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© 2003 American Society for Clinical Oncology Quality of Life in Good Prognosis Patients With Metastatic Germ Cell Cancer: A Prospective Study of the European Organization for Research and Treatment of Cancer Genitourinary Group/Medical Research Council Testicular Cancer Study Group (30941/TE20)
From the Norwegian Radium Hospital, Oslo, Norway; Rotterdam Cancer Institute and University Hospital, Rotterdam; University Hospital, Nijmegen; and The Netherlands Cancer Institute, Amsterdam, the Netherlands; Northern Centre for Cancer Treatment, Newcastle upon Tyne; Christie Hospital, Manchester; Royal South Hants Hospital, Southampton; and Medical Research Council Cancer Trials Unit, London, United Kingdom; and European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium. Address reprint requests to Sophie D. Fosså, MD, Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway; email: s.d.fossa{at}klinmed.uio.no.
Purpose: To describe global quality of life (GLQL) in patients with metastatic testicular cancer (TC) treated with four different schedules of bleomycin, etoposide, and cisplatin (BEP) chemotherapy (four v three cycles given over 5 v 3 days). Patients and Methods: Quality-of-life data were prospectively collected in 666 patients with metastatic TC entered into the European Organization for Research and Treatment of Cancer (EORTC) Trial 30941/United Kingdom Medical Research Council Trial TE20, using the EORTC Quality-of-Life Questionnaire C30 and a TC module. Data were analyzed by a mixed effects model and by evaluation of clinically relevant changes at 2 years.
Results: The pattern of GLQL changes was similar in the four groups. Two years after chemotherapy, 36% of patients displayed improved GLQL as compared with baseline, whereas GLQL had deteriorated in 13%. At 3 months, patients receiving the 3-day regimen experienced increased gastrointestinal (GI) toxicity more than those receiving the 5-day regimen, with the difference reaching the level of clinical relevance ( Conclusion: Because of the excess of acute GI toxicity and the increased risk of tinnitus after the 3-day regimen, we recommend the 5-day regimen if four cycles of BEP are planned. If only three cycles are to be given, then the 3-day regimen is acceptable, even given the increased risk of nausea/vomiting at 3 months.
HEALTH-RELATED quality of life (HRQL) during and after treatment has become an important topic in clinical oncology and includes physical, psychologic, and social functioning.1–6 Testicular cancer (TC) is a curable malignancy that often occurs in young men during a demanding period of their life. In most cross-sectional studies, long-term HRQL has been described as satisfactory in TC survivors.7–14 The only prospective HRQL analysis in TC15 was based on a nonvalidated questionnaire. The European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group and the United Kingdom Medical Research Council (MRC) Testicular Cancer Working Party assessed HRQL in trial EORTC 30941/MRC TE20.16 In patients with good prognosis metastatic germ cell cancer, the trial demonstrated equivalent efficacy of three and four cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy. BEP administration over 5 days was also compared with BEP delivered over 3 days. Physician-assessed sensory neuropathy was more frequent after four cycles than after three cycles. The 3-day regimen caused late ototoxicity more often than the 5-day schedule. This report provides an in-depth analysis of HRQL related to the four treatment alternatives, with emphasis on changes at 2 years.
Trial Design Eligible patients met the good prognosis criteria of the International Germ Cell Cancer Collaborative Group.17 Nonseminoma patients fulfilled all of the following criteria: testicular or retroperitoneal primary tumor, serum alpha-fetoprotein less than 1,000 U/L, serum human chorionic gonadotropin less than 5,000 U/L, lactate dehydrogenase less than 1.5 times the upper limit of normal, and no nonpulmonary visceral metastases. Seminoma patients of any primary site had no nonpulmonary visceral metastases, normal alpha-fetoprotein, and any serum level of human chorionic gonadotropin or lactate dehydrogenase. Patients were randomly allocated to one of four treatment alternatives given every 3 weeks: 1. 3BEP-1EP over 5 days (four cycles/5 days; standard treatment): Bleomycin 30 mg on days 2, 8, and 15; etoposide 100 mg/m2 on days 1 through 5; cisplatin 20 mg/m2 on days 1 through 5 (no bleomycin during cycle 4). 2. 3BEP-1EP over 3 days (four cycles/3 days): Bleomycin 30 mg on days 2, 8, and 15; etoposide 167 mg/m2 on days 1 through 3; cisplatin 50 mg/m2 on days 1 and 2. 3. 3BEP over 5 days (three cycles/5 days): Bleomycin 30 mg on days 2, 8, and 15; etoposide 100 mg/m2 on days 1 through 5; cisplatin 20 mg/m2 on days 1 through 5. 4. 3BEP over 3 days (three cycles/3 days): Bleomycin 30 mg on days 2, 8, and 15; etoposide 167 mg/m2 on days 1 through 3; cisplatin 50 mg/m2 on days 1 and 2. Hydration regimens and infusion times for cisplatin were the same for the four treatment schedules. Dose modifications were made on the basis of hematologic, biochemical, and clinical toxicity.16 Residual postchemotherapy masses were resected, frequently by retroperitoneal lymph node dissection (RPLND). British oncologists were allowed to randomly assign patients to only four or three cycles because many of them regarded the 3-day schedule as standard BEP treatment. These 131 patients, randomly assigned only regarding number of cycles and who received the 3-day schedule, are pooled together with those randomly assigned to the 3-day regimen. The trial was approved by the local institutional review boards, and all patients provided written informed consent before random treatment assignment.
HRQL Assessment: Questionnaires and Timing The EORTC QLQ-C30 assesses five functional domains and eight symptoms, together with financial problems and global quality of life (GLQL), and is available in all relevant European languages.19 The TC module18 evaluates specific physical chemotherapy-related symptoms and emotional and sexual items frequently affected in TC patients.
The items of the QLQ-C30 and of the TC module were linearly transformed.1 QLQ-C30 scales for function were scored from 0 (worst) to 100 (best). Symptom scores ranged from 0 (no symptoms) to 100 (worst symptoms). For all but two items of the TC module (HA, happy with management; SR, sexual relationship summary), a score of 0 indicated the best outcome and a score of 100 indicated the worst outcome. Changes of
Quality-of-Life Hypothesis and Statistical Power
Timing
Compliance to HRQL Evaluation
Statistical Methods Descriptive analysis of HRQL data comprised calculation of least-square means and SDs. Differences were assessed by an approximate student’s t test or a  2 test. A mixed-effects model assessed the longitudinal HRQL changes by three types of tests within the same chemotherapy schedule and between the four regimens at the five assessment times:
In addition, the percentage of patients with clinically relevant changes at 2 years was calculated in 286 patients with both baseline and 2-year questionnaires.
Patients At randomization, patients from the four chemotherapy groups were comparable in terms of demographic and treatment variables (Table 2  ). Postchemotherapy RPLND was performed on 16% of all patients.
EORTC QLQ-C30 At baseline, no intergroup differences were observed in terms of any of the HRQL parameters (Fig 1A and 1B). For functional dimensions, the lowest scores were observed for emotional function (EF) and GLQL (Table 3). Fatigue and sleep disturbances reached the highest symptom scores.
Functional Scales Functional scales are shown in Fig 1A  and in Tables 3 and 4.
General. At any time point, the patterns of changes of the functional scales were similar for the treatment groups. At 3 months, four cycles were associated with more functional reduction than three cycles, the number of days being less important. Except for cognitive functioning, the long-term functional scales improved above the baseline level.
GLQL.
At 3 months, GLQL had decreased by approximately eight (three cycles/5 days) to 12 points (four cycles/3 days). During the 2-year period, GLQL recovered slightly over baseline levels (approximately four points per year). Thirteen percent of the patients recorded clinically relevant worsening, whereas GLQL had increased in 36% (Table 3 Physical function. Four cycles reduced physical function (PF) at 3 months by approximately 14 points, compared with 10 points if three cycles were given (P = .0736). PF remained decreased at 6 months. PF recovered to baseline levels by approximately 1.5 points per year. At the 2-year assessment, PF had improved in 5% of the patients and had deteriorated in 9%. EF. At 6 months, EF had improved over baseline levels by approximately seven points. Forty-eight percent of the patients reported improvement of EF at 2 years, and 9% had become clinically worse. Cognitive function. Cognitive function (CF) was decreased at 3 months, though not at the level of clinical relevance, with recovery to baseline values over 2 years. As many as 19% of the patients recorded worsening of CF at the 2-year assessment. Role function. At 3 months, role function (RF) was impaired by 16 to 23 points, with recovery to almost baseline values during the following 3 months. RF improved over baseline by eight points per year. Seven percent of the patients recorded deterioration of RF at the 2-year assessment. Social function. In all groups, social function was decreased by more than 10 points at 3 months, with recovery at 6 months (annual recovery by approximately five points per year). At 2 years, clinically relevant improvement was reported by 41%, whereas 12% had experienced deterioration.
Symptoms Scales
General. Most symptoms worsened at the 3-month level but improved above baseline level after 2 years. Except for nausea/vomiting and appetite loss at 3 months, there were no intergroup differences in the patterns of change. Fatigue. At 3 months, fatigue increased clinically in all patients, with recovery within the next 3 months. In all groups, fatigue improved in the long term by approximately four points per year. Nineteen percent of patients experienced deterioration 2 years after the start of treatment. Nausea/vomiting. Four cycles/3 days increased nausea/vomiting (NV) by 17.3 points at 3 months. The comparable figure for four cycles/5 days was 9.4, the latter figure being similar after the three cycles/3 days regimen. NV was least if three cycles were given over 5 days. Pain. Pain relief was apparent as early as 3 months. The annual pain reduction was approximately 6 points per year and was similar in the four groups. Dyspnea. At 3 months, self-reported dyspnea had increased by approximately 18 points, similarly in all groups. The long-term levels did not differ from baseline levels. At the 2-year assessment, 16% of the patients recorded worsening of dyspnea. Appetite loss. At 3 months, the four cycles/3 days regimen was associated with the largest degree of appetite loss (AP), whereas changes of AP were similar for the other three treatment schedules. There were only minor changes in insomnia, constipation, and diarrhea (< five points on average). Financial difficulties represented a statistically significant problem at 3 months, with gradual improvement above baseline levels thereafter.
TC Module
Specific Physical Symptoms
Pain, numbness, and tingling in hands and feet. For all patients, pain, numbness, and tingling in hands and feet (PHF) had increased at 3 months (approximately 20 points) after four cycles; maximal values were reached at 6 months. The number of days had no influence on PHF. PHF scores remained elevated compared with baseline, with 22% of the patients recording worsening of PHF at 2 years, without intergroup differences. Pale and cold feet and toes and hands and fingers. Pale and cold feet and toes and hands and fingers (CHF) reached its maximum at 6 months and was greater in patients receiving four cycles of BEP than in those receiving three cycles. There was no significant difference in CHF when comparing 3 versus 5 days. At 2 years, 24% of the patients reported worsening of CHF.
Ringing in the ears.
At all time points, the increase of ringing in the ears (RE) was greatest in the group receiving four cycles/3 days. At 3 months, RE had increased by 31 points in this group, Difficulty hearing. The pattern of changes tended to differ between groups: At 6 months, the group receiving the four cycles/3 days regimen fared worse, having an increase of approximately 10 points from baseline as compared with four to six points in the other three groups (P = .0742). Four cycles/3 days also resulted in the largest yearly increase (six points per year; P = .0380). Overall, 21% of the patients recorded worsening of hearing at 2 years.
Sexual Items
Emotional Items Emotional items are shown in Fig 1C and Tables 6 and 9. At 3 months, "feeling less masculine" had decreased, more after 3 than after 5 days treatment, but without significant differences in the long term. At 2 years, concern about not being able to father a child had improved in 28% of the patients but had become worse in 11%. Seventeen percent of the patients expressed worsening of anxiety related to relapse 2 years after trial entry, whereas anxiety had decreased in 36%. At 6 months and thereafter, patient confidence in medical management (happy with medical management) increased slightly, without intergroup differences.
Several of our findings are important for the management of patients with TC. First, as expected, BEP chemotherapy leads to considerable 3-month impairment of GLQL and most other HRQL dimensions. NV and appetite loss is a greater problem if BEP is given over 3 than over 5 days, with this change reaching the level of clinical significance if four cycles are given. Second, approximately 35% of the patients display improved GLQL at 2 years compared with baseline, and approximately 13% experience deterioration of GLQL. Reduction of the number of cycles from four to three has no effect on 2-year GLQL. Third, clinically relevant peripheral sensory neuropathy and Raynaud-like phenomena develop during the first 6 months of chemotherapy with improvement thereafter and persist in 20% to 25% of the patients, the long-term prevalence being independent of the chemotherapy schedule. Fourth, long-term ototoxicity is reported by 20% to 25% of the patients. The 3-day regimen of BEP is associated with a higher risk of persisting tinnitus, reaching the level of clinical significance if four cycles are given.
More favorable 3-month HRQL scores were expected after three than after four cycles: Most patients who received three BEP cycles had a treatment-free interval of The lack of intergroup differences in GLQL at 2 years is in agreement with long-term studies.14,21–23 Most long-term surveys in TC patients7–14,17,21–23 have demonstrated satisfactory HRQL, independent of treatment and despite persisting physical symptoms in 10% to 25% of TC survivors.13,24 In the present series, sexual items in TC survivors seem less affected than in reports from the early 1990s, though a formal comparison is difficult to make because of the use of different questionnaires. This is probably the result of the reduction of treatment burden that occurred in the last decade, including fewer chemotherapy cycles16 and the introduction of postchemotherapy nerve-sparing RPLND.25 The increasing use of pretreatment sperm banking has also led to reduced posttreatment fertility problems. Our posttreatment results are related to baseline observations, obtained shortly after the diagnosis of a metastatic malignancy. However, compared with the individual prediagnostic patient’s situation, the baseline scores of, for example, physical and emotional function or pain may have been impaired because of the patient’s awareness of a life-threatening diagnosis and the physical symptoms of metastases. Some of these baseline scores are probably below the level of healthy individuals. Recovery to baseline values or even improvement should therefore only reluctantly be interpreted as normalization. Adjustment to unavoidable side effects during the 2-year period may further have led to a change in a patient’s expectation and standard as to his HRQL. Whether TC long-term survivors’ HRQL is comparable to that of age-matched men can only be investigated by comparison with HRQL results from the general population. We could not perform such a comparison because normative, pan-European data are not available for the QLQ-C30 questionnaire. Published national data from France14 and Sweden10 do not, however, suggest significant HRQL differences if TC survivors are compared with age-matched men from the general population. Long-term peripheral sensory neuropathy and Raynaud-like phenomena24,26,27 have been related to the cumulative dose of cisplatin27 and probably also to the dose-intensity. In this series, we could not confirm these observations using moderate cumulative doses. The reduction of the number of cycles decreased toxicity only during the first 6 months after randomization. Ototoxicity is a well-known side effect of cisplatin-based chemotherapy.28,29 Its incidence is related to the cumulative dose and to the dose of a single infusion. Tinnitus is reported to occur in 50% of the patients, and hearing loss for speech in 10%. Audiographic changes in the high-frequency region of the audiogram are described in 60% of all patients. Our results confirm that patient-perceived ototoxicity mainly presents as tinnitus. Furthermore, the 3-day schedule increased the risk of long-term tinnitus, particularly if four cycles had been administered. However, this phenomenon was also apparent when only three cycles were given. This indicates that the serum concentration of cisplatin is important for the development of tinnitus, even if only moderate cumulative doses are applied. Our data strongly indicate that the 3-day schedule should be avoided in patients in whom an excellent auditory function is essential for their professional activity (musicians, teachers, and so on). As many as 19% of the patients reported worsening of their cognitive function 2 years after chemotherapy. During recent years, increasing attention has been paid to the long-term effect of chemotherapy on cognition,30 which is of particular importance in young individuals during their education and/or at the start of their professional carrier. Prospective detailed studies will be necessary to describe such treatment-related cognitive changes in depth.
Our definition of clinical relevance is based on the observation by Osoba et al20 that patients described a change of Our study represents the first prospective evaluation of HRQL in TC patients using a validated and reliable cancer-specific questionnaire (QLQ-C30). Because of the lack of psychometric testing and extensive translation checks, the cross-cultural validity and reliability of the TC module is more uncertain. Our long-term observations on peripheral neuropathy, Raynaud-like phenomena, and ototoxicity are, however, in good agreement with clinical experience in these patients.23–26 We thus believe that our results are valid for HRQL assessment in relapse-free TC patients receiving three or four cycles of BEP chemotherapy. One may ask whether the current HRQL analysis has added valuable information beyond the physician-assessed toxicity rates.16 Our observations indicate that long-term ototoxicity is more prevalent if assessed by the patient himself than if it is physician-evaluated (> 20% v 12% after standard treatment). Furthermore, the 3-month NV and AP differences between the 3- versus 5-day regimens would have remained undetected without a formal HRQL analysis, as would the long-term ototoxicity related to the number of days per cycle. In conclusion, if three cycles are given, BEP chemotherapy can be administered over 3 days, though with transient, more pronounced gastrointestinal toxicity than after the 5-day application. Giving BEP over 3 days increases the risk of long-term ototoxicity, in particular if four cycles are administered. The risk of ototoxicity should also be considered even if only three cycles are planned. If four cycles are administered, we strongly recommend the use of the 5-day regimen in light of increased gastrointestinal side effects at 3 months and long-term tinnitus. Because the reason to administer four cycles of BEP or further chemotherapy are related to the presence of adverse prognostic factors in metastatic TC, the use of the four cycles/5 days schedule is warranted under these circumstances.
Testicular Cancer–Specific Module*
The following institutions contributed to the trial: Dr B. Paluchowska, M. Skowdowska, Curie Cancer Center, Warsaw, Poland; Dr G. Kaiser, Medizinische Klinik, Nürnberg, Germany; Dr J. Pont, Kaiser Franz Josef Spital, Vienna, Austria; Dr C.N. Sternberg, San Raffaele del Monte Tabor, Roma, Italy; Prof Dr A.M. Garin, Cancer Research Center (Clin Pharm), Moscow, Russia; Dr J. Mc Kendrick, Box Hill Hospital, Victoria, Australia; Prof Dr H. von der Maase, Aarhus Communenspital, Aarhus; Dr G. Daugaard, Rigshospitalet, Copenhagen, Denmark; Dr J.J. Croles, Willem Alexander Ziekenhuis, Den Bosch; Dr H.J. Keizer, University Hospital Leiden, Leiden; Dr T.A.W. Splinter, University Hospital Rotterdam, Rotterdam; Dr P.S.G.J. Hupperets, University Hospital Maastricht, Maastricht; Dr Th.J. Slee, St Antonius Hospital, Nieuwegein; Prof Dr D.Th. Sleijfer, University Hospital Groningen, Groningen; Dr R.C. Rietbroek, Academic Medical Center, Dr C.J. van Groeningen, University Hospital, Amsterdam, the Netherlands; Prof Dr A.T. van Oosterom, University Hospital Leuven, Leuven; Prof Dr J.B. Vermorken, University Hospital Antwerpen, Antwerpen; Dr J. Kerger, Institut Jules Bordet, Brussels, Belgium; Dr G. Rustin, Mount Vernon Hospital, Northwood; Dr M.H. Cullen, Queen Elizabeth Hospital, Birmingham; Dr M. Sokal, Nottingham City Hospital, Nottingham; Dr A.W. Hutcheon, Aberdeen Royal Infirmary, Aberdeen; Dr D.J. Fairlamb, New Cross Hospital, Wolverhampton; Prof S.B. Kaye, Beatson Oncology Centre, Glasgow; Prof A. Horwich, Royal Marsden National Health Service Trust, Sutton; Dr A.E. Champion, Weston Park Hospital, Sheffield; Dr M.V. Williams, Addenbrookes NHS Trust, Cambridge; Dr J.D. Graham, Bristol Oncology Centre, Bristol; Dr P.I. Clark Clatterbridge Centre for Oncology, Bebington; Dr J. Le Vay, Ipswich Hospital, Ipswich; Dr F.J.F. Madden, Leicester Royal Infirmary National Health Service Trust, Leicester; Prof. M.D. Mason, Velindre Hospital, Cardiff; Dr A.C.R. Robinson, Southend Hospital, Westcliff on Sea; Dr J.R. Owen, Gloucestershire Oncology Centre, Cheltenham; Dr A.D. Stockdale, Walsgrave Hospital, Walsgrave; A.L. Houghton, Northampton General Hospital, Northampton; Dr A.J. Rathmell, South Cleveland Hospital, Middlesborough; Dr W.G. Jones, Cookridge Hospital, Dr P. Johnson, St James’ Hospital, Leeds; Dr S.J. Harland, Middlesex Hospital, Dr P.G. Harper, Guys Hospital, Dr S.J. Karp, North Middlesex Hospital, Prof R.T.D. Oliver, St Bartholomew’s Hospital, London, United Kingdom.
Supported by grants 5U10 CA11488-24 through 2U10 CA11488-31 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. The contents of this article are the sole responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10-point change) if four cycles were given. The 3-day schedule increased the 2-year risk of tinnitus, with clinical relevance demonstrated after four cycles. Long-term peripheral neuropathy and Raynaud-like phenomena were not associated with the number of cycles or days per cycle. At 2 years, Raynaud-like phenomena, tinnitus, or reduced hearing were reported by 21% to 26% of the patients. 
