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REVIEW ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 4  |  Page : 1216-1219

Adjuvant treatment for Stage I seminoma: Why radiotherapy is better than carboplatin


Department of Radiotherapy and Oncology, Kasturba Medical College and Hospital, Manipal University, Manipal, Karnataka, India

Date of Web Publication7-Feb-2017

Correspondence Address:
M S Vidyasagar
Department of Radiotherapy and Oncology, Kasturba Medical College and Hospital, Manipal University, Manipal - 576 104, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.176171

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 > Abstract 

Adjuvant treatment options for Stage I seminoma include active surveillance, chemotherapy, and radiotherapy. Active surveillance may not be ideal for the average Indian patient. Of the two accepted adjuvant therapy options, namely single-dose carboplatin chemotherapy and radiotherapy to the retroperitoneal nodes, though it intuitively appears more appealing, a deeper review reveals the potential drawbacks of chemotherapy. This article highlights the misconceptions regarding carboplatin and provides reasons for an argument why radiotherapy is better when a patient with Stage I seminoma chooses to undergo adjuvant treatment.

Keywords: Adjuvant treatment, carboplatin, radiotherapy, seminoma, Stage I


How to cite this article:
Yathiraj PH, Sharan K, Fernandes DJ, Vidyasagar M S. Adjuvant treatment for Stage I seminoma: Why radiotherapy is better than carboplatin. J Can Res Ther 2016;12:1216-9

How to cite this URL:
Yathiraj PH, Sharan K, Fernandes DJ, Vidyasagar M S. Adjuvant treatment for Stage I seminoma: Why radiotherapy is better than carboplatin. J Can Res Ther [serial online] 2016 [cited 2017 Apr 26];12:1216-9. Available from: http://www.cancerjournal.net/text.asp?2016/12/4/1216/176171


 > Introduction Top


Testicular tumors are not very common in India – the estimated incidence in 2012 was 3300 patients (0.7% of all malignancies in adult males) with an estimated disease-specific mortality of 43.9% (1450 patients; 0.3% of all malignancies in adult males). Thus, while India contributed 6% (3298/55266) of all new cases of testicular tumors diagnosed worldwide in 2012, it accounted for 14% (1452/10,351) of disease-specific mortality.[1] Seminoma is the most common testicular cancer, and commonly presents as Stage I, with nearly 100% 5-year survival and 80–85% relapse-free survival even without adjuvant treatment.[2]


 > Surveillance Is not the Best Option for an Average Indian Patient Top


In an older Canadian study on surveillance of patients with Stage I testicular tumor, compliance with clinical examinations were 61.5% in the 1st year and 35.5% in the 2nd year whereas compliance with computed tomography (CT) was only 25% and 11.8%, respectively.[3] Even motivated patients, at times, eventually become noncompliant.[3],[4] There is paucity of Indian data on surveillance for seminoma testis, but the scenario is likely to be worse. The only study available was a retrospective single institution experience which showed a significantly worse 5-year disease-free survival (DFS) for surveillance as compared to radiotherapy (74% vs. 91%, P = 0.004).[4] Notably, among patients on observation, the estimated 5-year DFS and disease-specific survival was 74% and 89% as against 87% and 99% on active surveillance in the Western literature.[4],[5] More than 55% of patients died of disease following recurrence, suggesting that it was detected when advanced, rather than on surveillance. Moreover, the study reported an alarmingly high rate of scrotal violation (24.5%) revealing the poor quality of surgery at peripheral centers before they were referred to a higher center for adjuvant therapy. All these factors together make “Primum Non Nocere” an unattractive option for most Indian patients.[4],[6]


 > Risk-Adapted Approach for Surveillance Top


Additional efforts to refine the role of surveillance have concentrated on factoring adverse prognostic factors for a risk-adapted approach. The established poor prognostic factors for relapse are size of the tumor and invasion of the rete testis by the tumor. The presence of both, one, or none of the above-mentioned risk factors resulted in relapse rates of 31.5%, 15.9%, and 12%, respectively.[7] A recent paper from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) found both size and rete testis invasion to be independent prognostic factors, with relapse rates of 2.9% without any risk factor as against 21.7% with 1–2 risk factor.[8] Lymphovascular invasion and involvement of epididymis have also been found as risk factors for recurrence in patients among surveillance, but their association was not clear as they assumed significance only when the other factor was excluded.[9] Despite identification of these risk factors, more research is required before any recommendations can be made over their role in choosing patients for surveillance. In addition, active surveillance is expensive involving six monthly abdominal and pelvic CT scans for 2–3 years and annually thereafter for at least 5 years, something which may not be feasible in the average Indian patient.[6]


 > Non-Inferiority Study Does not Equate to Clinical Equivalence Top


The mature results of MRC TE19/EORTC 30982 study concluded that a single cycle of carboplatin of area under curve (AUC-7) was noninferior to Radiotherapy.[10] One criticism for the MRC study is that it was a “noninferiority study” which means that carboplatin is not significantly worse than radiotherapy (RT). For a clinical equivalence study with a two-sided 3% difference to be shown, the number of patients needed for the study would be around 7800.[11] Another critique about this study was that it was designed to exclude a 3% relapse risk in the carboplatin arm; it achieved an exclusion power of 3.5% (in the 90% confidence interval [CI]), the main goal consequently not being achieved.[2] Furthermore, there is a concern of inadequate long-term follow-up as the initial publication of 2005 had a median follow-up of 4 years and the subsequent publication in 2011 had a median follow-up of only 6.5 years- surprisingly low for a trial which closed accrual in 2001.[11]


 > A Single Cycle of Carboplatin (AUC 7) Appears Insufficient in the Presence of Poor Prognostic Factors Top


Carboplatin as the choice of drug has been proven to be inferior to cisplatin in advanced germ cell tumor (GCT).[12] Hence, it has been questioned why an inferior drug was chosen for adjuvant treatment while keeping a superior drug for salvage.[11] In addition, some investigators believe that utilization of only one course of a potentially suboptimal chemotherapeutic agent is inadequate. As an example, the Spanish germ cell cancer group reported two studies on adjuvant carboplatin (AUC 7 × 2 cycles) in a risk-adapted setting. In the first study, patients with one or two risk factors (tumor >4 cm or rete testis involvement) were offered adjuvant treatment whereas in the second study only patients with both risk factors received adjuvant treatment.[13],[14] Both studies concluded that with surveillance in patients with no risk factors, a relapse rate of 4.8–6% was reported as against 13–20% when rete testis was involved.[13],[14] The prognostic factors discussed above are also probable indicators of high relapse rates following singe agent carboplatin – relapse rate being 9.4% when 1–2 risk factors were present as against 2.7% when none were present as shown in the study by SWENOTECA group published in 2011.[8] The conclusion of the study were as follows: “One course of adjuvant carboplatin has a modest effect in preventing relapse in Stage I seminoma with 50–66% reduction of the risk of relapse. The rather low efficacy of carboplatin X 1 cycle opens up a discussion of exploring more potent adjuvant therapy.”[8]


 > Suboptimal Dose of Carboplatin is Inferior to RT Top


The original paper by Oliver et al. showed that when carboplatin <7 AUC was given, the 5 years DFS dropped to 92.6% as compared to 96% following radiotherapy.[10] It is worthwhile noting that the creatinine clearance for calculating the dose of carboplatin must be estimated using radioactive Cr-53 ethylene di-amine tetra acetic acid nuclear scan or by 24 hour urinary creatinine clearance (as a protocol deviation). These tests are cumbersome, expensive, not readily available, and prompting estimation of creatinine clearance by Cockroft-Gault formula. The use of the Cockroft-Gault formula for calculating creatinine clearance runs the risk of underdosing carboplatin and increases the risk of recurrence.[15]


 > Carboplatin Does not Reduce Contralateral Testicular Intraepithelial Neoplasm and Germ Cell Tumor Top


Another important conclusion of the MRC TE19/EORTC 30982 study was that adjuvant carboplatin significantly reduced the risk of contralateral testicular malignancies by nearly 80%.[10] Though the claim of relative risk (RR) reduction of contralateral GCT is large, the absolute 5 years incidence of contralateral GCT was 1.2% in the RT arm and 0.2% in the carboplatin arm as compared with 3–5% with surveillance alone. These results were first questioned by Dieckmann et al., who have proven that one cycle of carboplatin of AUC-7 does not reduce biopsy proven contralateral testicular intraepithelial neoplasm (TIN) in a significant proportion of patients.[16] The safest way of eradicating TIN is 20 Gy RT to the testis.[17] Furthermore, the incidence of contralateral GCT can be a late event, as late as 20 years or more.[18] In the 17-year UK experience of single-agent carboplatin, the authors clarified that the incidence of contralateral GCT was only delayed (median time to event 8.8 vs. 1.9 years in observation arm) and was as high as 3.9%.[19]


 > Radiotherapy Has Excellent Long-Term Results Top


Radiotherapy has been the mainstay of adjuvant treatment in clinical Stage I seminoma for more than four decades worldwide. A population-based study from the SWENOTECA study group has shown that with a median follow-up of 6 years, the 5-year DFS is 99.2% in the RT arm as compared with 96.1% for 3.4 years median follow-up for carboplatin.[20] Long-term results from a single institution treating Stage I tumors with linear accelerator-based RT has shown 10- and 20-year risk of relapse as 1% and 2% and a 20-year cause-specific cause survival of 99%.[21] The recent systematic review comparing surveillance and adjuvant therapy among 12,075 assessable patients (7351 for RT, 908 for carboplatin and 3618 for observation) confirmed a 11% absolute risk reduction in 5-year relapse free rate for either of the adjuvant treatments but did not significantly improve 5-year overall survival and importantly did not significantly increase the risk of death from other causes.[22]


 > Second Malignancies and Other Toxicities Are not Exclusive to Radiotherapy Top


The single reason for discouraging radiotherapy in most discussions is the fear of second malignancies. For example, one report suggests that a patient diagnosed with a seminoma at age 35 years, the cumulative risk of second solid malignancy over the next 40 years when treated with radiotherapy was 36% (as compared with 23% for the general population).[6],[23] Though this fear is real, it must be borne in mind that this is after >40 years of experience of radiotherapy, most of which was primitive with larger fields and higher doses. The risk of solid malignancy reduced significantly if the patient was diagnosed after 1975 compared to being diagnosed before 1975.[23] In a large series studying the incidence of second malignancies in over 40,000 survivors of testicular malignancies, the relative risks of increased solid cancers when treated with RT alone, chemotherapy alone, and combined CT-RT was 2.0 (95% CI = 1.9–2.2), 1.8 (95% CI = 1.3–2.5), and 2.9 (95% CI = 1.9–4.2), all of which were statistically significant when compared to patients who did not receive any treatment.[23]

The long-term effects of adjuvant carboplatin beyond the second decade are still unknown. The premise that carboplatin reduces radiation risk is not entirely true as 74% of patients receiving carboplatin relapse in the retroperitoneum necessitating the need for frequent CT scans at least for 3 years.[2],[23] A recent study examined the risk of second cancers in 2,569 testicular cancer patients who underwent a median of 10 diagnostic abdominal-pelvic CT scans during the first 5 years after diagnosis. With a median of 11.2 years follow-up, only 14 men who were >5 years from diagnosis developed a second abdominal-pelvic malignancy. However, the authors concluded that longer follow-up is needed to prove that low-dose radiation does not increase the risk of second malignancies.[24] Chemotherapy used for seminoma testis has been associated with hypertension, cardiac events, decreased kidney function, late metabolic events, impaired hearing, and hypogonadism.[8]


 > Conclusion Top


Though single-dose adjuvant carboplatin is attractive, caution must be exercised before favoring it over adjuvant radiotherapy, especially in Indian scenario. The evidence today for carboplatin is at best “not significantly worse” (not “equivalent” and definitely not “superior”) to RT. When suboptimal doses of carboplatin are administered (using Cockroft-Gault formula for dose calculation increases this possibility), the risk of recurrence is high. Chemotherapy also can cause second malignancy, and the long-term effect of carboplatin is still unknown. Long-term follow-up of carboplatin treated patients has proven that it does not reduce the risk of contralateral TIN and testicular cancers. Thus, in the average Indian setting, where frequent CT scans are expensive, follow-up is poor, and the incidence of recurrence is potentially higher, we recommend low-dose radiotherapy which allows for a less intense follow-up and reduces the long-term side effects of combination chemotherapy needed at recurrence.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Available from: http://www.globocan.iarc.fr/Pages/fact_sheets_population.aspx. [Last accessed on 2015 Jun 21].  Back to cited text no. 1
    
2.
Boujelbene N, Cosinschi A, Boujelbene N, Khanfir K, Bhagwati S, Herrmann E, et al. Pure seminoma: A review and update. Radiat Oncol 2011;6:90.  Back to cited text no. 2
    
3.
Hao D, Seidel J, Brant R, Alexander F, Ernst DS, Summers N, et al. Compliance of clinical stage I. J Urol 1998;160 (3 Pt 1):768-71.  Back to cited text no. 3
    
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Mahantshetty U, Banerjee S, Kakkar S, Murthy V, Bakshi G, Tongaonkar HB, et al. Treatment of stage I seminoma testis with extended field adjuvant radiation. Gulf J Oncolog 2012;11:20-4.  Back to cited text no. 4
    
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Kollmannsberger C, Tandstad T, Bedard PL, Cohn-Cedermark G, Chung PW, Jewett MA, et al. Patterns of relapse in patients with clinical stage I testicular cancer managed with active surveillance. J Clin Oncol 2015;33:51-7.  Back to cited text no. 5
    
6.
Vaughn DJ. Primum non nocere: Active surveillance for clinical stage I testicular cancer. J Clin Oncol 2015;33:9-12.  Back to cited text no. 6
    
7.
Warde P, Gospodarowicz MK, Banerjee D, Panzarella T, Sugar L, Catton CN, et al. Prognostic factors for relapse in stage I testicular seminoma treated with surveillance. J Urol 1997;157:1705-9.  Back to cited text no. 7
    
8.
Cohn-Cedermark G, Stahl O, Tandstad T; SWENOTECA. Surveillance vs. adjuvant therapy of clinical stage I testicular tumors – A review and the SWENOTECA experience. Andrology 2015;3:102-10.  Back to cited text no. 8
    
9.
Mortensen MS, Lauritsen J, Gundgaard MG, Agerbæk M, Holm NV, Christensen IJ, et al. A nationwide cohort study of stage I seminoma patients followed on a surveillance program. Eur Urol 2014;66:1172-8.  Back to cited text no. 9
    
10.
Oliver RT, Mead GM, Rustin GJ, Joffe JK, Aass N, Coleman R, 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 2011;29:957-62.  Back to cited text no. 10
    
11.
Bosl GJ, Patil S. Carboplatin in clinical stage I seminoma: Too much and too little at the same time. J Clin Oncol 2011;29:949-52.  Back to cited text no. 11
    
12.
Bajorin DF, Sarosdy MF, Pfister DG, Mazumdar M, Motzer RJ, Scher HI, et al. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: A multiinstitutional study. J Clin Oncol 1993;11:598-606.  Back to cited text no. 12
    
13.
Aparicio J, Germà JR, García del Muro X, Maroto P, Arranz JA, Sáenz A, et al. Risk-adapted management for patients with clinical stage I seminoma: The Second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol 2005;23:8717-23.  Back to cited text no. 13
    
14.
Aparicio J, Maroto P, del Muro XG, Gumà J, Sánchez-Muñoz A, Margelí M, et al. Risk-adapted treatment in clinical stage I testicular seminoma: The third Spanish Germ Cell Cancer Group study. J Clin Oncol 2011;29:4677-81.  Back to cited text no. 14
    
15.
Cathomas R, Klingbiel D, Geldart TR, Mead GM, Ellis S, Wheater M, et al. Relevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: Lessons from a stage I seminoma cohort. Ann Oncol 2014;25:1591-7.  Back to cited text no. 15
    
16.
Dieckmann KP, Matthies C, Kliesch S. Carboplatin does not prevent contralateral testicular tumors in patients with seminoma. J Clin Oncol 2011;29:2944-5.  Back to cited text no. 16
    
17.
Ruf CG, Gnoss A, Hartmann M, Matthies C, Anheuser P, Loy V, et al. Contralateral biopsies in patients with testicular germ cell tumours: Patterns of care in Germany and recent data regarding prevalence and treatment of testicular intra-epithelial neoplasia. Andrology 2015;3:92-8.  Back to cited text no. 17
    
18.
Dieckmann KP, Anheuser P, Sattler F, Von Kügelgen T, Matthies C, Ruf C. Sequential bilateral testicular tumours presenting with intervals of 20 years and more. BMC Urol 2013;13:71.  Back to cited text no. 18
    
19.
Chau C, Cathomas R, Wheater M, Klingbiel D, Fehr M, Bennett J, et al. Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: Results from a 17-year UK experience. Ann Oncol 2015;26:1865-70.  Back to cited text no. 19
    
20.
Tandstad T, Smaaland R, Solberg A, Bremnes RM, Langberg CW, Laurell A, et al. Management of seminomatous testicular cancer: A binational prospective population-based study from the Swedish norwegian testicular cancer study group. J Clin Oncol 2011;29:719-25.  Back to cited text no. 20
    
21.
Serdar L, Canyilmaz E, Topcu TO, Sahbaz A, Memis Y, Soydemir G, et al. Adjuvant radiotherapy in stage 1 seminoma: Evaluation of prognostic factors and results of survival. J Cancer Res Ther 2015;11:313-8.  Back to cited text no. 21
    
22.
Petrelli F, Coinu A, Cabiddu M, Ghilardi M, Borgonovo K, Lonati V, et al. Surveillance or adjuvant treatment with chemotherapy or radiotherapy in stage I seminoma: A systematic review and meta-analysis of 13 studies. Clin Genitourin Cancer 2015;13:428-34.  Back to cited text no. 22
    
23.
Travis LB, Fosså SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm H, et al. Second cancers among 40,576 testicular cancer patients: Focus on long-term survivors. J Natl Cancer Inst 2005;97:1354-65.  Back to cited text no. 23
    
24.
Van Walraven C, Fergusson D, Earle C, Baxter N, Alibhai S, MacDonald B, et al. Association of diagnostic radiation exposure and second abdominal-pelvic malignancies after testicular cancer. J Clin Oncol 2011;29:2883-8.  Back to cited text no. 24
    




 

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