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Postchemotherapy Retroperitoneal Surgery Remains Necessary in Patients With Nonseminomatous Testicular Cancer and Minimal Residual Tumor Masses

From the Departments of Medical Oncology, Pathology, Radiology, Surgical Oncology, and Clinical Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.

Address reprint requests to Sophie D. Fosså, MD, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway; e-mail: s.d.fossa{at}klinmed.uio.no.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To determine preoperative parameters that predict the histology of specimens obtained by retroperitoneal lymph node dissection (RPLND) in patients with nonseminomatous germ cell cancer (NSGCT) whose residual mass was 20 mm in diameter after modern cisplatin-based induction chemotherapy.

Patients and Methods: Eighty-seven patients with metastatic NSGCT underwent RPLND after having received cisplatin- or carboplatin-based induction chemotherapy. In all patients, the largest diameter of the residual mass on the transaxial plane was 20 mm, as assessed by abdominal computed tomography (CT) immediately before RPLND.

Results: Complete fibrosis or necrosis was found in 58 patients (67%), teratoma was found in 23 patients (26%), and vital malignant germ cell tumor was found in six patients (7%), including one patient with rhabdomyosarcoma in the RPLND specimen. In five of the six latter patients, the residual lesion was 10 mm at pre-RPLND CT. No pre- or postchemotherapy clinical or radiologic parameter was identified that significantly predicted the histology of the residual mass.

Conclusion: One third of retroperitoneal postchemotherapy lesions 20 mm contained residual vital tumor tissue, despite modern chemotherapy regimens. Therefore, postchemotherapy RPLND remains necessary in patients with minimal-size residual lesions to facilitate easy and safe follow-up and initiate additional therapy as early as possible, thus avoiding recurrences.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
TREATMENT OF metastatic nonseminomatous germ cell tumors (NSGCTs) consists of cisplatin-based chemotherapy followed by surgical removal of residual masses. The primary site of metastases and of residual tumor masses is the retroperitoneal space, and complete resection most often requires retroperitoneal lymph node dissection (RPLND). Residual masses contain complete fibrosis/necrosis in approximately 40% to 50% of the patients. Approximately 35% to 40% of patients display mature or immature teratomatous elements without other components, whereas vital malignant tumor is described in 10% to 15% of patients.¹ Although RPLND may have therapeutic significance in the latter two groups, the procedure is purely diagnostic in patients with fibrosis/necrosis. Except for being a moderately sized surgical procedure in most patients with unavoidable acute morbidity,^2,3 RPLND may lead to long-term sequelae such as loss of antegrade ejaculation⁴ or disturbance of temperature sensations in the legs.⁵ Limited RPLND, nerve-sparing RPLND, or the resection of the macroscopic tumor only are methods that have been introduced to reduce these long-term effects.^6–10

A further attempt to limit the prevalence of long-term sequelae in patients with testicular cancer is by omitting RPLND by preoperative identification of residual retroperitoneal masses that are likely to contain complete fibrosis/necrosis.^1,8,11,12 Based on patient data of patients predominantly treated in the 1980s, it has been advocated that the levels of serum tumor markers at diagnosis (alpha-fetoprotein [AFP], human choriogonadotropin [HCG], and lactate dehydrogenase [LDH]), the degree of tumor regression during chemotherapy, the diameter of the residual mass,⁷ or a combination of these parameters^11,13,14 enable the prediction of the histology of the residual mass. In particular, with residual masses 20 mm, the risk of finding vital malignant tumor tissue is considered minimal.¹⁵ Also, the histology of the primary tumor and, in particular, the presence and amount of teratomatous elements have been considered important predictors of the postchemotherapy histology.^11,13

In 1992, our group reported that 27 (35%) of 78 patients with residual masses 20 mm displayed teratoma (22 patients) or vital malignant tumor (five patients) in the postchemotherapy RPLND specimen.¹⁶ Because of these results, the Norwegian Radium Hospital (NRH) in Oslo, Norway, continued to perform postchemotherapy RPLND in all patients with prechemotherapy retroperitoneal masses, regardless of the size of the mass at postchemotherapy abdominal computed tomography (CT). With the more-effective cytotoxic treatments available in the 1990s, this policy might be challenged. Therefore, this study is aimed at evaluating the histology of postchemotherapy RPLND specimens in patients treated with modern chemotherapy for malignant germ cell tumors from 1990 onward and in whom the residual retroperitoneal mass was 20 mm. In particular, we wanted to assess whether it would be possible to predict the histology of the RPLND specimens by preoperative measures.

	PATIENTS AND METHODS

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Patients
Patients with a metastatic NSGCT were included if they fulfilled the following criteria: diagnosis made during 1990 to 2000 and primary chemotherapy received at the NRH; presence of a retroperitoneal mass at diagnosis and postchemotherapy residual retroperitoneal mass with a maximum diameter of 20 mm on the transaxial CT plane; and RPLND performed within 3 months after discontinuation of induction chemotherapy.

Routine Management
After diagnosis by orchiectomy (in case of a testicular cancer) or by biopsy (in case of an extragonadal germ cell malignancy), all patients had thoracic and abdominal CT. Clinical staging was performed according to the recommendations of the Royal Marsden Hospital¹⁷ (stage I, no metastases; stage II, retroperitoneal lymph node metastases; stage III, retroperitoneal and supradiaphragmatic lymph node metastases; and stage IV, parenchymatous metastases). Histology was recorded based on the World Health Organization classification.¹⁸ Serum AFP, HCG, and LDH were determined at the time of staging, before each chemotherapy cycle, and immediately before postchemotherapy RPLND (upper normal limit for AFP, 14 kU/L; upper normal limit for HCG, 5 U/L; and upper normal limit for LDH, 450 U/L).

Principally, all consenting patients were entered onto ongoing international trials if they fulfilled the protocol’s eligibility criteria.^19–21 This implied the use of etoposide and bleomycin in all patients and, in some good-risk patients, the application of carboplatin²⁰ (instead of cisplatin) or, in some high-risk patients, the application of ifosfamide,²¹ dependent on the individual trial. If carboplatin was used instead of cisplatin, the recommended dose of the carboplatin, etoposide, and bleomycin (CEB) regimen was five times the glomerular filtration rate +25²⁰ (carboplatin and etoposide, 120 mg/m² on days 1 to 3; and bleomycin, 30 U on day 2). Patients who could not be included in a formal trial received four cycles of bleomycin, etoposide, and cisplatin (BEP; bleomycin, 90 U, cumulative dose, 270 U/L; etoposide, 500 mg/m²; and cisplatin, 100 mg/m²). RPLND was routinely performed 6 to 8 weeks after completion of the last chemotherapy cycle, independently of the postchemotherapy serum levels of AFP and HCG, even though the postchemotherapy abdominal CT did not display any or only minimal tumor masses. Unilateral RPLND was considered sufficient in patients with minimal residual tumors, and a nerve-sparing procedure was performed as often as possible.⁹ The extent of the unilateral RPLND on the side of the primary tumor RPLND was the same as previously described,²² reaching from the level of the renal artery to the bifurcation of the ipsilateral arteria iliaca communis. In case of a right-sided testicular tumor and prechemotherapy enlarged lymph nodes on the left side, the RPLND also comprised the lymphatic tissue on the contralateral side proximally to the inferior arteria mesenterica. All perioperatively visible or palpable tumor masses were removed. In some cases, the urologist decided perioperatively that a more complete bilateral RPLND would be necessary to eradicate all visible tumor masses, but frozen sections were not used during the RPLND to decide on the extent of the operation. The RPLND was considered complete if there were free margins and if an abdominal CT scan, taken 8 weeks after RPLND, did not display any residual tumor mass.

The results of the histopathologic examination of the RPLND specimen was categorized as complete necrosis/fibrosis, pure teratoma (immature or mature), or vital malignant tumor. For vital malignant tumors, the different elements were described.

Patients with vital malignant tumor in the postchemotherapy RPLND specimen received two adjuvant cycles of cisplatin-based chemotherapy, preferably including drugs not applied preoperatively. In patients with complete necrosis/fibrosis or mature or immature teratoma, further treatment was withheld until relapse.

Follow-Up
All patients were observed at 2- to 4-month intervals at the NRH’s outpatient department. After completion of all treatment, an abdominal CT was performed to confirm the completeness of the RPLND. Thereafter, no further CTs were performed unless there was a clinical or serologic suspicion of relapse. In case of progression (increase of serum HCG or AFP, or new tumor lesions), patients received available second- or third-line chemotherapy or underwent additional surgery or radiotherapy or both. All patients were followed-up to time of death or to June 30, 2002.

Investigational Methods
For the purpose of the study, each patient’s CT scans before and after chemotherapy were reviewed by one radiologist (H.H.L.). The largest diameter of the retroperitoneal mass and its perpendicular diameter were measured on a transaxial CT plane. One pathologist (G.C.A.) reviewed all histologic specimens using the World Health Organization classification system.¹⁸ In the primary tumor, the amount of the teratoma (mature or immature) was estimated as more than 50%, 10% to 50%, or less than 10%. The histology of the RPLND specimen was classified as complete necrosis/fibrosis, teratoma, or vital malignant tumor and quantified.

All patients were grouped into three prognostic groups based on the guidelines of the International Germ Cell Consensus Classification.²³ According to Steyerberg et al,¹³ we calculated a necrosis score based on the presence or absence of teratoma in the primary tumor, elevation of serum tumor markers at diagnosis (AFP, HCG, and LDH), and tumor reduction 70%. For each of these five categories, a score of 0 or 1 was given, resulting in a score ranging from 0 to 5. A high score is expected to mirror a high probability of complete necrosis/fibrosis.

Statistical Analysis
The data were analyzed using the SPSS for Windows (version 10.0; SPSS, Inc, Chicago, IL) using descriptive statistics (median, range, minimum, and maximum). Differences between continuous variables were assessed by the Kruskal-Wallis test. Differences between categorical variables were evaluated using the ² test. Progression-free and overall survival was estimated using the Kaplan-Meier method, starting from the date of orchiectomy (diagnosis). A P value of less than .05 was regarded as statistically significant.

	RESULTS

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Patients
A total of 87 patients were included onto the study (testicular cancer, n = 86; extragonadal, n = 1; Table 1). Embryonal carcinoma with or without yolk sac elements was the most frequent histology of the primary tumor (51 patients). Sixty-six patients (76%) were considered as being in the good prognosis group and nine patients were in the poor prognosis group according to the International Germ Cell Consensus Classification. The maximum pretreatment diameter of retroperitoneal masses ranged from 9 to 130 mm (median, 25 mm).

Postchemotherapy Findings
After chemotherapy, the size of the residual masses ranged from 0 to 20 mm (median, 10 mm). A total of 54 patients (62%) had lymph nodes 10 mm; 21 of the patients had nodes with diameters of 5 mm. The median size reduction was 67% (Table 2), with size reductions of 68%, 60%, and 63% in patients with necrosis/fibrosis, teratoma, and vital malignant tumor, respectively. A total of 19 patients (22%) displayed elevated serum tumor markers, with abnormal HCG or AFP levels in only four of the 19 patients (Fig 1). We found vital malignant germ cell tumor in six patients (7%) and teratoma in 23 patients (26%; mature, n = 22; immature, n = 1) in the postchemotherapy RPLND specimen (Table 2). Complete necrosis was described in 58 operation specimens (67%). Of 23 patients with postchemotherapy teratoma, five patients belonged to the intermediate prognosis group and three belonged to the poor prognosis group. Of the six patients with postchemotherapy vital malignant tumor, one belonged to the intermediate prognosis group and none belonged to the poor prognosis group (Table 2). No statistical associations were observed between the histology of the primary tumor, the initial size of the retroperitoneal mass, the pretreatment serum levels of the tumor markers, and the postchemotherapy RPLND histology (² tests, all P > .05). Neither shrinkage of the retroperitoneal lesion during chemotherapy nor size of the residual mass predicted the postchemotherapy histology. Five of six lesions with vital malignant tumor at RPLND were found in masses 10 mm. The prevalence of residual masses with complete necrosis/fibrosis tended to decrease with increasing size of the postchemotherapy mass (Fig 1; linear by linear association, P = .05). Elevation of serum tumor markers before RPLND was not associated with postchemotherapy histology and was observed only in patients with residual necrosis/fibrosis or teratoma and not in patients displaying vital malignant tumor (Table 2 and Fig 1).

View larger version (11K): [in this window] [in a new window]   Fig 1. Patients with pre-retroperitoneal lymph node dissection elevated serum tumor markers. LDH, lactate dehydrogenase; HCG, human choriogonadotropin; AFP, alpha-fetoprotein; Ter, teratoma; N/F, necrosis/fibrosis; +, no. of patients; 1, median, range LDH (U/L); 2, individual HCG levels (U/L); 3, individual LDH level (U/L); 4, individual AFP level (kU/L).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study demonstrated that 33% of minimally sized ( 20 mm) postchemotherapy retroperitoneal lesions contained vital tumor (teratoma, 26%; and vital malignant tumor, 7%). As demonstrated in Table 2 and Figure 2, five out of a total of six lesions with vital malignant tumor histology were 10 mm. We could not identify any pretreatment or postchemotherapy parameters that significantly predicted the histopathology of the residual mass, although the prevalence of complete necrosis/fibrosis tended to increase with decreasing diameter.

View larger version (35K): [in this window] [in a new window]   Fig 2. Postchemotherapy histology and size of the retroperitoneal mass at computed tomography (CT).

During postchemotherapy RPLND, all visible retroperitoneal lesions are to be removed.^26,27 Two decades ago, this always meant bilateral lymph node dissection, including the retrocrural and ipsilateral iliac region.³¹ This is still relevant in patients with high-volume residual disease, but this policy has gradually been modified in patients with minimal lesions. Unilateral RPLND and nerve-sparing techniques or even resection of the tumor only have been introduced, with acceptable results.^6–10 Our surgeons prefer to perform a unilateral or bilateral nerve-sparing RPLND in these patients with minimal residual lesions whenever possible, thus preserving antegrade ejaculation in most patients.⁹ If the RPLND specimen contains teratoma or complete necrosis/fibrosis, we regard the surgical approach of unilateral RPLND as sufficient. However, this strategy may not completely avoid the risk of growing teratoma³² nearby the resection area, as evident in two of our patients (Table 5, patients 294 and 881). If vital malignant tumor is found in the RPLND specimen, in particular in the presence of non–germ cell elements (Table 4, patient 961), extensive surgery at an early phase of the disease is possibly indicated, as also discussed by Fizazi et al.²⁸ In such cases, we continue to use adjuvant chemotherapy, although its role can be debated.

Our principal strategy of chemotherapy followed by RPLND has to be discussed on the background of an alternative management policy, which involves the performance of primary RPLND in low-volume stage II patients. By such an approach, at least 50% of the patients may be cured by RPLND alone, without the need for chemotherapy.³³ However, primary RPLND in stage II patients is usually more extensive than postchemotherapy RPLND, with an increased risk of dry ejaculation. In addition, even though considered to be cured by surgery alone, 20% to 30% of patients will relapse during follow-up because micrometastases are not eradicated.³⁴ This implies a more difficult and more stressful follow-up in primarily operated patients without adjuvant chemotherapy than in patients with postchemotherapy RPLND. Furthermore, as also pointed out by Baniel et al,³⁴ a cancer center’s policy toward these patients has to consider the availability of specialized therapeutic care and the conditions provided by the health care service.

Our data confirm the observation from the Indiana group³⁵ that slightly elevated AFP or HCG after induction chemotherapy, with no increasing levels, do not represent a contraindication to RPLND of residual masses. Slightly elevated serum LDH levels were observed in as many as 17% of the patients. In only one patient, a highly increased LDH level (> x 2.5 of the upper normal range, Fig 1) together with a marginally elevated HCG would probably have warranted rapid tumor relapse after RPLND, despite complete necrosis in the RPLND specimen.

We found teratoma or vital malignant tumor in 33% of the patients (29 of 87 patients). This percentage is surprisingly high compared with earlier reports on relapses in comparable patient groups in whom no postchemotherapy surgery was performed. Napier et al¹² reported five relapses (19%) in 26 patients with residual masses 20 mm, which were not resected. In the experience of the Indiana group,³⁵ four (15%) of 27 patients relapsed after a conservative approach. The combined relapse rate is clearly, but not significantly, lower compared with the relatively high frequency of teratoma or vital malignant tumor in our RPLND specimen (nine of 53 v 29 of 87, respectively; ² test, P = .06). From these figures, one may argue that patients with retroperitoneal postchemotherapy lesions 20 mm can be safely observed without additional surgery. Not all residual lesions will regrow, and necessary surgery could be reserved for patients with subsequently enlarging masses. Such a strategy requires intensive follow-up for at least 5 years, preferably at centers with an experienced team of specialists. In many countries, as also in Norway, this is difficult to accomplish, especially because these young men frequently change their place of living, with long-lasting periods in foreign countries. Although the acute treatment-related morbidity may be prolonged by our strategy of immediate postchemotherapy RPLND in patients with residual masses 20 mm, long-term studies on quality of life in these patients do not demonstrate a negative impact of our policy of routine postchemotherapy RPLND on overall mental or physical health.³⁶

The observed discrepancies between histology of residual postchemotherapy tumors and observed relapses indicate variability in the biologic behavior of the residual tumor. Not every patient develops a relapse despite unresected postchemotherapy teratoma or vital malignant tumor. One may debate whether even the experienced pathologist is able to evaluate the true viability of the tumor cells of residual teratoma or malignant tumor in a postchemotherapy RPLND specimen. Some tumor cells may have been lethally damaged without morphologic alterations, as viewed by light microscopy, and may gradually disappear. In other cases, subsequent tumor growth may be caused by persisting malignant or teratomatous cells that were not damaged by chemotherapeutics. If these two alternatives exist, molecular biologic parameters in postchemotherapy RPLND specimens will hopefully assist in further identification of these two cohorts. The role of positron emission tomography³⁷ should also be investigated in relation to the discrimination of a varying biology of residual tumor. However, the low relapse rate of only 6% (five recurrences in 87 operated patients) in this study speaks in favor of the routine use of postchemotherapy RPLND when compared with the reported relapse rates of 15%³⁵ to 19%¹² in nonoperated patients.

In conclusion, even after modern induction chemotherapy in patients with advanced germ cell malignancy, one third of minimal residual postchemotherapy retroperitoneal masses contained teratoma or vital malignant tumor, whereas two thirds of the masses were categorized as completely necrotic/fibrotic. There were no clinical, radiologic, or serologic parameters available to predict the histopathology of the individual RPLND specimen at a clinically useful level. Therefore, we continue to recommend the routine performance of retroperitoneal surgery in patients with residual masses 20 mm.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted March 28, 2003; accepted June 9, 2003.

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