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ASCO GU 2018

ASCO GU 2018: Management of Marker Negative Stage IIA Testicular Cancer

San Francisco, CA (UroToday.com) Dr. Christian Kollmannsberger from the Vancouver Cancer Centre provided the Keynote Lecture for Testicular Cancer at the  GU ASCO 2018 meeting in San Francisco, discussing the management of marker negative Stage IIA Testicular Cancer. Dr. Kollmannsberger started by noting that stage IIA disease is summarized by retroperitoneal lymph nodes < 2cm, and historically has been treated with radiation or chemotherapy (seminoma) and primary RPLND +/- chemotherapy (nonseminoma). Importantly, he notes that stage IIA disease can be tumor marker positive or negative. 

Dr. Kollmannsberger highlighted several overriding principles of stage IIA marker negative disease: (i) prognosis is excellent with cure rates >98%, (ii) death from stage IIA disease is extremely rare, (iii) up to 40-50% of patients with suspected clinical stage IIA disease have no tumor (pathologic stage I), and (iv) quality of life is an important driver of decisions in stage IIA disease – on average, there is 30-40 years of additional life returned for each successful treatment, and there have been multiple reports of late effects of chemotherapy, radiation, and RPLND in curatively treated metastatic patients. As such, avoiding suboptimal management is essential. Certainly, there is a burden of treatment throughout the disease spectrum: acute toxicity (ototoxicity, infection, gastrointestinal, neurotoxicity, DVT/PE, hair loss, etc) associated with upfront treatment, the perils of ongoing follow-up imaging and risks of radiation exposure, and finally late toxicity (secondary malignancies, cardiovascular, neurotoxicity, ototoxicity, nephrotoxicity, etc). In fact, the mortality from long term complications in good/intermediate risk patients may be higher than mortality from the disease itself, secondary to late toxicity. Recent literature has suggested at the significance of the treating center with regards to survival outcomes. A study of the National Cancer Data Base (NCDB) showed that 93% of patients in the US are treated at centers with <20 cases/year and that treatment in elite volume centers (>20 cases per year) was associated with a significant survival benefit (HR 0.45). 

One of the problems with stage IIA disease is the false positive rate, considering that not all small volume CT changes represent disease. The MSKCC series of marker negative clinical stage IIA nonseminoma patients showed that 40% of patients were pathologic stage I at the time of primary RPLND [1]. Dr. Kollmannsberger postulates whether there is a role for FDG-PET for these patients, however the benefit over CT scan alone has not been established to date. It is difficult to differentiate between an inflammatory lymph node and metastatic lymph node, as well as differentiating between teratoma and benign lesions is difficult. Furthermore, a retrospective analysis validating the SEMPET trial noted that FDG-PET is less accurate in post-chemotherapy residual lesions <3 cm and has a sensitivity of only 50% and specificity of 88% [2]. 

In high volume centers, cure rate is 98% for stage IIA marker negative disease and is independent from the therapy option chosen. Minimizing toxicity while maintaining efficacy is the driver of treatment decisions. There are several important considerations, including (i) avoiding treatment for patients with benign lymph nodes, (ii) potential long-term complications, (iii) pre-existing conditions, and (iv) patient preferences. 

Treatment options according to Dr. Kollmannsberger include:

  1. Chemotherapy: BEP x 3 cycles (preferable) or EP x 4 cycles (seminoma relapse-free survival is 92-100%)
  2. Radiation: 30 Gy in 15 fractions (seminoma relapse-free survival is 92-95%)
  3. Chemotherapy BEP x 3 cycles (preferable) or EP x 4 cycles +/- RPLND (nonseminoma relapse-free survival is 92-98%)
  4. Primary nerve-sparing RPLND (+/- adjuvant chemotherapy), done open and in an expert, high volume center (preferably on study) (nonseminoma relapse-free survival is 98%)
In a meta-analysis assessing patient outcomes of clinical stage IIA treatment, relapse rates were essentially the same for chemotherapy and radiotherapy [3], aligning both as reasonable treatment options, although there are conflicting data regarding the extent of long-term toxicity. Primary nerve-sparing RPLND has several advantages, in that it clarifies the pathology, of which teratoma makes up 10-20% of cases of stage IIA nonseminoma [1]. Furthermore, there is a low relapse rate with primary nerve-sparing RPLND alone in expert centers using open techniques with a very low complication rate and in-field relapse rate [4]. The relapse rate in marker negative stage IIA disease treated with primary nerve-sparing RPLND is small (5-15%), and as such adjuvant chemotherapy with 2 cycles of BEP is most likely associated with long-term toxicity. Given this data, Dr. Kollmannsberger does not recommend for adjuvant chemotherapy after stage IIA primary nerve sparing RPLND. Given the high chance of non-malignant lymph nodes, excellent outcomes, and risk of long-term toxicity tumor marker negative small volume radiographic changes (< 2cm) should be confirmed by follow-up CT in 2-3 months or confirmed by biopsy prior to active therapy according to Dr. Kollmannsberger. However, he notes that immediate primary nerve-sparing RPLND is an alternative in carefully selected patients. 

Correct indication for treatment remains a challenge and no imaging method delivers reliable predictions. As such, better biomarkers are needed to correctly predict malignancy. Recently, plasma miRNA-371 has been assessed as a biomarker in testis cancer [5]. miRNA are small non-coding RNAs that regulate expression of various oncogenes or tumor suppressor genes. miRNA-371 is expressed in >90% of germ cell tumors, seminoma and nonseminoma, however it is not expressed in teratoma. Furthermore, serum levels appear to correlate with clinical stage, as well as associated with a rapid decrease and disappearance after successful treatment [5]. According to Dr. Kollmannsberger, miRNA-371 has the potential to be very effective in improving patient selection. 

A current study, Surgery in Early Metastatic Seminoma (SEMS), is a phase II trial of RPLND as first-line treatment for testicular seminoma with isolated retroperitoneal disease (1-3cm). According to Dr. Kollmannsberger the pro’s of this study are that (i) if done by an expert surgeon there is very little long-term morbidity, (ii) results should theoretically mirror radiation results by “sterilizing” the retroperitoneum, and (iii) we’ll have histologic confirmation of the disease stage. The trial identifier at clinicaltrials.gov is NCT02537548.

Dr. Kollmannsberger concluded with several important take-home messages: (i) marker negative stage IIA disease remains a diagnostic challenge and an observation period of 8 weeks with repeat imaging or biopsy are recommended to confirm disease; (ii) treatment should not be initiated unless metastatic disease is unequivocal (ie. growth or positive biopsy); (iii) prognosis of stage IIA disease is excellent; (iv) primary nerve-sparing PRLND, radiation therapy (seminoma), and chemotherapy are all treatment options; (v) minimizing long-term toxicity is a main driver of treatment decisions as all options yield similar results; (vi) surgery, when carried out at an expert center, has the least risk of long-term toxicity; (vii) miRNA-371 has the potential to greatly improve our diagnostic accuracy; (viii) a large North American trial examining miRNA in testis cancer is planned. 



Presented by: Christian Kollmannsberger,  MD, FRCPC, BC Cancer – Vancouver Cancer Centre, Vancouver, BC

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA

References: 

1. Stephenson AJ, Bosl GJ, Motzer RJ, et al. Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: Impact of patient selection factors on outcome. J Clin Oncol 2005;23(12):2781-2788.

2. Bachner M, Loriot Y, Gross-Goupil M, et al. 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) for postchemotherapy seminoma residual lesions: A retrospective validation of the SEMPET trial. Ann Oncol 2012;23(1):59-64.

3. Giannatempo P, Greco T, Mariani L, et al. Radiotherapy or chemotherapy for clinical stage IIA and IIB seminoma: A systematic review and meta-analysis of patient outcomes. Ann Oncol 2015;26(4):657-668.

4. Heidenreich A, Albers P, Hartmann M, et al. Complications of primary nerve sparing retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell tumors of the testis: Experience of the German Testicular Cancer Study Group. J Urol 2003;169(5):1710-1714.

5. Dieckmann KP, Radtke A, Spiekermann M, et al. Serum levels of microRNA miR-371a-3p: A sensitive and specific new biomarker for germ cell tumours. Eur Urol 2017;71(2):213-220.