PET-CT for the management of testicular seminoma patients with post-chemotherapy residual masses

Corsi, Oscar; Rada, Gabriel; Pe�a, Jos�

doi:10.5867/medwave.2019.04.7625

Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)

Medwave 2019;19(4):e7625 doi: 10.5867/medwave.2019.04.7625

PET-CT for the management of testicular seminoma patients with post-chemotherapy residual masses

Oscar Corsi, Gabriel Rada, Jos� Pe�a

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Key Words: PET-CT, testicular cancer, seminoma, Epistemonikos, GRADE.

Resumen

INTRODUCCI�N
En pacientes con c�ncer testicular avanzado tipo seminoma que tienen lesiones residuales post quimioterapia de m�s de 3 cm, el PET-CT podr�a seleccionar un subgrupo susceptible de ser manejado con seguimiento, evitando una resecci�n quir�rgica innecesaria de tumor no viable.

M�TODOS
Realizamos una b�squeda en Epistemonikos, la mayor base de datos de revisiones sistem�ticas en salud, la cual es mantenida mediante el cribado de m�ltiples fuentes de informaci�n, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metan�lisis y preparamos una tabla de resumen de los resultados utilizando el m�todo GRADE.

RESULTADOS Y CONCLUSIONES
Identificamos tres revisiones sistem�ticas que en conjunto incluyeron 11 estudios primarios, de los cuales, ninguno es un ensayo aleatorizado. Concluimos que el uso de PET-CT en la evaluaci�n de masas residuales post quimioterapia en pacientes con c�ncer testicular tipo seminoma podr�a evitar un porcentaje importante de cirug�as innecesarias (certeza de la evidencia baja). Adem�s, el uso de PET-CT podr�a presentar balances riesgo/beneficio y costo/beneficio favorables en el manejo de pacientes con c�ncer testicular tipo seminoma. Sin embargo, se requieren revisiones sistem�ticas y estudios primarios que eval�en directamente el impacto diagn�stico del test.

Problem

Testicular germ cell cancer is the most common cancer among males aged 15-44. Testicular germ cell tumors can be divided into two categories according to clinical management: seminoma and non-seminoma. About 30% of testicular germ cell cancers are diagnosed with metastatic disease or eventually develop systemic recurrences. For these cases, therapy is still administered with curative intent and consists on platinum-based chemotherapy plus surgery, in order to remove post-treatment residual masses. Survival rates for treated patients are among the highest in metastatic solid tumors, reaching up to 90% of cured patients in low-risk cases. Therefore, current studies seek to minimize treatment-related toxicities [1].

In seminoma germ cell tumors, treatment induces a desmoplastic reaction in the tumor tissue that increases both the complexity and the morbidity of its surgical resection. Furthermore, in several cases, these lesions contain unviable tumor tissue, regardless of their size. Considering these features, the safety of clinical follow up without surgery of post-chemotherapy lesions measuring <3 cm is widely accepted [2].

Nowadays, positron emission tomography-computed tomography (PET-CT) has become a commonly used technique to select testicular seminoma patients that could potentially benefit of surveillance of post-treatment residual masses, avoiding surgical resection, even in lesions> 3cm.

Methods

We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

The assessment of post-chemotherapy residual masses by PET-CT in testicular seminoma patients may reduce the number of unnecessary surgeries (low certainty of evidence).
The assessment by PET-CT could have a favorable cost/benefit and risk/benefit ratio for the management of testicular seminoma patients with post chemotherapy residual masses.
Systematic reviews along with primary studies assessing the diagnostic impact of this test are required.

About the body of evidence for this question

What is the evidence. See evidence matrix in Epistemonikos later	We found three systematic reviews [3], [4], [5] including eleven primary studies across 13 references [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]; however, none of them assessed the diagnostic impact of PET-CT. Instead, they reported the diagnostic accuracy of the test. This summary involves only testicular seminoma patients. Therefore, one of the abovementioned references was excluded due to the use of a separate analysis for seminomas and non-seminomas [4]. Another reference was also excluded because of methodological limitations [5]. Two studies [6], [7] were also excluded because their data could not be entered into the meta-analysis. Hence, this table and the summary in general are based on nine primary studies [8], [9], [10], [11], [12], [13], [14], [15], [16], using the diagnostic accuracy data provided by one of the reviews [3].
What types of patients were included*	Average age reported in these studies ranged from 29 to 42.5 years. Six studies exclusively reported testicular seminoma [9], [10], [11], [12], [13], [15], and other three included both seminoma and non-seminoma [8], [14], [16]. The profile of tumor markers could not be obtained from the systematic review included in this analysis [3]. A study included post-chemotherapy patients after the first line of treatment [8]; the rest were post-chemotherapy in the first-line and/or as salvage treatment [9], [10], [11], [12], [13], [14], [15], [16]. One study also included post-radiotherapy patients [13].
What types of interventions were included*	All studies used 18F-fluoro-deoxy-glucose (18F-FDG) [8], [9], [10], [11], [12], [13], [14], [15], [16]. Four studies used PET-CT/FDG [6], [13], [14], [17]. Post-chemotherapy time varied between 4-12 weeks. The 18F-FDG dosing and administration followed standardized protocols by each participating center. All studies compared against CT [8], [9], [10], [11], [12], [13], [14], [15], [16]. Gold standard utilized were: follow up in one study [12], histology obtained from surgery [10] and follow up or histology in the other seven studies [8], [9], [11], [13], [14], [15], [16].
What types of outcomes were measured	Given the absence of studies on the diagnostic impact, the diagnostic properties of this test were reported including sensitivity, specificity, predictive value (both positive and negative), and positive and negative likelihood ratio (LR+ and LR-, respectively) to identify the presence of viable tumor in post-chemotherapy residual masses. The reported follow up time ranged from 4 to 12 months.

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of findings

We could not identify systematic reviews assessing the diagnostic impact of PET-CT; the evidence was limited to diagnostic accuracy. Data and results were obtained from one systematic review [3] that included nine primary studies [8], [9], [10], [11], [12], [13], [14], [15], [16], whose diagnostic accuracy data were entered into a meta-analysis.

The summary of findings is as follows:

The assessment of postchemotherapy residual masses by PET-CT in testicular seminoma patients may potentially lower the number of unnecessary surgeries (low certainty of evidence).

Other considerations for decision-making

To whom this evidence does and does not apply

These results apply to testicular seminoma patients treated with chemotherapy and with residual tumor masses> 3cm. Patients with non-seminoma testicular cancers were excluded, therefore these conclusions do not apply to them. For these patients, PET-CT has been proven less useful due to several factors including a lower yield in teratomas and a smaller desmoplastic reaction induced by their treatment.

About the outcomes included in this summary

We searched studies assessing the diagnostic impact of PET-CT on testicular seminoma, however, we did not find systematic reviews answering this question. Hence, we modified our search and found systematic reviews on diagnostic accuracy. These studies reported sensitivity and specificity. We also calculated the likelihood ratio.
We acknowledge these results are not patient-centered, which is relevant for decision-making. We attempted to improve their interpretation by reporting the clinical outcomes resulting from the summarized measures of diagnostic accuracy.

Balance between benefits and risks, and certainty of the evidence

Given the absence of studies assessing the diagnostic impact, we evaluated hypothetical clinical decisions in every potential scenario: true/false positive and true/false negative. In this case, the overall accuracy of the test is high, however, the certainty of the diagnostic impact (i.e. the consequences for each outcome) is low.
The main benefit of this intervention is the number of patients that could avoid surgery, however, the certainty of the evidence for this is also low.
On the other hand, a handful of patients may not receive surgery despite having an indication for it, however the certainty of the evidence for this is low. In addition, a few patients could also undergo surgery, despite being unnecessary, following a positive PET-CT. Indeed, this is one of the main associated strategies we seek to prevent by applying this intervention.
A risk/benefit assessment would probably favor the inclusion of PET-CT in the evaluation of patients with residual masses.
All included studies did not assess mortality as a resulting outcome derived from the use of PET-CT in a decision-making algorithm. In fact, this could dramatically change the interpretation of the available evidence.

Resource considerations

Although this is a high-cost intervention, it could prevent a number of unnecessary surgical procedures associated with even higher costs. Therefore, a cost/benefit balance may favor this intervention. However, an economic assessment at a local level is required in order to provide a definitive conclusion.

What would patients and their doctors think about this intervention

This is a non-invasive intervention in a disease usually associated with good prognosis. Therefore, most patients should be in favor of this intervention. Also, avoiding unnecessary surgeries with their long-term associated morbidities using PET-CT is an attractive option for clinicians.

Differences between this summary and other sources

According with the recommendations and clinical guidelines provided by the National Comprehensive Cancer Network (NCCN) and the European Association of Urology, there is indication for PET-CT in testicular seminoma patients with residual masses >3 cm along with negative tumor markers following chemotherapy [19], [20]. This is in agreement with the systematic reviews identified.

Could this evidence change in the future?

Looking forward, it is probable that the results for every outcome will change in the future, especially if new systematic reviews or primary studies assessing the diagnostic impact of this test are published.
We identified an ongoing trial in the International Clinical Trials Registry Platform database from the World Health Organization that answers the clinical question addressed in this study [21]. On the other hand, we could not find ongoing systematic reviews in the PROSPERO database.

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: PET/CT for the management of testicular seminoma with residual mass after chemotherapy.

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier.

After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described here (http://dx.doi.org/10.5867/medwave.2014.06.5997)

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

Potential conflicts of interest

The authors do not have relevant interests to declare.

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