Is Postchemotherapy Retroperitoneal Surgery Necessary in Patients With Nonseminomatous Testicular Cancer and Minimal Residual Tumor Masses? By Sophie D. Foss6, Hanne Qvist, Anna E. Stenwig, Hans H. Lien, Sigurd Ous, and Karl E. Giercksky Purpose: At least one third of the patients with metastatic testicular cancer are rendered tumor-free by cisplatin-based chemotherapy. One may question, therefore, the routine use of postchemotherapy retroperitoneal lymph node dissection (RLND), especially if the residual masses are less than 20 mm in diameter. To define the role of such surgery, we analyzed the postchemotherapy histology in testicular cancer patients with minimal residual disease. Patients and Methods: Seventy-eight patients with advanced nonseminomatous testicular cancer underwent RLND after three to four cycles of cisplatin- or carboplatinbased chemotherapy. In all patients, the largest diameter of the residual retroperitoneal mass was less than 20 mm. Results: Complete fibrosis/necrosis was found in 51 patients, mature teratoma in 22, and vital malignant germ cell tumor in five. In two of the latter five patients, alphafetoprotein (AFP) had increased immediately before RLND. In the 76 patients with normal pre-RLND
tumor markers, the presence of undifferentiated malignant teratoma (MTU) in the primary tumor and normal prechemotherapy tumor markers were independent parameters predicting complete fibrosis/necrosis, which was demonstrated in all 15 patients with these two pretreatment parameters. Conclusions: Postchemotherapy RLND can be omitted in patients with MTU in the primary tumor who have normal AFP/human chorionic gonadotropin (AFP/HCG) before chemotherapy and whose residual retroperitoneal mass is less than 20 mm in diameter. If the pre-RLND tumor markers are normal, RLND should be performed in all other patients with small residual masses, even in the presence of a normal computed tomography (CT) and particularly if regular follow-up of the patients is not guaranteed. J Clin Oncol 10:569-573. © 1992 by American Society of Clinical Oncology.
T
cerebral anoxia after the first chemotherapy cycle. No further chemotherapy was given, and RLND was performed 8 weeks after the first cycle. Postchemotherapy histology revealed mature teratoma. Due to this unconventional chemotherapy this patient was excluded from all subsequent analysis.
ODAY'S STANDARD treatment of patients with metastases from nonseminomatous testicular cancer consists of three to four cycles of cisplatin-based chemotherapy followed by resection of residual tumor masses.1-8 In most patients, the residual tumor masses are located in the retroperitoneal space, and the resection requires retroperitoneal lymph node dissection (RLND). This operation often leads to 'dry ejaculation' as a significant long-term morbidity, even if a modified RLND 9 is performed. "1 Due to the morbidity associated with
RLND, the ability to identify those patients in whom the operation is a purely diagnostic procedure (those patients in whom chemotherapy has induced complete necrosis of the metastatic tumors) would be advantageous. The aim of the present study was to review our
institution's experience in patients who had undergone RLND shortly after receiving three to four cycles of
cisplatin- or carboplatin-based chemotherapy and to identify parameters that are predictive for complete
Initial Staging and Treatment After orchiectomy all patients had thoracic and abdominal computed tomography (CT). The largest diameter of the retroperitoneal mass and its perpendicular diameter were measured on a transverse CT plane. The product of these diameters represented the "tumor area." In 56 patients the largest diameter of the retroperitoneal mass was between 20 and 50 mm. The largest measured diameter was 83 mm. Serum alphafetoprotein (AFP) and human chorionic gonadotropin (HCG) were determined in all patients before each chemotherapy cycle and immediately before RLND (upper normal limit of AFP, 20 pg/L; upper limit for HCG, 10 U/L). Staging was performed according to the Royal Marsden classification system." Only those stage II patients were included in the present study whose largest retroperitoneal metastases were > 20 mm in diameter or whose tumor markers were elevated if the retroperitoneal lymph nodes were less than 20 mm in diameter (six patients). Twenty-five patients had lymph node metastases be-
fibrosis/necrosis before RLND. PATIENTS AND METHODS Seventy-nine patients with nonseminomatous testicular cancer and postchemotherapy residual masses less than 20 mm in diame8 ter underwent RLND after cisplatin-based chemotherapy (76 patients) or carboplatin combinations (three patients) (Tables 1 and 2). All patients were referred to The Norwegian Radium Hospital (NRH) for primary treatment during the years from 1980 to 1990. One patient developed a life-threatening septicemia with
From the Departments of Medical Oncology and Radiotherapy, Surgical Oncology, Pathology,and DiagnosticRadiology, The Norwegian Radium Hospital,Oslo, Norway. Submitted August 8, 1991; acceptedDecember 6, 1991. Supported by the Norwegian CancerSociety. Address reprint requests to Sophie D. Fossil, MD, PhD, The Norwegian Radium Hospital,Montebello, 0310 Oslo, Norway. © 1992 by American Society of Clinical Oncology. 0732-183X192/1004-0011$3.00/0
Journalof Clinical Oncology, Vol 10, No 4 (April), 1992: pp 569-573
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570
FOSSA. ET AL Table 3. Results
Table 1. Demographics No. of patients Median age, years (range) Histology Teratoma, differentiated Malignant teratoma Intermediate Undifferentiated Trophoblastic Stage* II 111 IV Risk groupt Small-volume Large-volume Very large-volume Median maximum diameter of retroperitoneal metastases at diagnosis (range) < 20 mm 20-50 mm > 50 mm Median prechemotherapy AFP, i.g/L (range) Median prechemotherapy HCG, U/L (range)
1 30 42 5 43 7 28 60 11 7 26 (11-83) 13 56 9 27 (5-81,000) 13 (5-16,800)
1
'Royal Marsden classification system." 2 tMedical Research Council grouping system.'
tween 20 mm and 30 mm. In five of the 28 stage IV patients, the retroperitoneal mass was less than 20 mm in diameter. The patients were subsequently allocated to risk groups as recommended by the Medical Research Council Testicular Cancer Working Party.12 The majority of patients belonged to the small-volume risk group. The histologic classification of the primary tumor was done according to the Pugh classification system." At a median of 3 weeks after the last cycle of chemotherapy, the patients underwent RLND. The postchemotherapy histology was categorized as complete fibrosis/necrosis, mature teratoma, or vital malignant tumor. Statistics The personal computer-based statistical program Medlog was used for calculation of medians and ranges. Distributions were assessed by X2 test. Parameters that in the univariate analysis Table 2. Treatment Median interval from last chemotherapy cycle to RLND, days (range) Type of RLND Bilateral Unilateral Preoperative tumor markers Normal Elevated Median reduction of tumor area,* %(range) Median maximum pre-RLND diameter, mm (range) < 10mm > 10mm *Product of the two measured diameters.
No. of Patients (no. of relapsing patients)
78 27 (15-57)
23 (1-285) 51 27 76 2 88 (24-100) 9 (0-19) 49 29
Necrosis Mature teratoma Vital malignant tumor Alive NED Dead NED of ics Dead of testicular cancer
51 (2) 22 (2) 5 (2) 72 2 4
Abbreviations: NED, no evidence of disease; ics, intercurrent disease.
predicted fibrosis/necrosis with aPvalue < .1 were tested by linear regression analysis, with complete necrosis as the end point.
RESULTS
In 49 of the 78 patients the largest diameter of the residual mass was < 10 mm (Table 2). Considering the largest tumor area of the retroperitoneal mass before and after chemotherapy, the median treatment-induced size reduction was 88% (range, 24% to 100%). All but two patients had normal AFP and HCG levels before RLND. In the latter two patients, the AFP level was normal before the start of the last chemotherapy cycle but had increased immediately before RLND. Completely necrotic tumor tissue was found in 51 patients, mature teratoma in 22, and vital malignant germ cell tumor in five patients (Table 3). Two patients from each of the three postchemotherapy histologic subcategories developed a recurrence, only one of them primarily in the retroperitoneal space. Not surprisingly, both patients with elevated tumor markers before RLND had residual vital malignant tumor (Table 4). These patients were excluded from further analysis. In the other three patients with vital malignant tumors, none of the preoperative investigations indicated the presence of residual vital malignant tumor. In particular, all three patients had residual masses < 10 mm in diameter after chemotherapy. Among the 76 patients with normal AFP and HCG levels before RLND, normal prechemotherapy tumor markers and the presence of undifferentiated malignant teratoma (MTU) in the primary tumor correlated with complete necrosis after chemotherapy (Table 5). The likelihood for necrosis was also high in patients who before chemotherapy had elevated HCG and in whom this marker decreased by at least 90% during the first two cycles. No similar impact of AFP was observed. In 11 of 49 patients with residual postchemotherapy masses < 10 mm in diameter, mature teratoma was found, and three had vital malignant tumor (Table 6). In a multivariate analysis, only the presence of normal prechemotherapy tumor markers and MTU of the pri-
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POSTCHEMOTHERAPY SURGERY FOR TESTICULAR CA Table 4. Patients With Residual Vital Malignant Tumor Patient Pugh 3 No. System" 18 264 288 46* 87*
Prechemotherapy Prechemotherapy Prechemotherapy Postchemotherapy AFP (ng/L) HCG (U/L) Stage diameter (mm) diameter (mm)
MTU MTU MTU MTU MTU
26 5 9 4,430 7,050
1,340 43 15 5 5
IV II II III II
25 10 20 40 80
5 10 6 18 15
Postchemotherapy Postchemotherapy AFP (pLg/L( HCG (U/L) 5 5 5 70 97
5 5 5 5 5
% Size Reduction
Outcome
96 40 91 78 94
Alive, NED Alive, NED Alive, NED Dead Dead
"*Excludedfrom univariate and multivariate analyses. mary tumor predicted complete necrosis (P = .003 and .008, respectively). Thus, complete necrosis/fibrosis was found in all 15 patients with MTU and normal prechemotherapy markers. Of these 15 patients, 10 had a normal postchemotherapy abdominal CT. In the remaining five, the largest diameter of the residual mass was 11 to 15 mm. Due to the low number of patients with elevated prechemotherapy HCG levels, the degree of HCG reduction during the first two cycles was not assessed by the multivariate analysis. Table 5. Predictive Factors: Univariate Analysis
Parameter
Prechemotherapy diameter (mm) < 20 > 20 Primary tumor histology MTU Non-MTU Postchemotherapy diameter (mm) • 10 > 10 Prechemotherapy AFP level Normal Elevated Prechemotherapy HCG level Normal Elevated Prechemotherapy markers Normal Elevated Size reduction* > 90% < 90% HCG reductiont (two cycles) > 90% < 90% AFP reductiont (two cycles) Ž 90% < 90%
Necrosis/ Fibrosis
Mature Teratoma/Vital Malignant Tumor (no. of patients) Total
7 44
6 19
13 63
31 20
9 16
40 36
35 16
14 11
49 27
27 24
8 17
35 41
29 22
6 19
35 41
22 29
2 23
24 52
24 27
10 15
34 42
15 6
7 12
22 18
17 6
12 5
29 11
41
.74
In a recent study by the Medical Research Council Testicular Cancer Study Group, "residual masses" were defined as CT-visible tumors with a diameter of at least 20 mm.'4 This was the cut-off point selected in the present investigation. A subgroup of these patients are those with normal CT. The definition of "normal CT" differs at the various institutions. According to G. Pizocarro (personal communication, May 1991), a normal CT implies no visible mass at all. Stomper et al"' use a cut-off point of 15 mm. The definitions of a normal CT used by Richie et al"'6 and us" allow for the presence of CT-visible lymph nodes < 10 mm. According to this definition, 65% of our patients from the present study had a normal postchemotherapy CT. During the last 10 years the principle policy of our institution has been to give primary chemotherapy to all nonseminoma patients presenting with _ stage IIb disease and to patients with elevated tumor markers, even if measurable metastases were not found or if metastases were less than 20 mm (if located retroperitoneally). Tumor marker-negative stage II patients with metastases less than 20 mm underwent primary RLND. It is well known that 50% to 70% of stage II patients with minimal retroperitoneal disease can be cured by primary RLND and never need chemotherapy."8 Of 31 stage II patients in the present series, 30 had retroperitoneal masses less than 30 mm and would probably have been candidates for primary surgical treatment at other institutions. However, the condition for such an apTable 6. Diameter of the Postchemotherapy Residual Mass and Histology Vital
*Size of the area = largest diameter x perpendicular diameter. assessable patients.
"t40
P
DISCUSSION
.061
Diameter (mm)
0 1-5 6-10 11-19 Total
Necrosis/ Fibrosis
Mature Teratoma
Malignant Tumor
Total
3 13 19 16 51
0 2 9 11 22
0 1 2 0 3
3 16 30 27 76
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FOSSA ET AL
proach is the feasibility of the frequent follow-up examination (including the possibility to perform frequent CT examinations). In the 1980s such frequent, specialized follow-up procedures were not possible for the relatively large amount of testicular cancer patients seen at NRH. Therefore, the described combined treatment approach was selected at our institution, representing the most feasible and safest means to achieve high cure rates. In metastatic nonseminomatous testicular cancer"8 the main therapeutic purpose of postchemotherapy surgery is to remove residual mature teratoma, which may be the origin of late recurrences either by malignant dedifferentiation 19 or manifesting as growing teratoma.2 In addition, the histologic examination of the operation specimen identifies those patients who do not need further treatment (those with completely necrotic/ fibrotic masses and those with radically resected mature teratoma). Patients with residual vital malignant tumor are usually treated by further chemotherapy, even though the tumor masses are resected radically. Thus, postchemotherapy RLND is a purely diagnostic procedure in patients with completely necrotic/fibrotic metastases. Several reports have dealt with the incidence of the three histologic types seen after chemotherapy (Table 7): complete fibrosis/necrosis, mature teratoma, and vital malignant tumor, which occur in about 45%, 35%, and 20% of the patients, respectively. During recent years the percentage of patients with vital malignant tumor seems to have decreased slightly, probably due to improved chemotherapy. In the present series of patients with small residual tumor masses, as many as 51 of 76 (67%) markernegative patients had complete fibrosis/necrosis in the RLND specimen and underwent surgery unnecessarily. This percentage is higher than the 40% to 50% reported in unselected patients." Only 7% of our patients had Table 7. Postchemotherapy Histology in Patients With Advanced Germ Cell Tumors Histology
First Author (year)
Total
Complete Necrosis/ Fibrosis
Bracken (1983)1 2 Tait (1984) Pizzocaro (1985)' Donohue (1987)4 Harding (1989)5 6 Toner (1990) 7 Mulder (1990) 8 Aass (1991) Total (%)
23 73 36 80 42 122 55 173 604
9 25 16 35 19 57 31 85 277 (46)
Malignant Teratoma
Vital Malignant Tumor
7 32 10 33 14 48 12 50 206 (34)
7 16 10 12 9 17 12 38 121 (20)
vital malignant tumor, which is lower than reported in series of consecutive patients. Rising tumor markers indicated residual vital malignant tumor in two cases. Retrospectively, these patients should not have undergone surgery at the time of tumor marker increase but should have received salvage chemotherapy. Can those patients be identified who have completely necrotic/fibrotic tumors and in whom RLND safely can be omitted after chemotherapy? In the univariate analysis the size of the residual mass or a normal CT did not significantly predict necrosis. Three of the patients with normal CT (lesions _ 90% size reduction was significantly correlated with the presence of complete necrosis. In 55 patients (nine of them with pure seminoma) Mulder et al 7 identified size reduction of greater than 70% as a predictive parameter. On the other hand, Toner et al6 did not find chemotherapy-induced size reduction to be a useful predictive parameter for posttreatment histology. In our patients with small residual postchemotherapy lesions, size reduction did not correlate with the incidence of fibrosis/necrosis. The only significant pre-RLND predictive factor was the presence of MTU in the primary tumor in patients who, before chemotherapy, presented with normal tumor markers. This combination predicted complete necrosis in 15 of our 15 patients. In this small group of highly selected patients with embryonal carcinoma, routine postchemotherapy RLND probably can be omitted if the residual mass is less than 20 mm in diameter. These observations are in agreement with results reported by Logothetis et a12 1 showing that complete response develops significantly more often in patients with pure embryonal carcinoma (- seminoma) than those with teratomatous elements in the primary tumor. The question remains as to whether all other patients with residual masses less than 20 mm in diameter should have postchemotherapy RLND and when. Many oncologists recommend observation of such patients, expecting that most of the small residual masses will resolve spontaneously. In patients with persisting or increasing postchemotherapy masses, RLND is performed after an
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POSTCHEMOTHERAPY SURGERY FOR TESTICULAR CA
observation time of several months. This policy may be safe as long as good patient compliance is guaranteed and frequent high quality CTs can be performed. As these residual tumors may be slow-growing, late recurrences may occur, and regular follow-up is necessary for several years. If the above requirements are not fulfilled, eg, due to sociogeographic conditions, we feel that routine RLND should represent the standard treatment
573 after chemotherapy in patients who present with a retroperitoneal mass initially, even if this mass has virtually disappeared during chemotherapy. In selected cases RLND may be performed unilaterally or as a nerve-sparing procedure,, thus preserving antegrade ejaculation. The applicability of more limited RLND will be addressed in a future study.
REFERENCES 1. Bracken BB, Johnson DE, Frazier H, et al: The role of surgery following chemotherapy in stage II germ cell neoplasms. J Urol 129:39-43, 1983 2. Tait D, Peckham MJ, Hendry WF, et al: Postchemotherapy surgery in advanced non-seminomatous germ-cell testicular tumours: The significance of histology with particular reference to differentiated (mature) teratoma. Br J Cancer 50:601-609, 1984 3. Pizzocaro G, Salvioni R, Pasi M, et al: Early resection of residual tumor during cisplatin, vinblastine, bleomycin combination chemotherapy in stage III and bulky stage II nonseminomatous testicular cancer. Cancer 56:249-255, 1985 4. Donohue JP, Rowland RG, Kopecky K, et al: Correlation of computerized tomographic changes and histological findings in 80 patients having radical retroperitoneal lymph node dissection after chemotherapy for testicular cancer. J Urol 137:1176-1179, 1987 5. Harding MJ, Brown IL, Macpherson SG, et al: Excision of residual masses after platinum based chemotherapy for nonseminomatous germ cell tumours. Eur J Cancer Clin Oncol 25:1689-1694, 1989 6. Toner GC, Panicek DM, Heelan RT, et al: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: Recommendations for patient selection. J Clin Oncol 8:1683-1694, 1990 7. Mulder PFA, Oosterhof GON, Boetes C, et al: The importance of prognostic factors in the individual treatment of patients with disseminated germ cell tumours. Br J Urol 66:425-429, 1990 8. Aass N, Klepp O, Cavallin-StAhl E, et al: Prognostic factors in unselected patients with non-seminomatous metastatic testicular cancer: A multicenter experience. J Clin Oncol 9:818-826, 1991 9. Whitmore WF Jr: Surgical treatment of clinical stage I nonseminomatous germ cell tumors of the testis. Cancer Treat Rep 66:5-10, 1982 10. Aass N, FossA SD, Lien HH, et al: Is routine primary retroperitoneal lymph node dissection still justified in patients with low stage non-seminomatous testicular cancer? Br J Urol 65:385390,1990 11. Peckham M, Barrett J, McElwain TJ, et al: Combined management of malignant teratoma of the testis. Lancet 2:267-270, 1979
12. Medical Research Council Working Party on Testicular Tumours: Prognostic factors in advanced non-seminomatous germ cell testicular tumours: Results of a multicentre study. Lancet 1:8-11, 1985 13. Collins DH, Pugh RCB: The pathology of testicular tumours. Br J Urol 36:1-11, 1964 (suppl) 14. Mead GM, Stenning SP, Parkinson MC, et al: The Second Medical Research Council Study of Prognostic Factors in Nonseminomatous Germ Cell Tumors. J Clin Oncol 10:85-94, 1991 15. Stomper PC, Jochelson MS, Garnick MB, et al: Residual abdominal masses after chemotherapy for nonseminomatous testicular cancer: Correlation of CT and histology. Am J Roentgenol 145:743-746, 1985 16. Richie JP, Garnick MB, Finberg H: Computerized tomography: How accurate for abdominal staging of testis tumours? J Urol 127:715-717, 1982 17. Fossl SD, Ous S, Lien HH, et al: Post-chemotherapy lymph node histology in radiologically normal patients with metastatic nonseminomatous testicular cancer. J Urol 141:557-559, 1989 18. Lange PH, Fraley EE: Controversies in the management of low volume stage II nonseminomatous germ cell testicular cancer. Semin Oncol 15:324-334, 1988 19. Ulbright TM, Loehrer PJ, Roth LM, et al: The development of non-germ cell malignancies within germ cell tumours. Cancer 54:1824-1833, 1984 20. Logothetis CJ, Samuels ML, Trindace A, Johnson DE: The growing teratoma syndrome. Cancer 50:1629-1635, 1982 21. Logothetis CJ, Swanson DA, Dexeus F, et al: Primary chemotherapy for clinical stage II nonseminomatous germ cell tumors of the testis: A follow-up of 50 patients. J Clin Oncol 5:906-911, 1987 22. Jewett MAS, Kong Y-SP, Goldberg SD, et al: Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation. J Urol 139:1220-1224, 1988 23. Donohue JP, Foster RS, Rowland RG, et al: Nerve-sparing retroperitoneal lymphadenectomy with preservation of ejaculation. J Urol 144:287-292, 1990
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