Canadian Urological Association consensus guideline: Management of testicular germ cell cancer Flashcards
What is the most common solid malignancy in males aged 15-29?
Testicular cancer.
What percentage of testicular cancers are primary germ cell tumors (GCTs)?
More than 90%.
How are primary germ cell tumors of the testes histologically divided?
Into seminomas and non-seminomas (NSGCT).
Which type of testicular GCT is rising at a faster rate?
Seminoma.
What kind of approach does the management of testicular GCT require?
A multidisciplinary and coordinated approach.
What potential benefits are there to GCT care being performed in, or coordinated with, experienced centers?
Improved survival, minimization of toxicity or overtreatment, experienced pathological review, specialist radiographic assessment, guideline-based recommendations, and timely delivery of multidisciplinary care.
When was the Canadian consensus document on the management of testicular germ cell cancer last updated before 2018?
In 2010.
What is the most common clinical presentation of germ cell tumors (GCTs)?
Most patients present with a palpable testicular mass that may or may not be painful.
What is the primary tumor site in approximately 5% of GCT patients?
The primary tumor site is extragonadal (i.e., retroperitoneum or mediastinum).
What diagnostic and staging examinations are mandatory for GCTs?
These include scrotal examination, determination of the serum tumor markers alpha-fetoprotein (AFP), ß-human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH), ultrasound to image the testicles, and a computed tomography (CT) scan of the thorax, abdomen, and pelvis.
What is the initial diagnostic and treatment maneuver for GCTs, barring rare exceptions?
Radical orchiectomy performed through an inguinal incision, removing the testicle and spermatic cord to the level of the internal inguinal ring.
When can orchiectomy be deferred in patients with GCTs?
Orchiectomy may be deferred in patients with life-threatening metastatic disease when a confirmed diagnosis of NSGCT (e.g., an unequivocally elevated AFP and/or HCG >5000 IU/L) or seminoma (e.g., biopsy of metastatic site) is made so as not to delay the start of chemotherapy. In such cases, orchiectomy should be performed after chemotherapy.
When should tumor markers be drawn and repeated in patients with GCTs?
Tumor markers should be drawn prior to orchiectomy and repeated postoperatively within 1–3 weeks, and repeated to ensure return to normal, given the known half-life kinetics of AFP (<7 days) and ß-HCG (<3 days).
What are the options if germ cell neoplasia in situ (GCNIS) is found in the remaining testicular tissue after organ-preserving surgery?
Options include completion orchiectomy, adjuvant radiotherapy, or surveillance, and discussion should include risk of cancer recurrence, hypogonadism, and fertility.
What should the histopathological report document in the case of GCTs?
The report should document the procedure, specimen laterality, tumor focality, tumor size, tumor extension, histological type, margin status, presence or absence of lymphovascular invasion, number of lymph nodes involved and examined, pathology stage classification, and additional pathological findings. Mixed GCTs should have the estimated proportion of each component reported as a percentage (%).
How should patients with metastatic disease be classified?
Patients with metastatic disease should be classified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification system.
What is a “burned out” primary in the context of advanced GCTs?
In advanced GCTs, the testicular primary tumor may spontaneously regress without treatment and at orchiectomy is described pathologically as a “burned out” primary.
What are the mandatory investigations for managing testicular germ cell cancer according to the Canadian Urological Association consensus guideline?
The mandatory investigations include a complete history and physical exam (including a scrotal exam), laboratory tests (Alpha-fetoprotein (AFP), ß-human chorionic gonadotrophin (ß-HCG), Lactate dehydrogenase (LDH)), and baseline imaging (Scrotal ultrasound, CT abdomen and pelvis, CT thorax).
What are the laboratory tests specified in the Canadian Urological Association consensus guideline for managing testicular germ cell cancer?
The laboratory tests specified are Alpha-fetoprotein (AFP), ß-human chorionic gonadotrophin (ß-HCG), and Lactate dehydrogenase (LDH).
What baseline imaging procedures are recommended in the Canadian Urological Association consensus guideline for managing testicular germ cell cancer?
The recommended baseline imaging procedures are Scrotal ultrasound, CT of the abdomen and pelvis, and CT of the thorax.
When are bone scans and brain imaging recommended in the management of testicular germ cell cancer?
Bone scans and brain imaging are recommended for patients with symptoms or poor prognosis metastatic disease.
What is the International Germ Cell Cancer Collaborative Group’s classification for Non-Seminoma Germ Cell Tumor (NSGCT) with a “Good” prognosis?
NSGCT with a “Good” prognosis includes those with a testicular or retroperitoneal primary, no non-pulmonary visceral metastases, and good markers, specifically: AFP <1000 ug/L, ß-HCG <5000 IU/L, and LDH <1.5 × Upper Limit of Normal (ULN).
What defines an “Intermediate” prognosis for NSGCT according to the International Germ Cell Cancer Collaborative Group’s classification?
NSGCT with an “Intermediate” prognosis includes those with a testicular or retroperitoneal primary, no non-pulmonary visceral metastases, and intermediate markers, specifically: AFP is between 1000 and 10,000 ug/L, or ß-HCG is between 5000 and 50,000 IU/L, or LDH is between 1.5 and 10 times the ULN.
What criteria define a “Poor” prognosis for NSGCT as per the International Germ Cell Cancer Collaborative Group’s classification?
NSGCT with a “Poor” prognosis includes those with a mediastinal primary, and/or non-pulmonary visceral metastases, and/or any poor marker, specifically: AFP >10,000 ug/L, or ß-HCG >50,000 IU/L, or LDH >10 × ULN.
What is the International Germ Cell Cancer Collaborative Group’s classification for a Seminoma with a “Good” prognosis?
Seminoma with a “Good” prognosis includes those with any primary site, no non-pulmonary visceral metastases, and normal AFP, regardless of ß-HCG and LDH levels.
What are the criteria for a Seminoma with an “Intermediate” prognosis according to the International Germ Cell Cancer Collaborative Group’s classification?
Seminoma with an “Intermediate” prognosis includes those with any primary site, non-pulmonary visceral metastases, and normal AFP, regardless of ß-HCG and LDH levels.
When should tumor markers be drawn in the context of testicular germ cell cancer management?
Tumor markers should be drawn prior to orchiectomy and repeated postoperatively within 1–3 weeks. They should be rechecked until they return to normal, considering the known half-life kinetics of AFP (<7 days) and ß-HCG (<3 days).
What is the recommended procedure in rare cases where there’s a possibility of a benign tumor?
In such cases, an excisional biopsy with a frozen section should be performed prior to definitive orchiectomy in an experienced center. This allows for the possibility of organ-sparing partial orchiectomy.
In which patients may partial orchiectomy be an alternative procedure to orchiectomy?
Partial orchiectomy may be an alternative in patients with synchronous bilateral tumors, metachronous contralateral tumors, or solitary testicles with normal preoperative testosterone levels. This procedure should be performed by an experienced surgeon.
What options are available if organ-preserving surgery is performed and germ cell neoplasia in situ (GCNIS) is found in the remaining testicular tissue?
Options include completion orchiectomy, adjuvant radiotherapy, or surveillance. The discussion should include the risk of cancer recurrence, hypogonadism, and fertility.
What should always be discussed with all patients undergoing therapy for germ cell tumors (GCT)?
A full discussion on semen cryo-preservation should take place for all patients undergoing therapy (surgery, chemotherapy, and/or radiation) for GCT.
What points should the histopathological report document?
The report should document the procedure, specimen laterality, tumor focality, tumor size, tumor extension, histological type, margin status, presence or absence of lymphovascular invasion, number of lymph nodes involved and examined, pathology stage classification, and additional pathological findings. For mixed GCTs, the estimated proportion of each component should be reported as a percentage. Immunohistochemistry is considered a useful adjunct to the diagnosis of testicular tumors.
Who should assess testicular tumors?
Testicular tumors should be assessed by a pathologist experienced in testis cancer pathology.
How should patients with metastatic disease be classified?
Patients with metastatic disease should be classified according to the IGCCCG classification system.
What are the requirements for a Clinical Stage I (CSI) seminoma?
A CSI seminoma requires:
An orchiectomy specimen containing pure seminoma only
Normalized markers post-orchiectomy
No history of an elevated AFP
Normal staging imaging
What is the risk of relapse in Clinical Stage I (CSI) seminoma cases, and where does it most commonly occur?
The risk of relapse in Clinical Stage I (CSI) seminoma cases is 15%, with most occurring in the retroperitoneum.
What are the treatment options for Clinical Stage I (CSI) seminoma?
Treatment options for Clinical Stage I (CSI) seminoma include:
Surveillance
Para-aortic ± pelvic radiotherapy
Chemotherapy (carboplatin x 1–2)
Why is surveillance the preferred approach for all Clinical Stage I (CSI) seminoma patients?
Surveillance is the preferred approach for all Clinical Stage I (CSI) seminoma patients because adjuvant treatment is associated with acute toxicities, the risk of late side effects, potential overtreatment in 85% of cases, and no improvement in survival.
What is important to consider when deciding the treatment for Clinical Stage I (CSI) seminoma patients?
All patients should have a shared discussion balancing the risk of relapse and the side effects of adjuvant treatment.
What is the range of relapse rates at five years for CSI seminoma based on non-randomized studies of surveillance?
The relapse rates at five years range from 11–20%.
What is the predominant site of relapse for CSI seminoma?
The predominant site of relapse is the para-aortic lymph nodes.
What is the median time to relapse in CSI seminoma and can late relapses occur?
The median time to relapse is 12–18 months, but late relapses (>4 years) have been reported.
What risk factors have been associated with relapse in CSI seminoma?
Tumor size >4 cm and rete testes involvement have been associated with relapse, although these risk factors have shown inconsistent results across studies.
What is the proposed risk-adapted strategy for managing CSI seminoma?
The Spanish Germ Cell Cancer Cooperative Study Group and the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) have proposed a risk-adapted strategy with surveillance for low-risk patients (0 risk factors) and adjuvant therapy for high-risk patients (1–2 risk factors).
What is the potential concern with non-risk-adapted surveillance in CSI seminoma?
The potential concern is the increased use of chemotherapy to salvage patients who relapse.
What is the effectiveness of radiotherapy as a sole salvage approach in CSI seminoma?
Most relapses occur in the retroperitoneum, where radiotherapy has proven to be an effective sole salvage approach.
What are the current debates in optimal follow-up surveillance strategy in CSI seminoma?
There is ongoing debate about the contribution of serial tumor marker assessments, the efficacy of MRI imaging compared to CT scans, and the number of scans in a surveillance schedule.
What is the role of adjuvant retroperitoneal radiotherapy in the management of testicular germ cell cancer?
Adjuvant retroperitoneal radiotherapy is limited to occasional circumstances where surveillance is not feasible.
Adjuvant retroperitoneal radiotherapy is limited to occasional circumstances where surveillance is not feasible.
The reported relapse rate is 4% (range 0.8–5%).
How common is relapse >3 years after radiotherapy in the treatment of testicular germ cell cancer?
Relapse >3 years after radiotherapy appears rare, occurring in only three of 1893 patients entered onto the MRC TE10, TE18, and TE19 adjuvant trials.
What does evidence from randomized trials say about the relapse rates for para-aortic nodal radiotherapy vs. extended volume to include ipsilateral pelvic nodes?
Evidence from randomized trials demonstrates similar overall relapse rates for para-aortic nodal radiotherapy vs. extended volume to include ipsilateral pelvic nodes (3.4% vs. 4%).
What is the recommendation for patients who didn’t have their pelvic recurrence included in the initial treatment volume?
Continued imaging to detect pelvic recurrence is recommended if this was not included in the initial treatment volume.
What are the three treatment options listed in the Canadian Urological Association consensus guideline for managing Clinical Stage I seminoma?
The three treatment options are Surveillance, Carboplatin x 1, and Radiation.
According to the Canadian Urological Association consensus guideline, what is the relapse rate when using Surveillance as a treatment option for Clinical Stage I seminoma?
The relapse rate for Surveillance is 15%.
What is the relapse rate for Clinical Stage I seminoma when treated with a single round of Carboplatin, as per the Canadian Urological Association consensus guideline?
The relapse rate for a single round of Carboplatin treatment is 5%.
Based on the Canadian Urological Association consensus guideline, what is the relapse rate when Radiation is used as a treatment option for Clinical Stage I seminoma?
The relapse rate for Radiation treatment is 4%.
What is the cancer-specific survival rate for all three treatment options (Surveillance, Carboplatin x 1, Radiation) for Clinical Stage I seminoma according to the Canadian Urological Association consensus guideline?
The cancer-specific survival rate for all three treatment options is 99%.
What is the role of adjuvant chemotherapy in the management of testicular germ cell cancer according to the Canadian Urological Association consensus guideline?
Adjuvant chemotherapy is limited to occasional circumstances where surveillance is not feasible.
What are the recommended cycles of carboplatin for adjuvant chemotherapy in the management of testicular germ cell cancer?
1-2 cycles of carboplatin are options, but it remains unclear whether one or two cycles are better.
What were the five-year relapse rates in the MRC TE19 study comparing adjuvant radiotherapy to one cycle of carboplatin in testicular germ cell cancer patients?
The five-year relapse rates were similar: 4.0% for adjuvant radiotherapy and 5.3% for one cycle of carboplatin.
According to non-randomized data, how does the number of carboplatin cycles affect the relapse rates in testicular germ cell cancer patients?
Non-randomized data suggest a reduction in relapses with two cycles of carboplatin (1.5-3% relapse rate) compared to one cycle (5% relapse rate).
What does the SWENOTECA data show regarding the relapse rates in lower-risk and higher-risk patients given one cycle of carboplatin compared to surveillance?
The SWENOTECA data shows a small risk reduction with one cycle of carboplatin compared to surveillance: 2.2% vs. 4.0% relapse rate in lower-risk patients and 9.3% vs. 15.5% relapse rate in higher-risk patients.
What are the potential disadvantages of adjuvant chemotherapy with carboplatin in the management of testicular germ cell cancer?
The reduction in relapse risk is not substantial (15% to 5%), most relapses occur in the retroperitoneum requiring CT scans similar to surveillance, recurrence after carboplatin may have worse biology, and long-term toxicity of carboplatin is unknown.
What are the implications of recurrence after carboplatin therapy in the management of testicular germ cell cancer?
Recurrence after carboplatin may result in a higher burden of disease at relapse, greater reliance on BEP as salvage, and a greater incidence of second relapse and death.
How are patients with rising tumor markers after orchiectomy, despite normal imaging, classified, and how should they be treated?
These patients are considered stage IS and should be treated with chemotherapy according to the corresponding IGCCCG group.
What is the recommended approach to discussing treatment options with patients?
Patients should be informed of all treatment options, including surveillance, adjuvant chemotherapy, adjuvant radiotherapy, and the potential benefits and side effects of each treatment. They should be involved in the decision-making process.
What is the preferred treatment option for a patient willing and able to adhere to a surveillance program?
Surveillance should be the preferred option.
Is a risk-adapted approach with surveillance for low-risk patients and adjuvant treatment for those at higher risk of relapse recommended?
No, a risk-adapted approach like this is not recommended.
What are the potential adjuvant therapies for testicular germ cell cancer?
If adjuvant therapy is chosen, carboplatin chemotherapy and radiation therapy are options.
If adjuvant therapy is given, is post-therapy imaging still required?
Yes, post-therapy imaging is still required, similar to surveillance schedules.
Is there a role for primary retroperitoneal lymph node dissection (RPLND) in stage I seminoma?
At present, there is no role for primary RPLND in stage I seminoma.
What is the recommended initial approach for patients with CSIIA seminoma without marker elevation?
An initial period of surveillance with repeat imaging in 6–8 weeks, as up to 30% of cases end up being false-positive nodal enlargement.
What are the treatment options for CSIIA seminoma?
Radiotherapy or chemotherapy. Note, there has been no randomized trial comparing these two options in this setting.
What is the outcome of radiation therapy in CSIIA seminoma?
Radiation therapy to the para-aortic and ipsilateral pelvic nodes with doses ranging from 30–35 Gy yields five-year relapse-free rates in excess of 90% in most modern series.
What are the treatment options for CSIIB seminoma?
Radiation therapy or chemotherapy, depending on the bulk of the disease and location of lymph nodes.
How do chemotherapy and radiation therapy perform in CSIIB disease according to meta-analysis?
They achieve similar disease control in CSIIA disease, but chemotherapy does modestly better in CSIIB disease (relapse rate 5% vs. 12%), with a lower incidence of late toxicity and secondary cancers.
What is the recommended treatment for CSIIC seminoma?
Chemotherapy. The relapse rate with radiation therapy approaches 50% in most series, and not all patients can be salvaged with chemotherapy.
What is the recommended chemotherapy for all CSII seminoma patients?
The same as that for IGCCCG good-prognosis patients.
What is the role of RPLND and reduced volume radiation therapy in combination with a single course of carboplatin in CSII seminoma?
It is the subject of clinical trials and not an established option outside of a trial setting.
What is the classification for non-seminomatous germ cell testicular cancer (NSGCT)?
Testicular cancer is classified as NSGCT if, histologically, the tumor contains any component of embryonal carcinoma, yolk sac tumor, choriocarcinoma, or teratoma. Also, patients with histologically pure seminoma but elevated serum AFP or markedly elevated HCG (generally regarded as >5000 IU/L) are considered to have NSGCT.
How is stage IS NSGCT defined and treated?
Patients with persistently elevated or rising markers 4–6 weeks after orchiectomy with normal imaging are considered stage IS NSGCT. They should be treated with chemotherapy according to their corresponding IGCCCG group.
What are the treatment options for Clinical Stage I (CSI) NSGCT?
Treatment options for CSI NSGCT include surveillance, chemotherapy (typically BEP x 1–2), or retroperitoneal lymph node dissection (RPLND).
What percentage of stage I NSGCT patients relapse without adjuvant treatment?
Approximately 20–30% of stage I NSGCT patients relapse without adjuvant treatment.
What is the preferred treatment approach for all CSI NSGCT patients?
Surveillance is the preferred treatment approach for all CSI NSGCT patients.
What are the risk factors associated with increased relapse in NSGCT patients?
The main risk factor associated with increased relapse is the presence of lympho-vascular invasion (LVI) in the orchiectomy specimen, which upstages NSGCT from pT1 to pT2 and overall CSIA to CSIB. Some data also show that embryonal predominance is associated with relapse, with the cutoff for defining embryonal predominance varying in the published series from >50% to 100%.
What is the associated risk of relapse if lympho-vascular invasion (LVI), embryonal predominance, or both are present in NSGCT patients?
If LVI, embryonal predominance, or both are present, the associated risk of relapse is approximately 50%.
What are the main risk factors in CSI patients that increase the relapse rate up to 50%?
Lymphovascular invasion (LVI) and embryonal predominance.
What percentage of patients on surveillance do not require any further therapy after orchiectomy?
74%
What is the traditional treatment method for patients who relapse during surveillance?
3-4 cycles of chemotherapy.
What is an argument against surveillance for high-risk CSI NSGCT?
The higher treatment burden for the 50% who experience a relapse compared to a strategy of upfront adjuvant therapy.
What is a recently demonstrated safe method for salvaging CSI NSGCT surveillance relapses?
Retroperitoneal lymph node dissection (RPLND).
What percentage of patients treated with RPLND did not require any subsequent chemotherapy?
73%
How does the chemotherapy burden of high-risk patients treated with surveillance and salvaged with RPLND compare to those treated with adjuvant BEPx1?
It’s similar. In a model, a theoretical cohort of 100 high-risk patients treated with surveillance and salvaged preferentially with RPLND had a similar chemotherapy burden to a group treated with adjuvant BEPx1.
What is the recurrence rate observed in non-randomized trials and a single randomized trial using adjuvant chemotherapy in CSI NSGCT?
The recurrence rate using a variety of platinum-based regimens is 3.8%.
What was the recurrence rate in high-risk patients treated with two cycles of BEP chemotherapy?
The relapse rate after two cycles of BEP chemotherapy ranged from 2.2–2.9%.
What was the relapse rate in the study by the SWENOTECA group comparing surveillance vs. BEP x1 in patients with Lymphovascular Invasion (LVI)?
In patients with LVI, 41.7% of patients on surveillance relapsed compared to 3.2% receiving BEP x1.
What was the 5-year cause-specific survival rate for the chemotherapy arm in the SWENOTECA group study?
The 5-year cause-specific survival was 100% for the chemotherapy arm, with no treatment-related mortality.
What were the results of the U.K. single-arm “111 Study” on the efficacy of BEP x1 in CSIB NSGCT?
The U.K. “111 Study” confirmed the efficacy of BEP x1 in CSIB NSGCT with a 3.1% relapse rate and one death with 49-month median follow-up.
Why is shared decision-making critical when considering adjuvant chemotherapy for testicular germ cell cancer?
Shared decision-making is critical due to limited information on very long-term follow-up (>20 years) relating to complications such as cardiovascular health after BEP x 1–2 treatment.
What are the treatment options for stage I non-seminomatous germ cell tumor (NSGCT)?
The treatment options for stage I NSGCT are surveillance, BEPx1 (a cycle of bleomycin, etoposide, and cisplatin), and retroperitoneal lymph node dissection (RPLND).
What is the relapse rate for NSGCT under surveillance?
The relapse rate for NSGCT under surveillance is 26%.
What is the relapse rate for NSGCT with a treatment of BEPx1?
The relapse rate for NSGCT with a treatment of BEPx1 is between 2% and 7%.
What is the relapse rate for NSGCT with a treatment of RPLND?
The relapse rate for NSGCT with a treatment of RPLND is 10%.
What is the cancer-specific survival rate for NSGCT under surveillance, BEPx1 treatment, and RPLND treatment?
The cancer-specific survival rate for NSGCT under surveillance, BEPx1 treatment, and RPLND treatment is 99%.
What does the 10% relapse rate for RPLND treatment of NSGCT include?
The 10% relapse rate for RPLND treatment of NSGCT includes giving adjuvant chemotherapy to select patients with positive nodes at RPLND.
What is a significant drawback of studies regarding adjuvant RPLND?
Most studies give two cycles of chemotherapy to patients with pathological nodal disease, making it unclear to determine the sole benefits of RPLND when compared to BEPx1 as upfront adjuvant therapy for high-risk CSI NSGCT.
What was the relapse rate difference between RPLND and BEPx1, according to the only randomized trial comparing them?
The relapse rate was significantly higher for RPLND (8%) compared to BEPx1 (0.5%).
How many patients who received RPLND had pathological stage II disease at surgery and received BEPx2? What was the relapse rate for these patients?
18.5% of the patients who received RPLND had pathological stage II disease at surgery and received BEPx2. No relapses were observed in these patients.
How many recurrences were observed in patients managed with RPLND alone?
13 recurrences were observed, seven of which were in the retroperitoneum.
What is one highlighted finding from the criticized trial that compared RPLND to BEPx1?
The trial highlighted that if RPLND is to be completed, it should be done at high-volume centers.
What does the retrospective series data tell us about the relapse and mortality rates post-RPLND?
About 10% relapse post-RPLND and less than 1% die of the disease.
What percentage of patients with pathological nodal disease found at RPLND, who do not receive adjuvant chemotherapy, relapse?
Approximately 20% of patients with pathological nodal disease found at RPLND, who do not receive adjuvant chemotherapy, relapse.
Figure 1. Clinical stage IIA/IIB non-seminomatous germ cell tumor treatment algorithm. PCRPLND: post-chemotherapy retroperitoneal lymph node dissection.
