Patients with relapsed/refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse. Patients who do poorly despite ABMT have a mediastinal primary site, true cisplatin-refractory disease, disease progression before ABMT, and/or markedly elevated beta-HCG at ABMT. New treatment modalities are needed for the latter group. This observation is in accordance with the view of Flechon and associates (2001) that new strategies are needed to improve the survival rate of poor prognosis germ cell tumor patients. Tandem transplants is an attempt to improve respnse in these situations. However, NCCN does not list tandem transplants and they remain investigational at this time.

Patients with relapsed/refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse, as this patient does.  High-dose chemotherapy has been shown in phase II trials to be an effective salvage strategy in poor-risk patients with a suggestion of an improvement in survival as compared to standard dose salvage chemotherapy, albeit through matched-pair analysis rather than randomized trials. High-dose chemotherapy has also been shown to be a potentially curative option for patients with second or subsequent relapses. NCCN lists autologous transplantation for this group.

Adra N, Abonour R, Althouse SK, Albany C, Hanna NH, Einhorn LH. High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience. J Clin Oncol. 2016;35(10):1096-1102.

http://nccn.org/professionals/physician_gls/PDF/testicular.pdf

Lori Wood et al, Canadian consensus guidelines for the management of testicular germ cell cancer. Can Urol Assoc J. 2010 Apr; 4(2): e19–e38

Boys and adolescents with stages III and IV testicular tumors are treated with surgical resection followed by four courses of standard or high-dose PEB (platinum, etoposide, bleomycin) therapy. The 6-year survival outcome for stage III and IV males younger than 15 years was 100%, with 6-year EFS of 100% and 94%, respectively. The use of high-dose PEB therapy did not improve the outcome for these boys but did cause increased incidence of ototoxicity. Excellent outcomes for boys with testicular germ cell tumors using surgery and observation for stage I tumors and carboplatin, etoposide, and bleomycin (JEB) and other cisplatin-containing chemotherapy regimens for stage II–IV tumors have also been reported by European investigators. Thus, surgery followed by standard-dose platinum-based chemotherapy is the recommended approach for stages II–IV testicular germ cell tumors in children younger than 15 years.

N. Marina, W. B. London, A. L. Frazier, S. Lauer, F. Rescorla, B. Cushing, M. H. Malogolowkin, R. P. Castleberry, R. B. Womer, and T. Olson
Prognostic Factors in Children With Extragonadal Malignant Germ Cell Tumors: A Pediatric Intergroup Study
J. Clin. Oncol., June 1, 2006; 24(16): 2544 – 2548

Paul C. Rogers, Thomas A. Olson, John W. Cullen, Deborah F. Billmire, Neyssa Marina, Frederick Rescorla, Mary M. Davis, Wendy B. London, Stephen J. Lauer, Roger H. Giller, Barbara Cushing, Treatment of Children and Adolescents With Stage II Testicular and Stages I and II Ovarian Malignant Germ Cell Tumors: A Pediatric Intergroup Study—Pediatric Oncology Group 9048 and Children’s Cancer Group 8891 Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3563-3569

PDQ – http://www.cancer.gov/cancertopics/pdq/treatment/extracranial-germ-cell/HealthProfessional/page8

Most of the research on PET in testicular cancer focused on restaging, because functional assessment of residual masses after chemotherapy is of great clinical interest. Staging is less well studied. In a 2003, CMS reviewed 11 studies of FDG-PET in testicular cancer and concluded that the literature suggests a possible role for FDG PET in staging testicular cancer, but that studies had significant limitations and that further research was needed to confirm this finding. PET in general is covered for the listed indications if the results of the PET exam could potentially impact clinical management. Medicare requires the ordering physician to document in the patient medical record the indication and justification for ordering a PET study, including a statement of how the PET findings might impact clinical management. There are several difficulties with using FDG PET for distinguishing NCCN does not recommend PET for either seminomatous or non-seminomatous testicular cancer.

There are several difficulties with using FDG PET for distinguishing recurrence and residual disease from benign masses. FDG PET was not useful in detecting tumor of less than 0.5cm or teratoma of any size secondary to a low proliferation rate and glucose metabolism. Furthermore, FDG PET cannot reliably distinguish between teratoma and necrosis. Since FDG PET cannot reliably distinguish between teratoma, cancer and necrosis, regardless of a positive FDG PET, you will still resect the testicular mass (or at least perform a retroperitoneal lymph node dissection post chemotherapy if serum tumor markers are not elevated) because the standard of care is to leave no mass (or suspected recurrence) unexamined for fear of malignant transformation or “growing teratoma syndrome.” Though many studies showed FDG PET with a high specificity for detecting residual tumor, the converse, that sensitivity is low, is also true. Given this relationship, a negative FDG PET scan does not provide complete assurance that the patient does not have a mass requiring resection, especially in patients with NSGCT. To improve sensitivity of FDG PET, some authors advocate avoiding its use in patients with high probability of having residual teratoma (i.e. patients with teratomatous elements in the primary tumor). Notwithstanding the reportedly high specificity of FDG PET for detecting residual tumor, authors note that false positive results secondary to FDG PET accumulating in tissue macrophages are a common problem, especially post chemotherapy or if the patient has an infection. Additionally, false negative results are common post chemotherapy because the chemotherapy drug leads to a transient suppression of metabolic activity in germ cell tumors regardless of their final response to therapy. Though some authors conclude that they cannot recommend the routine use of FDG PET scans in the evaluation of residual postchemotherapy masses in seminoma, one potential safeguard against the false negative results is to perform PET scans at least 2 weeks or more after chemotherapy. A recent guideline rated this modality as 4 on a 4/10 scale for staging testicular cancer. However NCCN now recommends this modality, with sureillance for negative results and biopsy or surgery, if positive, for seminoma but not for non-seminoma. nccn.org, testicular, p. 6, 2009

Technology Assessment submitted to AHRQ by the Duke Center for Clinical Health Policy Research and Evidence Practice Center, David B. Matchar, MD, Shalini L. Kulasingam, PhD, Laura Havrilesky, MD, et al., December 2003.

Choyke PL, Bluth EI, Bush WH Jr, Casalino DD, Francis IR, Jafri SZ, Kawashima A, Papanicolaou N, Rosenfield AT, Sandler CM, Segal AJ, Tempany C, Resnick MI, Expert Panel on Urologic Imaging. Staging of testicular malignancy. [online publication]. Reston (VA): American College of Radiology (ACR); 2005. 6 p. [57 references]

update 3/7/2009

Clinical stage I (CS I) seminoma has been the subject of various studies aimed at finding the ideal treatment. Due to its high radiosensitivity, radiotherapy has been the standard approach for decades. However, the fact that CS I seminoma has a recurrence rate of only 15-20% has prompted many suggestions for better treatment stratification offering surveillance therapy for a subgroup of patients. Moreover, carboplatinum-based monochemotherapy has been the topic of various retrospective studies demonstrating equal effectiveness for adjuvant chemotherapy with one cycle of carboplatin. Carboplatin ahs been coing into wider use for adjuvant therapy. Consensus suggests that adjuvant chemotherapy reduces the risk of relapse compared with surveillance, but that it is associated with immediate adverse effects (nausea, diarrhoea, and indigestion) and possible long-term risks of reduced fertility and development of secondary malignancies.

With surveillance most people can avoid the toxicity of adjuvant treatment but they must face the uncertainty of relapse as well as regular hospital follow up for as long as 10 years. Adjuvant radiotherapy and adjuvant chemotherapy can both substantially reduce the risk of relapse, but both are associated with mild immediate toxicity. Radiotherapy is also associated with a low but difficult to quantify long term risk of second malignancy and reduced fertility. The pattern of relapse also differs after adjuvant radiotherapy or chemotherapy. After radiotherapy, relapse in pelvic nodes, mediastinum, or supraclavicular area is most common. After chemotherapy, relapse is most common in the para-aortic nodes. Seminoma is a radio-sensitive tumour, and the current standard treatment for stage 1 seminoma is orchidectomy followed by infradiaphragmatic lymph node irradiation or two courses of carboplatin.

Oliver RTD, Mason MD, Mead GM, et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomized trial. Lancet 2005;366:293-300

nccn.org, testicular cancer 2014

http://www.library.nhs.uk/cancer/ViewResource.aspx?resID=102510

The newest guideline is Canadian and published in 2010. It says: ” It appears the best results for HDCT have been obtained if a tandem transplant has been performed and thus, patients should have enough stem cells collected for a planned tandem procedure”. Subsequently, triple transplant therapy has been published. Feldman et al. at Memorial Sloan-Kettering Cancer Center reported their TI-CE regimen for relapsed germ cell tumors using 2 cycles of preoperative chemotherapy (paclitaxel plus ifosfamide) before stem cell collection followed by triple transplantation with high-dose carboplatin and etoposide. They reported DFS in 5 of 21 patients in relapsed PMNSGCT (24%) with a median DFS of 8.6 months. Lorch et al10 report their long-term results with two different approaches to high-dose salvage chemotherapy. They are to be congratulated for initiating one of the few phase III studies in this patient population and for reporting the results with a median follow-up of 7.5 years. From November 1999 to November 2004, 211 patients were enrolled. They were randomly assigned to one cycle of VIP followed by three courses of high-dose carboplatin (1500 mg/m2) and etoposide (1,500 mg/m2) versus three cycles of VIP followed by a single cycle of high-dose carboplatin (2,200 mg/m2), etoposide (1,800 mg/m2), and cyclophosphamide (6,400 mg/m2). Despite the different doses and drugs with one cycle versus three cycles of high-dose chemotherapy, it was nevertheless disappointing that there was no difference in the 5-year progression-free survival (47% v 45%; P = .454). There was an improvement in 5-year survival favoring the three cycles of high-dose chemotherapy (49% v 39%; P = .057). However, this did not result from improved therapeutic efficacy but increased treatment-related mortality with the higher doses of the single cycle that also included cyclophosphamide (14% v 4%; P = .01).

L.E Einhorn, Salvage Chemotherapy for Patients With Germ Cell Tumors: Is There a Best Regimen?JCO March 10, 2012 vol. 30 no. 8 771-772

D.R. Feldman, J. Sheinfeld, D.F. Bajorin, et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol, 28 (2010), pp. 1706–1713

orch A, Kleinhans A, Kramer A, et al. (2012) Sequential versus single high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: Long-term results of a prospective randomized trial. J Clin Oncol 30:800–805.
NCCN.ORG, Testicular, 2016

http://www.uroweb.org/fileadmin/tx_eauguidelines/22891_Testicular_Cancer.pdf

Lazarus HM, Stiff PJ, Carreras J, Logan BR, Akard L, Bolwell BJ, Childs RW, Gale RP, Klein JP, Lill MC, Pérez WS, Stadtmauer EA, Rizzo JD.Utility of single versus tandem autotransplants for advanced testes/germ cell cancer: a center for international blood and marrow transplant research (CIBMTR) analysis.Biol Blood Marrow Transplant. 2007 Jul;13(7):778-89.

Lori Wood et al, Canadian consensus guidelines for the management of testicular germ cell cancer. Can Urol Assoc J. 2010 April; 4(2): e19–e38.

Revised 3/15/2016

Patients who are not cured with their initial BEP chemotherapy are usually treated with salvage chemotherapy. Approximately 50% of these testicular cancer patients will subsequently be cured with salvage chemotherapy with tandem transplant of high-dose chemotherapy with peripheral stem cell rescue. Long-term disease-free survival is possible with paclitaxel plus gemcitabine in those who progressed after high-dose chemotherapy, and had not received prior paclitaxel or gemcitabine, according to a recent phase II trial.

There are several reports of cisplatin and epirubicin.

http://www.tc-cancer.com/forum/showthread.php?t=5484

Extragonadal germinal cell syndromes are rare tumors that predominantly affect young males. Histologically, they mirror their gonadal counterparts with which they share the same chemosensitivity and radiosensitivity. Controversy remains regarding the origin of extragonadal germ cell tumors (EGGCTs). The classic theory suggests that germ cell tumors (GCTs) in these areas are derived from local transformation of primordial germ cells misplaced during embryogenesis but a recent alternative theory suggests that primary mediastinal presentations represent reverse migration of occult carcinoma in situ (CIS) lesions in the gonad; hence, they may be gonadal in origin. Some retroperitoneal extragonadal germ cell tumors may represent metastases from a testicular cancer, with subsequent spontaneous necrosis of the primary tumour.

For patients receiving intensive chemotherapy, 5-year survival rates of 40-65% have been reported.The mediastinum is the most common site of extragonadal germ cell tumors. Mediastinal germ cell tumors account for only 2-5% of all germinal tumors, but they constitute 50-70% of all extragonadal tumors. Treatment with 4 cycles of bleomycin, etoposide, and cisplatin (BEP) is the current standard of care. Radiotherapy or surgery can be used after chemotherapy in bulky mediastinal seminomas. Among those whose disease relapses after or progressed on first-line chemotherapy, or those in high risk, or whose disese could not be resected, surgery shuld be attmepted. Otherwise, it is rare to achieve complete remission despite salvage therapy with cisplatin-based regimens, high-dose chemotherapy, paclitaxel, or oral etoposide. High dose therapy is the best hope for these patients, but it is not yet etablished and continues to be investigated, for example: Paclitaxel, Ifosfamide, and Carboplatin Followed By Autologous Stem Cell Transplant in Treating Patients With Germ Cell Tumors That Did Not Respond to Cisplatin, NCT00423852.

A randomized controlled trial compared conventional doses of salvage chemotherapy to high-dose chemotherapy with autologous marrow rescue in 263 patients with recurrent or refractory germ cell tumors. Of the 263 patients, 43 of whom had extragonadal primary tumors, more toxic effects and treatment-related deaths were seen in the high-dose arm without any improvement in response rate or overall survival. One would have to consider transplantation as investigational at this time for this disease.

H. J. Schmoll, R. Souchon, S. Krege, P. Albers, J. Beyer, C. Kollmannsberger, S. D. Fossa, N. E. Skakkebaek, R. de Wit, K. Fizazi, et al.
European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG)
Ann. Onc., September 1, 2004; 15(9): 1377 – 1399.

H. J. Schmoll, R. Souchon, S. Krege, P. Albers, J. Beyer, C. Kollmannsberger, S. D. Fossa, N. E. Skakkebaek, R. de Wit, K. Fizazi, et al.
European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG)
Ann. Onc., September 1, 2004; 15(9): 1377 – 1399.

Pico JL, Rosti G, Kramar A, et al.: A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann Oncol 16 (7): 1152-9, 2005.

After RPLND, NCCN accepts chest CT as clinically indicated.

PET or MRI  is not recommended for surveillance by NCCN or any other guideline to my knowledge.

NCCN TEST-16, 2020

https://www.auanet.org/guidelines/testicular-cancer-guideline, 2019

Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Horwich A, Laguna MP. Guidelines on testicular cancer. Arnhem, The Netherlands: European Association of Urology (EAU); 2008 Mar. 54 p. [35 references]

1.Retroperitoneal lymph node dissection (RPLND) – mostly for stage IA. This has the advantage of a high cure rate and the disadvantages of major surgery with its complications and the possibility of the loss of ejaculation.

2.Careful observation with frequent (usually monthly) doctor visits and tests for several years. This has the advantage of no surgery or chemotherapy side effects. Its disadvantage is that the cancer can return and without careful watching can grow so large that it may not be curable. So far, this has not happened in men who saw their doctor for follow-ups as scheduled. About 80% of relapses occur in the first 12 months, and most of the rest in the next 12 months.

3.For stage IB – 2 cycles of chemotherapy. Most guidelines recommend PEB (platinum, etoposide, bleomycin).

When the patient refuses bleomycin, I consider carboplatin/Etoposide in the appropriate doses for this protocol ( somewhat higher than when given with bleomycin)appropraite. THis si based on studies in good prognosis testicular cacner that showed equivalence of these two regimens. No such studies have been carried for adjuvant treatment of stage IB testicular cancer but they would be difficult to initiate and complete due to rarity of this cancer. There would be no other option if the patient refuses PEB.

Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Horwich A, Laguna MP. Guidelines on testicular cancer. Arnhem, The Netherlands: European Association of Urology (EAU); 2008 Mar. 54 p. [35 references]

http://annonc.oxfordjournals.org/cgi/reprint/18/suppl_2/ii42