Diffusion of Robotics in Urology: Responsible Introduction of Surgical Innovation

The use of robotic surgery in urology began in 2001 with the advent of robot assisted radical prostatectomy (RARP). Since then, it has diffused throughout the field, providing an alternative to the open approach in numerous urologic procedures. However, the evidence for the utility and added benefits of the robotic approach is limited and varies among procedures. Given the fact that robotic-assisted procedures cost the patient an additional $1000 and the hospital nearly $100,000 annually, it is necessary to investigate the benefits of this technology and to determine for which procedures and which patients it is worth this increased cost. Furthermore, it is critical to assess whether the early introduction of this technology is safe for patients. Not only is the data supporting the use of robotics unclear, but also, in retrospect, the introduction of robotics may have led to unfavorable patient outcomes in certain settings. This blog will serve as overview of some of the early data regarding the use of robotics in the surgical management of three index cancers and will end with a brief discussion of safety during the initial diffusion of robotic prostatectomy.

    

RADICAL PROSTATECTOMY

Most of the initial data regarding RARP came from small, retrospective, single-center studies, most of which reported less blood loss, lower rates of transfusion, shorter length of stay and fewer short term complications. A recent prospective, multi-center, controlled trial from Sweden showed that RARP was associated with 500cc less blood loss, shorter length of stay by one day, and lower rates of reoperation during the initial hospital stay [1]. Therefore, at least in the short term, there seems to be good evidence for RARP improving perioperative outcomes.

Figure 1. RARP is associated with better short-term outcomes including less blood loss, shorter length of stay, and less rates of reoperation.  From Wallerstedt, et al. [1].

Data regarding long-term outcomes are more controversial. Based on numerous studies, it is difficult to interpret whether there is any benefit or drawback to achieving the "trifecta" of oncologic control, continence, and potency with robotic assistance. A recent prospective, non-randomized study from Sweden suggests that there may be some benefit to RARP with regard to potency, but no difference for oncologic control or continence [2]. Of note, the only randomized trial that sought to investigate this was terminated due to slow patient enrollment. Therefore, some evidence points to the benefits of RARP, some to its detriment, but most suggest equivalence between open and robotic.

 

PARTIAL NEPHRECTOMY

The use of robotics in partial nephrectomy (PN) is a different story. PN is the preferred surgical management of small renal masses (when technically feasible) because of its ability to preserve kidney function (i.e. nephron-sparing) with equivalent oncologic control. Minimally invasive PN has been shown to be associated with less blood loss, shorter length of stay, faster recovery, and less post-operative pain compared to the open flank incision [3]. Within the category of minimally invasive surgery, Pierorazio et al. showed that robotic assisted partial nephrectomy (RAPN) is associated with shorter operative time, less blood loss, and shorter warm ischemia time (WIT) [4]. Regarding complications, Mullins et al. found no difference in complication rates, but when stratified by Clavien grade, the RAPN cohort was more likely to have lower grade complications [5]. A meta-analysis comparing robotic vs. laparoscopic PN found no differences in operative times, blood loss, conversion rates, complications, or length of stay. However, RAPN was associated with shorter WIT, the key to renal preservation, which ultimately is the primary goal of PN [6].

Figure 2. RAPN is associated with shorter WIT.  From Aboumarzouk, et al. [6].

Robotic technology has led to an increased use of PN, due in part to the superior range of motion that aids in tumor excision and reconstruction under ischemic time constraints. This has been shown to be a real phenomenon, with a demonstrable increase in PN compared to radical nephrectomy in the years of robotic diffusion. [7] In addition, robotics has allowed urologists to tackle more complex renal tumors, such as tumors invading the large veins of the kidney and retroperitoneum (i.e. IVC thrombectomies), intrarenal, and posterior tumors, with comparable functional outcomes and less risk of conversion to radical nephrectomy [8-10].

 

RPLND

Retroperitoneal lymph node dissection (RPLND) is a treatment option for men with stage I and select stage II nonseminomatous germ cell tumors and is particularly useful for men who want to avoid long term surveillance or chemotherapy. Laparoscopic RPLND has been shown to have comparable oncologic outcomes with superior perioperative outcomes compared to open [11, 12]. The data regarding robotic RPLND is scant due to its nascency in the field, however a recent study shows that early on, robotic RPLND is comparable to laparoscopic in terms of perioperative outcomes [13]. Given the increased cost and risk of serious complications due to the intimacy with the great vessels during this procedure, the role of robotics in RPLND remains largely unknown at this point.

 

DIFFUSION AND PATIENT SAFETY

Given the variable and unclear data, particularly regarding RARP, how did robotics diffuse so rapidly and widely among urologists? First, it is important to note that in order to introduce new technology, one only needs a 510(k) clearance from the FDA. In the case of RARP, da Vinci received FDA clearance in 2000, the first RARP was in 2001, and the first population-based outcomes study was published in 2009. So many were performing RARP blindly without any population based data on efficacy or safety. Parsons et al. sought to retrospectively investigate if there was an effect on patient safety during this diffusion period using patient safety indicators (PSI). They found that in the year before the "tipping point," a set point indicating when RARP diffused from centers of excellence to more general urologists, there was a two-fold increase in PSI [14].

Figure 3. RARP during diffusion era is associated with a two-fold increase in PSI.  From Parsons, et al. [14].

These results highlight the importance of responsibility with regards to the introduction of new technology. Is a compromise to patient safety in the initial years of dissemination necessary? Does new technology always come with risk? How do we know when to stop pursuing a given technique? When is a reasonable time to assess whether it is inferior and causing more harm than good? Was RARP even worth this increased risk given its limited utility and increased cost? Finally, is the culprit here technology, or does innovation by nature have barriers at first?

 

SUMMARY

The role of robotics in urology today raises many questions regarding comparative efficacy, cost justification, and patient safety with innovation. Radical prostatectomy and partial nephrectomy illustrate a juxtaposition of results – RAPN seems to have succeeded while RARP has yet to show a demonstrable benefit other than less blood loss. It has also raised questions about patient safety during the dissemination of new technology and bears the question, how does an innovator responsibly report results while marketing and patient demand accelerate the innovation's diffusion? Moving forward, standardized training and credentialing programs as well as systematic reporting to non-industry groups could be instituted in order to diffuse innovation while keeping the patient first.

This blog was written by Kelly Harris, a medical student at Johns Hopkins Medical School.  Kelly recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "The Diffusion of Robotic Surgery in Urology" from which this blog is inspired. Kelly is looking forward to a career in urology.

1. Wallerstedt A, Tyritzis SI, Thorsteinsdottir T, et al. Short-term Results after Robot-assisted Laparoscopic Radical Prostatectomy Compared to Open Radical Prostatectomy. Eur Urol 2015: 67:660-70
2. Haglind E, Carlsson S, Stranne J, et al. Urinary Incontinence and Erectile Dysfunction After Robotic Versus Open Radical Prostatectomy: A Prospective, Controlled, Nonrandomised Trial. Eur Urol 2015
3. Hung AJ, Cai J, Simmons MN, Gill IS. "Trifecta" in partial nephrectomy. J Urol 2013: 189:36-42
4. Pierorazio PM, Mullins JK, Eifler JB, et al. Contemporaneous comparison of open vs minimally-invasive radical prostatectomy for high-risk prostate cancer. BJU Int 2013: 112:751-7
5. Mullins JK, Feng T, Pierorazio PM, Patel HD, Hyams ES, Allaf ME. Comparative analysis of minimally invasive partial nephrectomy techniques in the treatment of localized renal tumors. Urology 2012: 80:316-21
6. Aboumarzouk OM, Stein RJ, Eyraud R, et al. Robotic versus laparoscopic partial nephrectomy: a systematic review and meta-analysis. Eur Urol 2012: 62:1023-33
7. Patel HD, Mullins JK, Pierorazio PM, et al. Trends in renal surgery: robotic technology is associated with increased use of partial nephrectomy. J Urol 2013: 189:1229-35
8. Ball MW, Gorin MA, Jayram G, Pierorazio PM, Allaf ME. Robot-assisted radical nephrectomy with inferior vena cava tumor thrombectomy: technique and initial outcomes. Can J Urol 2015: 22:7666-70
9. Harris KT, Ball MW, Gorin MA, Curtiss KM, Pierorazio PM, Allaf ME. Transperitoneal Robot-Assisted Partial Nephrectomy: A Comparison of Posterior and Anterior Renal Masses. J Endourol 2014: 28:655-9
10. Curtiss KM, Ball MW, Gorin MA, Harris KT, Pierorazio PM, Allaf ME. Perioperative outcomes of robotic partial nephrectomy for intrarenal tumors. J Endourol 2015: 29:293-6
11. Bhayani SB, Ong A, Oh WK, Kantoff PW, Kavoussi LR. Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell testicular cancer: a long-term update. Urology 2003: 62:324-7
12. Steiner H, Peschel R, Janetschek G, et al. Long-term results of laparoscopic retroperitoneal lymph node dissection: a single-center 10-year experience. Urology 2004: 63:550-5
13. Harris KT, Gorin MA, Ball MW, Pierorazio PM, Allaf ME. A Comparative Analysis of Robotic versus Laparoscopic Retroperitoneal Lymph Node Dissection for Testicular Cancer. BJU Int 2015
14. Parsons JK, Messer K, Palazzi K, Stroup SP, Chang D. Diffusion of surgical innovations, patient safety, and minimally invasive radical prostatectomy. JAMA Surg 2014: 149:845-51

Centralizing Care for Testicular Cancer

A number of studies and a growing body of evidence indicates that high hospital and surgeon volume can be associated with improved outcomes for a number of surgical diseases. Research involving the Institute of Medicine[1] and a number of large, national databases including SEER (Surveillance, Epidemiology, and End Results) Cancer Program,[2] National Inpatient Sample [3] and others [4,5] indicate associations between hospital volume and outcome for a variety of cardiovascular and oncologic surgeries. While not specifically focused on urologic oncology, these studies demonstrate modest but significant improvements in mortality for radical cystectomy and nephrectomy.[3,5]
In the urologic literature, significant improvements have been demonstrated for the treatment of prostate,[6-11] bladder,[3,5,12-16] and kidney cancer[3,17-18] at high-volume centers and by high-volume surgeons. There is less, well-established literature in the treatment of testicular cancer (TC) and this blog will focus on the relationship between hospital volume and outcomes for TC.

 
A study of the Irish Testicular Tumor Registry (1980-1985) evaluated 246 patients over 41 hospitals. Inferior survival outcomes were associated with patients who received incomplete orchiectomy, were not staged by tumor markers, did not receive appropriate chemotherapy, had less frequent imaging or marker surveillance and did not have a urologist and/or oncologist involved in their care.[19] In an early study from the SWENOTECA (Swedish Norweigan Testicular Cancer) Project (1981-1986), high-volume cancer centers were associated with improved care – especially in patients with large volume, advanced disease.[20] Of 440 men treated in Scotland, 87% of 235 men treated at the highest volume center were alive at 5 years. Of the 194 treated at other, smaller centers, only 73% were alive at 5 years – much of this difference was attributed to various treatment protocols independent of other prognostic variables.[21]

In the United States, 172 men with advanced testicular cancer in the national, SEER database were matched to 133 men from MSKCC (Memorial Sloan Kettering Cancer Center) in New York (1978-1984). Survival rates were higher at MSKCC despite similar treatment regimens. The benefit at MSKCC was highest in men with minimal to moderate disease and therefore attributed to the combination of surgery and chemotherapy at this tertiary care center.[22] This relationship was validated in 380 patients with metastatic TC enrolled in an EORTC (European Organization for Research and Treatment of Cancer) Trial. The trial was conducted over 49 sites, and patients treated at the 26 sites with the fewest patients (five or fewer) had inferior survival outcomes.[23]

More recent studies from Japan have investigated the volume-outcome relationship, demonstrating increasing volume of treatment to be associated with improved survival.[24] However the rates did not achieve the survival rates demonstrated in western countries like the US or countries of Europe. Based on these data, efforts have been made to centralize TC care in a risk-adapted algorithm – as severity of disease increases, patients are referred to more centralized, specialized referral centers. One study evaluating this "centralization" demonstrated markedly improved and excellent survival in patients receiving induction chemotherapy, with the majority of patients receiving care at one, large center.[25]

While much of the data regarding hospital volume and outcome for TC patients is dated, the argument for centralization of care is poignant. As outcomes for a variety of urologic malignancies including prostate, bladder and kidney cancer are established to be improved in high-volume centers, it is rational that TC care could also be better served by centralized care – TC is a rare disease that often requires multi-disciplinary care and a thorough understanding of management options and outcomes (especially for men with advanced disease). A risk-adapted centralization, where following a diagnosis of TC patients are referred to an increasingly experienced center for the stage of their disease, may help improve outcomes for patients.  For instance, a man with early stage disease who is a candidate for active surveillance can be followed by his local urologic oncologist, and the man with high-volume metastatic disease should be referred to a large, tertiary care center with extensive experience treating men in the region.  In addition, while this blog does not discuss the costs associated with the treatment of advanced TC, centralization may provide improved population-based outcomes in a cost-effective manner and this is a disease where reimbursements may reinforce quality care.

This blog was written by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology and Director of the Division of Testicular Cancer.

 

1. E.A. Halm, C. Lee, M.R. Chassin. Is volume related to outcome in health care? A systematic review and methodologic critique of the literature. Ann Intern Med, 137 (2002), p. 511
2. C.B. Begg, L.D. Cramer, W.J. Hoskins, M.F. Brennan. Impact of hospital volume on operative mortality for major cancer surgery. JAMA, 280 (1998), p. 1747
3. J.D. Birkmeyer, A.E. Siewers, E.V. Finlayson, T.A. Stukel, F.L. Lucas, I. Batista,et al. Hospital volume and surgical mortality in the United States. N Engl J Med, 346 (2002), p. 1128
4. R.A. Dudley, K.L. Johansen, R. Brand, D.J. Rennie, A. Milstein. Selective referral to high-volume hospitals: estimating potentially avoidable deaths. JAMA, 283 (2000), p. 1159
5. J.D. Birkmeyer, T.A. Stukel, A.E. Siewers, P.P. Goodney, D.E. Wennberg, F.L. Lucas. Surgeon volume and operative mortality in the United States. N Engl J Med, 349 (2003), p. 2117
6. F.J. Bianco Jr, P.T. Scardino, M.W. Kattan, A.C. Rhee, J.A. Eastham. Surgeon volume is predictor of improved outcomes in radical prostatectomy patients. J Urol, 171 (suppl.) (2004), p. 211 abstract 796
7. C.B. Begg, E.R. Riedel, P.B. Bach, M.W. Kattan, D. Schrag, J.L. Warren, et al. Variations in morbidity after radical prostatectomy. N Engl J Med, 346 (2002), p. 1138
8. J.A. Eastham, M.W. Kattan, E. Riedel, C.B. Begg, T.M. Wheeler, C. Gerigk, et al. Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. J Urol, 170 (2003), p. 2292
9. L.M. Ellison, J.A. Heaney, J.D. Birkmeyer. The effect of hospital volume on mortality and resource use after radical prostatectomy. J Urol, 163 (2000), p. 867
10. J.C. Hu, K.F. Gold, C.L. Pashos, S.S. Mehta, M.S. Litwin. Role of surgeon volume in radical prostatectomy outcomes. J Clin Oncol, 21 (2003), p. 401
11. S.L. Yao, G. Lu-Yao. Population-based study of relationships between hospital volume of prostatectomies, patient outcomes, and length of hospital stay. J Natl Cancer Inst, 91 (1999), p. 1950
12. L.S. Elting, C.A. Pettaway, H.B. Grossman, B.N. Bekele, K.R. Saldin, C.P.N. Dinney. Relationship between postoperative in-hospital mortality and annual hospital volume of cystectomies: the effect of centres of experience. J Urol, 169 (suppl.) (2003), p. 336 abstract 1301
13. H.W. Herr, J.R. Faulkner, H.B. Grossman, R.B. Natale, R. DeVere White, M.F. Sarosdy, et al. Surgical factors influence bladder cancer outcomes: a cooperative group report. J Clin Oncol, 22 (2004), p. 2781
14. H.W. Herr, J.A. Smith, J.E. Montie. Standardization of radical cystectomy: time to count and be counted. BJU Int, 94 (2004), p. 481
15. B.R. Konety, V. Dhawan, V. Allareddy, S.A. Josyln. Impact of hospital and surgeon volume on in-hospital mortality from radical cystectomy: data from the Health Care Utilization Project. J Urol, 173 (2005), p. 1695
16. B.R. Konety, V. Dhawan, V. Allareddy, M.A. O'Donnell. Association between volume and charges for most frequently performed ambulatory and nonambulatory surgery for bladder cancer is more cheaper? J Urol, 172 (2004), p. 1056
17. E.V. Finlayson, P.P. Goodney, J.D. Birkmeyer. Hospital volume and operative mortality in cancer surgery: a national study. Arch Surg, 138 (2003), p. 721
18. D.A. Taub, D.C. Miller, J.A. Cowan, J.B. Dimick, J.E. Montie, J.T. Wei. Impact of surgical volume on mortality and length of stay after nephrectomy. Urology, 63 (2004), p. 862
19. J.A. Thornhill, A. Walsh, R.M. Conroy, J.J. Fennelly, D.G. Kelly, J.M. Fitzpatrick. Physician-dependent prognostic variables in the management of testicular cancer. Br J Urol, 61 (1988), p. 244
20. N. Aass, O. Klepp, E. Cavallin-Stahl, O. Dahl, H. Wicklund, B. Unsgaard, et al. Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: a multicenter experience. J Clin Oncol, 9 (1991), p. 818
21. M.J. Harding, J. Paul, C.R. Gillis, S.B. Kaye. Management of malignant teratoma: does referral to a specialist unit matter? Lancet, 341 (1993), p. 999
22. E.J. Feuer, C.M. Frey, O.W. Brawley, S.G. Nayfield, J.B. Cunningham, N.L. Geller, et al. After a treatment breakthrough: a comparison of trial and population-based data for advanced testicular cancer. J Clin Oncol, 12 (1994), p. 368
23. L. Collette, R.J. Sylvester, S.P. Stenning, S.D. Fossa, G.M. Mead, R. de Wit, et al. Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst, 91 (1999), p. 839
24. Suzumura S, Ioka A, Nakayama T, Tsukuma H, Oshima A, Ishikawa O. Hospital procedure volume and prognosis with respect to testicular cancer patients: a population-based study in Osaka, Japan. Cancer Sci. 2008 Nov;99(11):2260-3. doi: 10.1111/j.1349-7006.2008.00920.x.
25. Inai H, Kawai K, Kojima T, Joraku A, Shimazui T, Yamauchi A, Miyagawa T, Endo T, Fukuhara Y, Miyazaki J, Uchida K, Nishiyama H. Oncological outcomes of metastatic testicular cancers under centralized management through regional medical network. Jpn J Clin Oncol. 2013 Dec;43(12):1249-54. doi: 10.1093/jjco/hyt152. Epub 2013 Oct 6.

Long-Term Effects of Chemotherapy for Testicular Cancer: Secondary Malignancy

Chemotherapy is widely believed to be the best first-line treatment for many patients with early-stage and low-volume, node-positive testicular cancer (TC). When evaluating population-based data, chemotherapy offers the highest chance of cure with a single modality to the most patients. For instance, the SWENOTECA experience indicates that a single dose of BEP (Bleomycin, Etoposide and Cisplatinum) chemotherapy cures >97% of men with Stage I NSGCT (non-seminomatous germ cell tumors).[1] For men with metastatic seminoma, chemotherapy can cure upwards of 90% of men.[2] Chemotherapy is not without a cost, most men experience some short-term side effects and some will experience long-term side effects. A prior blog briefly discusses short- and long-term effects of chemotherapy (http://bradyurology.blogspot.com/2014/03/stage-1-testis-cancer-recommendations.html). The long-term side effects are especially important for the TC population – which is, in general, young, fertile and healthy with a long life expectancy. The first dose of modern, curative chemotherapy for TC was given in the mid-1970's (http://bradyurology.blogspot.com/2014/08/classic-manuscript-in-urology-einhorn.html) – so we are just beginning to understand the long-term side effects form these medications.

This series of blogs will focus on the current data and understanding and long-term risks of chemotherapy in the TC population.

 

SECONDARY MALIGNANCIES

Studies examining patients from the 1940's to the present time indicate that any patient diagnosed with TC is at a higher lifetime risk of developing a second malignancy. This is likely related to improved long-term surveillance (compared to the rest of the population), and perhaps related to the underlying biological mechanisms that allowed TC to blossom. However, patients who received radiation treatment (RT) and chemotherapy are at the highest risk of secondary malignancy as they age.

Solid Malignancies

A study of >40k men in 14 population-based tumor registries across Europe and North America, demonstrated a risk of secondary, solid malignancy of 31-36% for patients with seminoma or NSGCT – compared to 23% for the general population. This study demonstrated increased risks of cancer of the pleura (mesothelioma), lung, esophagus, bladder, colon, pancreas and stomach (nearly 60% of all cancers were of one of these types). The risk of 2^nd cancer was higher for younger patients and persisted for at least 35 years following diagnosis. For radiotherapy and chemotherapy alone, the risk of 2^nd malignancy was approximately 2-fold compared to the remainder of the population. If a patient received both RT and chemotherapy, the risk of 2^nd malignancy was nearly 3-fold.[3] These results were corroborated by a number of large, population-based studies.[4,5] A US-based study, looking at a more contemporary time period, found that the risk of 2^nd solid malignancy was 50% higher in patients receiving chemotherapy rather than surgery for NSGCT. There was an increased risk of kidney, thyroid, and soft tissue cancers from 12 to 20 years following chemotherapy.

Hematologic Malignancies

The risk of hematologic malignancies (leukemia, lymphoma) has been reported to be 2 to 37-fold higher in patients receiving chemotherapy for TC.[4,6] The risk of hematologic 2^nd malignancy may be related to dose and regimen: high cumulative doses of etoposide given over a short period of time appear to be less leukemogenic that similar doses given over a longer period of time.[6] For standard dose cisplatinum (650mg), the risk of leukemia is approximately 3-fold – and increased to 6-fold with higher doses of platinum-based chemotherapy.[7]

In general, the risks of 2^nd cancers should be tempered – part of the reason for the high relative risks is that cancers, in general, are relatively rare in a young population. Therefore, even a small absolute increased risk of cancer can lead to a high relative risk of cancer. For instance, while the risk of leukemia after cisplatinum-based chemotherapy is 3-fold higher than the normal population, this only translates into 16 cases of leukemia in 10,000 patients.[7]

 
Stay tuned for discussions of cardiovascular toxicity, gonadotoxicity and fertility, neurotoxicities and quality of life.

 

Phillip M. Pierorazio, MD is the Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  

Hopkins Testicular Cancer Websites:

Johns Hopkins Testis Cancer: http://urology.jhu.edu/testis/cancer.php

Testis Cancer Survivors: https://www.facebook.com/testiscancersurvivor

[1] Cohn-Cedermark G1, Stahl O, Tandstad T; SWENOTECA. Surveillance vs. adjuvant therapy of clinical stage I testicular tumors - a review and the SWENOTECA experience. Andrology. 2014 Oct 1. doi: 10.1111/andr.280. [Epub ahead of print]
[2] D. Gholam, K. Fizazi, M.J. Terrier-Lacombe, et al. Advanced seminoma–treatment results and prognostic factors for survival after first-line, cisplatin-based chemotherapy and for patients with recurrent disease: a single-institution experience in 145 patients. Cancer, 98 (2003), p. 745.
[3] Travis LB, Fosså SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm H, Hall P, Holowaty E, Andersen A, Pukkala E, Andersson M, Kaijser M, Gospodarowicz M, Joensuu T, Cohen RJ, Boice JD Jr, Dores GM, Gilbert ES. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. 2005 Sep 21;97(18):1354-65.
[4] Richiardi L, Scélo G, Boffetta P, Hemminki K, Pukkala E, Olsen JH, Weiderpass E, Tracey E, Brewster DH, McBride ML, Kliewer EV, Tonita JM, Pompe-Kirn V, Kee-Seng C, Jonasson JG, Martos C, Brennan P. Second malignancies among survivors of germ-cell testicular cancer: a pooled analysis between 13 cancer registries. Int J Cancer. 2007 Feb 1;120(3):623-31.
[5] van den Belt-Dusebout AW, de Wit R, Gietema JA, Horenblas S, Louwman MW, Ribot JG, Hoekstra HJ, Ouwens GM, Aleman BM, van Leeuwen FE. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol. 2007 Oct 1;25(28):4370-8.
[6] 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.
[7] Travis LB, Andersson M, Gospodarowicz M, et al. Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst 2000;92(14):1165-1171.

Testicular Self-Exam: Why There Is Nothing Wrong with a Regular Feel

This blog entry is a continuation of "The Importance of Testicular Self-Examination," posted December 1, 2014.

In summation, the cure rate for localized testicular cancer approaches 99% and drops to 75% for men with metastatic disease – often requiring chemotherapy and/or major surgery to achieve cure. The United States Preventative Services Task Force (USPSTF) recommends against regular testicular self-exam (TSE), citing a "moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits."[1] The USPSTF recommendation is based on the relatively low incidence of testicular cancer, the high cure rate, unknown performance statistics of examination (when performed by patient or physician) for diagnosis and uncertainty if TSE leads to finding earlier stage disease; and the risks and costs associated with a false-positive test.

Each of the shortcomings mentioned by the USPSTF are addressed here:

LOW INCIDENCE, HIGH CURE RATE

It is true that testicular cancer only affects 8,000 men per year and that the survival for all comers in approximately 95%.[2] Thankfully, only a few hundred men die per year of testicular cancer – however that means there are hundreds of thousands of survivors in the US and around the world. These young men have been exposed to chemotherapy, radiation treatments, major surgeries and repeated CT scans for surveillance. Most, if not all treatments, influence hormone function, fertility and general quality-of-life – translating into a huge impact on a young population with many life-years ahead of them! Therefore, while there are fewer testicular cancer patients than other diseases, these patients have longer to live and the consequences of treatment are just as important as other cancers!!

UNKNOWN PERFORMANCE OF TESTICULAR SELF-EXAMINATION

It has to be conceded that there is no evidence that TSE is effective for the diagnosis of testicular cancer or helps find men at an earlier stage of disease. However, lack of evidence does not mean that TSE is not effective – it means that no study has effectively investigated the role of TSE in an at-risk population. We do know that length of patient- and physician-related delay is directly related to the stage of cancer at diagnosis; the median delay for men with Stage I, II and III cancer was 75, 101 and 134 days respectively.[3] In addition, delay in diagnosis has been associated with higher rates of chemotherapy and lower survival rates.[4]

THE RISKS/HARMS OF TESTICULAR SELF-EXAM

TSE is a painless, easy to perform self-examination technique. The risks of performing a TSE are undergoing an unnecessary office visit, ultrasound or surgery for a benign mass. Associated with a false-positive TSE can be anxiety-provoking and lead to other psychological stresses. Overcoming the risks of TSE requires education; both that an abnormality on TSE does not necessarily mean cancer and that when found early, the treatments are minor and the cure-rate high!

COST-EFFECTIVENESS

A recent study by Aberger and colleagues, from the University of Kansas Medical Center, investigated the costs associated with TSE in a theoretical model.[5] The most expensive treatment for testicular cancer is the combination of chemotherapy and surgery for an advanced testicular cancer, costing on average $50,000 per patient. Compared only to the immediate costs of an office-visit with a physician or a scrotal ultrasound, the treatment of one advanced stage testicular cancer is equal to:

• 320 office visits for a benign, but worrisome TSE
• 185 office visits with a scrotal ultrasound for a worrisome TSE
• 81 office visits with scrotal ultrasound and tumor markers for a suspicious TSE
• 6-7 office visists with scrotal ultrasound and tumor markers leading to a radical orchiectomy
• 2-3 early-stage testicular cancers treated with active surveillance for five years

Given the nearly $48 million spent on the men with metastatic cancer in 2013, any improvement in early diagnosis and stage could dramatically improve costs for this disease. Importantly, this cost analysis does not consider the long-term sequelae of the treatment of testicular cancer including hormone replacement or fertility treatments which can be extremely expensive over a lifetime.

 

SUMMARY

The USPSTF recommendations regarding TSE are based on very little existing evidence. From the perspective of the USPSTF, the potential for harms, outweighs the lack of demonstrable benefit for TSE. I would respectfully disagree, stating that while the cure rate of testicular cancer is wonderful, the burden of the disease is greatly underappreciated. Even if a free, painless self-examination leads to an unnecessary doctor's visit, saving one man from advanced disease is well worth the "risks and costs" of TSE.

 

This blog was written by Phillip M. Pierorazio, MD, Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.

 








[1] U.S. Preventive Services Task Force. Screening for Testicular Cancer: U.S. Preventive Services Task Force Reaffirmation Recommendation Statement. Ann Intern Med. 2011;154(7):483-486.

[2] SEER Stat Fact Sheets: Testis Cancer, http://seer.cancer.gov/statfacts/html/testis.html

[3] Bosl, G. J., N. J. Vogelzang, A. Goldman, E. E. Fraley, P. H. Lange, S. H. Levitt, et al. 1981. Impact of delay in diagnosis on clinical stage of testicular cancer. Lancet 2:970–973.
[4] Moul JW, Paulson DF, Dodge RK, et al: Delay in diagnosis and survival in testicular cancer: impact of effective therapy and changes during 18 years. J Urol 1990; 143: pp. 520-523
[5] Aberger M, Wilson B, Holzbeierlein JM, Griebling TL, Nangia AK. Testicular self-examination and testicular cancer: a cost-utility analysis. Cancer Med. 2014 Aug 8. doi: 10.1002/cam4.318. [Epub ahead of print]

The Importance of Testicular Self-Examination

Testicular Cancer is the most common malignancy in men aged 15-34 years old. While there are less than 10k cases of testicular cancer diagnosed every year, the cure rate is greater than 95% for all new cases – leaving hundreds of thousands of survivors in the US at any given moment.[1]  Men with cancer confined to the testicle are almost guaranteed a cure – the long-term survival is approximately 99%. While the cure rate for men with metastatic disease (or cancer spread from the testicle) is still 75%, these men are often subjected to chemotherapy and/or surgery. Read our prior blog on the life-saving additional of Platinum-based Chemotherapy to the Treatment of Metastatic Testicular Cancer.

While most men present with a painless testicular mass, upwards of 15-60% of men will still present with testicular cancer that has spread.[2]  One of the challenges in treating this disease is therefore trying to get more men to present with early-stage, confined testicular cancer before they develop metastatic disease. In the US, on average, men wait 4-6 months prior to seeking a professional opinion for an abnormality in their scrotum and this can lead to higher rates of chemotherapy and worse survival rates.[3,4]

The best means for early-diagnosis and treatment is Testicular Self-Examination (TSE). It is recommended that men examine themselves in a shower once per month for any lumps, bumps, firmness or abnormalities in their testicles. TSE is advocated for by a number of Testicular Cancer advocacy groups including the Testicular Cancer Awareness Foundation (TCAF, www.tcafinfo.org). The TCAF describes how to perform TSE:

• The best time to self-exam is after a warm bath or shower when the scrotal skin is relaxed.
• Examine each testicle gently with both hands by rolling the testicle between the thumb a forefingers.
• Find the epididymis, the soft tube-like structure behind the testicle that collects and carries sperm. If you are familiar with this structure, you won't mistake it for an abnormal mass.

• Look for any lumps or irregularities. Remember that lumps or bumps may also present themselves as painless.
• Look for any changes in size, shape, or texture. Remember it's normal for one testicle to be slightly larger.

The most important step in TSE is to seek a medical opinion if something abnormal is felt.

 
Testicular cancer can grow and spread incredibly quickly and seeking a timely opinion from a testicular cancer expert is of utmost importance – a timely diagnosis can help diagnose the disease early and prevent the need for chemotherapy or extensive surgery. 

For any man with a testicular abnormality - especially those 15-35 - the first thought should be testicular cancer. 

These men should be evaluated immediately with a scrotal ultrasound; if an abnormality, tumor markers (see our prior blog on Testicular Tumor Markers); and should be referred to an urologist or testicular cancer expert. Men should not be treated with antibiotics or anti-inflammatories without an ultrasound or evaluation by an expert.

Of note, the US Preventive Services Task Force (USPSTF) recommends against TSE, citing "moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits". A future blog will address the shortcomings of the USPSTF recommendation and the evidence supporting TSE.

 

This blog was written by Phillip M. Pierorazio, MD; Assistant Professor of Urology and Oncology and Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.










[1] SEER Stat Fact Sheets: Testis Cancer, http://seer.cancer.gov/statfacts/html/testis.html
[2] Stephenson, A. J., and T. D. Gilligan. 2012. Neoplasms of the testis. Pp. 837–870 in A. J. Wein, L. R. Kavoussi, A. C. Novick, A. W. Partin and C. A. Peters, eds. Campbell-Walsh urology. Chapter 31, vol. 1, 10 ed. Elsevier Saunders, Philadelphia, PA.
[3] Moul JW, Paulson DF, Dodge RK, et al: Delay in diagnosis and survival in testicular cancer: impact of effective therapy and changes during 18 years. J Urol 1990; 143: pp. 520-523
[4] Stephenson AJ, Russo P, Kaplinsky R, et al: Impact of unnecessary exploratory laparotomy on the treatment of patients with metastatic germ cell tumor. J Urol 2004; 171: pp. 1474-1477

Classic Manuscript in Urology: Einhorn and Donohue. Journal of Urology, 1977.

Lawrence Einhorn, MD

In the 1960's, metastatic testicular cancer was a death sentence - with a greater than 90% mortality within 1 year of diagnosis.  In 1965,  cisplatinum  chemotherapy was discovered by Dr. Rosenberg at Michigan State University.[47] The drug was tried in testicular cancer in 1971, with a number of complete responses to treatment but with terrible side effects including permanent renal failure.[49]  Shortly thereafter, Drs. Einhorn and Donahue added cisplatinum to the combination of vinblastine and bleomycin, a chemotherapy with some known efficacy in testicular cancer.  The results were astounding - the cure rate went from 10% to 70% and the treatment of testicular cancer was changed forever.

Einhorn LH, Donohue JP.  Improved chemotherapy in disseminated testicular cancer.  J Urol. 1977 Jan;117(1):65-9.
Pubmed.
Journal of Urology.

In this manuscript, Drs. Einhorn and Donohue describe their initial experience with a platinum-based regimen for the treatment of metastatic testis cancer.  Twenty-seven patients received either a regimen of adriamycin, bleomycin and vincristine or platinum, vinblastine and bleomycin (PVB).  The patients receiving PVB had an outstanding response with 16 of 21 (76%) achieving a complete response (no visible cancer), 4 (20%) with a partial response and only 1 with no response.  Considering all patients treated by Dr. Einhorn during this time period, complete remission was achieved with PVB chemotherapy alone in 85% and 93% with additional surgery.

Unfortunately, the response was not durable in all patients. In the manuscript, Dr. Einhorn speculates in the discussion,

"Although we do not have long-term followup data on any of our patients treated with [PVB], it seems quite reasonable to expect at least 50 percent of our patients in complete remission will have cures..."

In fact, the durable cure rate was closer to 70% -- a logarithmic increase in the survival for men with advanced germ cell tumors!

Another important point from this paper was that the "Einhorn Regimen" involved more than just PVB.  By hydrating patients with copious fluids, Dr. Einhorn mitigated many of the toxicities, including nephrotoxicity.  Shortly after this publication, Dr. Einhorn would work to design, implement and add antiemetics to the regimen.  The results were so impressive the FDA (Food & Drug Administration) approved the "Einhorn Regimen" for advanced testicular cancer without any further studies.

Take home: Metastatic testis cancer was fatal in nearly all patients before this study.  Careful selection of chemotherapeutic agents based on mechanistic principles changed the paradigm for testis cancer (and many other malignancies).  Attention to side effect profiles and adjuvant therapies to mitigate side effects can improve outcomes in patients receiving cytotoxic chemotherapy.

Classic Manuscripts in Urology will be posted on this blog on regular basis.  These articles are meant to highlight the achievements of our predecessors, recognize the work from which we build our careers and stimulate new conversations and discussion on a variety of urological topics.  Please feel free to comment on this manuscript, help point out its strengths and weaknesses, or suggest a new manuscript and topic. 

Surgery for Testicular Cancer: Orchiectomy

While scrotal ultrasound and serum tumor markers (beta-human chorionic gonadotropin, alpha-fetoprotein, and lactate dehydrogenase) are the first steps in the diagnosis of a testis cancer, the diagnosis is not confirmed until an orchiectomy (surgical removal of the testicle) is performed.  The standard-of-care for the removal and treatment of testis cancer is a radical orchiectomy.  This is the most common operation performed for testis cancer worldwide. However, as our understanding of this disease and surgical technique has improved, testis-sparing surgery or partial orchiectomy has become an option for some patients.

This blog entry will briefly discuss important considerations for men undergoing orchiectomy for testis cancer.

RADICAL ORCHIECTOMY

Rationale

This surgery involves removing the testicle and spermatic cord where it exits the body to identify and likely treat the majority of cancers localized to the testis.  As a male fetus develops, the testes develop near the fetal kidneys.  As the fetus grows, the testicles separate from the kidneys and, at about the eighth month of pregnancy, the testicles exit the body wall to rest in the scrotum (this is why premature infants have a higher likelihood of having undescended testicles).  Therefore the blood supply, lymphatic drainage and nerves to the testicle originate near the kidney on that side.  Once these structures exit the body through the internal inguinal ring they fuse with muscles of the body wall to form the spermatic cord.  To correctly stage and prevent any cancer from spreading, the spermatic cord must be taken as high toward or inside the body as possible -- hence the incision in the groin rather than the scrotum.

For men whose cancer has spread from the testicle and who have metastatic testis cancer (elsewhere in the body) or in the lymph nodes of the retroperitoneum, radical orchiectomy is an important first step in the diagnosis and management of disease.  Knowing the type of cancer may help guide chemotherapy or radiation treatments.

Surgery

Adapted from Gottesman JE. In: Crawford ED, editor.
Current genitourinary cancer surgery.
Philadelphia: Lea & Febiger; 1990. p. 319.

The surgery can be performed under general or local anesthetic.  An approximately 5-10cm incision is made in the groin, just above the pubic tubercle (pubic bone) near the inguinal ligament.  This incision facilitates access to both the testicle and the proximal inguinal canal.  The skin incision is relatively painless, so a larger incision should be made to facilitate delivery of a large testicular tumor or to help with access to the spermatic cord.  The incision is carried down to the external oblique fascia (the outermost layer of the body wall).  The external oblique creates a tunnel through which the spermatic cord travels -- a hernia can form when there is weakness in these layers of the body wall.  Once the external oblique fascia is identified, the cord can then be identified exiting the external spermatic ring.  The cord should be isolated and the external fascia will need to be opened to gain access to the internal ring and to take the spermatic cord where it exits the body.  This can be done in either order.  Care should be taken to separate and preserve the ilioinguinal nerve which travels along the spermatic cord.  Once the cord is isolated, an occlusive, but non-crushing clamp or elastic drain can be used to stop blood supply to and from the testicle.  This prevents any "shedding" of tumor cells when the testicle is manipulated.  The testicle can then be "delivered" from the scrotum.  To deliver the testicle the scrotum can be inverted until the testicle is visible, facilitating dissection of the testicle from its scrotal contents.

Once the testicle and spermatic cord are entirely free from the inguinal canal, the testicle can be removed.  The spermatic cord should be ligated in two packets - one containing the gonadal artery and one containing the vas deferens (sperm duct) and its associated artery.  A large, non-absorbable suture should also be tied to the distal spermatic cord to facilitate easy identification in the case that a retroperitoneal lymph node dissection needs to be performed in the future.  Care should be taken to close the external oblique fascia to the level of the external ring to prevent future hernia.

Complications

The biggest risk of a radical orchiectomy is hematoma (or bleeding into the scrotum).  It is very common for the scrotum to be bruised, swollen and tender for 2-4 weeks after surgery.  However, a large, purple-appearing scrotum can indicate a hematoma.  Hematoma can be prevented with a compressive dressing, tight-fitting undergarments and/or ice packs.
Ilioinguinal nerve injury can occur if the nerve is damaged during dissection of the spermatic cord.  This is more common in men who underwent prior inguinal surgery (usually for an undescended testicle or hernia repair) and can occur during dissection or be inadvertently trapped in the closure of the external oblique fascia.  The deficit is often decreased sensation to the medial thigh, scrotum or base of the penis.  It is often transient, but can take several weeks or months to improve.
Inguinal hernia can occur if the external oblique fascia is not closed properly or if the closure breaks down.  It is important to minimize strenuous activities for 2-4 weeks to prevent development of a hernia.

Made by Coloplast. 

Testicular Prosthesis

Prostheses should be offered to all men undergoing orchiectomy.  Not all men want a prosthesis -- it is a personal decision.  The prosthesis should be measured in the operating room with the patient asleep.  The goal should be to match the remaining testicle in size taking into account a cancerous testicle can be larger or smaller than normal, and the scrotal skin will make a prosthesis look larger once implanted.

TESTIS-SPARING SURGERY (PARTIAL ORCHIECTOMY)

Rationale

While radical orchiectomy remains the standard-of-care for the diagnosis and treatment of testis cancer, there are a couple of circumstances where testis-sparing surgery is advocated.  The primary indications are in men with:

• bilateral testis cancers (either synchronous, at the same time; or metachronous, that develop some time after the first testicle is removed)
• the standard-of-care would be to remove both testicles under suspicion of cancer, however the implications regarding fertility and testosterone replacement are well-established
• small, palpable testis masses and normal serum tumor markers
• these men have a low, but significant risk of having a benign mass or non-germ cell cancer that does not require orchiectomy
• if a testis cancer is confirmed, a radical orchiectomy is completed
• small, non-palpable, ultrasound detected testis mass with normal tumor markers
• approximately 80% likelihood of benign mass [1] 

Some urologists advocate for testis-sparing surgery even for men with germ cell tumors of the testicle.  While some evidence indicates that this can be done safely in some patients, it is not a proven or well-established technique.[2,3]  Before undergoing testis-sparing surgery, an extensive consultation should occur with the patient and their family regarding expectations and possible outcomes in the operating room.

Surgery

Tumor being identified with
intra-operative ultrasound.

The beginning portion of a testis-sparing surgery is identical to a radical orchiectomy.  Once the testicle is "delivered," the testis-sparing portion should begin.  The tunica vaginalis should be opened vertically to expose the testicle and intraoperative ultrasound should be used to identify the mass, rule-out other masses and create a surgical plan.  The testicle should be iced down for 10 minutes prior to placing a tourniquet or non-crushing clamp on the spermatic cord.  Once the testicle has been iced, a clamp or tourniquet should be placed on the cord.  The tunica albuginea (which houses the tubules of the testicle) should be opened horizontally above the mass.  The mass can often be "shelled" out of the surrounding tubules with a margin of 3-5mm.  Surgical loupes or a microscope can be used to facilitate dissection with a clean margin.  Bipolar forceps can be used to control any bleeding to prevent injury to the remaining tubules.  The mass should then immediately go to pathology for frozen analysis - an expert genitourinary pathologist should evaluate the mass when possible.

If the patient has a normal contralateral testicle and cancer is confirmed in the mass, a completion radical orchiectomy should be performed.

Tumor (in clamp) being dissected from normal testis.

If the patient has (or had) cancer in the contralateral testicle, the pathologist should confirm negative margins before leaving the remainder of the testicle.  If any suspicion of residual cancer, the testicle should be removed.  Once again, the standard-of-care is bilateral orchiectomy and testosterone can easily be replaced.

Complications

The complications are the same for radical orchiectomy and testis-sparing surgery.  In addition, even if testis-sparing surgery is performed, surgery can result in infertility or hypogonadism if the internal blood supply to the testicle is harmed or if the tubules are disrupted.

Summary

Radical orchiectomy is the standard-of-care for men with suspicion of testis cancer and is therefore the most common operation done for testicular cancer.  Testis-sparing surgery (or partial orchiectomy) is a novel approach suitable for some patients.

Phillip M. Pierorazio, MD is the Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  










[1] Giannarini G, Dieckmann KP, Albers P, Heidenreich A, Pizzocaro G.  Organ-sparing surgery for adult testicular tumours: a systematic review of the literature.Eur Urol. 2010 May;57(5):780-90. doi: 10.1016/j.eururo.2010.01.014. Epub 2010 Jan 20.
[2] Brunocilla E, Gentile G, Schiavina R, Borghesi M, Franceschelli A, Pultrone CV, Chessa F, Romagnoli D, Ghanem SM, Gacci M, Martorana G, Colombo F.  Testis-sparing surgery for the conservative management of small testicular masses: an update.  Anticancer Res. 2013 Nov;33(11):5205-10.
[3] Leonhartsberger N, Pichler R, Stoehr B, Horninger W, Steiner H.  Organ preservation technique without ischemia in patients with testicular tumor.  Urology. 2014 May;83(5):1107-11. doi: 10.1016/j.urology.2013.12.021. Epub 2014 Feb 21.

Additional References/Resources:
Joel Sheinfeld MD and George J. Bosl MD.  Surgery of Testicular Tumors in Campbell-Walsh Urology, Tenth Edition. 2012,  871-892.

Donald A. Elmajian and Dennis D. Venable.  Radical orchiectomy in Hinman's Atlas of Urologic Surgery, Third Edition.  2012. 353-356.

AUA Highlights: Testis Cancer, by Dr. Pierorazio

Although a relatively rare malignancy, testis cancer affects approximately 9k men and boys each year.  While not as common or popular as some other urological malignancies, representation in the scientific sessions at the 2014 American Urological Association (AUA) Annual Meeting in Orlando, Florida was excellent.  Here are some of the thematic highlights, click on the links below to read the abstracts:

1. Access to care, epidemiological variation and cost-effectiveness in the treatment of testis cancer.

Because testis cancer is a rare disease, understanding of early symptoms, screening and access to health care can have huge implications regarding the treatment and eventual outcomes of disease.  The following presentations addressed some of these issues.  

In a study of nearly 6,000 men in the SEER (Surveillance, Epidemiology, End Results) database, uninsured men were more likely to present with advanced or metastatic disease, get radiation therapy if they had Seminoma (indicating advanced disease) and die of testis cancer.
PD5-02: The impact of lack of insurance on testicular cancer prognosis in young patients in the United States. Data from the SEER data base. Mohamed Kamel*, Mohammed Elfaramawi, Supriya Jadhav, Rodney Davis, Little Rock, AR.

In another study involving the National Cancer Database Registry, investigators from Vanderbilt University looked at compliance rates with the National Comprehensive Cancer Network (NCCN) Guidelines - which recommend serum tumor markers be drawn prior orchiectomy.  The authors found that young patients, low income patients, those treated at an academic center outside of the South or Midwest were more likely to be treated in compliance with the NCCN Guidelines.
MP10-03: The Influence of Access to Care on Adherence to Clinical Practice Guidelines for Testis Cancer.  C.J. Stimson*, Zachary Reardon, Nashville, TN, Sanjay Patel, Chicago, IL, Harras Zaid, Samuel Kaffenberger, Daniel Barocas, Matthew Resnick, Sam Chang, Nashville, TN

In a second study using the National Cancer Database Registry, researchers looked at over 75k men with testis cancer and found that non-Caucasian men had higher rates of advanced (Stage III) disease and worse overall survival.  African-American men had the highest rates of testis cancer-specific death.

MP10-05: Influence of race on outcomes in testicular cancer: Analysis of 75902 patients in the National Cancer Database.  Claudio Jeldres*, Craig R. Nichols, Khanh Pham, Seattle, WA, Sia Daneshmand, Los Angeles, CA, Christian Kollmannsberger, Vancouver, Canada, Brandon Hayes-Lattin, Portland, OR, Erika Wolff, Katherine Odem-Davis, Christopher R. Porter, Seattle, WA

In a cost-effectiveness analysis, researchers from Kansas City, Kansas examined the role of testicular self-examination in asymptomatic men.  Using Medicare reimbursements to estimate costs, they calculated that the cost of treating an advanced stage testis cancer was roughly $50k, while the costs of office evaluation ranged from $150-600, and the cost of an orchiectomy for early-stage disease is approximately $20k.  Therefore, they concluded - contrary to the recommendation of the US Preventative Services Task Forces (USPSTF) - that testicular self-examination is cost-effective and should not be discouraged.
MP10-11: TESTICULAR SELF-EXAMINATIONS: A COST ANALYSIS. Michael Aberger*, Bradley Wilson, Jeffrey Holzbeierlein, Tomas Griebling, Ajay Nangia, Kansas City, KS

2. Treatment of early stage disease.

The treatment of Clinical Stage 1 testis cancer is evolving (click here to see our blog on the treatment of clinical stage 1 NSGCT).  Most patients are cured with orchiectomy alone, and the remainder can be salvaged with chemotherapy and/or surgery.  Therefore active surveillance is emerging as the most common management strategy for these patients with primary retroperitoneal lymph node dissection (RPLND) and chemotherapy as second options.  However, given the young age and relatively good health of men with testis cancer, the long-term implications of each management strategy are not fully realized.  These presentations address this topic.

To investigate the use of active surveillance for Stage 1 testis cancer, researchers in this study used data from the 75k men in the National Cancer Database Registry with testicular cancer.  For Clinical Stage 1 Seminoma, they found the rates of active surveillance increased from 25% to 55% over the time period from 1998-2011 with a concomitant decrease in radiation from 72% to 28%.  Interestingly, for non-seminomatous germ cell tumors the rates of active surveillance remained stable (58-66%) while rates of primary chemotherapy increased (28%) and retroperitoneal lymph node dissection (RPLND) decreased (12.9%) in 2011.  However, in 2011, 50% of patients with cT1a disease received chemotherapy and not active surveillance.
PD5-04: United States trends in patterns of care in clinical stage I testicular cancer: Results from the National Cancer Data Base (1998-2011).  Claudio Jeldres*, Craig R. Nichols, Khanh Pham, Seattle, WA, Sia Daneshmand, Los Angeles, CA, Christian Kollmannsberger, Vancouver, Canada, Brandon Hayes-Lattin, Portland, OR, Erika Wolff, Katherine Odem-Davis, Christopher R. Porter, Seattle, WA

In a retrospective study of 48 men with clinical stage 1 seminoma on active surveillance, only 2 patients recurred giving a 95% recurrence free survival at 3 years.
MP10-06: Lower-Than-Expect Relapse Rate Among Contemporary Patients with Clinical Stage I Seminoma Managed on Surveillance.  Cesar Ercole*, Cleveland, OH, Estefania Linares, Madrid, Spain, Maria Mir, Yaw Nyame, Daniel Greene, Timothy Gilligan, Andrew Stephenson, Cleveland, OH

In an update of prospective, single arm, phase II clinical trial, 40 patients with high-risk clinical stage 1 non-seminomatous germ cell tumors received one cycle of BEP (Bleomycin, Etoposide and Cisplatinum chemotherapy).  With 15-years of follow-up, one patient recurred and died of metastases, three developed a contralateral testis tumor and three developed a secondary malignancy.
MP10-09: Fifteen years after treatment with one adjuvant cycle of Etoposide, Bleomycin and Cisplatin chemotherapy outcomes in patients with high risk nonseminomatous germ cell tumors clinical stage I. Extended follow up of a prospective single arm clinical trial cohort. Alvaro Vidal Faune*, George N. Thalmann, Martin Fey, Urs E. Studer, Bern, Switzerland

3. Retroperitoneal lymph node dissection (RPLND) for advanced (retrocrural) disease

While the overall survival rate for patients with testis cancer is excellent, after chemotherapy, some patients will develop chemotherapy-resistant teratoma that must be resected surgically.  One of the more challenging locations for a teratoma is behind the diaphragm in the retrocrural space.  At Johns Hopkins, we do these surgeries with either thoracic or vascular surgeons depending on the location and appearance of the tumor.

Two of the leading centers in the treatment of advanced testicular cancer, Indiana University and Memorial Sloan Kettering Cancer Center in New York, presented their experiences with retrocrural metastases.  In both series, the majority of tumors were teratoma.  A variety of incisions were described, with the most common being an abdominal approach with trans-diaphragmatic access when necessary.  Both centers prescribed to joint surgery involving both urology and thoracic surgery.  At Johns Hopkins, we do these surgeries with either thoracic or vascular surgeons depending on the location and appearance of the tumor.
PD5-05: SURGICAL MANAGEMENT OF RETROCRURAL DISEASE IN TESTIS CANCER: OUTCOMES AND EVOLUTION OF PRACTICE.  Hristos Kaimakliotis*, K Clint Cary, Jose Pedrosa, Timothy Masterson, Richard Bihrle, Kenneth Kesler, Richard Foster, Indianapolis, IN
PD5-06: Retrocrural dissection during retroperitoneal lymph node dissection for testicular cancer.  Itay Sternberg*, Brett Carver, Melanie Bernstein, Joel Sheinfeld, New York, NY

Read the entire abstracts:
For podium presentations (PD5-), click here.
For poster presentations (MP10-), click here.


Phillip M. Pierorazio, MD is the Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  

The Basics of Testis Cancer Diagnosis: Epidemiology & Presentation

Testis Cancer is a rare cancer, with approximately 9,000 boys and men being diagnosed each year.  Fortunately, the cure rates are excellent -- only 400 men will die of testis cancer each year -- leaving about 20,000 survivors with cancer and 200,000 cured of the disease in the US at any given moment.[1] Testis cancer affects mostly young men and boys, therefore the diagnosis can create tremendous anxiety and uncertainty for the patient and their family.

Here we review the Basics of Testis Cancer Diagnosis.

EPIDEMIOLOGY

As stated above, approximately 9,000 men and boys are diagnosed with testis cancer each year; 400 will die of the disease, 20,000 are surviving with the disease and 200,000 have been cured.  Testis cancer is the most common malignancy among men 20-40 years old and is the 2nd most common malignancy in young men 15-19 years old (leukemia is #1).[2]  Corresponding to these statistics, there are three, well-known age peaks for testis cancer:

• Infancy
• Age 30-40 years
• Age 60

Most cases (about 70%) present as a unilateral mass confined to the testicle (a cancer in only one testicle).  Approximately 30% of men will present with metastatic disease -- the most common sites being the retroperitoneum and the lungs.[3]  Bilateral tumors (tumors in both testicles) can appear synchronously or metachronously (at the initial diagnosis or develop later), but is extremely rare, occuring in 2% or less of patients.[4]

RISK FACTORS

There are 4 risk factors for testis cancer:

• Cryptorchidism (an undescended testicle) [5-7]
• 4 to 6-fold risk of developing cancer in the undescended testicle
• 2 to 3-fold risk is orchidopexy (surgical lowering of the testicle) occurs before puberty.
• A slight increased risk also exists in the normal, descended testicle (relative risk 1.74).
• Family history of testicular cancer [8-11]
• 8 to 12-fold risk if a brother with testis cancer
• 2 to 4-fold risk if father with testis cancer
• Average age at diagnosis is 2-3 years younger than general population if a first-degree relative has testicular cancer
• Personal history of testicular cancer [4,12]
• Only 2% of testis cancer patients will have cancer in both testicles, but...
• 12-fold risk if a history of testis cancer
• higher in younger men
• higher in seminoma
• Intratubular germ cell neoplasia (ITGCN) [13,14]
• Most testis cancer arise from the precursor lesion known as ITGCN (or carcinoma-in-situ, CIS)
• ITGCN is present adjacent to testis cancer in 80-90% of patients
• If ITGCN is present, the risk of subsequent testis cancer is:
• 50% at 5 years
• 70% at 7 years

CLINICAL PRESENTATION

Most testis cancers present as a mass confined to the testicle.  Therefore, the most common presentation is a painless testicular mass.  Most of these masses are palpable and of significant size (a few to several centimeters).  Small, non-palpable lesions without pain and in the absence of distant disease have a higher likelihood of being a benign tumors.  In a number of studies, upwards of 80% of non-palpable, asymptomatic masses that are 2cm or smaller will be benign tumors.[15-18]  Benign lesions may include testicular cysts, small infarcts, Leydig cell nodules, or small Leydig cell or Sertoli cell tumors.

Serious, acute pain is associated with rapidly growing tumors and associated hemorrhage or infarction (if the tumor outgrows its blood supply).  Most patients with pain complain of dull scrotal discomfort or heaviness.  Rarely trauma can lead to a diagnosis, mostly because it brings a mass or pain to the patient's awareness.  

For the upwards of 30% of men who present with metastatic cancer, symptoms of metastases can be the presenting complaint. Bulky retroperitoneal lymphadenopathy can lead to abdominal mass; abdominal, flank or back pain due to direct invasion or obstruction of muscles, blood vessels or the ureters; lower extremity swelling if the IVC is compressed or gastrointestinal symptoms if the intestines are involved.  Pulmonary metastases can present as chest pain, shortness of breath and cough.

As testis cancers can lead to diminished spermatogenesis, infertility can be the initial presentation in rare men.  

DIAGNOSIS

The mainstays of diagnosis are scrotal ultrasound and serum tumor markers.

Serum tumor markers are covered in a previous blog (click here).  

Scrotal Ultrasound

Scrotal ultrasound often demonstrates an intratesticular, hypoechoic (dark) mass.  Testis cancers are often vascular (or hypervascular), although the absence of blood flow does not rule out a testis cancer.  Even in patients with suspicion of metastatic cancer, a scrotal ultrasound should be used to identify an active primary tumor or a "burned-out" testicular mass -- which is typically a small, impalpable scar or calcification.  Radical orchiectomy should strongly be considered for any intra-testicular mass and suspicion of testis cancer.

Advanced Imaging

Abdominal and Pelvic CT scan can be performed before or after orchiectomy to evaluate the retroperitoneum.  An initial chest x-ray should be performed to rule-out involvement in the lungs.  Chest CT is only warranted if suspicion of pulmonary disease on x-ray.  Routine imaging of the brain or bones is not recommended unless specific symptoms.   

Summary

• Testis cancer is a rare entity, affecting approximately 9,000 men and boys each year; however the cure rate is excellent, leaving approximately 200,000 survivors in the US.
• Testis cancer is the most most common cancer in men aged 20-40, and 2nd most common in men age 15-19 years old.
• The main risk factors for testis cancer are cryptorchidism (undescended testis), a family or personal history of testis cancer or ITGCN.
• The most common presentation is a painless, palpable testis mass.
• 70% of cancers are confined to the testicle.
• Symptoms are often related to metastatic invasion in the retroperitoneum or lungs.
• Diagnosis involves routine imaging and bloodwork involving scrotal ultrasound, serum tumor markers and abdominal imaging.

To read more about Testis Cancer follow this link.

This blog was written by Phillip M. Pierorazio, MD, Director of the Division of Testis Cancer at the Brady Urological Institute at Johns Hopkins.









[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.
[2] Horner MJ, Ries LAG, Krapcho M,et al: SEER Cancer Statistics Review, 1975–2006. Bethesda (MD): National Cancer Institute, 2009.
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