCT only | 10 (30.3) |
| No salvage chemotherapy | 18 (35.3) |
Abbreviations: BEP, Bleomycin, etoposide, and cisplatin; CDCT, Conventional‐dose chemotherapy; EP, Etoposide‐cisplatin; GCT, Germ cell tumor; HDCT, High‐dose chemotherapy; IQR, Interquartile range; TC, Testicular cancer; VIP, Etoposide‐ifosamide‐cisplatin.
The index date was defined as the initiation date of the first observed palliative chemotherapy regimen that was not followed at any point by a salvage chemotherapy regimen.
The index palliative chemotherapy regimen was defined as the first palliative chemotherapy regimen that was preceded by but not followed by a first‐line or salvage chemotherapy regimen.
Regimen frequencies are not mutually exclusive.
FIGURE 1.
Prior treatment sequences leading to palliative chemotherapy initiation†,‡. Abbreviations: 1L: First‐line chemotherapy; CDCT: Conventional‐dose chemotherapy; GCT: Germ cell tumor; HDCT: High‐dose chemotherapy; TC: Testicular cancer. †The treatment sequences of patients with a palliative chemotherapy regimen and continuous health plan coverage were summarized with the index palliative chemotherapy as the anchoring point. The index palliative chemotherapy was defined as the first palliative chemotherapy that was preceded but not followed by a first‐line or salvage chemotherapy. ‡The nodes represent all testicular GCT‐related chemotherapy regimens observed as of the first observed TC diagnosis up to the index palliative chemotherapy. The links represent the proportion of patients receiving the regimen of therapy at each node. Treatment regimens were collapsed at the chemotherapy line‐level (i.e., first line, CDCT, HDCT) to represent the transition from first‐line chemotherapy treatment to palliative chemotherapy.
About two‐thirds of patients (33 [64.7%]) had ≥ 1 salvage chemotherapy; among these patients, 30.3% received CDCT only, 45.5% received HDCT only, and 24.2% received both HDCT and CDCT. Over one‐third of patients (18 [35.3%]) had no observed salvage chemotherapy prior to palliative chemotherapy; among these patients, the median time from end of first‐line chemotherapy to the initiation of palliative chemotherapy was 4.1 months (IQR: 2.4–8.0 months), and 13 (72.2%) had evidence of renal insufficiency.
Index palliative chemotherapy regimens observed included gemcitabine‐oxaliplatin (19 [37.3%]), oral etoposide (8 [15.7%]), gemcitabine‐oxaliplatin‐paclitaxel (8 [15.7%]), gemcitabine‐paclitaxel (6 [11.8%]), and other single‐agent or combination of agents recommended by the NCCN Guidelines (10 [19.6%]). The median time from first observed TC diagnosis to the initiation of palliative chemotherapy was 12.5 months (IQR: 9.0–16.8 months), and the median duration of the index palliative chemotherapy regimen was 2.1 months (IQR: 1.2–3.4 months).
3.2. Objective 2
3.2.1. Patient Characteristics
Among the 248 patients who received palliative chemotherapy, 97 (39.1%) had sufficient data to confirm prior salvage chemotherapy exposure, and of those patients, 80 (82.5%) met the criteria for the clinical outcome analysis for Objective 2 (Figure S2). The patient characteristics are presented in Table 1. Of the 80 patients, the median age on the index date was 33 years; 31 patients were White (non‐Hispanic; 38.8%), 12 (15.0%) were Hispanic or Latino, 3 (3.8%) were Black or African American, and 3 (3.8%) were Asian or Pacific Islander. Most patients had commercial (41 [51.3%]) or Medicaid (34 [42.5%]) insurance. Index palliative chemotherapy regimens observed included gemcitabine‐oxaliplatin (38 [47.5%]), oral etoposide (11 [13.8%]), gemcitabine‐paclitaxel (11 [13.8%]), and gemcitabine‐oxaliplatin‐paclitaxel (6 [7.5%]). At the time of the initiation of palliative chemotherapy, common metastatic sites included lung (35.0%), bone (32.5%), lymph nodes (31.3%), and brain (26.3%).
3.2.2. TTrwP And rwOS
Prior to the initiation of palliative chemotherapy, 49 of the 80 patients (61.3%) were exposed to HDCT±CDCT, and 31 (38.8%) were exposed to CDCT only.
Over a median of 40.2 months (IQR: 25.9–63.5 months) from the initiation of palliative chemotherapy to the end of data availability, rwP events were observed in 93.8% of patients (Table 3). The first observed rwP event commonly included radiation in 26 (32.5%) patients (median time to event: 2.8 months [IQR: 1.4–4.6 months]), treatment discontinuation in 25 (31.3%) patients (median time to event: 2.1 months [IQR: 1.0–3.9 months]), and treatment addition/switch in 18 (22.5%) patients (median time to event: 4.7 months [IQR: 3.0–6.1 months]). Death was observed in 73 (91.3%) patients (including the 3 patients with death as their rwP event) and occurred at a median of 2.4 months (IQR: 1.4–5.3 months) from the rwP event.
TABLE 3.
Observed rwP events after palliative chemotherapy initiation.
| First rwP event after palliative chemotherapy initiation | Objective 2 (clinical outcomes) N = 80 | |||
|---|---|---|---|---|
| Patients with rwP event, N (%) | Time to event, median (IQR) months | Patients who died, N (%) | Time from rwP to death, median (IQR) months | |
| Radiation a | 26 (32.5) | 2.8 (1.4–4.6) | 26 (100.0) | 3.0 (1.9–6.3) |
| Treatment discontinuation b | 25 (31.3) | 2.1 (1.0–3.9) | 25 (100.0) | 1.8 (1.3–3.1) |
| Treatment addition/switch c | 18 (22.5) | 4.7 (3.0–6.1) | 16 (88.9) | 3.8 (3.2–6.1) |
| Common treatment sequences | ||||
| Etoposide oral ➔ gemcitabine‐oxaliplatin | 3 (16.7) | |||
| Gemcitabine‐oxaliplatin ➔ etoposide oral | 2 (11.1) | |||
| Hospice d | 3 (3.8) | 9.9 (0.5–17.1) | 3 (100.0) | 0.3 (0.3–3.0) |
| Death | 3 (3.8) | 30.4 (3.8–32.0) | 3 (100.0) | 0.0 (0.0–0.0) |
| No progression e | 5 (6.3) | 0 (0.0) | ||
Abbreviations: IQR, Interquartile range; rwP, Real‐world progression.
Radiation was defined as a radiation procedure observed ≥ 28 days of the index date (i.e., after the first palliative chemotherapy regimen cycle).
Discontinuation was defined as the absence of the index palliative chemotherapy regimen for ≥ 45 days since the last day of supply and was considered a progression event when death or admission to hospice was observed within 180 days of the discontinuation date.
Treatment addition/switch was defined as an addition of an agent to the index palliative chemotherapy regimen or a switch in palliative chemotherapy regimen.
Hospice was defined as admission to hospice.
When no progression event was observed, the patient's follow‐up time was censored at the end of data availability.
Median TTrwP was 3.8 months (95% CI: 2.6–4.7 months) overall, 3.5 months (95% CI: 2.3–4.7 months) for patients exposed to HDCT±CDCT, and 4.0 months (95% CI: 1.7–6.6 months) for those exposed to CDCT only. The probabilities of rwP‐free survival at 6 months were 27.5% overall, 24.5% for those exposed to HDCT±CDCT, and 32.3% for those exposed to CDCT only; the corresponding probabilities of rwP‐free survival at 12 months were 11.3%, 8.2%, and 16.1%, respectively (Figure 2).
FIGURE 2.
TTrwP among patients R/R after salvage chemotherapy treated with palliative chemotherapy, stratified by prior exposure to HDCT±CDCT or CDCT only†,‡. Abbreviations: CDCT: Conventional‐dose chemotherapy; CI: Confidence interval; HDCT: High‐dose chemotherapy; R/R: Relapsed/refractory; rwP: Real‐world progression; TTrwP: Time to real‐world progression. †TTrwP was estimated using the Kaplan–Meier estimator as the time from the initiation of palliative chemotherapy to the earliest of (1) radiation after the first cycle of palliative chemotherapy, (2) treatment discontinuation prior to death, (3) treatment addition/switch, (4) hospice admission, or (5) death, censored at the end of data availability. ‡Patients were stratified by prior exposure to HDCT±CDCT, or CDCT only. Patients may systematically differ across strata, and TTrwP curve estimates do not adjust for the number or duration of prior lines of chemotherapy. Probability of rwP and median TTrwP estimates should therefore not be compared across strata.
Median rwOS was 7.7 months (95% CI: 6.3–9.6 months) overall, 6.4 months (95% CI: 5.6–9.6 months) for those exposed to HDCT±CDCT, and 9.3 months (95% CI: 7.5–22.0 months) for those exposed to CDCT only. The 6‐month rwOS rates were 63.8% overall, 59.2% for those exposed to HDCT±CDCT, and 71.0% for those exposed to CDCT only, and the corresponding 12‐month rwOS rates were 25.0%, 16.3%, and 38.7%, respectively (Figure 3).
FIGURE 3.
RwOS among patients R/R after salvage chemotherapy treated with palliative chemotherapy, stratified by prior exposure to HDCT±CDCT or CDCT only†,‡,§. Abbreviations: CDCT: Conventional‐dose chemotherapy; CI: Confidence interval; HDCT: High‐dose chemotherapy; R/R: Relapsed/refractory; rwOS: Real‐world overall survival. †The rwOS curve was estimated using the Kaplan–Meier estimator and was estimated as the time from the initiation of palliative chemotherapy to (1) the date of patient death, (2) the last date of claims activity following the last hospice claim, or (3) the last date of claims activity with no subsequent open claims activity for ≥ 3 months prior to end of data availability, censored at the end of data availability. ‡Patients were stratified by prior exposure to HDCT with or without CDCT, or CDCT only. Patients may systematically differ across strata, and survival curve estimates do not adjust for the number or duration of prior lines of chemotherapy. RwOS probability and median rwOS estimates should therefore not be compared across strata. §Patients with ≤ 12 months between the index date and the end of data availability were omitted from this analysis to diminish the influence of systematic censoring.
4. Discussion
Research and treatment advances in metastatic testicular GCT have lagged behind other areas of uro‐oncology, with few therapeutic breakthroughs since the introduction of cisplatin‐based chemotherapy nearly 50 years ago, which achieved high cure rates in this patient population [25]. However, substantial unmet needs remain for the subset of patients with R/R disease without remaining curative treatment options. To the authors' knowledge, this is the first US‐based real‐world study to characterize treatment journeys and outcomes among this rare but clinically important patient subgroup with R/R testicular GCT.
The treatment patterns observed in this study reflect the current US treatment landscape for R/R testicular GCT, with heterogeneous treatment journeys and no definitive standard of care beyond first‐line chemotherapy. While most patients who received first‐line chemotherapy were quickly treated following diagnosis, primarily with BEP, aligning with clinical guidelines [22, 25], subsequent lines of chemotherapy, including salvage chemotherapy and palliative chemotherapy, were diverse, highlighting the continued clinical uncertainty in managing patients in the initial salvage and later‐line setting.
No clear choice between HDCT and CDCT was observed for salvage chemotherapy. Notably, 30% of patients who progressed after first salvage chemotherapy received only CDCT and did not proceed to third‐line HDCT, despite being considered a remaining curative option [22]. The lower utilization of HDCT may be reflective of some patients being unfit for intensive treatment, or challenges in accessing ASCT owing to logistical or financial factors, including the non‐availability of HDCT at all treating centers [18, 19]. Surprisingly, more than one‐third of patients initiating palliative chemotherapy were not observed to receive any prior salvage chemotherapy, neither CDCT nor HDCT. These patients appeared to experience fast disease progression after first‐line treatment (median of 4 months), and over 70% had evidence of renal insufficiency, which may have rendered them ineligible for salvage chemotherapy [26]. While the ongoing TIGER trial (NCT02375204) comparing CDCT vs. HDCT plus ASCT is expected to help direct initial salvage strategies [21], further research is warranted to understand the barriers to salvage chemotherapy that may exist and the potential need for other treatment options. Furthermore, the pattern of palliative chemotherapy in this study was heterogeneous, with no predominant single or combination regimen observed. This underscores the limited evidence available to guide treatment decisions in this setting and highlights the need for novel therapies to improve survival outcomes for patients with R/R testicular GCT.
While some studies have reported unexpectedly favorable individual responses to palliative chemotherapy among patients with R/R testicular GCT, such as through salvage surgery or specific palliative management strategies [13, 23], the OS outcomes remain poor, consistent with clinical trial results [6, 7, 8, 9, 10, 11, 12, 14]. In parallel to our study, Oing and colleagues presented a conference abstract similarly assessing palliative management among patients with R/R testicular GCT using registry data in a European setting [23], which reported that after a median follow‐up of 8 months, median PFS from first palliative chemotherapy was estimated at 3.0 months (95% CI: 2.5–3.6 months) and median OS at 9.0 months (95% CI: 8.0–10.0 months) [23], concordant with the median TTrwP of 3.8 months (95% CI: 2.6–4.7 months) and median rwOS of 7.7 months (95% CI: 6.3–9.6 months) estimated in the current study. The Oing et al. study also reported a 29.4% 6‐month PFS rate and 35.0% 12‐month OS rate, largely aligning with those in the current study that were based on proxies of real‐world progression events (27.5% and 25.0%, respectively); the slightly higher OS rate in Oing et al. could partially be due to the study population being treated at GCT expert centers, where patients may have access to specialized healthcare teams and resources that may help improve survival. By the end of follow‐up, over 85% of patients in Oing et al. [23] had died from disease progression, whereas deaths were observed in 91% of patients in the current study.
Collectively, our real‐world study based on US claims data aligns with the early findings presented from European cohorts, highlighting the unfavorable outcomes of patients with R/R testicular GCT who have exhausted all available curative options. Given the rarity of this population, compounded by the heterogeneous treatment landscape and lack of standard‐of‐care chemotherapy for those progressing after salvage chemotherapy, conducting robust randomized clinical trials is challenging. Real‐world data, such as that presented in the current study, are therefore crucial to provide benchmarks for novel therapy comparisons to help drive much‐needed clinical innovation and further demonstrate that US real‐world data can be used to evaluate such research questions. Insights from this study emphasize the need for therapeutic advancements and support the role of real‐world evidence in guiding clinical development and improving outcomes for patients with R/R testicular GCT.
The current study findings are subject to the limitations inherent to claims‐based analyses, including left censoring, which may limit the ability to capture comprehensive treatment patterns. To account for left censoring in this study, a washout period prior to the first observed TC diagnosis and/or observation of a first‐line chemotherapy was required. Using this approach, the proportion of patients for whom a first‐line chemotherapy was not observed was less than 10%. Nonetheless, the requirement for continuous health plan coverage from ≥ 12 months before the first observed TC diagnosis could have favored patients with stable insurance coverage, limiting the generalizability of the findings to those with no or unstable insurance coverage. Furthermore, as this study focused on a rare population of patients with testicular GCT who progressed to palliative chemotherapy, the final sample size remained relatively small despite the use of a large national claims database and broader selection criteria intended to maximize sample size; as such, the findings may be subject to selection bias and limited generalizability to the broader testicular GCT population, including patients outside KRD+. In addition, disease progression status is not available in claims data, and mortality data are incomplete. To mitigate this, the current study used real‐world proxies of disease progression/death based on previously established algorithms and/or inputs from clinical experts to estimate TTrwP and rwOS. Given that the patient population in this study had exhausted curative treatment options, traditional proxies for progression in real‐world data, such as initiation of a next line of therapy [27], had limited relevance; proxies based on electronic health records were also not applicable to this claims‐based study [28]. Despite population‐specific proxy events, including end‐of‐life care, the TTrwP and rwOS results may be under‐ or overestimated. Nonetheless, these findings are largely in line with results from a recent registry‐based study. Additionally, the current study was limited by the lack of inclusion of patients with primary mediastinal and other extragonadal primary tumor sites and the probable inclusion of a small number of patients with testicular tumors of non‐GCT histology. Further, the ability to capture late relapse patients was limited due to insufficient long‐term follow‐up. However, the small number of patients affected by these limitations is not expected to have substantially altered the median TTrwP and rwOS observed and would, if anything, likely have led to an overestimation of outcomes.
5. Conclusions
The current study is the first to use claims data to describe treatment journeys and estimate clinical outcomes of patients with R/R testicular GCT receiving palliative chemotherapy in the US. The real‐world data were able to capture heterogeneous treatment patterns and poor survival outcomes in this understudied population. Surprisingly, more than one‐third of patients did not receive a salvage chemotherapy regimen prior to palliative chemotherapy, and of those who did, more than a third did not receive HDCT; rapid progression and renal insufficiency may be major reasons for the lack of salvage chemotherapy use. Overall, the short TTrwP and rwOS of the R/R testicular GCT population highlight the poor prognosis of this patient population and the need for novel therapies to improve clinical outcomes.
Author Contributions
Darren R. Feldman: Conceptualization, validation, writing – reviewing and editing. Patrick Gagnon‐Sanschagrin: Investigation, methodology, project administration, supervision, writing – reviewing and editing. Jessica Maitland: Investigation, methodology, project administration, writing – original draft. Kana Yokoji: Formal analysis, investigation, methodology, writing – original draft. Annie Guérin: Investigation, methodology, project administration, supervision, writing – reviewing and editing. Victoria Guan: Conceptualization, funding acquisition, supervision, writing – reviewing and editing. George Joseph: Conceptualization, funding acquisition, supervision, writing – reviewing and editing.
Funding
This study was funded by BioNTech.
Ethics Statement
The study was considered exempt research under 45 CFR § 46.104(d)(4) as it involved only the secondary use of data that were de‐identified in compliance with the Health Insurance Portability and Accountability Act (HIPAA), specifically 45 CFR § 164.514.
Conflicts of Interest
Darren R. Feldman has received research funding from BioNTech, Telix Pharmaceuticals, Exelixis, and Bristol‐Myers Squibb/Roche; consulting fees from BioNTech, Telix Pharmaceuticals, Debiopharm, Exelixis, Renibus Therapeutics, and Xencor; and royalties from UpToDate. Darren R. Feldman was supported by the National Institutes of Health (NIH) P30 Cancer Center Support Grant No. P30 CA008748. Victoria Guan and George Joseph are employees of BioNTech and own stock/stock options. Patrick Gagnon‐Sanschagrin, Jessica Maitland, Kana Yokoji, and Annie Guérin are employees of Analysis Group Inc., a consulting company that has provided paid consulting services to BioNTech, which funded the development and conduct of this study.
Supporting information
Table S1: List of selected therapy regimens.
Table S2: List of codes for other primary malignancies.
Table S3: List of codes for salvage chemotherapy proxies.
Table S4: List of codes for hospice and radiation.
Figure S1: Study design.
Figure S2: Patient selection.
Acknowledgements
Medical writing assistance was provided by professional medical writer, Flora Chik, PhD, MWC, an employee of Analysis Group Inc., and funded by BioNTech. Part of the material in this manuscript was presented at the American Society of Clinical Oncology (ASCO) Annual Meeting held May 31–June 4, 2024, in Chicago, IL, USA, and at the ASCO Genitourinary Cancers Symposium held February 13–15, 2025, in San Francisco, CA, USA, as poster presentations.
Data Availability Statement
The data that support the findings of this study are available from Komodo Health Solutions. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the authors with the permission of Komodo Health Solutions.
References
- 1. McHugh D. J., Gleeson J. P., and Feldman D. R., “Testicular Cancer in 2023: Current Status and Recent Progress,” CA: A Cancer Journal for Clinicians 74, no. 2 (2024): 167–186. [DOI] [PubMed] [Google Scholar]
- 2. Nigam M., Aschebrook‐Kilfoy B., Shikanov S., and Eggener S., “Increasing Incidence of Testicular Cancer in the United States and Europe Between 1992 and 2009,” World Journal of Urology 33, no. 5 (2015): 623–631. [DOI] [PubMed] [Google Scholar]
- 3. Gillessen S., Sauve N., Collette L., et al., “Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium,” Journal of Clinical Oncology 39, no. 14 (2021): 1563–1574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. The Surveillance, Epidemiology, and End Results (SEER) Program , Cancer Stat Facts: Testicular Cancer National Cancer Institute, 2024 available from, https://seer.cancer.gov/statfacts/html/testis.html.
- 5. Alsdorf W., Seidel C., Bokemeyer C., and Oing C., “Current Pharmacotherapy for Testicular Germ Cell Cancer,” Expert Opinion on Pharmacotherapy 20, no. 7 (2019): 837–850. [DOI] [PubMed] [Google Scholar]
- 6. Bokemeyer C., Beyer J., Metzner B., et al., “Phase II Study of Paclitaxel in Patients With Relapsed or Cisplatin‐Refractory Testicular Cancer,” Annals of Oncology 7, no. 1 (1996): 31–34. [DOI] [PubMed] [Google Scholar]
- 7. Bokemeyer C., Gerl A., Schoffski P., et al., “Gemcitabine in Patients With Relapsed or Cisplatin‐Refractory Testicular Cancer,” Journal of Clinical Oncology 17, no. 2 (1999): 512–516. [DOI] [PubMed] [Google Scholar]
- 8. Einhorn L. H., Brames M. J., Juliar B., and Williams S. D., “Phase II Study of Paclitaxel Plus Gemcitabine Salvage Chemotherapy for Germ Cell Tumors After Progression Following High‐Dose Chemotherapy With Tandem Transplant,” Journal of Clinical Oncology 25, no. 5 (2007): 513–516. [DOI] [PubMed] [Google Scholar]
- 9. Einhorn L. H., Stender M. J., and Williams S. D., “Phase II Trial of Gemcitabine in Refractory Germ Cell Tumors,” Journal of Clinical Oncology 17, no. 2 (1999): 509–511. [DOI] [PubMed] [Google Scholar]
- 10. Kollmannsberger C., Beyer J., Liersch R., et al., “Combination Chemotherapy With Gemcitabine Plus Oxaliplatin in Patients With Intensively Pretreated or Refractory Germ Cell Cancer: A Study of the German Testicular Cancer Study Group,” Journal of Clinical Oncology 22, no. 1 (2004): 108–114. [DOI] [PubMed] [Google Scholar]
- 11. Kollmannsberger C., Rick O., Klaproth H., et al., “Irinotecan in Patients With Relapsed or Cisplatin‐Refractory Germ Cell Cancer: A Phase II Study of the German Testicular Cancer Study Group,” British Journal of Cancer 87, no. 7 (2002): 729–732. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Miller J. C. and Einhorn L. H., “Phase II Study of Daily Oral Etoposide in Refractory Germ Cell Tumors,” Seminars in Oncology 17, no. 1 Suppl 2 (1990): 36–39. [PubMed] [Google Scholar]
- 13. Bokemeyer C., Oechsle K., Honecker F., et al., “Combination Chemotherapy With Gemcitabine, Oxaliplatin, and Paclitaxel in Patients With Cisplatin‐Refractory or Multiply Relapsed Germ‐Cell Tumors: A Study of the German Testicular Cancer Study Group,” Annals of Oncology 19, no. 3 (2008): 448–453. [DOI] [PubMed] [Google Scholar]
- 14. Feldman D. R., Patil S., Trinos M. J., et al., “Progression‐Free and Overall Survival in Patients With Relapsed/Refractory Germ Cell Tumors Treated With Single‐Agent Chemotherapy: Endpoints for Clinical Trial Design,” Cancer 118, no. 4 (2012): 981–986. [DOI] [PubMed] [Google Scholar]
- 15. Horwich A., Shipley J., and Huddart R., “Testicular Germ‐cell Cancer,” Lancet 367, no. 9512 (2006): 754–765. [DOI] [PubMed] [Google Scholar]
- 16. Kozakova K., Mego M., Cheng L., and Chovanec M., “Promising Novel Therapies for Relapsed and Refractory Testicular Germ Cell Tumors,” Expert Review of Anticancer Therapy 21, no. 1 (2021): 53–69. [DOI] [PubMed] [Google Scholar]
- 17. Kollmannsberger C. and Bokemeyer C., “Salvage Chemotherapy After Failure of First‐Line Chemotherapy in Patients With Metastatic Testicular Cancer,” Current Opinion in Supportive and Palliative Care 2, no. 3 (2008): 167–172. [DOI] [PubMed] [Google Scholar]
- 18. Flannelly C., Tan B. E., Tan J. L., et al., “Barriers to Hematopoietic Cell Transplantation for Adults in the United States: A Systematic Review With a Focus on Age,” Biology of Blood and Marrow Transplantation 26, no. 12 (2020): 2335–2345. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Majhail N. S., Omondi N. A., Denzen E., Murphy E. A., and Rizzo J. D., “Access to Hematopoietic Cell Transplantation in the United States,” Biology of Blood and Marrow Transplantation 16, no. 8 (2010): 1070–1075. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Pico J. L., Rosti G., Kramar A., et al., “A Randomised Trial of High‐Dose Chemotherapy in the Salvage Treatment of Patients Failing First‐Line Platinum Chemotherapy for Advanced Germ Cell Tumours,” Annals of Oncology 16, no. 7 (2005): 1152–1159. [DOI] [PubMed] [Google Scholar]
- 21. ClinicalTrials.gov , NCT02375204. Standard‐Dose Combination Chemotherapy or High‐Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors, 2025 available from, https://clinicaltrials.gov/study/NCT02375204.
- 22. National Comprehensive Cancer Network, Inc. 2025. All Rights Reserved ., Referenced With Permission From the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Testicular Cancer V.1, 2025. accessed February 14, 2025, https://www.nccn.org/.
- 23. Oing C., Seidel C., Giannatempo P., et al., “704P Characteristics and Palliative Management of Patients With Cisplatin‐Refractory Germ Cell Tumours: A Global Germ Cell Cancer Collaborative Group (G3) Retrospective Registry Study,” Annals of Oncology 35 (2024): S541–S542. [Google Scholar]
- 24. McDermott C. L., Fedorenko C., Kreizenbeck K., et al., “End‐Of‐Life Services Among Patients With Cancer: Evidence From Cancer Registry Records Linked With Commercial Health Insurance Claims,” Journal of Oncology Practice 13, no. 11 (2017): e889–e899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Oldenburg J., Berney D. M., Bokemeyer C., et al., “Testicular Seminoma and Non‐Seminoma: ESMO‐EURACAN Clinical Practice Guideline for Diagnosis, Treatment and Follow‐Up,” Annals of Oncology 33, no. 4 (2022): 362–375. [DOI] [PubMed] [Google Scholar]
- 26. Lauritsen J., Mortensen M. S., Kier M. G. G., et al., “Renal Impairment and Late Toxicity in Germ‐Cell Cancer Survivors,” Annals of Oncology 26, no. 1 (2015): 173–178. [DOI] [PubMed] [Google Scholar]
- 27. Griffith S. D., Miksad R. A., Calkins G., et al., “Characterizing the Feasibility and Performance of Real‐World Tumor Progression End Points and Their Association With Overall Survival in a Large Advanced Non‐Small‐Cell Lung Cancer Data Set,” JCO Clinical Cancer Informatics 3 (2019): 1–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Carrigan G., Whipple S., Capra W. B., et al., “Using Electronic Health Records to Derive Control Arms for Early Phase Single‐Arm Lung Cancer Trials: Proof‐Of‐Concept in Randomized Controlled Trials,” Clinical Pharmacology and Therapeutics 107, no. 2 (2020): 369–377. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: List of selected therapy regimens.
Table S2: List of codes for other primary malignancies.
Table S3: List of codes for salvage chemotherapy proxies.
Table S4: List of codes for hospice and radiation.
Figure S1: Study design.
Figure S2: Patient selection.
Data Availability Statement
The data that support the findings of this study are available from Komodo Health Solutions. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the authors with the permission of Komodo Health Solutions.