Patients with stage II germ cell tumors, which comprise patients with metastases confined to the retroperitoneum (TxN1-3M0S0-1), are by definition considered good risk according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification with attendant excellent clinical outcomes. For practical purposes, patients that present with Stage II disease or develop retroperitoneal disease on surveillance for stage I disease (TanycN1-N3M0S0-1 relapse) are managed similarly. For patients with nonseminomatous germ cell tumors (NSGCT), the treatment options consist of systemic chemotherapy +/- post-chemotherapy retroperitoneal lymph node dissection (RPLND) or primary RPLND +/- systemic chemotherapy. For patients with Stage II seminoma, radiation therapy is the locoregional option instead of RPLND, and is generally only used in chemotherapy-naïve patients. Almost all patients with stage II GCT are cured regardless of the initial choice of treatment modality, and an utmost priority is to minimize the toxicity of the selected treatment.1, 2 Chemotherapy results in possibility of cardiovascular disease, metabolic syndrome, hypogonadism, pulmonary toxicity, Raynaud phenomenon, ototoxicity, neuropathy, infertility, renal failure, and secondary malignancy.3, 4 While nerve-sparing RPLND for low volume retroperitoneal disease (clinical stage IIA), in expert hands at high volume centers, has practically no long-term complications, nevertheless surgical risks and long-term risks of ejaculatory dysfunction and bowel obstruction do exist. In this article, we discuss practical considerations in managing patients with Stage II GCT.5
Stage IIA disease
Clinical management of stage IIA germ cell tumors, regardless of histology, starts with the understanding that, ultimately, 20-25% of these patients (TanycN1M0S0) will have pN0 disease.6 As such, it is prudent to wait and repeat short interval imaging (6-8 weeks) as well as tumor markers prior to making a hasty management decision, as suggested by AUA and EAU guidelines.7, 8 If the node has involuted, the patient can safely be observed; if it is stable or enlarged, appropriate therapy (RPLND or chemotherapy for NSGCT, radiotherapy, chemotherapy, or surgery preferably in the context of clinical trial for seminoma) can be administered. Not only does this strategy potentially identify patients that were destined to be cured by orchiectomy alone (ie those that would have been pN0), it also selects out patients that have significant short interval disease progression (multiple enlarged nodes (pN2), extraretroperitoneal disease, etc.) that were unlikely to be cured by locoregional therapy alone. Our practice for patients with clinical stage IIA NSGCT is to schedule for RPLND 6-8 weeks from consultation, with repeat imaging and serum tumor markers 1 week prior to surgery. If the patient has involution of nodes or significant radiographic or marker progression, surgery is canceled.
Primary RPLND is desirable due to avoiding chemotherapy in the majority (85%) of patients with pN1 disease, pathologically negative lymph nodes, chemo-resistant teratoma, and 98-100% long-term cancer-specific survival after primary RPLND with or without adjuvant chemotherapy.1, 2, 9-11 As such, many testicular cancer experts have started to advocate for primary RPLND as the preferred treatment modality in clinical stage IIA GCT and particularly in NSGCT.
Conversely, RPLND may not be curative in up to 50% of stage II patients and high-quality RPLND might not be readily available.1, 2, 9 Induction chemotherapy is attractive with high complete response rates, access in community-based facilities, and excellent long-term survival approaching 100%.2, 9, 12 However, patients are exposed to long-term toxicity and may relapse with chemo-refractory GCT, malignant transformation, or teratoma.9, 13, 14 Nerve-sparing technique, full bilateral template, and curative intent by adhering to proper anatomic principles are all emphasized in the AUA guidelines and discussed at length in our review chapter. Another recently published review by Kollmannsberger focuses similarly on how a primary nerve-sparing RPLND is diagnostic and therapeutic in stage IIA NSGCT and that it should be the preferred choice over primary chemotherapy.15 The authors underscore that such an approach allows the identification of false negative patients, successfully treats those with pathological N1 disease and avoids additional treatment in the vast majority of patients. In addition, they point that patients who recur after primary RPLND rarely if ever die of their disease. For post-orchiectomy marker negative NSGCT stage IIA, primary RPLND or chemotherapy can be used while stage IIB/IIC requires risk-adapted multiagent chemotherapy except in select cases.
Our review article is congruent with the American Urological Association guidelines recently published for the first time.7, 8 These guidelines state that stage IIA and IIB seminomas with lymph node size < 3 cm can be treated with radiation or multiagent chemotherapy while stage IIB with larger node size and stage IIC require systemic chemotherapy. There is renewed interested in primary RPLND for stage II seminoma in an attempt to avoid systemic consequences of radiotherapy and chemotherapy. Two trials directly addressing this question are underway; the US trial has completed accruing and will be expected to read out in the next 2 years (ClinicalTrials.gov NCT02537548; NCT2015053664).
Primary chemotherapy and RPLND are the two treatment strategies exclusively used in stage II NSGCT. Despite the increased awareness on the long-term toxicity of systemic multi-agent chemotherapy and on the benefits of primary RPLND as emphasized in the AUA guidelines and the review articles discussed above, the nationwide use of primary RPLND remains at 22% and 12% for stages IIA and IIB, respectively.6 A better understanding of the principles we discuss in our review article may result in a wider adoption of primary RPLND as the treatment strategy of choice in clinical stage IIA NSGCT.
The management of Stage II germ cell tumor patients is complex and requires a comprehensive understanding of the various treatment options that are available in any given clinical context. It is mandatory to be familiar with which factors may incline a patient and provider to select one treatment option over another. For instance, a patient with pure teratoma on orchiectomy specimen and a solitary 2.5 cm marker-negative retroperitoneal lymph node (cN2) would likely be best served with upfront RPLND. Further, all options (chemotherapy, radiotherapy, RPLND) should be available and accurately presented to patients with stage II disease, highlighting the need to treat at high volume centers with experience and expertise.16 When treating patients with stage II disease, careful and deliberate management is paramount to guarantee excellent cure rates are maintained and to ensure these young cancer survivors do not have to contend with iatrogenic injuries for the rest of their lives.
Written by: Rashed Ghandour, MD, Nirmish Singla, MD, and Aditya Bagrodia, MD, Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Stephenson, A.J., G.J. Bosl, R.J. Motzer, et al., Nonrandomized comparison of primary chemotherapy and retroperitoneal lymph node dissection for clinical stage IIA and IIB nonseminomatous germ cell testicular cancer. J Clin Oncol, 2007. 25(35): p. 5597-602.
- Weissbach, L., R. Bussar-Maatz, H. Flechtner, et al., RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell tumors? Results of a prospective multicenter trial including quality of life assessment. Eur Urol, 2000. 37(5): p. 582-94.
- Kerns, S.L., C. Fung, P.O. Monahan, et al., Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study. J Clin Oncol, 2018. 36(15): p. 1505-1512.
- Fung, C., H.D. Sesso, A.M. Williams, et al., Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy. J Clin Oncol, 2017. 35(11): p. 1211-1222.
- Ghandour, R.A., N. Singla, and A. Bagrodia, Management of Stage II Germ Cell Tumors. Urol Clin North Am, 2019. 46(3): p. 363-376.
- Ghandour, R., C. Ashbrook, Y. Freifeld, et al., Nationwide Patterns of Care for Stage II Nonseminomatous Germ Cell Tumor of the Testicle. Eur Urol Oncol, 2019.
- American Urological Association, AUA Guidelines on Diagnosis and Treatment of Early Stage Testicular Cancer. 2019.
- Albers, P., W. Albrecht, F. Algaba, et al., Guidelines on Testicular Cancer: 2015 Update. Eur Urol, 2015. 68(6): p. 1054-68.
- Wein, A.J., L.R. Kavoussi, A.W. Partin, and C. Peters, Campbell-Walsh urology. 11th Edition ed. Vol. 1. 2016: Elsevier.
- Pizzocaro, G., Retroperitoneal lymph node dissection in clinical stage IIA and IIB nonseminomatous germ cell tumours of the testis. Int J Androl, 1987. 10(1): p. 269-75.
- Donohue, J.P., J.A. Thornhill, R.S. Foster, R.G. Rowland, and R. Bihrle, Clinical stage B non-seminomatous germ cell testis cancer: the Indiana University experience (1965-1989) using routine primary retroperitoneal lymph node dissection. Eur J Cancer, 1995. 31a(10): p. 1599-604.
- Culine, S., C. Theodore, B.H. Court, J.L. Perrin, and J.P. Droz, Evaluation of primary standard cisplatin-based chemotherapy for clinical stage II non-seminomatous germ cell tumours of the testis. Br J Urol, 1997. 79(2): p. 258-62.
- Stephenson, A.J., G.J. Bosl, R.J. Motzer, et al., Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. J Clin Oncol, 2005. 23(12): p. 2781-8.
- Stephenson, A.J. and E.A. Klein, Surgical management of low-stage nonseminomatous germ cell testicular cancer. BJU Int, 2009. 104(9 Pt B): p. 1362-8.
- Kollmannsberger, C.K., L. Nappi, and C. Nichols, Management of Stage II Germ Cell Tumors: Be Sure, Be Patient, Be Safe. J Clin Oncol, 2019. 37(22): p. 1856-1862.
- Woldu, S.L., J.T. Matulay, T.N. Clinton, et al., Impact of hospital case volume on testicular cancer outcomes and practice patterns. Urol Oncol, 2018. 36(1): p. 14.e7-14.e15.