Routine chest X-rays have no additional value in the detection of relapse during routine follow-up of patients treated with chemotherapy for disseminated non-seminomatous testicular cancer

J. A. Gietema1,+, M. T. Meinardi1, D. T. Sleijfer1, H. J. Hoekstra2 and W. T. A. van der Graaf1

Departments of 1 Internal Medicine and 2 Surgical Oncology, University Hospital Groningen, The Netherlands

Received 24 December 2001; revised 22 March 2002; accepted 12 April 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The routine follow-up of patients with disseminated non-seminomatous testicular cancer (DNSTC) treated with the combination of orchidectomy, polychemotherapy, and if needed, resection of the residual mass, consists of regular physical examinations, chest X-rays (CXR) and tumor marker assessments. Most guidelines for this routine follow-up originate from multi-center trials. In order to estimate the value of CXR in the detection of tumor relapse after complete remission, we reviewed all patients with disseminated testicular cancer treated with chemotherapy at the University Hospital Groningen.

Patients and methods:

Three hundred and fifty-three consecutive patients with DNSTC treated between February 1977 and February 1999 at our institution were reviewed. Two hundred and ninety (82.2%) patients, who were in complete remission after cisplatin-containing chemotherapy followed by, if necessary, resection of the residual mass, entered this analysis. The follow-up schedule consisted of regular physical examinations, tumor marker assessment (lactate dehydrogenase, ß-human chorionic gonadotropin and {alpha}-FP) and CXR. In all patients the first diagnostic sign of tumor relapse was documented.

Results:

During a median follow-up of 107 months (range 8–261) a tumor relapse was documented in 33 patients (11.4%). Median time to relapse was 17 months (range 6–179) after the start of chemotherapy. In 27 patients, tumor relapse was first detected by a rise in tumor markers. Two patients presented their relapse with neurological complaints. Both were diagnosed with brain metastasis. In four patients the relapse was detected by both increase in tumor markers and abnormalities in the physical examination. In none of the 33 relapsed patients was routine CXR during follow-up involved in the detection of tumor recurrence. All but one of the relapsed patients had elevated tumor markers before the start of chemotherapy. The total number of CXR made during follow-up in all 290 patients was 10 160; none were diagnostic for the detected relapses.

Conclusions:

These data suggest that routine CXR has no additional value in the detection of tumor relapses during follow-up after chemotherapy in the subset of patients who present their DNSTC with increased tumor markers and are in complete remission after treatment. In order to save valuable resources, CXR can be omitted from the follow-up schedule after chemotherapy for marker-positive non-seminomatous testicular cancer in complete remission.

Key words: chemotherapy, chest X-rays, follow-up, testicular cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The majority of patients with metastatic non-seminomatous testicular cancer can be cured with cisplatin-based chemotherapy followed by, if feasible, surgical resection of any residual mass [1, 2]. Despite these high cure rates for patients with advanced germ-cell tumors, about 20% of all patients with disseminated disease fail to achieve a durable complete response to chemotherapy regimens consisting of cisplatin plus etoposide with or without bleomycin. Factors associated with treatment failure include large tumor volume, the presence of liver, bone or brain metastases, grossly elevated tumor markers and an extragonadal primary site, particularly the mediastinum [3]. Patients who have a relapse after complete remission have a 25–35% chance of achieving another durable response with a regimen containing ifosfamide and cisplatin given as second-line therapy [46]. The chance of second durable remission seems to increase with early initiation of salvage chemotherapy, low tumor volume and a low serum level of ß-human chorionic gonadotropin (ß-HCG) at the start of this second-line chemotherapy [79]. This underlines the importance of early detection of tumor relapses after successful first-line chemotherapy.

After the first clinical study with cisplatin-based combination chemotherapy for disseminated testicular cancer by Einhorn and Donohue [10], subsequent multi-center studies coordinated by large cooperative groups [Eastern Cooperative Oncology Group (ECOG), South West Oncology Group (SWOG), European Organisation for Research and Treatment of Cancer (EORTC) and Medical Research Council (MRC)] defined the current ‘gold standard’ in chemotherapy treatment consisting of bleomycin, etoposide and cisplatin (BEP) [1114]. During those studies vigorous follow-up schedules were used after successful chemotherapy treatment with or without retroperitoneal lymph node dissection (RPLND). Although these follow-up schedules for early disease relapse detection are not evidence based, they are still recommended and routinely applied.

This routinely used follow-up schedule of patients with disseminated testicular cancer in complete remission with chemotherapy consists of regular physical examinations, chest X-rays (CXR) and serum tumor marker assessment. There are, however, no firm data on the necessity of performing these CXR.

At our institution we previously investigated follow-up strategies for stage I testicular cancer patients. We demonstrated that the use of CXR is of limited value in detecting a tumor relapse in stage I patients [15]. To estimate the value of CXR in detecting a tumor relapse in patients with disseminated non-seminomatous testicular cancer (DNSTC) in complete remission we reviewed all the patients treated with cisplatin combination chemotherapy at our institution.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Three hundred and fifty-three consecutive patients with DNSTC treated between September 1977 and February 1999 at the University Hospital Groningen, The Netherlands were reviewed. Most of these patients were treated with chemotherapy within EORTC trials. Two hundred and ninety of 353 (82.2%) patients were in complete remission after cisplatin-containing chemotherapy, followed by resection of a residual mass, if necessary, and entered this analysis (Table 1 for patient characteristics). For the current analysis a complete remission after treatment was defined as normalized tumor markers [lactate dehydrogenase (LDH), ß-human chorionic gonadotropin (ß-HCG) and {alpha}-FP] after completion of chemotherapy with no radiological signs of tumor activity (no abnormalities on computed tomography scan of chest and abdomen), or in case of a residual mass for which a surgical resection was performed with an histology of fibrosis/necrosis or completely resected teratoma. The follow-up schedule of the patients, which at every out-patient visit consisted of a physical examination, serum tumor marker assessment (LDH, ß-HCG and {alpha}-FP) and standard chest X-ray (CXR), monthly for the first year, 2 monthly for the second year, 3 monthly for the third year, then 6 monthly to 5 years, and then annually. All follow-up investigations of the 290 patients were done at our institution. In January 2000, the first diagnostic sign of a tumor relapse was documented for all patients.


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Table 1. Characteristics of patients included in this analysis
 

    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
During a median follow-up of 107 months (range 8–261) a tumor relapse was documented in 33 patients (11.4%). Median time to relapse occurred 17 months (range 6–179) after the start of first-line chemotherapy. Ten patients relapsed after 2 years, whereas three of these had very late relapses >9 years after chemotherapy. Pretreatment characteristics of these 33 relapsed patients are shown in Table 2. In 27 patients, the tumor relapse was first detected by a rise in one or more tumor markers. In eight of them, increased tumor markers were the only indication of relapse, subsequent staging investigations did not reveal abnormalities. Two patients first presented their relapse with neurological complaints. Both were diagnosed with brain metastasis. In four patients the relapse was detected by both increase in tumor markers and complaints (lower back pain in two patients) or an abnormal physical examination (thromboembolism in a lower limb in 2 patients). In none of the 33 patients with a tumor relapse was the routine CXR during follow-up involved in the detection of tumor recurrence. All but one of the relapsed patients had elevated tumor markers before the start of chemotherapy. Characteristics of the 33 patients at the time of their relapse are shown in Table 3. The total number of CXR made during follow-up in all 290 patients was 10 160; none of these CXR were diagnostic for the detected relapse.


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Table 2. Pretreatment characteristics of 33 patients who relapsed after first line treatment for disseminated non-seminomatous testicular cancer
 

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Table 3. Characteristics of 33 relapsed patients at time of their relapse
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The benefit of early detection of recurrence of testicular cancer after successful treatment with cisplatin combination chemotherapy depends on the chance of achieving another durable remission with salvage treatment [79]. The premise that early recognition of recurrence and treatment can prolong survival will increase with more effective salvage therapies [16, 17]. However, the optimal regimen of physical examination, tumor marker estimations and chest X-rays for use in the follow-up of patients after initial treatment has not been determined. The widely used follow-up strategies descend from large multi-institutional chemotherapy trials, which defined the optimal chemotherapy combination for DNSTC during the last two decades. However, the primary focus of this particular follow-up was to define the efficacy of the first-line treatment regimen and not to evaluate the value of follow-up examinations. Furthermore there are few data in the medical literature concerning the effectiveness of these follow-up regimens. In daily practice the aim of follow-up after successful chemotherapy is to timely detect a tumor relapse without unnecessary procedures. The current single institution data-set suggests that routine CXR have no additional value in the detection of a tumor relapse during follow-up after chemotherapy in patients who have a complete biochemical response and no residual masses.

The available literature on the value of CXR in follow-up of treated testicular cancer is scarce. We reported in 1995 that CXR in the follow-up of clinical stage I patients with non-seminomatous testicular cancer have no additional value in detection of disease recurrence [15]. In none of the 42 relapses in 154 stage I patients was CXR the first indication of recurrence.

The lack of value of CXR during post-treatment surveillance after radiation therapy for low early stage seminoma was reported by Buchholz et al. [18]. Rathmell et al. [19] reported relapse patterns of 29 patients who recurred following treatment for metastatic germ-cell tumors of the testis (both seminoma and non-seminoma) [19]. They showed that in two cases (7%) CXR gave first evidence of tumor relapse. However, several of the studied patients had residual masses which were not surgically removed after chemotherapy as is currently considered to be part of standard therapy for DNSTC. This probably influenced the reported data on the value of CXR on relapse patterns and makes comparisons with our data difficult and less valid. Recently the European Society for Medical Oncology (ESMO) released minimum clinical recommendations for diagnosis, treatment and follow-up of mixed or non-seminomatous germ-cell tumors (NSGCT). Recommended follow-up for patients after chemotherapy consists of clinical review, chest X-ray and tumor markers 2 monthly for 1 year, 3 monthly for the second year, than 6 monthly to 5 years, and then annually [20]. If the frequency of ESMO recommended follow-up visits had been applied to our 290 patients instead of the one described in the current paper, this still would have resulted in a little over 6000 CXRs.

For other tumor types, the value of CXR during surveillance after treatment is in several cases somewhat better documented. Studies on follow-up testing for breast cancer, colon cancer and endometrial carcinoma have highlighted the limited usefulness of CXR during follow-up. In a randomized study in breast cancer patients, intensive surveillance including regular CXR after primary treatment did not result in a survival benefit compared with less intensive follow-up regimen during which only clinical indicated tests like CXR were performed [21]. The diagnostic yield of CXR for relapse detection in this study was 24 of 655 patients (3.6%). In patients with colon cancer, the diagnostic yield for potential curative disease with CXR during post-surgical surveillance is also limited and is estimated to be around 1% (12 of 1356 patients) [22]. In a recent report on endometrial cancer recurrence after radiation therapy, routine follow-up CXR showed no value in earlier detection of recurrent disease in 390 patients [23]. For patients with sarcomas of the extremities, however; CXR during surveillance after definitive surgery seems to be effective. In a study by Whooley et al. [24] on follow-up tests after surgery for primary extremity sarcomas 57 of 141 patients (40%) developed distant metastatic disease. In 52% of the cases this distant disease recurrence in the lung was detected by routine follow-up CXR.

Although the current data on routine chest X-rays during follow-up after chemotherapy for DNSTC are just a single-center experience, the conclusion that its use is of limited value seems valid. Because only patients who were in complete response after chemotherapy were eligible for the analysis this subset of patients may have a lower relapse rate which might have underestimated the value of CXR during follow-up.

There is little doubt that the major reason for a patient attending follow-up after treatment is to be assured that his disease has not relapsed. However, this need for reassurance has to be balanced against the anxiety provoked by extensive follow-up testing and the chance of false positive findings, both of which can provoke stress disorders in patients. Therefore from a cost-effectiveness point of view, as well as from a patient psychological well-being perspective, routine chest X-rays can be omitted from routine follow-up. Since there were only a few patients in this study with normal tumor markers before the start of chemotherapy the value of routine CXRs during follow-up in these patients was not sufficiently investigated.

In conclusion, these data demonstrate that routine CXRs have no additional value in the detection of tumor relapses in patients with DNSTC who achieved a complete response after chemotherapy and, if necessary, surgical resection of a residual mass. In order to save valuable resources and improve patient care, CXRs can be omitted from the follow-up schedule after chemotherapy for patients with non-seminomatous testicular cancer who have elevated tumor markers at the start of chemotherapy and who are in complete remission after treatment.


    Acknowledgements
 
This study was in part supported by a grant from the University Hospital Groningen, the Netherlands.


    Footnotes
 
+ Correspondence to: Dr J. A. Gietema, Division of Medical Oncology, Department of Internal Medicine, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. Tel: +31-50-3616161; Fax: +31-50-3614862; E-mail: j.a.gietema{at}int.azg.nl Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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