Episode 128: Testicular Cancer Series, Pt 2 - Stage 1 and 2

Jan 29

Written By TheFellowOnCall HemeOncPodcast

This week, we continue on our testicular cancer journey, focusing on Stage 1 and 2 disease. If you haven’t done so, we highly recommend checking out Episode 127 for our overview of this disease!

How do we approach a patient with stage 1 seminoma?

In stage 1 seminoma, long-term disease specific survival is nearly 100%!
Options include:

Active surveillance (q3months then spread out after 1 year)
Carboplatin (AUC 7) X 1-2 cycles
Radiation to RP LN’s (20 Gy in 10 fractions) X2 weeks

Active Surveillance

Large Danish registry study in European Urology Journal investigated relapse rates among stage 1 testicular cancer patients (2000 with seminoma) undergoing active surveillance
At median 15 year follow-up, 19% relapse rate with nearly 100% survival
Most relapses occurred within 2 years with a median time to relapse of 13 months (only 5% after 2 years)

What about radiation vs. chemotherapy?

A 2011 cooperative group non-inferiority trial run by EORTC randomized 1500 patients to carboplatin X1 cycle or radiation
Carboplatin was found non-inferior to radiation based on a similar 5-year relapse rate (5% with carboplatin vs. 4% with radiation)
Carboplatin was stated to significantly reduce the risk of contralateral testicular cancer (HR 0.22)
However, the baseline risk of contralateral relapse is only 0.01%, so this benefit is trivial

How do we risk stratify patients to determine a treatment approach?

Tumor size and rete testis invasion were identified as risk factors for relapse in multiple studies
Based on a 2018 systematic review of 20 studies, evidence for using tumor size and rete testis invasion prognostically to guide clinical decision-making was lacking with a high risk for overtreatment of patients

The Fellow on Call Take Home Messages

In general, we recommend active surveillance for most patients with stage I seminoma to prevent long-term treatment-related toxicity, overtreatment, and risk of secondary malignancy
If patients are not reliable for follow-up or do not wish to pursue surveillance, then it is reasonable to offer either radiation or chemotherapy but in all cases disease-specific survival is essentially 100%

How do we approach a patient with stage I non-seminoma?

When seeing a patient with stage I non-seminoma, it is crucial to know if their tumor markers normalized post-orchiectomy
If tumor markers do not normalize => repeat staging imaging

If re-staging imaging is negative, then patients are deemed stage IS and are treated with chemotherapy for presumed disseminated disease

If tumor markers normalize, then our options are:

Active surveillance
Bleomycin + etoposide + cisplatin (called BEP) x 1 cycle
Retroperitoneal lymph node dissection (RPLND)

There is no difference in survival with any of these approaches

In the Danish registry study investigating relapse rates, 1400 patients with stage I non-seminona had a 30% relapse rate and 96% survival rate at median 15 years follow-up with active surveillance
Patients who relapsed were salvaged with chemotherapy or RPLND

What about chemotherapy vs. RPLND?

A phase 3 trial by a German cooperative group randomized 400 patients to BEP X1 cycle vs. RPLND
2-year recurrence-free survival was 99% in the chemotherapy arm and 92% in the surgery arm (7% absolute reduction in recurrence with chemotherapy)
No difference in OS
With RPLND, 1 in 10 patients will relapse and still need chemotherapy
With chemotherapy, only 1 in 100 patients will relapse and require more chemotherapy
Concern for late side effects of therapy:

BEP: Risk of secondary hematologic malignancy, pulmonary toxicity with bleomycin, neuropathy, and potential cardiac side effects
RPLND: Risk of ejaculatory dysfunction (~10%)

Risk factors for relapse include predominant (>50%) embryonal component and/or lymphovascular invasion.
These are NOT recommended as reasons to influence management given low level of evidence.
The Fellow on Call Take Home Messages

Active surveillance is the preferred strategy for most patients with stage I non-seminoma who can follow up reliably
Same overall survival with surveillance, BEP X1, and RPLND
Overall low rate of relapse (~30%) in patients with active surveillance, avoiding need for chemotherapy in the majority of patients

How do we approach a patient with stage 2 seminoma (retroperitoneal lymph node involvement)?

For stage 2 seminoma, remember the number 2!
For lymph nodes less than 2 cm, both radiation and chemotherapy are options
For lymph nodes greater than 2 cm, chemotherapy is required

Pivotal 2015 meta-analysis in Annals of Oncology including 13 studies comparing chemotherapy to radiotherapy
No difference in relapse rates for nodes less than 2cm
Improved relapse rate favoring chemotherapy for nodes greatre than 2 cm (5% with chemotherapy vs. 12% with radiation)

Chemotherapy is given as BEP (bleomycin + etoposide + cisplatin) x 3 cycles or EP (etoposide + cisplatin) x 4 cycles

Cisplatin superior to carbolpatin! (https://pubmed.ncbi.nlm.nih.gov/8386751/)

Radiation is given as 30Gy over a few weeks

What about RPLND?

Single arm phase 2 SEMS trial included 55 patients with isolated retroperitoneal lymphadenopathy (1-3 cm) who underwent RPLND
Median follow-up of ~3 years
2 year recurrence rate of 22%
All relapsed patients were successfully salvaged with chemotherapy
RPLND is an option for patients with clinically low-volume adenopathy

How do we approach a patient with stage 2 non-seminoma (with resolution of tumor markers)?

For patients with stage 2 non-seminoma and normalization of tumor markers, options are RPLND or chemotherapy depending on number and size involved nodes
Remember the rule of 2!
If any node is greater than 2cm => patient requires chemotherapy with BEP X3 or EP X4
If nodes are less than 2cm, RPLND is the preferred approach, but chemotherapy can be considered

Historically, RPLND was the standard of care in the 1970’s
A 1984 study looked at adjuvant chemotherapy with cisplatin + vinblastine + etoposide
Discovered that patients could be successfully salvaged at time of relapse rather than providing adjuvant chemotherapy to all patients
Improved rates of overtreatment with chemotherapy with relatively low risk surgical procedure and high cure rates

After RPLND (nodes <2cm), NCCN guidelines recommend adjuvant chemotherapy depending on final node pathologic evaluation

If nodes are <2cm and less than 5 involved (N1 disease), surveillance is preferred
If any node is >2cm or more than 5 involved (N2 disease), EP X2 is preferred*, but surveillance is an option

This recommendation has been questioned*
Initial relapse rate of 50% is likely over-estimated due to changes in staging system (N2 used to represent nodes up to 10cm)
University of Indiana prospective database found no differences in relapse free survival with or without adjuvant chemotherapy for N1 and N2 patients
Among 97 patients (46 with pN2 disease), 5 year RFS was 85%, suggesting this population should be considered for active surveillance (with salvage chemotherapy at time of relapse)