Should Chemotherapy Replace Retroperitoneal Lymphadenectomy for Clinical Stage II Testicular Tumors?
1995; Elsevier BV; Volume: 70; Issue: 9 Linguagem: Inglês
10.1016/s0025-6196(11)63950-5
ISSN1942-5546
Autores Tópico(s)Sarcoma Diagnosis and Treatment
ResumoCombination chemotherapy for nonseminomatous germ cell testicular tumors (NSGCTT) is highly successful and facilitates control of even widely disseminated disease. In fact, these programs are so effective that primary chemotherapy is the preferred option for patients with supradiaphragmatic lymphatic metastatic lesions, visceral metastatic tumors, or “bulky” retroperitoneal disease, followed by elective surgical treatment of residual masses. Traditionally, however, for patients who have gross but not bulky retroperitoneal metastatic lesions and no distant disease (stage II), management has been a retroperitoneal lymph node dissection (RPLND) first, followed by chemotherapy as an adjuvant or for any subsequent relapse.1Donohue JP Thornhill JA Foster RS Bihrle R Rowland RG Einhorn LH The role of retroperitoneal lymphadenectomy in clinical stage B testis cancer: the Indiana University experience (1965 to 1989).J Urol. 1995; 153: 85-89Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Unfortunately, because the rate of relapse after RPLND in patients with clinical stage II NSGCTT is high, many patients require chemotherapy despite having undergone RPLND.1Donohue JP Thornhill JA Foster RS Bihrle R Rowland RG Einhorn LH The role of retroperitoneal lymphadenectomy in clinical stage B testis cancer: the Indiana University experience (1965 to 1989).J Urol. 1995; 153: 85-89Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Because chemotherapy was highly successful in patients with advanced disease, in the mid-1980s some investigators began to offer chemotherapy for initial management of patients with clinical stage II NSGCTT, hoping to control all disease with only one therapeutic modality and to avoid “double therapy” in some patients.2Vugrin D Whitmore Jr, WF The role of chemotherapy and surgery in the treatment of retroperitoneal metastases in advanced nonseminomatous testis cancer.Cancer. 1985; 55: 1874-1878Crossref PubMed Scopus (33) Google Scholar, 3Logothetis CJ Swanson DA Dexeus F Chong C Ogden S Ayala AG et al.Primary chemotherapy for clinical stage II nonseminomatous germ cell tumors of the testis: a follow-up of 50 patients.J Clin Oncol. 1987; 5: 906-911Crossref PubMed Scopus (59) Google Scholar, 4Horwich A Norman A Fisher C Hendry WF Nicholls J Dearnaley DP Primary chemotherapy for stage II nonseminomatous germ cell tumors of the testis.J Urol. 1994; 151: 72-77Abstract Full Text PDF PubMed Google Scholar Despite the experience of at least a decade, however, relatively few clinicians recommend primary chemotherapy for clinical stage II NSGCTT. The advocates are now joined by Lerner and colleagues, who present their experience in this issue of the Mayo Clinic Proceedings (pages 821 to 828). I completely agree with Lerner and associates that survival rates should approach 100% for patients with limited stage II disease and that finding the approach with the least associated morbidity should be the primary issue today. Lerner and colleagues report that 27 of their 28 patients (96%) achieved a complete response—20 (71%) after chemotherapy only and an additional 7 (25%) with chemotherapy plus surgical treatment. I applaud their success in sparing 71% of patients dual therapy—that is, chemotherapy plus RPLND. I question, however, whether primary chemotherapy is the optimal way to achieve this laudable goal. Primary Chemotherapy in Personal Series of Patients.— My colleagues and I managed a comparable series of patients with primary chemotherapy in the early and mid1980s at The University of Texas M. D. Anderson Cancer Center. Our results were similar, 97% (61 of 63 patients) having complete responses; 78% (49 patients) had been given chemotherapy only.5Swanson DA Logothetis CJ Primary chemotherapy for clinical stage II nonseminomatous testicular carcinoma.Adv Urol. 1988; 1: 129-144Google Scholar Our data, like those from the Mayo Clinic, showed that RPLND was most likely to be needed after chemotherapy for large masses. In contrast, however, we noted a stronger association with histologic type than they did. Only 3 of 31 patients (10%) with mixed tumors without teratomatous elements in the primary tumor required RPLND after chemotherapy, in comparison with 10 of 29 patients (34%) with teratoma in the primary lesion, regardless of size. In fact, only one of nine patients (11%) with a mass of at least 5 cm but no teratoma required RPLND. We concluded that the histologic features of the primary tumor profoundly influenced the need for RPLND after chemotherapy in this group of patients; thus, we resumed recommending primary RPLND for patients with teratoma in their primary tumor who had resectable masses in the peritoneum (less than 10 cm in diameter) and no evidence of distant disease. Primary RPLND in Personal Series of Patients.—Recently, we reviewed the results of that change in policy.6 Since 1985, 34 of our patients with clinical stage II disease and teratoma in the primary tumor underwent initial RPLND. We found metastatic disease in the retroperitoneal lymph nodes in all 20 patients who had definite radiographic evidence of a mass, 0 of 5 patients whose x-ray findings were only suggestive of a mass (that is, clinical overstaging in 15%), and 8 of 9 patients with increased biomarkers but no radiographic evidence of a mass. After RPLND, no further therapy was needed for 21 of 34 patients (62%), all of whom are alive and free of disease 9 to 97 (median, 45) months later. The other 13 patients (38%) had a relapse after RPLND and required chemotherapy. Four of these patients had pulmonary metastatic tumors, three had supraclavicular or pelvic lymph node metastatic lesions (all outside the operative field), and six had increasing biomarkers (the markers never normalized in three), but all are alive 17 to 68 (median, 45) months later. Several factors seemed prognostic for whether chemotherapy would be necessary after RPLND. Relapses occurred in 10 of 11 patients who had 5 or more “positive” lymph nodes (with metastatic involvement), 6 of 7 patients with vascular invasion, and 2 of 5 patients with a mass 4 em or larger. During this same period, 24 additional patients with clinical stage II NSGCTT with teratoma received initial chemotherapy instead of RPLND for various reasons. Nine of these 24 patients (38%) required RPLND, a rate similar to that in our earlier study, in which 10 of 29 patients (34%) required RPLND after chemotherapy.5Swanson DA Logothetis CJ Primary chemotherapy for clinical stage II nonseminomatous testicular carcinoma.Adv Urol. 1988; 1: 129-144Google Scholar Morbidity Associated With Chemotherapy Versus RPLND.—The data show that use of only RPLND can cure some patients with clinical stage II NSGCTT who have teratoma, but many patients require subsequent chemotherapy. Conversely, some patients will be cured by primary chemotherapy, but many will require RPLND after chemotherapy—22% in our published experience,5Swanson DA Logothetis CJ Primary chemotherapy for clinical stage II nonseminomatous testicular carcinoma.Adv Urol. 1988; 1: 129-144Google Scholar which corresponds to the Mayo Clinic rate of 29% reported in this issue. The most important factor is that virtually all such patients can be cured. The unanswered question, however, is which approach is associated with the least morbidity. If one modality could be effective independently, knowing the associated morbidity of RPLND vis-à-vis chemotherapy would be important. Determining the toxicity associated with chemotherapy is difficult because different institutions use diverse chemotherapeutic agents, combinations, doses, schedules, and even number of courses. Even using a chemotherapeutic program with “reduced toxicity,” however, Lerner and colleagues observed moderate to severe toxicity in 10 patients (36%). The most frequent complication (in 46% of patients) was tinnitus or paresthesias, which can persist for a long time. They also noted one case of bleomycin-associated pulmonary toxicity, which potentially increases the morbidity associated with any subsequent surgical procedure. Fertility, however, was documented in 11 of 15 patients (73%) who tried to have children. Although surgical complications associated with RPLND are rarely serious, infertility attributable to impaired ejaculation occurs in a substantial proportion of patients after a transitional RPLND.7Baniel J Foster RS Rowland RG Bihrle R Donohue JP Complications of primary retroperitoneal lymph node dissection.J Urol. 1994; 152: 424-427PubMed Google Scholar Over the years, however, this problem has been dramatically alleviated first by modifications to the boundaries of dissection (templates) and then, more recently, by the discovery that protecting and sparing the autonomic nerves that control ejaculation are possible.8Jewett MA Kong YS Goldberg SD Sturgeon JF Thomas GM Alison RE et al.Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation.J Urol. 1988; 139: 1220-1224PubMed Google Scholar, 9Donohue JP Foster RS Rowland RG Bihrle R Jones J Geier G Nerve-sparing retroperitoneal lymphadenectomy with preservation of ejaculation.J Urol. 1990; 144: 287-291PubMed Google Scholar In almost all patients with clinical stage I disease, ejaculation can be preserved. Preservation of ejaculation is more difficult in patients with clinical stage II disease, but experienced surgeons have reported successful results in this group also.8Jewett MA Kong YS Goldberg SD Sturgeon JF Thomas GM Alison RE et al.Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation.J Urol. 1988; 139: 1220-1224PubMed Google Scholar, 9Donohue JP Foster RS Rowland RG Bihrle R Jones J Geier G Nerve-sparing retroperitoneal lymphadenectomy with preservation of ejaculation.J Urol. 1990; 144: 287-291PubMed Google Scholar, 10Weidner W Zõller G Sauerwein D Fischer C Hummel G Kallerhoff M et al.A modified technique for nerve-sparing retroperitoneal lymph node dissection in stage II nonseminomatous germ cell tumors using intraoperative measurement of bladder neck pressure alterations following sympathetic nerve fiber electrostimulation.Eur Urol. 1994; 26: 67-70PubMed Google Scholar Morbidity Associated With Chemotherapy Plus RPLND.—Although the relative morbidity of RPLND versus chemotherapy (including the issues of cost and risk-to-benefit ratio)11Baniel J Foster RS Rowland RG Bihrle R Donohue JP Complications of post-chemotherapy retroperitoneal lymph node dissection.J Urol. 1995; 153: 976-980Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar is likely to be debated for some time, it seems axiomatic, if not somewhat simplistic, that RPLND plus chemotherapy is associated with more morbidity than either modality alone. Unfortunately, the data clearly show that curing all patients with only one modality is not currently possible, nor can the optimal modality invariably be chosen on the basis of known clinical and pathologic features. Tumor volume, marker increases, pathologic stage, histologic findings, and presence of vascular invasion have all been shown by various investigators, and with varied reliability, to be helpful in predicting the response to chemotherapy or the possibility of relapse after RPLND, but additional data are needed to help resolve some of the uncertainties and help provide an accurate prediction of the likelihood of cure by either RPLND or chemotherapy alone. In the meantime, when therapy is selected for a patient with clinical stage II NSGCTT, I believe it is important to consider carefully the potential consequences of the order of therapy—that is, the added morbidity of chemotherapy after RPLND versus the added morbidity of RPLND after chemotherapy—for patients who require both modalities. Baniel and coworkers12Baniel J Roth BJ Foster RS Donohue JP Cost and risk benefit in the management of clinical stage II nonseminomatous testicular tumors.Cancer. 1995; 75: 2897-2903Crossref PubMed Scopus (26) Google Scholar have clearly shown the increase in surgical complications and morbidity of RPLND performed after chemotherapy. Furthermore, preserving ejaculation in patients who undergo RPLND after chemotherapy is considerably more difficult than in those who undergo RPLND before chemotherapy, and this goal is likely to be achieved only by surgeons who have considerable experience with this technique.8Jewett MA Kong YS Goldberg SD Sturgeon JF Thomas GM Alison RE et al.Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation.J Urol. 1988; 139: 1220-1224PubMed Google Scholar, 13Jones DR Norman AR Horwich A Hendry WF Ejaculatory dysfunction after retroperitoneal lymphadenectomy.Eur Urol. 1993; 23: 169-171PubMed Google Scholar Other investigators have reported that limiting the dissection after chemotherapy may be possible in carefully selected patients, which might decrease the effect on fertility and increase the potential for sparing of nerves, but this claim needs to be confirmed by additional experience.14Aprikian AG Herr HW Bajorin DF Bosl GJ Resection of postchemotherapy residual masses and limited retroperitoneal lymphadenectomy in patients with metastatic testicular nonseminomatous germ cell tumors.Cancer. 1994; 74: 1329-1334Crossref PubMed Scopus (92) Google Scholar In the current report by Lerner and associates, 11 men successfully fathered children after receiving chemotherapy, but only 2 of these men underwent RPLND after chemotherapy. In contrast, the morbidity associated with chemotherapy is not increased by giving it after RPLND. Conclusions.—I believe that these arguments all support the initial use of RPLND for most patients with clinical stage II NSGCTT. This approach ensures that the surgical morbidity is lowest and the potential for nerve-sparing is the highest, and it eliminates clinical overstaging (which was 15% in our experience presented earlier6Swanson DA von Eschenbach AC Babaian RJ Dinney CPN The advantages of retroperitoneal lymph node dissection instead of initial chemotherapy for clinical stage II nonseminomatous germ cell testicular tumors [abstract].J Urol. 1995; 153: 244AGoogle Scholar and 23% in the report by Donohue and colleagues1Donohue JP Thornhill JA Foster RS Bihrle R Rowland RG Einhorn LH The role of retroperitoneal lymphadenectomy in clinical stage B testis cancer: the Indiana University experience (1965 to 1989).J Urol. 1995; 153: 85-89Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar), At least for patients with teratoma in their primary tumor, no disadvantages are associated with initial RPLND—we found no increase in the number of patients who required both RPLND and chemotherapy in our series of 34 patients.6Swanson DA von Eschenbach AC Babaian RJ Dinney CPN The advantages of retroperitoneal lymph node dissection instead of initial chemotherapy for clinical stage II nonseminomatous germ cell testicular tumors [abstract].J Urol. 1995; 153: 244AGoogle Scholar Some patients will have risk factors generally accepted as predictive of relapse after RPLND (for example, multiple positive lymph nodes or retroperitoneal masses 5 cm or larger, high percentage of embryonal carcinoma, vascular invasion, or very high biomarkers). When that risk is high enough (the threshold will vary for each team of surgeon plus medical oncologist), the best approach may be to initiate chemotherapy and concede that some patients will need subsequent surgical treatment. (At my institution, we reserve this approach for patients with no teratoma.) Even in this group of high-risk patients, however, some may benefit from initial RPLND plus two courses of adjuvant chemotherapy, a plan that might cause morbidity intermediate between that associated with RPLND and RPLND plus chemotherapy for relapse. This concept has been tested and found safe and effective for patients with pathologic stage II disease,15Williams SD Stablein DM Einhorn LH Muggia FM Weiss RB Donohue JP et al.Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer.N Engl J Med. 1987; 317: 1433-1438Crossref PubMed Scopus (309) Google Scholar but it requires further evaluation, I believe, for patients who undergo RPLND for clinical stage II disease. Similarly, this approach may, in fact, be optimal for patients with stage II disease by virtue of increased markers and no radiographic evidence of disease, especially if RPLND revealed no metastatic involvement in the lymph nodes; however, a clinical trial would be needed to confirm the efficacy. In the absence of such trials, initial chemotherapy seems a reasonable approach and will continue to provide important data for further refinements. Our approach at M. D. Anderson Cancer Center for patients with increased markers and no radiographic evidence of metastatic lesions is to perform RPLND if the primary tumor has a substantial proportion of teratoma and no vascular invasion is present; otherwise, we initially use chemotherapy. I commend Lerner and colleagues on their success at avoiding double therapy (in 71% of their patients) and at preserving fertility (in 73%). Until we can better predict which patients will have a complete response to only chemotherapy, however, initial RPLND still has important advantages for at least some patients. Nerve-sparing modifications decrease the morbidity associated with RPLND and render moot some of the old comparisons with the morbidity of chemotherapy. Those comparisons are most important in patients who might be cured by either modality alone. Many patients still require both RPLND and chemotherapy for maximal tumor control, however, and for this group-a group difficult to identify prospectively—morbidity is far lower when RPLND is done first.
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