Stage 1 Testis Cancer: Recommendations from Hopkins

Testicular cancer is one of the true success stories in modern medicine.  With modern chemotherapy regimens, the overall cure rate for men with early stage (Clinical Stage I, CSI) testis cancer approaches 100%.  Given that these patients are often young men - each with a long life expectancy - consideration of side-effect profiles, specifically "late-effect" profiles (those occurring 10 or greater years after treatment), are of paramount consideration.

Focusing on men with non-seminomatous germ cell tumors (NSGCT), the National Cancer Comprehensive Network (NCCN) outlines three management strategies for men with CSI NSGCT:

• Active Surveillance (AS)
• Primary Chemotherapy
• Nerve-Sparing Retroperitoneal Lymph Node Dissection (RPLND)

When choosing a management strategy for CSI NSGCT, the primary point of distinction is the presence of lymphovascular invasion (LVI) in the primary tumor in the testicle.  If no LVI is present, the risk of recurrence is low (15% or less) and these patients are classified as Clinical Stage Ia.  If LVI is present, the risk of recurrence is much higher (approaching 50%) and those patients are considered Clinical Stage Ib.  However, both CSIa and CSIb men have excellent cure rates with even those patients who recur being salvaged with chemotherapy and/or surgery.

Recently there has been a large impetus for active surveillance for men with CSI NSGCT.[1,2]  Here we review the management options, some of the literature and debate on this topic.

Active Surveillance for Clinical Stage I Disease

According to the NCCN Guidelines, AS is a relatively time- and radiology-intense follow-up that eases only after 5 years and continues indefinitely (see table).  AS has been demonstrated to be safe and effective treatment for CSI NSGCT.[3-7]  Protocols have been refined to be less intense, and continue to demonstrate excellent long-term survival rates.[8,9]  However, some of the issues with AS include: 

• Compliance - the testis cancer population, in general, is young and mobile; adherence to AS protocols can be difficult
• Radiation Exposure - repeat CT imaging over a life-time has a small, but not insignificant radiation exposure that should be addressed in young men
• Salvage - if recurrence while on AS, the most likely next treatment is chemotherapy, with the potential long-term side effects of chemotherapy (discussed in next section)

NCCN Guidelines for Surveillance of Patients with CSI NSGCT.

Primary Chemotherapy for Clinical Stage I Disease

The typical chemotherapy for patients with CSI NSGCT is BEP (a combination of bleomycin, etoposide and cisplatin) for one- or two-cycles.  Primary chemotherapy in this setting reduces the risk of recurrence to <1%, however will overtreat 50-85% of men.  The short-term side effects of chemotherapy are well-known (hair loss, nausea and vomiting, etc) and, in general, short-lived and well-tolerated in this young, healthy population.  Of important consideration, is that these men are subjected to the long-term side effects of chemotherapy without actually needing the drug.  

Late-effect side effects of chemotherapy:

• Secondary Malignancy: 
• Solid tumors: Relative Risk 1.8-2.1 [10,11] 
• Leukemia: 0.5-2% based on dose of etoposide [12], variably increased based on the dose of cisplatinum [13]
• Cardiovascular Toxicity: demonstrated increased risks of early-onset angina, myocardial infarcation (heart attack) with related hyperlipidemia, metabolic syndrome [14-16]
• Single-Organ Dysfunction:
• Neurotoxicity: approximately 20% have neurologic symptoms [17]
• Nephrotoxicity: 30% long-term reduction in glomerular filtration rate (kidney filtering) [18,19]
• Pulmonary Toxicity: 
• Increased risk of pulmonary disease and death from pulmonary disease [20]
• Most of this toxicity is related to bleomycin, as it can have long-term effects on pulmonary function by causing pulmonary fibrosis
• This was a major reason Lance Armstrong sought to avoid this chemotherapy.
• Hypogonadism (Decreased Testosterone)
• Infertility
• Unknown toxicities: cisplatinum chemotherapy can be found in the blood of patients 10 years after receiving a dose.  The long-term side effects of this medication are currently unknown. [21]

Other considerations before accepting chemotherapy include: (1) most recurrences after parimary chemotherapy are teratoma and occur in the retroperitoneum, necessitating serial abdominal imaging similar to an AS protocol, and (2) treatment for recurrence after chemotherapy is RPLND.  Post-chemotherapy RPLND can be a challenging and dangerous operation.  While complications are rare they can be serious, occasionally catastrophic and include:

• life-threatening bleeding requiring blood transfusion or reconstruction of vascular structures
• removal of adherent adjacent organs (small bowel, kidney, etc.)
• permanent anejaculation
• chylous ascites

Primary Retroperitoneal Lymph Node Dissection (RPLND) for Clinical Stage I Disease

The primary landing zone for metastases from testis cancer are the lymph nodes of the retroperitoneum, around and between the aorta and inferior vena cava at the level of the kidneys.  For many years, RPLND was a mainstay of therapy for CSI NSGCT as it better staged disease and offered a therapeutic benefit for many patients.  However, upwards of 70% of patients will never need an RPLND and are overtreated by surgery.  RPLND has fallen out of favor with many physicians and organization due to the morbidity of the procedure and high-risk of overtreatment.

Traditionally, RPLND is done through a large, midline incision (along the entire abdomen) and only performed at high-volume, centers of excellence due to the rarity of disease and technical challenges of the surgery.  More recently, minimally-invasive RPLND has become an option for men with testis cancer, dramatically reducing the convalescence of the operation and offering the benefits of avoiding chemotherapy and rigorous AS.[22]  Minimally-invasive RPLND changes the thought-process for CSI testis cancer, as it changes the ratio of risk to benefit as the morbidity associated with the procedure is dramatically reduced compared with the traditional, open surgery.  In addition, post-chemotherapy RPLND is a dramatically different operation (discussed above).  Avoiding a post-chemotherapy RPLND can prevent many undesirable side-effects in young men.

What do we recommend for men with CSI NSGCT?

One of the common sayings in testis cancer is, "All roads lead to Rome," and that patients need to choose the road that most suits their personality, lifestyle and concerns.  Basically, nearly 100% of men with CSI NSGCT will be cured.  Some (actually a minority) will require chemotherapy, some surgery and some a combination of both.  We often recommend that patients consider what treatment they would like to avoid most and prioritize the order of the treatments (if needed) from there.  

We often recommend that patients consider what treatment they would like to avoid most and prioritize the order of the treatments (if needed) from there. 

While every patient is an individual and individual health risks and preferences need to be considered, in general, we make the following recommendations at the Brady Urological Institute at Johns Hopkins for the treatment of CSI NSGCT.

Clinical Stage Ia (Tumor Confined to the Testicle, No Lymphovascular Invasion)

Men with CSIa have an incredibily low-risk of recurrence (5-15%).  Therefore we do not routinely recommend primary treatment (chemotherapy or RPLND) as most patients will be overtreated by these therapies.

• Active Surveillance is preferred
• Upwards of 90-95% of men are cured with orchiectomy alone
• AS involves tumor markers and CT scans every 3-4 months after surgery
• Primary Chemotherapy is an option
• for patients concerned about the risk of relapse 
• for patients with compliance or insurance issues
• Primary Minimally-Invasive RPLND is an option
• for patients concerned about the risk of relapse 
• patients with compliance or insurance issues
• patients who wish to avoid a post-chemotherapy RPLND

Clinical Stage Ib (Tumor Confined to the Testicle, Lymphovascular Invasion present)  

Men with CSIb NSGCT have upwards of a 50% chance of recurrence.  Therefore, we usually recommend primary chemotherapy or minimally-invasive RPLND as treatment for these men.  

• Minimally-Invasive RPLND
• most patients are discharge one day after surgery (although full recovery certainly can take weeks)
• nodal yields and ejaculatory function are excellent with a unilateral template surgery
• patients with one-positive lymph node (N1) can be monitored following surgery without necessitating chemotherapy
• we recommend adjuvant chemotherapy for all patients with greater than one positive lymph node (N2)
• Primary Chemotherapy
• will cure many patients with high-risk, CSIb disease
• patients must consider that they will require a post-chemotherapy RPLND
• patients must consider late-term side effects of chemotherapy (excellent treatment for older patients)
• Active Surveillance remains an option
• for patients desiring to avoid all additional treatments
• patients need to recognize that those who recur after a period of AS, will require full-dose chemotherapy (3-4 cycles of BEP) and potentially more side effects

Phillip M. Pierorazio, MD is the Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  If you or a loved one was recently diagnosed with testis cancer and would like a consultation please call the Urology Clinic at 410 955 6100.  If you or a loved one is a survivor of testis cancer, please take a look at our Facebook page for "Testis Cancer Survivors."  The page is designed to be a forum for patients to meet and discuss issues around Testis Cancer.  We will supply the page with updates and data regarding Testis Cancer.

Resources:

NCCN website: http://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf

[1] Nichols CR1, Roth B, Albers P, Einhorn LH, Foster R, Daneshmand S, Jewett M, Warde P, Sweeney CJ, Beard C, Powles T, Tyldesley S, So A, Porter C, Olgac S, Fizazi K, Hayes-Lattin B, Grimison P, Toner G, Cathomas R, Bokemeyer C, Kollmannsberger C.  Active surveillance is the preferred approach to clinical stage I testicular cancer.  J Clin Oncol. 2013 Oct 1;31(28):3490-3. doi: 10.1200/JCO.2012.47.6010. Epub 2013 Sep 3.

[2] Schmidt C. Debates emerge over active surveillance in testicular cancer.  J Natl Cancer Inst. 2014 Feb;106(2):dju040. doi: 10.1093/jnci/dju040.

[3] Duran I, Sturgeon JF, Jewett MA, et al: Initial versus recent outcomes with a non-risk adapted surveillance policy in stage I non-seminomatous germ cell tumors (NSGCT). J Clin Oncol 25:240s, 2007 (suppl; abstr 5021) 

[4] Kollmannsberger C, Moore C, Chi KN, et al: Non-risk-adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors: Diminishing treatment-related morbidity while maintaining efficacy. Ann Oncol 21: 1296-1301, 2010

[5] Kollmannsberger C, Tyldesley S, Moore C, et al: Evolution in management of testicular seminoma: Population-based outcomes with selective utilization of active therapies. Ann Oncol 22:808-814, 2011

[6] Tandstad T, Smaaland R, Solberg A, et al: Management of seminomatous testicular cancer: A binational prospective population-based study from the Swedish Norwegian Testicular Cancer Study Group. J Clin Oncol 29:719-725, 2011.

[7] Tandstad T, Dahl O, Cohn-Cedermark G, et al: Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: The SWENOTECA management program. J Clin Oncol 27:2122-2128, 2009.

[8]  Rustin GJ, Mead GM, Stenning SP, et al. (2007) Randomized trial of two or five computed tomography scans in the surveillance of patients with stage I nonseminomatous germ cell tumors of the testis: Medical Research Council Trial TE08, ISRCTN56475197–the National Cancer Res Institute Testis Cancer Clinical Studies Group. J Clin Oncol 25:1310–1315.

[9] Cathomas R, Helbling D, Stenner F, et al. (2010) Interdisciplinary evidence-based recommendations for the follow-up of testicular cancer patients: A joint effort. Swiss Med Wkly 140:356–369.

[10] Travis LB, Fossa SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005;97(18):1354-1365.

[11] van den Belt-Dusebout AW, de Wit R, Gietema JA, et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2007;25(28):4370-4378.

[12] Kollmannsberger C, Hartmann JT, Kanz L, et al. Therapy-related malignancies following treatment of germ cell cancer. Int J Cancer 1999;83(6):860-863.

[13] Travis LB, Andersson M, Gospodarowicz M, et al. Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst 2000;92(14):1165-1171.

[14] Meinardi MT, Gietema JA, van der Graaf WT, et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 2000;18(8):1725-1732.

[15] van den Belt-Dusebout AW, Nuver J, de Wit R, et al. Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2006;24(3):467-475.

[16] Haugnes HS, Aass N, Fossa SD, et al. Components of the metabolic syndrome in long-term survivors of testicular cancer. Ann Oncol 2007;18(2):241-248.

[17] Mykletun A, Dahl AA, Haaland CF, et al. Side effects and cancer-related stress determine quality of life in long-term survivors of testicular cancer. J Clin Oncol 2005;23(13):3061-3068.

[18] Hansen SW, Groth S, Daugaard G, et al. Long-term effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer. J Clin Oncol 1988;6(11):1728-1731.

[19] Fossa SD, Aass N, Winderen M, et al. Long-term renal function after treatment for malignant germ-cell tumours. Ann Oncol 2002;13(2):222-228.

[20] Fossa SD, Gilbert E, Dores GM, et al. Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst 2007;99(7):533-544.

[21] Travis LB, Beard C, Allan JM, Dahl AA, Feldman DR, Oldenburg J, Daugaard G, Kelly JL, Dolan ME, Hannigan R, Constine LS, Oeffinger KC, Okunieff P, Armstrong G, Wiljer D, Miller RC, Gietema JA, van Leeuwen FE, Williams JP, Nichols CR, Einhorn LH, Fossa SD.Testicular cancer survivorship: research strategies and recommendations. J Natl Cancer Inst. 2010 Aug 4;102(15):1114-30. doi: 10.1093/jnci/djq216. Epub 2010 Jun 28.

[22] Hyams ES1, Pierorazio P, Proteek O, Sroka M, Kavoussi LR, Allaf ME.Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell tumor: a large single institution experience. J Urol. 2012 Feb;187(2):487-92. doi: 10.1016/j.juro.2011.10.035. Epub 2011 Dec 16.