Testicular Cancer Treatment (Professional) (cont.)
Stage I Testicular Cancer
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Stage I Seminoma
Stage I seminoma has a cure rate of greater than 95% regardless of whether or not postorchiectomy adjuvant therapy is given.
Standard treatment options:
- Radical inguinal orchiectomy with no retroperitoneal node radiation therapy followed by periodic determination of serum markers, chest x-rays, and computed tomographic (CT) scans of the abdomen and pelvis (surveillance). These studies are typically performed every 4 months for the first 3 years, then every 6 months for 3 years, and then annually for an additional 4 years.
Results of multiple clinical series, including more than 1,200 patients with stage I seminoma managed by postorchiectomy surveillance, have been reported.[1,2,3,4,5,6,7,8] The overall 10-year tumor recurrence rate is 15% to 20%, and nearly all patients whose disease recurred were cured by radiation therapy or chemotherapy. Thus, the overall cure rate is indistinguishable from that achieved with adjuvant radiation therapy or carboplatin chemotherapy. Relapses after 5 years are unusual but can occur in as many as 4% of patients. Independent risk factors for relapse include tumor size greater than 4 cm and invasion of the rete testis. The 5-year risk of relapse is about 10% without either risk factor, 16% with one risk factor, and 32% with both risk factors.
- Radical inguinal orchiectomy followed by either one or two doses of carboplatin adjuvant therapy.
In a large randomized controlled equivalency trial comparing para-aortic (or dog-leg field, if clinically indicated) radiation to a single dose of carboplatin (concentration-versus-time curve [AUC] × 7) after radical inguinal orchiectomy, relapse-free survival (RFS) and overall survival (OS) rates were equivalent after a median follow-up of 4 years.[Level of evidence: 1iiA] Three-year RFS was 94.8% with carboplatin versus 95.9% with radiation therapy. In this trial, AUC dosing was based on radioisotope measurement of glomerular filtration rate; dosing based on calculations of creatinine clearance is not equivalent, has not been validated in this setting, and is discouraged.
Phase II studies, including several with more than 4 years median follow-up, have consistently reported lower relapse rates (0%–3.3%) when two doses of carboplatin were administered either 3 or 4 weeks apart and dosed either at 400 mg/m2 or at an AUC of 7.[2,3,11,12,13,14,15] Administration of two doses of carboplatin has never been compared to a single dose nor to radiation therapy in a randomized trial.
- Removal of the testicle via radical inguinal orchiectomy followed by radiation therapy is an approach that is associated with a 5-year relapse-free survival of 95% to 96% and a 5-year disease-specific survival in excess of 99% in multiple large series and randomized controlled trials.[16,17,18,19,20,21,22]
Two treatment fields are commonly used: a para-aortic strip covering the retroperitoneal nodes or a dog-leg field that includes the ipsilateral iliac lymph nodes as well as the retroperitoneum. The dose ranges from 20 Gy to 26 Gy. Relapse rates and toxic effects were studied in a randomized comparison of para-aortic radiation therapy alone versus para-aortic radiation therapy with an added ipsilateral iliac lymph node field. Three-year RFS rates were virtually identical (96% vs. 96.6%) as were OS rates (99.3% vs. 100%). Pelvic RFS rates were 98.2% versus 100%; the 95% confidence interval (CI) for the difference in pelvic RFS rates was 0% to 3.7%. A statistically significant increase was observed in leukopenia and diarrhea associated with the ipsilateral iliac radiation therapy. In a randomized trial (MRC-TE18), radiation to 20 Gy over 10 daily fractions was clinically equivalent to 30 Gy over 15 fractions after a median follow-up of 61 months in both RFS and OS. Patient-reported lethargy and ability to perform normal work were better in the lower-dose regimen.[Level of evidence: 1iiA]
Stage I Nonseminoma
Stage I nonseminoma is highly curable (>99%). Orchiectomy alone will cure about 70% of patients but the remaining 30% will relapse and require additional treatment. The relapses are highly curable, and thus post-orchiectomy surveillance is a standard treatment option, but some physicians and patients prefer to reduce the risk of relapse by having the patient undergo either a retroperitoneal lymph node dissection (RPLND) or one or two cycles of chemotherapy. Each of these three approaches has unique advantages and disadvantages, and none has been shown to result in longer survival or superior quality of life.
Standard treatment options:
- Radical inguinal orchiectomy followed by a regular and frequent surveillance schedule.
Typically, patients are seen monthly during the first year, every 2 months during the second year, every 3 months during the third year, every 4 months during the fourth year, every 6 months during the fifth year, and annually for the subsequent 5 years.[23,24,25] At each visit, the history is reviewed, a physical examination is given, determination of serum markers are performed, and a chest x-ray is obtained (sometimes at alternating visits). An additional key aspect of surveillance involves abdominal or abdominopelvic CT scans, but the preferred frequency of such scans is controversial.
A randomized controlled trial (MRC-TE08) compared a schedule that used only two scans at 3 months and 12 months to a schedule that used five scans at 3, 6, 9, 12 and 24 months. With over 400 randomly assigned patients and a median follow-up of 40 months, all relapsing patients had either good- or intermediate-risk disease, and there were no differences in the stage or extent of disease at relapse between the two arms. No deaths were reported. Nonetheless, some organizations recommend CT scans every 3 to 4 months during the first 3 years of follow-up and continuing but less-frequent CT scans thereafter. While this study would appear to indicate that scans at 3 and 12 months are adequate during the first year, longer follow-up will be needed to assess whether discontinuing scans after 12 months is safe.[Level of evidence: 1iiA] With regard to chest imaging, disease recurrence is rarely detected by chest x-ray alone, so chest x-ray may play little or no role in routine surveillance but is nonetheless included in the mainstream surveillance schedules.
The need for long-term follow-up has not been adequately investigated. Surveillance series with long follow-up have reported that fewer than 1% of clinical stage I patients relapse after 5 years.[27,28] Late relapses often occur in the retroperitoneum when they do occur. Hence, some schedules discontinue CT scans after 12 months, while others recommend at least annual scans for 10 years.
The option of a radical inguinal orchiectomy followed by a regular and frequent surveillance schedule should be considered only if:
- CT scan and serum markers are negative.
- The patient accepts the need for and commits to frequent surveillance visits. Children are adequately followed by serum markers alpha-fetoprotein (AFP), chest x-rays, and clinical examination.
- The physician accepts responsibility for seeing that a follow-up schedule is maintained as noted.
- Removal of the testicle through the groin followed (in adults) by RPLND.
A nerve-sparing RPLND that preserves ejaculation in virtually every patient has been described in clinical stage I patients and appears to be as effective as the standard RPLND.[30,31,32] Surgery should be followed by monthly determination of serum markers and chest x-rays for the first year and every other month determinations for the second year.
Men undergoing RPLND who are found to have pathological stage I disease have a roughly 10% risk of relapsing subsequently, whereas men with pathological stage II disease (i.e., those who are found to have lymph node metastases at RPLND) have as much as a 50% risk of relapse without further treatment.Two cycles of post-RPLND chemotherapy using either bleomycin, etoposide, and cisplatin (BEP) or etoposide plus cisplatin (EP) lowers the risk of relapse in men with pathological stage II disease to about 1%.[34,35] The vast majority of reported patients in studies of RPLND underwent the operation at a center of excellence with a urological surgeon who had performed hundreds of such operations. The ability of less-experienced urologists to achieve similar results is unknown.
In patients with pathologic stage I disease after RPLND, the presence of lymphatic or venous invasion or a predominance of embryonal carcinoma in the primary tumor appears to predict for relapse.[36,37,38] In a large Testicular Cancer Intergroup Study, the relapse rate among men with pathological stage I disease was 19% in those with vascular invasion versus 6% in those without vascular invasion. One study reported that the relapse rate for men with pathological stage I disease was 21.2% (18 of 85 men relapsed) if their tumors were predominantly embryonal carcinoma and 29% if there was a predominance of embryonal carcinoma plus lymphovascular invasion, versus 3% (5 of 141 men relapsed) if there was not a predominance of embryonal carcinoma.[36,37]
Among pathological stage II patients, the relapse rate was 32% among men with embryonal carcinoma-predominant tumors compared with15.6% in the other stage II patients. The risk of metastatic disease (i.e., either pathological stage II disease or relapsed pathological stage I disease) in men with tumors showing a predominance of embryonal carcinoma plus lymphovascular invasion was 62% compared with 16% in men with neither risk factor.
These data have shown that high-risk patients undergoing RPLND have a substantial risk of subsequently receiving chemotherapy. Data from one institution have shown that about half of men with stage I pure embryonal carcinoma undergoing RPLND will subsequently receive cisplatin-based chemotherapy.
Retroperitoneal dissection of lymph nodes is not helpful in the management of children, and potential morbidity of the surgery is not justified by the information obtained. In men who have undergone RPLND, chemotherapy is employed immediately on first evidence of recurrence.
- Adjuvant therapy consisting of one or two courses of BEP chemotherapy in patients with clinical stage I disease.
A randomized controlled trial compared a single cycle of BEP chemotherapy to RPLND in 382 patients. The 2-year recurrence-free survival rates were 99.5% with chemotherapy versus 91.9% with RPLND (absolute difference = 7.6%; 95% confidence interval, 3.1%–12.1%). There were no treatment-related or cancer-specific deaths in either arm of the study.
A Swedish and Norwegian study reported results of a risk-adapted therapy protocol in which patients with nonseminomas with lymphovascular invasion underwent postorchiectomy chemotherapy with one or two cycles of BEP chemotherapy, while those without lymphovascular invasion underwent either surveillance or a single cycle of BEP. The study included 745 patients and, with a median follow-up of 4.7 years and 2-year follow-up of 89% of patients, there were no deaths from testicular cancer, although one patient died of a stroke immediately after completing chemotherapy for relapsed disease. Overall survival and cause-specific survival were 98.9% and 99.9%, respectively. Both of these studies were conducted at community-based hospitals and demonstrated that postorchiectomy chemotherapy could be delivered at a regional or national level without depending on centers of excellence.
Several phase II studies and case series reporting the results after two cycles of BEP in intermediate- or high-risk patients have reported relapse rates ranging from 0% to 4% (average = 2.4%). Fewer than 1% of patients in these series died of testicular cancer. While chemotherapy produces the lower relapse rate and a comparable disease-specific survival rate compared to RPLND or surveillance, it is unknown whether a brief course of chemotherapy results in late toxicity or an increased risk of late relapse. Longer follow-up is awaited.
There is no consensus about the optimal management of men with stage I nonseminomas, but each of the three strategies above produces a disease-specific survival rate of about 99%. Some clinicians have advocated a risk-adapted approach such that low-risk patients undergo surveillance, while others undergo either RPLND or chemotherapy. The goal of such an approach is to minimize the side effects of treatment, but risk-adapted therapy has never been demonstrated to result in better outcomes. Some experts prefer a surveillance strategy generally so as to minimize unnecessary treatment. Others prefer RPLND to obtain more accurate staging, to reduce the risk of needing chemotherapy (and hence chemotherapy's side effects and toxicity) and to, theoretically, reduce the risk of late relapse. At the same time, many experts reject RPLND as insufficiently effective at lowering relapse rates and prefer chemotherapy. Surveillance and chemotherapy have been tested at the regional and national level with excellent results, whereas the limited data concerning RPLND in the regional setting have shown higher than expected in-field relapse rates but no deaths.[40,41]
With regard to risk stratification, data suggest that relapse rates are higher in patients with histologic evidence of lymphatic or venous invasion or a predominance of embryonal carcinoma.[17,27,36,37,43] Tumors that consist of mature teratoma appear to have a lower relapse rate.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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- Aparicio J, García del Muro X, Maroto P, et al.: Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage I seminoma. Ann Oncol 14 (6): 867-72, 2003.
- Aparicio J, Germà JR, García del Muro X, et al.: Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol 23 (34): 8717-23, 2005.
- Choo R, Thomas G, Woo T, et al.: Long-term outcome of postorchiectomy surveillance for Stage I testicular seminoma. Int J Radiat Oncol Biol Phys 61 (3): 736-40, 2005.
- Chung P, Parker C, Panzarella T, et al.: Surveillance in stage I testicular seminoma - risk of late relapse. Can J Urol 9 (5): 1637-40, 2002.
- Daugaard G, Petersen PM, Rørth M: Surveillance in stage I testicular cancer. APMIS 111 (1): 76-83; discussion 83-5, 2003.
- Horwich A, Alsanjari N, A'Hern R, et al.: Surveillance following orchidectomy for stage I testicular seminoma. Br J Cancer 65 (5): 775-8, 1992.
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- Oliver RT, Mason MD, Mead GM, et al.: Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet 366 (9482): 293-300, 2005 Jul 23-29.
- Oliver RT, Mead GM, Rustin GJ, et al.: Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol 29 (8): 957-62, 2011.
- Dieckmann KP, Brüggeboes B, Pichlmeier U, et al.: Adjuvant treatment of clinical stage I seminoma: is a single course of carboplatin sufficient? Urology 55 (1): 102-6, 2000.
- Krege S, Kalund G, Otto T, et al.: Phase II study: adjuvant single-agent carboplatin therapy for clinical stage I seminoma. Eur Urol 31 (4): 405-7, 1997.
- Oliver RT, Boublikova L, Ong J, et al.: Fifteen year follow up of the Anglian Germ Cell Cancer Group adjuvant studies of carboplatin as an alternative to radiation or surveillance for stage I seminoma. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-780, 196a, 2001.
- Reiter WJ, Brodowicz T, Alavi S, et al.: Twelve-year experience with two courses of adjuvant single-agent carboplatin therapy for clinical stage I seminoma. J Clin Oncol 19 (1): 101-4, 2001.
- Steiner H, Höltl L, Wirtenberger W, et al.: Long-term experience with carboplatin monotherapy for clinical stage I seminoma: a retrospective single-center study. Urology 60 (2): 324-8, 2002.
- Bamberg M, Schmidberger H, Meisner C, et al.: Radiotherapy for stages I and IIA/B testicular seminoma. Int J Cancer 83 (6): 823-7, 1999.
- Classen J, Schmidberger H, Meisner C, et al.: Para-aortic irradiation for stage I testicular seminoma: results of a prospective study in 675 patients. A trial of the German testicular cancer study group (GTCSG). Br J Cancer 90 (12): 2305-11, 2004.
- Fosså SD, Horwich A, Russell JM, et al.: Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol 17 (4): 1146, 1999.
- Jones WG, Fossa SD, Mead GM, et al.: Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I Testicular Seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol 23 (6): 1200-8, 2005.
- Logue JP, Harris MA, Livsey JE, et al.: Short course para-aortic radiation for stage I seminoma of the testis. Int J Radiat Oncol Biol Phys 57 (5): 1304-9, 2003.
- Oliver RT, Mason M, Von der Masse H, et al.: A randomised comparison of single agent carboplatin with radiotherapy in the adjuvant treatment of stage I seminoma of the testis, following orchidectomy: MRC TE19/EORTC 30982. [Abstract] J Clin Oncol 22 (Suppl 14): A-4517, 386, 2004.
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- National Comprehensive Cancer Network.: NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer. Version 2.2009. Fort Washington, PA: National Comprehensive Cancer Network, 2009. Available online. Last accessed January 18, 2012.
- Rustin GJ, Mead GM, Stenning SP, et al.: 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 Research Institute Testis Cancer Clinical Studies Group. J Clin Oncol 25 (11): 1310-5, 2007.
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