Abstract
Background
Over the past two decades, our group has conducted five multicenter trials focusing on first-line systemic therapy for patients with advanced pancreatic cancer. The current pooled analysis was designed to evaluate prognosis over time and the impact of clinical characteristics on survival.
Patients and methods
Individual patient data were derived from five prospective, controlled, multicenter trials conducted by the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO): ‘Gem/Cis’, ‘Ro96’, ‘RC57’, ‘ACCEPT’ and ‘RASH’, which recruited patients between December 1997 and January 2017.
Results
Overall, 912 patients were included. The median overall survival (OS) for all assessable patients was 7.1 months. OS significantly improved over time, with a median OS of 8.6 months for patients treated from 2012 to 2017 compared with 7.0 months from 1997 to 2006 [hazard ratio (HR) 1.06; P < 0.004]. Eastern Cooperative Oncology Group performance status (HR 1.48; P < 0.001), use of second-line treatment (HR 1.51; P < 0.001), and Union for International Cancer Control (UICC) stage (III versus IV) (HR 1.34, P = 0.002) had a significant impact on OS. By contrast, no influence of age and gender on OS was detectable. Comparing combination therapy with single-agent chemotherapy did not demonstrate a survival benefit, nor did regimens containing epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as afatinib or erlotinib, compared with chemotherapy-only arms. Patients with early-onset pancreatic cancer (age at study entry of ≤50 years, n = 102) had a similar OS compared with those >50 years (7.1 versus 7.0 months; HR 1.13; P = 0.273). The use of a platinum-containing regimen was not associated with better outcomes in patients with early-onset pancreatic cancer.
Conclusions
Within this selected group of patients treated within prospective clinical trials, survival has shown improvement over two decades. This effect is likely attributable to the availability of more effective combination therapies and treatment lines, rather than to any specific regimen, such as those containing EGFR-TKIs. In addition, concerning age and sex subgroups, the dataset did not provide evidence for distinct clinical behavior.
Key words: pancreatic cancer, clinical trial, metastatic cancer
Highlights
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Survival improved for patients treated within clinical trials for advanced pancreatic cancer in the course of two decades.
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The survival advantage is mainly attributable to more effective treatments and salvage treatment options.
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Performance status prevailed as a strong prognostic factor.
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Age and gender did not influence overall survival.
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A more individualized use of a special chemotherapy regimen for younger patients remains elusive.
Introduction
The incidence of pancreatic cancer is increasing, and pancreatic ductal adenocarcinoma (PDAC) is currently the fourth most common cause of cancer death in Europe.1 The highest incidence of pancreatic cancer is among patients in their 60s to 80s and rather low for patients aged <50 years.2,3 An analysis of the data from the National Program of Cancer Registries database, covering 65% of the United States population, suggested that the incidence of pancreatic cancer among individuals younger than 55 years is increasing more rapidly than in those aged ≥55 years, and also more quickly in women than in men.4 Pancreatic cancer is more common in men (5.5 per 100 000) than in women (4.0 per 100 000).2 However, the incidence increases with age for both sexes.5 The available data on treatment outcomes for pancreatic cancer, dependent on sex, are scarce. However, sex and gender disparities are noted in epidemiology, pathophysiology, clinical manifestation, disease progression, and response treatment.6
Despite relevant advances in the therapeutic management of certain, very small subgroups of PDAC through molecularly stratified treatments, for example, for tumors with germline BRCA1/2 mutations, NTRK and NRG1 gene fusions, or with mismatch repair deficiency, chemotherapy remains the mainstay of treatment.7 Combination regimens of chemotherapy agents such as FOLFIRINOX or gemcitabine + nab-paclitaxel offered more effective treatment options during the past decade.8,9 Nevertheless, for most patients with PDAC, there seems to be no clear survival benefit during the past 30 years, although multiple new agents and combinations have been evaluated in numerous clinical trials. An analysis conducted by Golan et al.,10 which involved 57 263 patients with metastatic pancreatic cancer receiving standard treatment outside of clinical trials, extracted from the Surveillance, Epidemiology, and End Results (SEER) database, revealed no significant extension in the median overall survival (OS) between 1993 and 2013. Personalized medicine in combination with individualized therapy regimens that take into account clinical characteristics such as gender and age is considered a new approach in modern medicine to improve the outcome of difficult-to-treat diseases. However, the question of whether, for example, older patients with PDAC should be treated differently from younger patients remains unclear.11 In addition, very little is known about whether the disease of younger patients with PDAC differs pathophysiologically from that of older patients.12 Two recent publications have delved deeper into the hypothesis suggesting that younger patients with pancreatic and gastrointestinal cancers may exhibit distinct pathogenetic patterns in their tumors. Consequently, they might require more personalized treatment options.13,14
During the past two decades, the Munich group has conducted [within the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO) study group for pancreatic cancer; NCT00440167] five clinical trials investigating systemic therapy for advanced pancreatic cancer, overall including >900 patients. In particular, we sought to assess changes in prognosis over time and the impact of intensified therapy on survival in patient cohorts that differed by age (particularly in patients who were aged <50 years at baseline) and sex. In addition, the impact of other clinical characteristics such as tumor stage, performance status (PS), and use of follow-up treatments and treatment patterns [e.g. combination treatment versus monotherapy, use of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs)] was planned to be evaluated.
Patients and methods
For the current exploratory analysis, data from five randomized clinical phase II and phase III trials [‘Gem/Cis’, ‘Ro96’, ‘RC57’, ‘ACCEPT’ (NCT01728818), and ‘RASH’ (NCT01729481)], evaluating efficacy and safety of different first-line treatment regimens in pancreatic cancer, were pooled. Details on trial designs, patient characteristics, study treatments, statistical assumptions, and outcome parameters can be found in Table 1 and Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.102944, and the published original reports.12,15, 16, 17, 18, 19 The overall recruiting period for these five studies was from December 1997 to January 2017. All analyses were carried out based on the respective intention-to-treat population. A clinical database was established including baseline patient characteristics such as age, Eastern Cooperative Oncology Group (ECOG) PS, sex, primary tumor location, and survival data. Detailed survival analyses were carried out using subgroups defined by treatment regimens, age, sex, Union for International Cancer Control (UICC) stage, ECOG, and the use of second-line therapy. Of note, the ‘Gem/Cis’, ‘Ro96’, and ‘RC57’ trials included both patients with locally advanced pancreatic cancer and patients with metastatic pancreatic cancer, whereas the two latest trials ‘RASH’ and ‘ACCEPT’ only recruited patients with metastatic disease. Three trials had a phase II design, whereas two studies were phase III protocols.
Table 1.
Demographic and baseline characteristics
| Characteristics | All patients (n = 912) | Gem/Cis (n = 190) | Ro96 (n = 188) | RC57 (n = 274) | ACCEPT (n = 115) | RASH (n = 145) |
|---|---|---|---|---|---|---|
| Age (years) | ||||||
| Median | 63.0 | 59.0 | 63.0 | 64.0 | 73.0 | 63.0 |
| Range | 24.0-89.0 | 32.0-82.0 | 40.0-75.0 | 32.0-78.0 | 37.0-89.0 | 24.0-75.0 |
| Sex, n (%) | ||||||
| Male | 556 (61.0) | 119 (62.6) | 120 (63.8) | 165 (60.2) | 65 (56.5) | 87 (60.0) |
| Female | 356 (39.0) | 71 (37.4) | 68 (36.2) | 109 (39.8) | 50 (43.5) | 58 (40.0) |
| ECOG performance status, n (%) | ||||||
| 0 | 291 (31.9) | 36 (18.9) | 21 (11.2) | 79 (28.8) | 67 (58.3) 48 (41.7) |
88 (60.7) 57 (39.3) |
| 1 | 493 (54.1) | 108 (56.8) | 141 (75.0) | 139 (50.7) | ||
| 2 | 87 (9.5) | 20 (10.5) | 23 (12.2) | 44 (16.1) | ||
| Unknown | 41 (4.5) | 26 (13.7) | 3 (1.6) | 12 (4.4) | ||
| Site of primary tumor, n (%) | ||||||
| Cauda | 104 (11.4) | 38 (20.0) | 26 (22.6) | 40 (45.5) | ||
| Caput | 214 (23.5) | 96 (50.5) | 52 (45.2) | 66 (45.5) | ||
| Corpus | 86 (9.4) | 38 (20.0) | 23 (20.0) | 25 (17.2) | ||
| Unknown/Others | 508 (55.7) | 18 (9.5) | 188 (100.0) | 274 (100.0) | 14 (12.2) | 14 (9.7) |
| Tumor stage, n (%) | ||||||
| Locally advanced | 154 (16.9) | 38 (20.0) | 73 (38.8) | 43 (15.7) | ||
| Metastatic | 758 (83.1) | 152 (80.0) | 115 (61.2) | 231 (84.3) | 115 (100.0) | 145 (100.0) |
| Further line therapy, n (%) | ||||||
| Yes | 442 (48.5) | 31 (16.3) 159 (83.7) |
106 (56.4) | 154 (56.2) | 65 (55.7) 51 (44.3) |
87 (60.0) 58 (40.0) |
| No | 459 (50.3) | 79 (42.0) | 112 (40.9) | |||
| Unknown | 11 (1.2) | 3 (1.6) | 8 (2.9) | |||
| Recruiting period | December 1997 to January 2002 | July 2002 to June 2004 | May 2006 to December 2008 | April 2013 to January 2017 | July 2012 to July 2015 | |
| Phase of trial | III | II | III | II | II | |
| Primary Endpoint | OS | PFS after 3 months | TTF after first- and second-line therapy (TTF2; noninferiority design) | OS | 1-year survival rate in patients with rash positivity ≥40% | |
| Eligibility criteria | ||||||
| Age (years) | ≥18 | 18-75 | 18-75 | ≥18 | 18-75 | |
| ECOG | — | — | — | 0-1 | 0-1 | |
| Karnofsky score | ≥70% | ≥60% | ≥60% | — | — |
ECOG, Eastern Cooperative Oncology Group; OS, overall survival; PF, progression-free survival; TTF, time to failure of treatment strategy.
All statistical analyses were carried out using SPSS version 29 for Windows (IBM, New York, NY, USA). In the univariable analysis, categorical variables were compared using the chi-square test, and continuous variables were compared by nonparametric Mann–Whitney U test to evaluate patient-, tumor-, and treatment-related characteristics associated with prolonged survival in advanced and metastatic pancreatic cancer. Significant factors underwent further multivariable analysis using linear and binary logistic regression models. The survival estimates were analyzed using the Kaplan–Meier method and described by median values. Comparisons of survival-based outcomes were conducted using log-rank tests and Cox regression analyses that were described as hazard ratios (HRs) with 95% confidence intervals (95% CIs). The chi-square statistic was used to analyze the data and determine whether any significant associations or differences existed among the variables. P-values <0.05 were considered statistically significant.
Results
Patient cohort
Overall, data from 912 patients were included in the pooled analysis; of these, 888 patients had available data regarding follow-up and survival. At the time of the final analysis, 804 had died (death from any cause). Detailed baseline characteristics of patients are summarized in Table 1: 556 patients were male (61.0%) and 356 patients were female (39.0%). Their median age was 63 years (range 24-89 years). A total of 442 patients (48.5%) received second-line therapy (defined as at least one additional treatment after progression during first-line treatment within the trial) and 459 patients did not receive any follow-up therapy (50.3%); 154 patients were classified as UICC stage III (locally advanced pancreatic cancer) and 758 patients as UICC stage IV (metastatic disease). The ‘RASH’ and ‘ACCEPT’ trials only included UICC stage IV patients.
Survival analyses
The median OS of the overall cohort was 7.1 months (95% CI 6.5-7.6 months). The survival outcome for the respective trial and treatment arm is summarized in Table 2. Patients who remained negative for skin rash following a 4-week lead-in treatment with gemcitabine/erlotinib and subsequently transitioned to FOLFIRINOX within the ‘RASH trial’ exhibited the numerically highest median OS (10.9 months). The lowest median OS was found in the ‘Gem/Cis’ trial (6.0 months for gemcitabine as a single-agent treatment).
Table 2.
Survival by treatment arms
| Trial | n | Overall survival (months) |
|---|---|---|
| Gem/Cis | 190 | |
| A: Gem/Cis | 95 | 7.5 |
| B: Gem | 95 | 6.0 |
| Ro96—treatment arm | 188 | |
| A: Cap/Gem | 64 | 9.0 |
| B: Cap/Ox | 61 | 8.1 |
| C: Gem/Ox | 63 | 6.9 |
| RC57 | 274 | |
| A: Cap/Erlo | 131 | 6.9 |
| B: Gem/Erlo | 143 | 6.2 |
| ACCEPT | 115 | |
| A: Gem/Afa | 77 | 7.3 |
| B: Gem | 38 | 7.4 |
| RASH (after run-in phase) | 117 | |
| A: Gem/Erlo | 90 | 10.1 |
| B: Gem/Erlo–FOLFIRINOX | 27 | 10.9 |
Afa, afatinib; Cap, capecitabine; Cis, cisplatin; Erlo, erlotinib; Gem, gemcitabine; Ox, oxaliplatin.
The recruitment period for all five trials spanned almost two decades, commencing with the ‘oldest’ trial, ‘Gem/Cis’, in December 1997 (until January 2002), followed by the ‘Ro96 trial’ (July 2002 until May 2004), ‘RC57 trial’ (May 2006 until December 2008), ‘RASH trial’ (July 2012 until July 2015), and the most recent ‘ACCEPT trial’, which began recruitment in April 2013 and concluded with the last patient in January 2017. We thus defined four patient groups based on the date of randomization, with each group covering 5 years of recruitment (1997-2001, n = 189; 2002-2006, n = 216; 2007-2011, n = 223; 2012-2017, n = 260). Survival analysis showed a significant OS difference within the four groups (HR 1.06, P < 0.004), with the longest median OS in the recruitment group of 2012 until 2017 of 8.6 months (Table 3 and Figure 1A).
Table 3.
Subgroup analyses
| Subgroup | n | Overall survival (months) | P value | HR (95% CI) |
|---|---|---|---|---|
| Year of randomization | ||||
| 1997-2001 | 189 | 7.0 | ||
| 2002-2006 | 216 | 7.0 | ||
| 2007-2011 | 223 | 6.2 | ||
| 2012-2017 | 260 | 8.6 | <0.004 | 1.06 (0.99-1.12) |
| Use of second-line chemotherapy | ||||
| Yes | 427 | 9.6 | ||
| No | 450 | 4.7 | <0.001 | 1.51 (1.50-1.99) |
| Gender | ||||
| Female | 349 | 7.8 | ||
| Male | 539 | 6.9 | 0.178 | 0.91 (0.78-1.04) |
| Age groups (years) | ||||
| 21-30 | 1 | 16.8 | ||
| 31-40 | 13 | 5.3 | ||
| 41-50 | 88 | 7.1 | ||
| 51-60 | 239 | 8.0 | ||
| 61-70 | 362 | 7.0 | ||
| 71-80 | 170 | 6.4 | ||
| 81-89 | 15 | 6.0 | 0.266 | 1.09 (1.02-1.18) |
| ECOG performance status | ||||
| 0 | 285 | 8.9 | ||
| 1 | 479 | 7.0 | ||
| 2 | 84 | 3.7 | <0.001 | 1.48 (1.31-1.67) |
| Tumor stage | ||||
| Locally advanced | 142 | 9.6 | ||
| Metastatic | 744 | 6.8 | 0.002 | 1.34 (1.11-1.62) |
| Combination therapy versus single-agent gemcitabine | ||||
| Combination therapy | 727 | 7.4 | ||
| Single-agent gemcitabine | 133 | 6.7 | 0.328 | 1.10 (0.91-1.34) |
| EGFR-TKI based versus non-TKI based | ||||
| EGFR-TKI based | 440 | 7.5 | ||
| Non-EGFR-TKI based | 420 | 7.0 | 0.645 | 1.03 (0.90-1.19) |
| Patients with EO pancreatic cancer versus patients with non-EO pancreatic cancer | ||||
| Patients with EO pancreatic cancer | 102 | 7.1 | ||
| Patients with non-EO pancreatic cancer | 786 | 7.0 | 0.273 | 1.13 (0.91-1.40) |
| Platinum-containing regimen in patients with EO pancreatic cancer versus patients with non-EO pancreatic cancer | ||||
| Patients with EO pancreatic cancer | 37 | 7.2 | ||
| Patients with non-EO pancreatic cancer | 191 | 7.1 | 0.560 | 1.11 (0.78-1.59) |
CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; EO, early-onset pancreatic cancer patient; HR, hazard ratio; TKI, tyrosine kinase inhibitor (i.e. age at study entry <50 years).
Figure 1.
Kaplan–Mayer survival analysis in relevant subgroups. (A) Analysis regarding randomization group over two decades. (B) Analysis regarding the use of second-line therapy. (C) Analysis regarding Eastern Cooperative Oncology Group (ECOG) status at randomization.
In 877/912 (96.2%) patients, data regarding second-line therapy were available: 427 (48.7%) patients received at least one sequential therapy line after progression on the first-line study regimens. The highest rate of any second-line therapy was found within the ‘RASH trial’, with 87/145 patients (60.0%), followed by the ‘Ro96 trial’ (106/185 patients, 57.3%), the ‘RC57 trial’ (154/274, 56.2%), and the ‘ACCEPT trial’ (64/115 patients, 55.7%). The lowest rate of second-line therapy was found within the ‘Gem/Cis trial’ (31/190 patients, 16.3%). The chi-square test/Pearson chi-square was significant at P < 0.001.
Furthermore, there was a significant correlation between the use of second-line therapy and the date of randomization (5-year recruitment groups), with the highest rate of second-line therapy in the recruitment period of 2012 until 2017 (151/260 patients, 58.1%) and the lowest rate in the 1997-2001 recruitment group (30/189 patients, 15.9%; P < 0.001). The median OS of patients with second-line therapy was 9.6 months in comparison to patients without second-line therapy, whose median OS was 4.7 months (P < 0.001; Table 3 and Figure 1B).
There was no significant difference in survival in terms of gender, with a median OS of 7.8 months for female patients and 6.9 months for male patients (P = 0.178; Table 3). The survival analysis based on age demonstrated consistent outcome results, with similar findings observed when age groups were categorized for each decade (P = 0.266; Table 3).
Patients with an ECOG PS of 0 (n = 285) at randomization had a median OS of 8.9 months, those with an ECOG PS of 1 (n = 479) had 7.0 months, and those with an ECOG PS of 2 (n = 84) had 3.7 months (HR 1.48, P < 0.001; Table 3 and Figure 1C).
The tumor stage also had a statistically significant impact on survival. The median OS for UICC stage III patients was 9.6 months versus 6.8 months for UICC stage IV patients (HR 1.34, P = 0.002; Table 3).
Our pooled dataset had a relevant share of younger patients (age at study entry <50 years; n = 102). These patients with ‘early-onset’ (EO) pancreatic cancer had a similar OS compared with those aged >50 years (7.1 versus 7.0 months; HR 1.13, 95% CI 0.91-1.40; P = 0.273; Table 3).
Treatment arms
An overview of different treatment arms and the corresponding survival outcomes is summarized in Table 2.
Analyses over different treatment arms were carried out to elaborate cross-trial outcome data regarding combination- versus single-agent therapy and EGFR-TKI-based regimens. For the respective allocation of treatment subgroups for the analyses, see Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.102944. In a further step, we evaluated whether gender or age (in predefined groups of 24-59, 60-69, and 70-89 years) could impact the outcome in the respective subgroups (see Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.102944).
Combination therapy versus single-agent gemcitabine
A total of 727 patients (84.5%) received a treatment combination, whereas 133 (15.5%) received single-agent chemotherapy with gemcitabine (arm B ‘Gem/Cis trial’ and arm B ‘ACCEPT trial’). The median OS for the combination regimens was 7.4 months, whereas that for gemcitabine monotherapy was 6.7 months (HR 1.10, 95% CI 0.91-1.34; P = 0.328; Table 3). A comparison of combination therapy versus single-agent therapy indicated no survival benefit in the subgroup of male and female patients (male P = 0.374, female P=0.572; Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.102944). In addition, neither younger patients nor older patients benefited from combination therapy. The subgroup analysis regarding age and sex showed no survival advantages for the respective subgroups if combination therapy was used.
The use of first-line platinum-based chemotherapy did not reveal a benefit toward OS for patients with EO pancreatic cancer (n = 37, OS 7.2 months) compared with patients aged >50 years (n = 191; OS 7.1 months; HR 1.11, P = 0.560; Table 3).
EGFR-TKI versus other treatment arms
A total of 440 patients received EGFR-TKI-based treatment regimens (erlotinib: arms A and B in the ‘RC57 trial’ and arm A in the ‘RASH trial’; afatinib: arm A in the ‘ACCEPT trial’). The median OS in patients receiving EGFR-TKI-based treatment regimens was 7.5 months, compared with 7.0 months for all other treatments free of a first-line EGFR-TKI (Table 3).
Neither female (P = 0.645) nor male (P = 0.274) nor different age groups showed a statistical difference in the OS (see Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.102944).
Discussion
Within the current pooled analysis of >900 patients with advanced pancreatic cancer from multicenter AIO studies (conducted in Germany over two decades of clinical research), the authors did observe—in contrast to the population-based analysis using SEER data by Golan et al.10—a statistically significant increase in survival during the past 20 years. This advantage is most likely attributed to the emergence of more effective treatment regimens established since 2010, for example, FOLFIRINOX and gemcitabine + nab-paclitaxel in the first-line and nanoliposomal irinotecan + 5-fluorouracil and folinic acid in the second-line setting.8,9 The availability of more treatment options has led to a broader use of these protocols in first- and second-line settings.20,21 In this analysis, we also observed an increasing use of further-line treatments over time: from 15.9% between 1997 and 2001 to 58.1% between 2012 and 2017. The use of second-line therapy was also associated with increased survival in our analysis. Because of the retrospective and explorative nature of this analysis, where patients were not randomized to receive second-line treatment or not, but rather the decision was based on the patient’s wish or physician’s judgment, it cannot be straightforwardly concluded that the use of second-line therapy was beneficial for all patients. The favorable prognostic impact of a patient ‘being fit for second-line treatment’ likely contributed significantly to the improved outcome compared with second-line treatment alone. Nonetheless, it is reasonable to assume that for the comprehensive care of patients with pancreatic cancer, it is essential to provide side-effect-oriented further-line therapies to enhance quality of life and extend survival.
In the past years, supportive therapy has played a significant role in the effective treatment of patients with cancer. Unfortunately, within the scope of the present studies, nutritional therapy or other supportive therapies were not recorded.
As expected, the strong prognostic impact of baseline PS, as repeatedly shown in previous reports,22 was also confirmed in our pooled analysis. These data suggest that PS is one of the major prognostic factors over all stages of pancreatic cancer. Being aware of this knowledge, one must consider the limitations of a retrospective cross-trial analysis: due to inclusion criteria, there was an overrepresentation of patients with ECOG PS 0-1 in the ‘RASH’ (60%) and ‘ACCEPT’ (55.7%) trials, certainly partly also explaining the improved outcomes seen in patients treated between 2012 and 2017. However, in contrast to the older trials, these two trials only included patients with metastatic pancreatic cancer (UICC stage IV), whereas the other trials had a share of patients with locally advanced tumors (UICC stage III), with the latter carrying a better prognosis. One could say that this ‘disadvantage’ towards OS in the 2012-2017 cohort with a higher share of metastatic patients was balanced by better ECOG PS compared to the other cohorts in our analysis. This assumption supports the above-claimed hypothesis that the availability of more effective treatments and more intensive use of further-line therapies may explain a longer survival during recent years.
The relationship between ECOG and the survival of a cancer condition has been well studied. However, specific details as to what exactly influences ECOG scores are not well-known. Whether a poorer ECOG is due to comorbidities, a more pronounced wasting syndrome, or a more aggressive cancer remains unclear by mere collection of the score. Hence, it is also challenging to determine whether better treatment of comorbidities has an impact on the survival of the cancer condition. Future clinical studies would benefit from longitudinal assessments of ECOG and an expansion of the supportive therapy concept by addressing comorbidities.
In the analysis using data from the SEER database, improvement of prognosis correlated with younger age, namely aged <50 years at first diagnosis.10 During direct comparisons with the SEER database, it is important to remember that the database has evaluated standard treatment outside of clinical trials. To elucidate the impact of age on the outcome of patients with PDAC, we evaluated treatment efficacy in different age groups (24-59, 60-69, and 70-89 years) and found no differences in survival outcomes depending on different age cohorts. With the average age of 63 years, our cohort of patients is younger compared with an average age at first diagnosis of pancreatic cancer, which is between 70 and 75 years.23,24 This was, however, not true for the ‘ACCEPT trial’ where patients had a median age of 73 years. When assessing the impact of age on cancer outcomes, it is important to consider confounders such as PS and treatment density.25 Thus one has to consider that patients in the ACCEPT trial had better ECOG and more second-line treatment than in other trials. Nevertheless, we could conclude that numerical age alone does not seem to be a strong prognostic factor for survival in pancreatic cancer. This was also true for the patients with EO pancreatic cancer.
A potential advantage for the use of platinum compounds is repeatedly discussed, especially in these younger patients with EO PDAC, mainly because of their improved efficacy in tumors with impaired DNA-repair mechanisms.26 In a recent, large retrospective analysis including genomic data from patients with EO PDAC, a higher rate of KRASwt tumors was found, carrying a higher proportion of targetable alterations such as DNA damage repair deficiency. These patients also seemed to profit from targeted therapies.13 The analysis found a higher PFS and OS for patients with EO pancreatic cancer versus older patients (≥70 years of age) in the metastatic setting. Patients with EO pancreatic cancer were more frequently treated with 5-FU (and oxaliplatin-containing) treatments. However, in a subgroup analysis on the first-line use of gemcitabine + nab-paclitaxel, a longer OS for patients with EO pancreatic cancer versus older patients was observed as well (outcome data for the use of platinum agents were not shown).13
In our analysis, we did not observe any advantage for the use of platinum agents in patients with EO pancreatic cancer. However, given the retrospective nature of the study and the absence of molecular profiling, it would be premature to draw conclusions regarding the use of platinum compounds in this patient population. Instead, the data underscore the unmet need for more personalized treatment approaches in younger patients with pancreatic cancer, highlighting the necessity for further investigation.
In recent years, there has been increasing awareness that gender could have an impact on the efficacy and the clinical course of cancer.26 Nipp et al.24 showed that, especially among those with late-stage cancer, male patients had a worse median OS than females. In our cohort, gender did not influence the median OS or the long-term survival. Numerically, women had a slightly better median OS (8 months) compared with men (OS 7 months), which is similar to an analysis of 7470 patients from the Netherlands.27 There were also no differences in survival regarding different treatment regimens in women or men.
Furthermore, we tried to explore whether there was any advantage in using a combination of treatments within our cohort. However, we did not find any statistical differences for the gemcitabine monotherapy (n = 133) versus any combination therapy (n = 727). This is likely because many of the therapy combinations used in experimental arms failed to demonstrate clinically meaningful advantages in our study and other clinical trials, leading to their lack of adoption in clinical practice. A weakness of our study is the relatively small number of patients who received the currently recommended combination therapy of FOLFIRINOX or gemcitabine + nab-paclitaxel. Only 28 patients within the ‘RASH trial’ received FOLFIRINOX as a study-defined treatment and presented a median OS of 10.9 months. The median OS of 6.7 months for patients who received the gemcitabine-only treatment matches the results of more recent clinical trials for metastatic pancreatic cancer.8,9,28 As expected, a pooled analysis of EGFR-TKI-based treatments (erlotinib and afatinib) did not show a survival benefit versus other treatments. Due to its limited clinical benefit, erlotinib is rarely utilized in current clinical practice.
Conclusions
Over two decades, we observed an improvement in survival for patients with advanced pancreatic cancer treated within five prospective AIO trials in Germany. This effect is presumably mainly a result of more effective regimens and more intensive use of salvage treatments. PS is one of the most important prognostic factors. Recommendations toward a more individualized treatment of subgroups (e.g. according to age or gender) remain elusive and should be addressed in specific sex- and age-sensitive clinical trials.
Acknowledgments
Funding
None declared.
Disclosure
LW has received honoraria for scientific presentations and reports an advisory board role in Roche and Servier; and travel accommodation expenses from Amgen. VH has received honoraria for talks and advisory board role from Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS, MSD, Novartis, Terumo, OncoSil, NORDIC, Seagen, and GSK; and research funding from Merck, Amgen, Roche, Sanofi, Boehringer-Ingelheim, SIRTEX, and Servier. ARS has received honoraria from Amgen, Roche, Merck Serono, BMS, MSD, MCI Group, and AstraZeneca; for advisory and consultancy from Amgen, Roche, Merck Serono, BMS, MSD, AstraZeneca, and Pierre Fabre; research grant/funding from Roche, Celgene, Ipsen, Amgen, Alexion Pharmaceuticals, AstraZeneca, Lilly, Servier, AIO-Studien-gGmbH, Rafael Pharmaceutics, Erytech Pharma, and BioNTech; and travel expenses Roche, Amgen, and Pierre Fabre. JTS receives honoraria as a consultant or for continuing medical education presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Immunocore, MSD Sharp Dohme, Novartis, Roche/Genentech, and Servier; his institution receives research funding from Abalos Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eisbach Bio, and Roche/Genentech; and he holds ownership and serves on the board of directors of Pharma15, all outside the submitted work. MS has received honoraria from Lilly, Roche, and Servier. KD has received travel support from Servier, GSK, and BMS; as well as honoraria from AstraZeneca. DZ has received honoraria and travel support from AstraZeneca. CBW has received honoraria from Amgen, Bayer, BMS, Chugai, Celgene, Falk, GSK, MSD, Merck, Janssen, Ipsen, Roche, Servier, Sirtex, and Taiho; has served on advisory boards for Bayer, BMS, Celgene, Janssen, MSD, Servier, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, and Roche; has received travel support from Bayer, Celgene, Janssen, RedHill, Roche, Servier, and Taiho; research grants (institutional) from Roche; serves as an officer for European Society of Medical Oncology (ESMO), Deutsche Krebshilfe (DKH), and Arbeitsgemeinschaft Internistische Onkologie (AIO); and is a member of the EU Commission expert group: Mission Board for cancer. SB had a consulting and advisory role for Celgene, Servier, Incyte, Fresenius, Janssen-Cilag, AstraZeneca, MSD, and BMS; and has received honoraria for scientific presentations from Roche, Celgene, Servier, and MSD. MH has received travel support from Servier and honoraria for scientific presentations from the Falk Foundation. All other authors have declared no conflicts of interest.
Data sharing
Available from the corresponding author upon reasonable request.
Ethical approval, informed consent, and consent to participate/to publish
All five clinical trials reported here were conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guidelines, and local regulatory requirements.
All study protocols were reviewed and approved by the lead Ethics Committee of Ludwig-Maximilians-University, Munich, Germany, and additionally by the Ethics Committees of the participating centers.
Written informed consent for trial participation and for publication of trial results was obtained from each patient before any study-specific procedure.
Supplementary data
References
- 1.Ferlay J., Colombet M., Soerjomataram I., et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer. 2018;103:356–387. doi: 10.1016/j.ejca.2018.07.005. [DOI] [PubMed] [Google Scholar]
- 2.Rawla P., Sunkara T., Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J Oncol. 2019;10(1):10–27. doi: 10.14740/wjon1166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Bosetti C., Bertuccio P., Negri E., La Vecchia C., Zeegers M.P., Boffetta P. Pancreatic cancer: overview of descriptive epidemiology. Mol Carcinog. 2012;51(1):3–13. doi: 10.1002/mc.20785. [DOI] [PubMed] [Google Scholar]
- 4.The Lancet Gastroenterology Hepatology Cause for concern: the rising incidence of early-onset pancreatic cancer. Lancet Gastroenterol Hepatol. 2023;8(4):287. doi: 10.1016/S2468-1253(23)00039-0. [DOI] [PubMed] [Google Scholar]
- 5.Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492. [DOI] [PubMed] [Google Scholar]
- 6.Mauvais-Jarvis F., Bairey Merz N., Barnes P.J., et al. Sex and gender: modifiers of health, disease, and medicine. Lancet. 2020;396(10250):565–582. doi: 10.1016/S0140-6736(20)31561-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Taieb J., Abdallah R. How I treat pancreatic cancer. ESMO Open. 2020;4(suppl 2) doi: 10.1136/esmoopen-2020-000818. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Von Hoff D.D., Ervin T., Arena F.P., et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–1703. doi: 10.1056/NEJMoa1304369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Conroy T., Desseigne F., Ychou M., et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825. doi: 10.1056/NEJMoa1011923. [DOI] [PubMed] [Google Scholar]
- 10.Golan T., Sella T., Margalit O., et al. Short- and long-term survival in metastatic pancreatic adenocarcinoma, 1993-2013. J Natl Compr Canc Netw. 2017;15(8):1022–1027. doi: 10.6004/jnccn.2017.0138. [DOI] [PubMed] [Google Scholar]
- 11.Lewis A., Nagrial A. Systematic review of single-agent vs. multi-agent chemotherapy for advanced pancreatic adenocarcinoma in elderly vs. younger patients. Cancers (Basel) 2023;15(8):2289. doi: 10.3390/cancers15082289. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Jayakrishnan T., Nair K.G., Kamath S.D., et al. Comparison of characteristics and outcomes of young-onset versus average onset pancreatico-biliary adenocarcinoma. Cancer Med. 2023;12(6):7327–7338. doi: 10.1002/cam4.5418. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Castet F., Fabregat-Franco C., Castillo G., et al. Clinical and genomic characterisation of early-onset pancreatic cancer. Eur J Cancer. 2023;194 doi: 10.1016/j.ejca.2023.113338. [DOI] [PubMed] [Google Scholar]
- 14.Ben-Aharon I., van Laarhoven H.W.M., Fontana E., Obermannova R., Nilsson M., Lordick F. Early-onset cancer in the gastrointestinal tract is on the rise-evidence and implications. Cancer Discov. 2023;13(3):538–551. doi: 10.1158/2159-8290.CD-22-1038. [DOI] [PubMed] [Google Scholar]
- 15.Boeck S., Hoehler T., Seipelt G., et al. Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer. Ann Oncol. 2008;19(2):340–347. doi: 10.1093/annonc/mdm467. [DOI] [PubMed] [Google Scholar]
- 16.Haas M., Siveke J.T., Schenk M., et al. Efficacy of gemcitabine plus erlotinib in rash-positive patients with metastatic pancreatic cancer selected according to eligibility for FOLFIRINOX: a prospective phase II study of the ‘Arbeitsgemeinschaft Internistische Onkologie’. Eur J Cancer. 2018;94:95–103. doi: 10.1016/j.ejca.2018.02.008. [DOI] [PubMed] [Google Scholar]
- 17.Haas M., Waldschmidt D.T., Stahl M., et al. Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: the randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the ‘burden of therapy’ method. Eur J Cancer. 2021;146:95–106. doi: 10.1016/j.ejca.2020.12.029. [DOI] [PubMed] [Google Scholar]
- 18.Heinemann V., Quietzsch D., Gieseler F., et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006;24(24):3946–3952. doi: 10.1200/JCO.2005.05.1490. [DOI] [PubMed] [Google Scholar]
- 19.Heinemann V., Vehling-Kaiser U., Waldschmidt D., et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104) Gut. 2013;62(5):751–759. doi: 10.1136/gutjnl-2012-302759. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Taieb J., Prager G.W., Melisi D., et al. First-line and second-line treatment of patients with metastatic pancreatic adenocarcinoma in routine clinical practice across Europe: a retrospective, observational chart review study. ESMO Open. 2020;5(1) doi: 10.1136/esmoopen-2019-000587. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Aprile G., Negri F.V., Giuliani F., et al. Second-line chemotherapy for advanced pancreatic cancer: which is the best option? Crit Rev Oncol Hematol. 2017;115:1–12. doi: 10.1016/j.critrevonc.2017.03.025. [DOI] [PubMed] [Google Scholar]
- 22.Tas F., Sen F., Odabas H., Kılıc L., Keskın S., Yıldız I. Performance status of patients is the major prognostic factor at all stages of pancreatic cancer. Int J Clin Oncol. 2013;18(5):839–846. doi: 10.1007/s10147-012-0474-9. [DOI] [PubMed] [Google Scholar]
- 23.Howlader N, Noone AM, Krapcho M, et al. SEER cancer statistics review (CSR) 1975-2017. Bethesda, MD: National Cancer Institute; 2020. Available at https://seer.cancer.gov/csr/1975_2017/. Accessed April 1, 2020.
- 24.Nipp R., Tramontano A.C., Kong C.Y., et al. Disparities in cancer outcomes across age, sex, and race/ethnicity among patients with pancreatic cancer. Cancer Med. 2018;7(2):525–535. doi: 10.1002/cam4.1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Elias R., Cockrum P., Surinach A., Wang S., Chul Chu B., Shahrokni A. Real-world impact of age at diagnosis on treatment patterns and survival outcomes of patients with metastatic pancreatic ductal adenocarcinoma. Oncologist. 2022;27(6):469–475. doi: 10.1093/oncolo/oyac028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Heinrich K., Modest D.P., Ricard I., et al. Gender-dependent survival benefit from first-line irinotecan in metastatic colorectal cancer. Subgroup analysis of a phase III trial (XELAVIRI-study, AIO-KRK-0110) Eur J Cancer. 2021;147:128–139. doi: 10.1016/j.ejca.2021.01.025. [DOI] [PubMed] [Google Scholar]
- 27.Pijnappel E.N., Schuurman M., Wagner A.D., et al. Sex, gender and age differences in treatment allocation and survival of patients with metastatic pancreatic cancer: a Nationwide Study. Front Oncol. 2022;12 doi: 10.3389/fonc.2022.839779. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Cunningham D., Chau I., Stocken D.D., et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009;27(33):5513–5518. doi: 10.1200/JCO.2009.24.2446. [DOI] [PubMed] [Google Scholar]
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