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Keywords:

  • germ cell cancer;
  • survival;
  • treatment toxicity;
  • treatment intensity;
  • older patients

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

Germ-cell cancer (GCC) patients aged ≥40 years have a two-fold higher GCC-specific mortality. It has been hypothesized that reduced treatment intensity combined with increased treatment related toxicity could be the explanation. The objective was to analyze chemotherapy intensity, treatment related toxicity and survival in patients aged ≥40 years treated with standard chemotherapy for GCC compared with a younger control group that received similar treatment during the same period.

METHODS

From 1984 to 2011, 135 patients aged ≥40 years with disseminated GCC treated with bleomycin, etoposide and cisplatin (BEP). A control-group of 135 patients aged 18–35 years was randomly selected matched on year of BEP treatment. Cumulated doses of BEP as well as bone marrow toxicity, renal- and lung functions were recorded before, during and after termination of treatment. All patients were followed until death or October 1, 2011.

RESULTS

The cumulated doses of BEP were comparable between the two groups, however, more patients aged ≥40 years were reduced in bleomycin doses based on a decrease in carbon monoxide diffusion capacity corrected for haemoglobin (P = 0.03). No differences between the two groups were found regarding bone marrow toxicity or mean percentage changes in lung- or renal function. Patients aged ≥40 year had increased cancer specific mortality, HR = 4.8 (P = 0.005). In particular patients with disease progression after first line chemotherapy had increased mortality (P = 0.015). Moreover, the 5-year overall survival for patients aged ≥40 years was 82.5% compared to the expected 5-year survival of the background population of 96.3% (P <0.001).

CONCLUSIONS

Treatment related toxicity could not explain the increased cancer specific mortality in patients aged ≥40 years compared to a younger control-group, and while there were no differences in the administrated doses of cisplatin/etoposide, a decreased number of bleomycin doses were administered in the older patients. Apart from this, the inferior prognosis could be related to tumour biology, increased co-morbidity, or more severe toxicity in relation to second line treatment. Cancer 2014;120:43–51. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Germ cell cancer (GCC) mainly affects young men, and approximately 70% of patients are aged <40 years at the time of diagnosis.[1] With cisplatin-based chemotherapy,[2] most patients with GCC will be long-term survivors, and their 5-year survival rate exceeds 90%.[3] However, it has recently been demonstrated that patients aged ≥40 years have a 2-fold higher GCC-specific mortality,[4] and it is hypothesized that reduced treatment intensity combined with increased treatment-related toxicity in this age group may be the explanation.[4-6] The objective was to analyze treatment-related toxicity, treatment intensity and survival in patients aged ≥40 years who received standard chemotherapy for disseminated GCC compared with a younger control group.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Study Design and Patient Population

The study population comprised 270 patients with disseminated GCC who received treatment at Rigshospitalet (Copenhagen, Denmark) during the period from 1984 to 2011 with either 3 or 4 cycles of bleomycin, etoposide, and cisplatin (BEP) (cisplatin 20 mg/m2 on days 1-5, etoposide 100 mg/m2 on days 1-5, and bleomycin 15,000 IU /m2 weekly) every 3 weeks. All patients were followed until death or October 1, 2011.

During the study period, 152 patients aged ≥40 years received treatment for disseminated GCC, and 138 of those patients received BEP. Three of the 138 patients were excluded because they had incomplete data; thus, the population aged ≥40 years consisted of 135 patients. Over the same period, 446 patients ages 18 to 35 years received BEP treatment for disseminated GCC; among them, 135 patients who were matched on year of BEP treatment were selected randomly as a control group. The median time from entry to the end of study was 14.1 years (range, 0.3-27 years) in the patients aged ≥40 years and 13.6 years (range, 0.8-27 years) in the control group.

Before 2001, the standard chemotherapy regimen for disseminated GCC was 4 cycles of BEP; since 2001, the standard regimen has been 3 cycles of BEP for patients with a good prognosis and 4 cycles of BEP for patients with an intermediate or poor prognosis.[7] Bleomycin was discontinued if the carbon monoxide diffusion capacity corrected for hemoglobin (DLCO) decreased >25% during treatment. Granulocyte-colony–stimulating factor (G-CSF) was administered to patients who experienced febrile neutropenia; and, from 2007 onward, all patients aged ≥40 years routinely received G-CSF because of a >20% risk of febrile neutropenia according to the guidelines of the American Society of Clinical Oncology.[8]

Thorough reviews of patient charts were performed. Charlson comorbidity index (CCI), tobacco use, and alcohol consumption were recorded before treatment. Tobacco consumption was categorized as nonsmoker, former smoker, light smoker (≤20 cigarettes per day), or heavy smoker (>20 cigarettes per day). Alcohol consumption was categorized as nonuser, moderate consumption (≤21 U/12 grams per week), or heavy consumption (>21 U/12 grams per week). The cumulated doses of BEP, including salvage cycles, were recorded. Lung function tests (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and DLCO) were measured before every cycle; at the end of chemotherapy; and at 1 to 2 years, 3 to 4 years, and 5 years after treatment. All measurements were compared with the expected value according to patient age and height. Renal function was estimated using chromium 51-ethylene diamine tetra-acetic acid clearance at the same time points, except during chemotherapy. Bone marrow toxicity was graded on days 1, 8, and 15 during each cycle of BEP and 1 month after the final cycle according to Common Toxicity Criteria (CTC) version 3.0 (available at: http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf on the 10th of September 2013). Further testing was performed for CTC grade >3.

Disease progression was defined as the time from treatment initiation to the first GCC-related event: either disease relapse or GCC-specific mortality. The cause of death was categorized as GCC, other malignancy, or other cause.

Statistical Methods

Chi-square tests or Fisher exact tests were used for tests of independence, and the t test was used to compare continuous data between the 2 groups. Exact 95% confidence intervals (CIs) for proportions were calculated. Kaplan-Meier survival analysis was used to estimate the time to disease progression, overall survival, and cancer-specific survival; and log-rank analysis was used to compare survival between the study groups. Cox regression analysis was used to estimate the risk of GCC death in the group aged ≥40 years. The Schoenfeld test was used to assess the Cox model assumptions. The expected overall survival in the 2 groups was calculated using vital statistics from Statistics Denmark (available at: http://www.statistikbanken.dk/statbank5a/default.asp?w=1680, accessed November 1, 2012) matched by age and the year BEP was started. One sample log-rank test was done comparing the observed survival with the expected survival in each group.[9] All tests were 2-sided, and P values < .05 were considered statistically significant. Statistical analysis was performed with the SAS software package (version 9.2, SAS Institute Inc., Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Baseline characteristics are outlined in Table 1. The distribution of seminoma in the patients aged ≥40 years was higher compared with the control group; and, although there were more patients aged ≥40 years with extragonadal tumors, the 2 groups were well matched according to prognostic categories (P = .72). There were significantly more current or previous smokers in the group aged ≥40 years (73%) compared with the control group (49%; P < .001); more patients aged ≥40 years had higher alcohol consumption (P = .002); and, although the difference was not significant, there was a trend toward higher CCI in the group aged ≥40 years (P = .06). Baseline renal function was significantly lower in the group aged ≥40 years (P < .001), whereas age-adjusted lung function was comparable between the 2 groups.

Table 1. Baseline Characteristics, Comorbidity, Renal and Lung Function, Tobacco Use, and Alcohol Consumption
 No. of Patients (%) 
 Patients Aged ≥40 Years, n = 135Control Group, n = 135P
  1. Abbreviations: CI, confidence interval; DLCO, carbon monoxide diffusion capacity corrected for hemoglobin; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GFR, glomerular filtration rate; NA, not available.

Age: Median/range, y47/40–7329/18–35 
Histology   
Seminoma60 (44.4)30 (22.2)<.001
Nonseminoma74 (54.8)104 (77) 
NA1 (0.7)1 (0.7) 
Primary tumor site  .07
Testis112 (83)122 (90.4) 
Extragonadal23 (17)13 (9.6) 
Prognostic group  .72
Good97 (71.8)87 (64.4) 
Intermediate24 (17.8)24 (17.8) 
Poor14 (10.4)24 (17.8) 
Charlson comorbidity index  .06
0113 (83.7)126 (93.3) 
115 (11.1)8 (5.9) 
≥27 (5.2)1 (0.7) 
Tobacco use  <.001
Nonsmoker29 (21.5)55 (40.7) 
Former smoker12 (8.9)3 (2.2) 
Light smoker31 (23)35 (25.9) 
Heavy smoker34 (25.2)15 (11.1) 
NA29 (21.5)27 (20) 
Alcohol consumption  .002
Nonuser33 (24.4)43 (31.9) 
Moderate39 (28.9)56 (41.4) 
Heavy17 (12.6)4 (3) 
NA46 (34.1)32 (23.7) 
Renal function: Mean % of expected [95% CI]
GFR95.8 [92.7–99]106 [103.4–108]< .001
Lung function: Mean % of expected [95% CI]
FVC97.2 [91.9–102.5]102.4 [97.1–107.7].48
FEV198.1 [94.1–102.2]97.3 [93.6–101].76
DLCO87.9 [83.8–92]88.9 [84–93.9].74

Treatment Intensity and Toxicity

There were no differences in the accumulated doses of chemotherapy received between the 2 groups (Table 2). Although the accumulated doses of bleomycin were comparable, more patients aged ≥40 years received reduced bleomycin doses based on a decrease in DLCO (P = .03). Of the 25 patients aged ≥40 years who received reduced bleomycin (median, 3 administrations; range, 1-12 administrations), there were 4 patients in the poor prognostic group, 7 in the intermediate prognostic group, and 14 in the good prognostic group. Five patients in the good prognostic group received 3 cycles of cisplatin and etoposide, and the remaining patients received 4 cycles. Thus, the latter 9 patients were treated sufficiently despite receiving reduced doses of bleomycin, leaving 16 patients who did not receive the full dose. In the control group, of 14 patients who received reduced bleomycin (median, 2.5 administrations; range, 1-7 administrations), there were 4 patients in the poor prognostic group, 2 in the intermediate prognostic group, and 8 in the good prognostic group. Three patients in the good prognostic group received 4 cycles. Thus, 11 patients did not receive the doses of bleomycin.

Table 2. Treatment Intensity, Response to Treatment, Relapse, and Mortality
 Patients Aged ≥40 Years, n = 135Control Group, n = 135 
VariableNo. (%)Median [Range]No. (%)Median [Range]P
  1. Abbreviations: BEP, combined bleomycin, etoposide, and cisplatin; CR, complete response; GCC, germ cell cancer; G-CSF, granulocyte–colony-stimulating factor; PD, progressive disease; PR, partial response.

  2. a

    Two patients aged ≥40 years died during the first BEP cycle, and 1 patient aged ≥40 years changed chemotherapy regimen because of clinical progression after the first BEP cycle. One patient in the control group changed chemotherapy regimen after the second BEP cycle.

  3. b

    This included patients who had pretreatment height and weight (ie, body surface area) and cumulated chemotherapy dosage available.

  4. c

    One patient aged ≥40 years died during BEP treatment with an unknown treatment response.

  5. d

    One patient had PD during BEP treatment.

No. of primary BEP cyclesa    .25
13 (2.2) 0 (0)  
20 (0) 1 (0.7)  
353 (39.2) 51 (37.7)  
479 (58.5) 83 (61.5)  
Salvage BEP    .80
One extra cycle1 (0.7) 3 (2.2)  
Two extra cycles6 (4.4) 6 (4.4)  
G-CSF    .001
Prophylaxis19 (14.1) 4 (3)  
After febrile neutropenia19 (14.1) 11 (8.1)  
Cumulated chemotherapy doses     
Cisplatin, mg 760 [510–1939] 800 [519–1600].19
Etoposide, mg 3742.5 [1990–9160] 4000 [2595–8000].08
Bleomycin, IU 270,000 [0–390,000] 286,075 [60,000–360,000].15
Full dose according to body surface area, m2     
Cisplatin117/120b (97.5) 129/131b (98.5) .60
Etoposide119/119b (100) 132/132b (100)  
Bleomycin95/120 (79.2)b 118/132b (89.4) .03
No. of cycles in which bleomycin was omitted 3 [1–12] 2.5 [1–7] 
Final response ratec    .05
CR     
After BEP61 (45.5) 67 (49.6)  
After BEP and surgery45 (33.6) 54 (40)  
Incomplete response     
PR with negative markers     
After BEP7 (5.2) 1 (0.7)  
After BEP and surgery11 (8.2) 11 (8.1)  
PD9 (6.7) 2 (1.5)  
Died of GCC during treatment1 (0.7) 0 (0)  
NAc1 (0.7)    
Disease progression    .06
Relapse after obtaining CR on primary treatment10 7  
After obtaining PR on primary treatment7 8  
PD during primary treatment9 2  
Died of GCC during treatment1 0  
Mortality     
Overall40 (29.6) 8 (5.9)  
GCC-specific17 (12.6) 4 (3) .005
CR3 2  
PR6 0  
PDd8 2  
Death occurring during BEP treatment2 (1.5) 0 (0)  
Other malignancy6 (4.4) 1 (0.7)  
Other causes15 (11.1) 3 (2.2)  

Bone marrow toxicity was modest; and, overall, there were no difference between the 2 groups (Table 3). However, 17% of patients aged ≥40 years experienced CTC grade 4 leucopenia, including those patients who received G-CSF prophylaxis, compared with 10% in the control group (P = .02). When the comparison was performed after G-CSF was routinely administered to all patients aged ≥40 years, this difference was eliminated. In total, 2% of patients aged ≥40 years had treatment delayed for more than 7 days compared with 2.2% in the control group (P = .68). Generally, there were no differences in the mean percentage changes in lung function or renal function between the 2 groups, and no episodes of bleomycin pulmonary toxicity were observed.

Table 3. Bone Marrow Toxicity During Chemotherapy Treatment in the 2 Study Groups
 Patients Aged ≥40 Years, n = 135Control Group, n = 135 
Overall CTC Grade During TreatmentNo.%No.%P
  1. Abbreviations: CTC, Common Toxicity Criteria; NA, not available.

No. of cycles474 499  
CTC grade     
Hemoglobin    .35
≤126054.929058.1 
217737.312625.3 
3122.550.5 
40010.01 
NA255.37715.4 
Leukocyte    .43
≤113728.911923.8 
211925.114428.9 
311323.810921.8 
47916.75010 
NA265.57715.4 
Thrombocyte    .43
≤129362.431162.3 
25211387.6 
3418.6265.2 
46213.1469.2 
NA265.57815.6 

Treatment Response

The treatment response could be evaluated in 134 of the 135 patients aged ≥40 years and in all patients in the control group (Table 2). Three patients died during treatment—all were in the group aged ≥40 years: 1 patient died 9 days after the initiation of treatment because of “white lungs” (recorded as GCC death), 1 patient died from a pulmonary embolism (this patient had unknown treatment status and, thus, was excluded from treatment evaluation), and the third patient died from septic shock after 3 cycles of chemotherapy. The latter death was not related to leucopenia, and an autopsy revealed no evidence of disease; thus, death in this patient was recorded as “other cause.” In total, 106 of 134 patients (79.1%) aged ≥40 years had a complete response (CR) compared with 121 of 135 patients (89.6%) in the control group (P = .05). Of the remaining patients aged ≥40 years, 13.4% had a partial response (PR), 6.7% developed progressive disease (PD) during treatment, and 1 patient died of GCC during treatment (see above). In the control group, 8.9% had a PR, and 1.5% had PD.

Of the 18 patients who achieved a PR in the group aged ≥40 years, 13 patients had seminoma; and there were 10 patients in the good prognostic group, 4 in the intermediate prognostic group, and 4 in the poor prognostic group. Eleven patients were admitted for surgery, and 10 patients underwent only partial surgery, because radical removal of the tumor was not possible. The other patient had a malignant tumor in the removed specimen. Of the remaining 7 patients, 1 patient received radiotherapy instead of surgery; 1 patient was managed conservatively because of comorbidity; in 2 patients, radical surgery was not possible, and surgery was omitted; 2 patients with seminoma had negative positron emission tomography-computed tomography scans, and observation was chosen; and 1 patient declined further treatment. Overall, the no evidence of disease (NED) rate for the patients aged ≥40 years who achieved a PR was 61.1% (11 of 18 patients). In the control group, 11 of 12 patients who achieved a PR underwent surgery with partial removal; and the other patient was managed with cisplatin, paclitaxel, and gemcitabine. Two patients had seminoma; and there were 2 patients in the good prognostic group and 5 each in the intermediate or poor prognostic groups. The NED rate for patients in the control group who obtained a PR was 33.3% (4 of 12 patients).

Disease Progression and Death From Germ Cell Cancer

In total, 20.1% (27 of 134 patients; excluding the patient who died during treatment with unknown response) of the group aged ≥40 years had PD compared with 12.6% (17 of 135 patients) of the control group (P = .06) (Fig. 1). The median time to progression for patients in the group aged ≥40 years who initially obtained a CR or a PR was 0.8 years (range, 0.2-8.4 years) after treatment. There were no platinum-resistant relapses (≤1 month), whereas there were 7 late relapses (>2 years). In the control group, the median time to progression was 0.9 years (range, 0.3-5.0 years). In addition, no platinum-resistant relapses were observed in the control group, whereas there were 4 late relapses. The 5-year progression-free survival rate in the group aged ≥40 years was 79.8% (95% CI, 72.7%-86.9%) compared with 88% (95% CI, 82.5%-93.5%) in the control group (hazard ratio [HR], 1.8; 95% CI, 1.0-3.3).

image

Figure 1. Kaplan-Meier estimates of survival probabilities are illustrated stratified by group. The plot indicates the P value for the log-rank test comparing the 2 groups (patients with germ cell cancer [GCC] aged ≥40 years [40+] and the control group of patients with GCC ages 18 to 35 years) and the hazard ratio (HR) with 95% confidence interval (CI). Disease progression was defined as the time from the initiation of treatment to the first GCC-related event: either disease relapse or GCC-specific mortality. The number of patients at risk at time 0, 12 months, 24 months, and 36 months is indicated below the x-axis, and the number of events is provided on the left.

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Of the 17 patients who died of GCC in the group aged ≥40 years (Table 2), there were 8 patients in the good prognostic group (3 patients had PD during treatment; 2 patients who attained a PR progressed; 2 patients who had a CR developed PD after 3 months and 4 months, respectively; and the remaining patient had a late relapse). One patient in the intermediate prognostic group achieved a PR and developed PD after 3 months; and, of the 8 patients in the poor prognostic group, 5 developed PD during treatment, and 3 who achieved a PR developed PD within 3 months. Of the 4 patients who died of GCC in the control group (Table 2), 2 patients in the good prognostic group had transformed teratoma to sarcoma as part of their primary tumor and died of it, 1 patient in the intermediate prognostic group had a late relapse, and 1 patient in the poor prognostic group primarily had a CR but developed PD after 4 months with central nervous system metastases.

The estimated 5-year cancer-specific survival rate for the patients aged ≥40 years was 88.2% (95% CI, 81.2%-92.7%) compared with 97% (95% CI, 92.1%-98.8%) in the control group (HR, 4.8; 95% CI, 1.6-14.3; P = .005) (Fig. 2). Patients who developed disease progression had significantly increased GCC mortality in the group aged ≥40 years compard to the control group (P = .015). Sixty-three percent (95% CI, 42.4%-80.6%) of patients aged ≥40 years died of GCC compared with 23.5% (95% CI, 6.8%-49.9%) of patients in the control group. There was no significant different survival between patients aged ≥40 years and the control group among those who received reduced doses of bleomycin (P = .13)

image

Figure 2. Kaplan-Meier estimates of cancer-specific survival probabilities stratified by group are illustrated. The plot indicates the P value for the log-rank test comparing the 2 groups (patients with germ cell cancer aged ≥40 years [40+] and the control group of patients ages 18 to 35 years) and the hazard ratio (HR) with 95% confidence interval (CI). The number of patients at risk at time 0, 12 months, 24 months, and 36 months is indicated below the x-axis, and the number of events is provided on the left.

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Overall Mortality

In total, 40 patients in the group aged ≥40 years and 8 patients in the control group died (P < .001). In addition to the 17 patients who died of GCC in the group aged ≥40 years, 6 patients died from other malignancies, 3 from colorectal cancer, 2 from lung cancer, and 1 from prostate cancer. Of the remaining 17 patients, 2 died during treatment (see above), 5 deaths were caused by cardiovascular disease, 5 were caused by alcohol abuse, 2 died of acquired immunodeficiency syndrome (AIDS), 1 died of pneumonia, 1 died of a peptic ulcer, and 1 patient with severe Parkinson disease was discovered dead. In the control group, 4 patients died of GCC, 1 patient died of a highly malignant sarcoma 6 years after treatment (a transformed teratoma could not be excluded), 1 patient died of AIDS, 1 death was caused by alcoholic abuse, and the remaining death was narcotic related.

The 5-year overall survival rate in the group aged ≥40 years was 82.5% (95% CI, 74.7%-88%) compared with 97% (95% CI, 92.1%-98.8%) in the control group (Fig. 3). The group aged ≥40 years had significantly impaired 5-year overall survival compared with the expected survival of the background population (96.3%; P < .001), and the difference could not be explained solely by GCC deaths. There was a trend toward impaired survival in the control group compared with their expected 5-year survival (99.4%; P = .044).

image

Figure 3. Kaplan-Meier estimates of overall survival probabilities are illustrated for the 2 groups (patients with germ cell cancer aged ≥40 years [40+] and the control group of patients ages 18 to 35 years). Expected survival for both groups was calculated by extracting survival data for each patient matched by date and age at the start of treatment. The curves were truncated at the last event.

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Subanalysis in Patients Aged ≥40 Years

Patients who had primary tumors in the testis had better GCC survival compared with patients who had primary extragonadal tumors (P = .007), which also was the case for patients in the good prognostic group compared with patients in the poor prognostic group (P < .0001). The age at BEP treatment (P = .90), year of treatment (P = .32), histology (P = .30), CCI (P = .99), tobacco use (P = .10), alcohol consumption (P = .08), receipt of prophylactic G-CSF (P = .61), number of treatment cycles (P = .21), reduced doses of bleomycin (P = .11), and decreased renal function (P = .18) were not associated significantly with GCC mortality. However, patients with impaired lung function before treatment had increased GCC mortality. Patients with <80% of the expected FVC had an HR of 4.5 (P = .03); patients with <80% of the expected DLCO had an HR of 4.6 (P = .02); and, although the difference was not significant, patients with <80% of the expected FEV1 had increased GCC mortality (P = .05). Patients who received reduced bleomycin doses had significantly lower baseline FVC (P = .002) and FEV1 (P = .007); however because of the limited number of GCC events, we were not able correct for these differences in a multivariate analysis.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

The current study confirms that patients aged ≥40 years have significantly increased GCC-specific mortality compared with a younger control group. This may be caused by decreased sensitivity to treatment, because patients aged ≥40 years have a significantly lower response rate to BEP treatment as well as higher mortality if they develop disease progression after BEP treatment. The increased mortality was not caused by lower treatment intensity of cisplatin/etoposide or treatment-related toxicity. However, fewer of bleomycin administrations were observed in patients aged ≥40 years, and this may have affected GCC mortality. Other factors associated with GCC-specific mortality were decreased lung function and renal function before BEP treatment as well as recognized risk factors, such as poor prognostic group and primary extragonadal tumor.[10, 11] The current results advocate against the assumptions that the increased mortality in older patients with testicular GCC is mainly because of reduced treatment intensity combined with increased treatment-related toxicity or a less favorable stage distribution. Different biologic behavior of the tumors or increased comorbidity also may be part of the explanation.[4-6, 12-14]

In this study, the tolerability of BEP treatment was similar in older and younger patients when the group aged ≥40 years received G-CSF and the cumulated doses of bleomycin were comparable in both groups. During the entire study period, it was our standard to discontinue bleomycin treatment if the DLCO declined >25% during treatment. This resulted in the omission of a median of 3 bleomycin doses in 20.8% of patients aged ≥40 years compared with the omission of a median of 2.5 bleomycin doses in 10.6% of the control group (Table 2). Some studies have reported increased bleomycin-related toxicity in older patients with testicular GCC,[15, 16] and 1 report even suggested that bleomycin should not be used routinely in patients aged ≥40 years who have testicular GCC because of an increased risk of bleomycin-induced pulmonary toxicity.[17] However, this was not supported by the current study, in which the majority of patients aged ≥40 years tolerated full doses of bleomycin if their lung function was monitored carefully. Although the difference was not significant, there was a trend toward higher GCC mortality in patients aged ≥40 years who received reduced doses of bleomycin in the current study, in agreement with previous studies, which demonstrated that bleomycin was an important part of GCC treatment, because both disease-free and overall survival were superior when bleomycin was part of the treatment.[7, 18-21] In 2 recent studies, toxicity related to the treatment of GCC was examined in patients aged ≥50 years.[22, 23] Both of those studies reported that all chemotherapy-related toxicities were manageable, and a general chemotherapy dose reduction in elderly patients has not been recommended.[24] Our study supports this finding.

Although there was a trend toward higher CCI in the group aged ≥40 years, the patients did not have substantial comorbidities in general, and we were not able to demonstrate an association between CCI and GCC mortality. However, decreased lung function at baseline was associated with increased GCC-specific mortality in patients aged ≥40 years, suggesting that these patients tolerated bleomycin worse or that comorbidity not detectable with the CCI could be associated with a worse prognosis.

Age has been suggested as an independent prognostic factor in Hodgkin lymphoma,[25, 26] in which the incidence peaks in the third and fourth decade and 80% of patients are expected to be long-term survivors.[26, 27] For older patients who are staged and treated in the same way as younger patients, the risk of treatment failure is comparable; however, older patients with relapse have a greater Hodgkin disease-specific mortality.[25] Like older patients with GCC, it remains to be clarified whether age, comorbidity, or tumor biology plays the most important part in the increased mortality. An increased toxicity related to second-line treatment could also be considered.

Our control group comprised patients who were randomly selected after being matched on year of BEP treatment. More patients aged ≥40 years had seminomas compared with the control group, as expected. Although more patients aged ≥40 years had primary extragonadal tumors, there were no significant differences regarding prognostic groups. Therefore, we do not believe that matching the control group on more parameters would have changed our results. Again, because of the limited number of GCC events, we have not been able to control for the differences in a multivariate analysis.

Conclusions

Patients with disseminated GCC aged ≥40 years who received standard chemotherapy had increased GCC-specific mortality compared with a younger control group and had decreased overall survival compared with the expected survival of the general population. This increased mortality was not caused by treatment toxicity, and there were no differences in the administrated doses of cisplatin/etoposide, whereas the group aged ≥40 years received a decreased number of bleomycin doses. Apart from this, the inferior prognosis may be related to tumor biology, increased comorbidity, or more severe toxicity in relation to second-line treatment. Future studies should further elucidate the role of tumor biology and comorbidity on mortality in older patients with GCC.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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    Hayes-Lattin B, Nichols CR. Testicular cancer: a prototypic tumor of young adults. Semin Oncol. 2009;36:432438.
  • 2
    Einhorn LH, Williams SD. Combination chemotherapy with cis-dichlorodiammineplatinum(II) and Adriamycin for testicular cancer refractory to vinblastine plus bleomycin. Cancer Treat Rep. 1978;62:13511353.
  • 3
    Verdecchia A, Francisci S, Brenner H, et al. Recent cancer survival in Europe: a 2000–2002 period analysis of EUROCARE-4 data. Lancet Oncol. 2007;8:784796.
  • 4
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