medicina

Systematic Review
A Systematic Review Investigating the Difference between
1 Cycle versus 2 Cycles of Adjuvant Chemotherapy in Stage I
Testicular Germ Cell Cancers
Emanuiela Florentina Rohozneanu 1,2 , Ciprian Deac 2 and Călin Ioan Căinap 1,2, *

1 Department of Oncology, the Oncology Institute “Prof. Dr. Ion Chiricuţă” Cluj-Napoca,
“Iuliu Hatieganu” University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania
2 Department of Oncology, “Iuliu Hatieganu” University of Medicine and Pharmacy,
400012 Cluj-Napoca, Romania
* Correspondence: [email protected]

Abstract: Standard care for stage I testicular germ cell cancers (seminomatous—STC or non-seminomatous—
NSTC) is orchiectomy followed by active surveillance, 1 or 2 cycles of adjuvant chemotherapy, surgery or
radiotherapy. The decision on the adjuvant therapeutic approach is guided by the associated risk factors of
the patient and the potential related toxicity of the treatment. Currently, there is no consensus regarding the
optimal number of adjuvant chemotherapy cycles. Although in terms of overall survival, there is no proven
inconsistency regarding the number of cycles of adjuvant chemotherapy, and the rate of relapse may vary.

Keywords: stage I testicular germ cell cancers; seminomatous—STC; non-seminomatous—NSTC

1. Introduction
Background
Testicular cancer is a rare type of tumor that accounts for about 1% of all cancers in
adults [1]. In 98% of cases, the cell of origin is represented by a germ cell that failed to
Citation: Rohozneanu, E.F.; Deac, C.; differentiate and continued to express its pluripotency which is afterward translated into
Căinap, C.I. A Systematic Review an uncontrolled malignant growth due to the accumulation of chromosomal aberrations [2].
Investigating the Difference between The uncontrolled proliferation can lead to the genesis of two histological types of testic-
1 Cycle versus 2 Cycles of Adjuvant ular cancer, represented by seminoma and non-seminoma, the latter being characterized
Chemotherapy in Stage I Testicular within the pathology report as being a component of embryonal carcinoma, yolk sac tumor,
Germ Cell Cancers. Medicina 2023, 59, choriocarcinoma or immature teratoma. Orchiectomy is required for diagnosis and is also
916. https://doi.org/10.3390/ the initial therapeutic approach. Further treatment depends on the histopathological fea-
medicina59050916 tures, tumor markers reference interval (α-feto protein, β-human chorionic gonadotropin,
Academic Editor: Dah-Shyong Yu lactate dehydrogenase) and imaging-based diagnostic analysis. Stage I testicular cancer
is defined by the absence of metastasis on the retroperitoneal lymph nodes and distant
Received: 25 March 2023 organs on the CT scan. The different adjuvant therapeutic approaches depicted by one or
Revised: 21 April 2023
two cycles of Carboplatin, radiotherapy of the para-aortic and ipsilateral iliac lymph nodes
Accepted: 2 May 2023
or active surveillance for stage I seminoma and chemotherapy using one or two cycles of
Published: 10 May 2023
BEP, RPLND or active surveillance for stage I non-seminoma provide a similar outcome in
terms of overall survival [3,4]. However, it can alter the risk of relapse which can fluctuate
from 15–30% for stage I seminoma to 40–50% for stage I non-seminoma [5,6] Adequate
Copyright: © 2023 by the authors.
management of this stage is required, as the 5-year survival rate is close to 100% [3–6].
Licensee MDPI, Basel, Switzerland. When chemotherapy is administered, guidelines variably recommend the administra-
This article is an open access article tion of one or two cycles, but the specific number of cycles is not well defined yet. The aim
distributed under the terms and of this systematic review is to assess the difference between one versus two administered
conditions of the Creative Commons cycles of chemotherapy in stage one testicular germ cell cancers (STC and NSTC) with
Attribution (CC BY) license (https:// reference to overall and disease-free survival, short-term and long-term toxicities. Given
creativecommons.org/licenses/by/ the high rates of survival among the patient population and the associated risk of relapse,
4.0/). it is necessary to identify the right approach for this stage of the disease.

Medicina 2023, 59, 916. https://doi.org/10.3390/medicina59050916 https://www.mdpi.com/journal/medicina

Medicina 2023, 59, 916 2 of 11

2. Methods
2.1. Literature Search Strategy
The articles reviewed for this paper needed a systematic search conducted in PubMed
(1970–December 2022) using the following key words: ’testicular neoplasms’, ’testicu-
lar cancer’, ’germinal testicular cancer’ and ’non-seminomatous tumors’ combined with
’chemotherapy’ or ’treatment’.

2.2. Selection Criteria

Papers that were reviewed for this article included the following criteria:
- Articles written and published in English
- Evidence-based clinical practice guidelines
- Randomized and non-randomized studies referring to stage I seminoma or non-
seminoma treated with adjuvant chemotherapy that reported a rate of recurrence
and/or survival and/or toxicity of the treatment
- If any article included other stages of seminoma or non-seminoma, outcome was
reported separately for stage I disease
- If any article included other options of treatment for stage I seminoma or non-
seminoma (surveillence, radiotherapy and surgery), outcome was reported separately
for the patients who received chemotherapy

3. Results
3.1. Literature Search Results
We identified 30 articles that met the selection criteria of this paper and included
3 clinical practice guidelines, 2 randomized studies and 25 non-randomized studies. The
results of the literature search are summarized in Table 1. The PRISMA guidelines were
followed for drafting of this paper.

Table 1. Literature search results.

Study Type Number [References]

Clinical practice guidelines 3 [7–9]
Randomized controlled studies 2 [10,11]
Non-randomized studies 25 [12–36]

3.2. Clinical Practice Guidelines

Three clinical practice guidelines were reviewed for this paper and the recommenda-
tions are summarized in Table 2.

Table 2. Guideline recommendations.

Guideline Stage I Seminoma Stage I Non-Seminoma

1 × Carboplatin AUC 7 2 × Carboplatin AUC 7 1 × BEP 2 × BEP
Recognizes better results,
ESMO [7] X X N/A
but limited data available
EAU [8] X N/A X X
Not indicated because of
NCCN [9] X X X
adverse events
BEP—Bleomycin, Cisplatin, Etoposid; ESMO—European Society for Medical Oncology; NCCN—National Com-
prehensive Cancer Network; EAU—European Association of Urology.

3.2.1. Clinical Stage I Seminoma

ESMO [7] and EAU [8] guidelines recognize tumor size > 4 cm and invasion of rete
testis as risk factors for recurrence and recommend the administration of chemotherapy
Medicina 2023, 59, 916 3 of 11

in the presence of any of these factors. Moreover, the ESMO [7] guideline highlights the
potential benefit of the administration of two courses of Carboplatin; however, due to
insufficient evidence, it is not recommended. In contrast, the NCCN [9] guideline does
not support stratification of the patients using the aforementioned risk factors due to
limited evidence that fails to prove their predictive value and, therefore, recommends
the administration of one or two cycles of chemotherapy whenever active surveillance is
not feasible.

3.2.2. Clinical Stage I Non-Seminoma

All three guidelines recommend active surveillance whenever it is feasible or one cycle
of BEP in the presence of risk factors.
NCCN8 does not recommend two cycles given the possible associated adverse events,
but EAU9 recognizes it as a potential option.

3.3. Randomized and Non-Randomized Studies

3.3.1. Clinical Stage I Seminoma
When deciding on the adjuvant treatment for stage I seminoma, several studies
suggested that the administration of chemotherapy should be guided by the presence of
one of the two risk factors, represented by tumor size and invasion of rete testis [37]. Only
one of the twelve studies exposed in Tables 3 and 4 investigating the efficacy of adjuvant
chemotherapy for clinical stage I seminoma used these factors to stratify the patients.
Chemotherapy was mostly administered as an option of treatment chosen either by the
physician or the patient.

Table 3. Studies of single cycle adjuvant chemotherapy in seminomatous testicular cancer.

Median
Number of Chemotherapy Number of
Study Eligibility Follow-Up
Patients Regimen Relapses
(Months)
1 × Carboplatin
Oliver et al. [12] (1994) - 25 29 0
AUC 7
Dieckmann et al. [13] 1 × Carboplatin
- 93 48 8
(2000) 400 mg/mp
Oliver et al. [10] 1 × Carboplatin
Randomized 573 48 27
(2005) AUC 7
Dieckmann et al. [14] 1 × Carboplatin
- 362 30 18
(2016) AUC 7
Tanstad et al. [15] 1 × Carboplatin
- 188 40 7
(2011) AUC 7
Chau et al. [16] 1 × Carboplatin
- 517 47.2 21
(2015) AUC 7
Diminutto et al. [17] 1 × Carboplatin
- 115 22.1 6
(2015) AUC 7

Single-cycle adjuvant Carboplatin provided satisfactory results in multiple studies [15–17].

In the randomized prospective study published in 2005, Oliver et al. [10] not only proved
the non-inferiority of Carboplatin to radiotherapy for stage I seminoma, but after a median
follow-up of 4 years, the relapse rate in the single cycle chemotherapy arm was only 4.7%.
Medicina 2023, 59, 916 4 of 11

Table 4. Studies of 2 cycles of adjuvant chemotherapy in seminomatous testicular cancer.

Number of Chemotherapy Follow-Up Number of

Study Eligibility
Patients Regimen (Months) Relapses
Oliver et al. [12] 2 × Carboplatin
- 53 51 1
(1994) AUC 7
Dieckmann et al.
2 × Carboplatin
[13] - 32 48 0
400 mg/mp
(2000)
Reiter et al. [18] 2 × Carboplatin
- 107 74 0
(2001) 400 mg/mp
Steiner et al. [19] 2 × Carboplatin
- 108 59.8 2
(2002) 400 mg/mp
Argirovic D [20] 2 × Carboplatin
- 163 48 3
(2005) 400 mg/mp
T > 4 cm
Aparicio et al. [21] 2 × Carboplatin
Rete testis 214 34 7
(2005) AUC 7
involvement
Koutsoukos et al. 2 × Carboplatin
- 138 5
[22] (2016) AUC 6
Dieckmann et al.
2 × Carboplatin
[14] - 66 30 1
AUC 7
(2016)
T—tumor size.

In 2016, Dieckmann et al. [14] published a prospective non-randomized study that

included a total of 725 patients with clinical stage I seminoma. Adjuvant treatment was
decided by local physicians and included active surveillance, radiotherapy or chemotherapy
(1 or 2 cycles of Carboplatin). After a median follow-up of 30 months, stratification of tumor
size revealed that in the group of patients who received one cycle of Carboplatin, tumor
dimension > 4 cm can predict a higher risk of relapse than those whose tumor is below this
limit (6.8% versus 2.3%). Moreover, the risk of relapse was statistically higher for tumor
sizes >5 cm (9.3%). Although the direct comparison of the number of relapses was not
significantly lower for the patients treated with two courses of Carboplatin (1.5% versus
5%; p = 0.2048), it appears that large tumor size can predict a low efficacy of one course of
Carboplatin. Similar results were obtained by Chau et al. [16] who revealed a relapse-free
survival of 97.4% after one cycle of chemotherapy with Carboplatin but with a relapse rate
that was nearly double for the patients with tumor size above 4 cm (5.9% versus 3.3%).
Tumor size was recognized as a prognostic factor in other studies as well [22] but limited
data exist regarding the role of rete testis invasion in the risk of relapse [21]. On the other
hand, Oliver et al. [12] (1994) found no significant correlation between tumor size and risk
of relapse which is in accordance with the results of other studies [15]. Moreover, his trial
did not reveal any additional benefit in the administration of two cycles of Carboplatin
when compared to one cycle, showing instead higher rates of acute and late toxicities. In
contrast, the study published by Dieckmann et al. [13] (2000) revealed no relapses after
two courses of Carboplatin compared to 8.6% for those treated with one cycle (p = 0.088).
Toxicity on the reproductive system was reported, but after 20 months the median FSH
levels returned to the normal range.
Reiter et al. [18] also obtained favorable results after two courses of Carboplatin with-
out any relapses when a group of 107 patients having stage I seminoma and a toxicity profile
of WHO grade I or II underwent treatment. In the study published by Steinner et al. [19],
the 5-year relapse-rate after two courses of Carboplatin was 1.85% but exhibited a more
hematological toxicity than previously reported: 44.4% developed thrombocytopenia, 2.8 of
which was grade 4.
Medicina 2023, 59, 916 5 of 11

Aparicio et al. [21] also obtained a favorable relapse rate of 3.3% at a median follow
up of 36 months and an overall 5-year survival of 100% after two cycles of Carboplatin
AUC 7. Patients were stratified by tumor size (>4 cm) and invasion of rete testis, and
there was a significant correlation between invasion of rete testis and relapse (DFS of
99.2% versus 91.6%; p = 0.0108).

3.3.2. Clinical Stage I Non-Seminoma

Tables 5 and 6 include selected trials that investigated the role of adjuvant chemother-
apy in patients diagnosed with high-risk clinical stage I non-seminoma. Although the
definition of high-risk disease varied, all studies had at least one risk factor in common.

Table 5. Studies of single cycle adjuvant chemotherapy in non-seminomatous testicular cancer.

Number of Chemotherapy Follow-Up Number of

Study Eligibility
Patients Regimen (Months) Relapses
VI
LI
Absence of yolk sac elements
Presence of
Oliver et al. [23]
• Undifferentiated areas 46 1 × BEP 33 3
(2004)
• Malignant teratoma
• Undifferentiated or
malignant trophoblastic
teratoma
VI
LI
Gilbert et al. [24]
Absence of yolk sac elements 22 1 × BEP 122 0
(2006)
Presence of undifferentiated
elements
Albers et al. [11]
Randomized 191 1 × BEP 56 2
(2008)
VI
Westermann et al. [25]
LI 40 1 × BEP 96 1
(2008)
≥50% embryonal carcinoma
Tandstad et al. [26] VI+ 157 1 × BEP 57 5
(2009) VI− 155 1 × BEP 49 2
Vidal et al. [27] VI
40 1 × BEP 186 1
(2015) >50% embryonal carcinoma
VI
Cullen et al. [28] (2020) 236 1 × BEP 49 4
Combined seminoma + NSGCTT
BEP—Bleomycin, Cisplatin, Etoposid; VI—vascular inasion; LI—lymphatic invasion; NSGCTT—nonseminomatous
germ cell tumors of the testis.

Only two studies conducted a direct comparison between the outcome of patients
receiving one versus two cycles of BEP. Oliver et al. [23] (2004) observed that after a median
follow-up of 33 months, relapses were seen in 6.5% (3/46) of patients treated with one cycle
of BEP and only in 3.6% (1/28) of patients treated with two cycles of the same regimen.
No significant toxicities were reported except for permanent ototoxicity in a music teacher
that led to the inability to teach. Although he was treated with two cycles of BEP, many of
the studies included in this paper reported ototoxicity even after one cycle of BEP [25,27]
In the SWENOTECA large prospective study, Tandstad et al. [26] stratified the patients
according to the LVI invasion and offered surveillance or one cycle of BEP to those without
LVI and two cycles of BEP to those LVI +. Results showed that one cycle of BEP reduces
the risk of relapse by 90% to both LVI + and LVI—compared to surveillance. Furthermore,
after 2 cycles of BEP relapse-free survival after a median follow-up of 60 months was
Medicina 2023, 59, 916 6 of 11

100%, with no significant additional adverse events compared to one cycle of BEP except
for obstipation.

Table 6. Studies of 2 cycles of BEP in non-seminomatous testicular cancer.

Number of Chemotherapy Follow-Up Number of

Study Eligibility
Patients Regimen (Months) Relapses
VI
Studer et al. [29]
pT > 1 41 2 × BEP 42 1
(1993)
Presence of embryonal carcinoma
Pont et al. [30]
VI 29 2 × BEP 79 2
(1996)
Any 3 of the following criteria:
• VI
• LI
Cullen et al. [31]
• Absence of yolk 114 2 × BEP 48 2
(1996)
sac elements
• Presence of
undifferentiated elements
VI
Bohlen et al. [32] LI
59 2 × BEP 93 1
(1999) pT > 1
Presence of embryonal carcinoma
VI
LI
Absence of yolk sac elements
Presence of
Oliver et al. [23]
• Undifferentiated areas 28 2 × BEP 33 1
(2004)
• Malignant teratoma
• Undifferentiated or
malignant trophoblastic
teratoma
Chevreau et al. [33] VI
40 2 × BEP 113.2 0
(2004) Presence of embryonal carcinoma
VI
Maroto et al. [34] Local invasion of adjacent
231 2 × BEP 40 2
(2005) structures
Presence of embryonal carcinoma
VI
LI
Guney et al. [35] (2009) pT > 1 71 2 × BEP 26 4
≥80% embryonal carcinoma
Preorchiectomy AFP ≥ 80 ng/dL
Tandstad et al. [26] VI+ 70 2 × BEP 60 0
(2009) VI− 2 2 × BEP 34 0
VI
LI
Bamias et al. [36] Invasion of tunica vaginalis,
142 2 × BEP 79 1
(2011) spermatic cord, rete testis or
scrotal wall
>50% embryonal carcinoma
BEP—Bleomycin, Cisplatin, Etoposid; VI—vascular inasion; LI—lymphatic invasion; pT—pathologycal stage of
tumor according to TNM staging.

The most encouraging outcome regarding the administration of one cycle of BEP was
obtained by Gilbert et al. [24]: no relapses were observed after a median follow up of
10.2 years. Similar results were published by Vidal et al. [27] and Westerman et al. [25] that
Medicina 2023, 59, 916 7 of 11

obtained a relapse rate of only 2.5% and 2.7%, respectively. Results may be influenced by
the small number of patients included in the studies mentioned above. Albers et al. [11]
conducted a randomized phase III trial that included 191 patients comparing retroperi-
toneal lymph node dissection to one cycle of BEP. The authors achieved a statistically
significant recurrence-free survival in favor of chemotherapy with only two relapses in
the chemotherapy arm and fifteen relapses in the surgery arm after a median follow-up
of 4.7 years (p = 0.0011). The largest and most recent prospective trial investigating the
efficacy of one cycle of BEP was conducted by Cullen et al. [28] that included 246 of stage I
NSGCTT. With four relapses at a median follow-up of 49 months, results showed a two
year metastatic recurrence of 1.3% which is similar to the results reported for two cycles of
BEP but having the advantage of low levels of serious adverse events.
Currently, there are more studies published in the literature that investigated the
efficacy of two cycles of BEP than of one cycle of BEP as summarized in Table 6. In a large
prospective study conducted by Cullen et al. [31], at a median follow-up of 4 years, 2 out of
114 patients had a relapse with no long-term toxicity on fertility and lung function being
observed. However, the authors reported the death of a 45-year-old patient caused by a
cerebrovascular event eight days after the administration of the first cycle of BEP without
having hematological changes that could explain the affection. The link to the treatment
was unclear. Tha data published by Maroto et al. [34] also relied on a large number of
patients suffering of high-risk stage I NSGCTT (n = 231). After the administration of
two cycles of BEP, only two reoccurrences have been observed. Regarding the toxicity
on the reproductive system, out of the 19 patients who have fathered a child, only one
needed to use cryopreserved semen. A total of 1.3% developed a tumor affecting the
contralateral testicle.
In a non-randomized prospective trial, Studer et al. [29] obtained a relapse-free survival
of 97.5% after the administration of two cycles of BEP at a median follow up of 42 months,
with only one relapse that was mature teratoma treated surgically and without late toxicities
reported. The results are consistent with the data published by Pont et al. [30] that registered
2/42 relapses after two cycles of BEP for high-risk stage I NSGCTT with no significant
acute or late adverse events compared to the control group. Similar rates of relapses were
reported by Guney et al. [35] (4/71).
Long-term results after the administration of two cycles of BEP were published by
Bohlen et al. [32], revealing only one relapse in 59 patients followed for a median time
of 93 months. One case of transient nephrotoxicity, one of neurotoxicity and one of car-
diotoxicity were reported. The long-term efficacy of two cycles of BEP was also studied by
Chevreau et al. [33]. At a median follow-up of 113.2 months, no relapses were observed in
the 40 patients receiving two cycles of chemotherapy. Two patients developed a second
cancer in the contralateral testis and no impact on fertility was observed as previously re-
ported by other studies [30,31]. Another prospective study conducted by Bamias et al. [36]
reported one relapse after a median follow-up of 79 months of 142 patients.

4. Discussion
Historically, adjuvant chemotherapy with Carboplatin in stage I testicular seminoma
was used as an alternative to radiotherapy because of the growing concerns of the side
effects to this treatment [13]. Currently, adjuvant Carboplatin may be administered as
an option to all patients or in the presence of risk factors (tumor size > 4 cm, invasion
of rete testis). However, these risk factors have been the subject of a long debate in the
past years since no prospective study has been conducted in order to validate them. In
this setting, a tumor size > 4 cm was correlated with an increase in the risk of relapse in
contrast to rete testis invasion that lacked evidence in most of the trials [14,16,22]. The first
studies that assessed the efficacy of Carboplatin in eradicating micro-metastasis used two
cycles of adjuvant chemotherapy, but subsequent evidence revealed that one cycle might
be equivalent. [12]. However, one course of adjuvant Carboplatin seems to be insufficient
to lower this risk when tumor size is above 4 cm [14].
Medicina 2023, 59, 916 8 of 11

When comparing studies that investigated the role of adjuvant BEP in stage I non-
seminoma, one should be aware that different studies used different groups of risk factors,
and this could be a risk of bias. One risk factor that was common in all the studies
was lymphovascular invasion. The right definition of high-risk disease for stage I non-
seminoma has been investigated by many trials. One of the most significant was a meta-
analysis published by Vergouwe et al. [38] that examined 23 studies and analyzed a total of
2587 patients with stage I NSTC. 29% of the patients had occult metastasis diagnosed either
during follow up or at retroperitoneal lymph node dissection. Several predictors for occult
metastasis were identified, but the strongest was vascular invasion defined as venous and
lymphatic invasion (OR, 5.2; 95% CI, 4.0 to 6.8). The presence of embryonal carcinoma,
a high pathologic stage or size of the primary tumor were also statistically significantly
associated with the presence of occult metastasis but with a weaker effect.
Adjuvant chemotherapy with BEP for stage I NSTC was first explored around 1990
with the argument that using more limited chemotherapy in patients with high-risk disease
will restrict exposure to a higher amount of chemotherapy in case of a relapse [39]. Although
the first studies published used two cycles of chemotherapy, more recent trials proved
similar results with one cycle of BEP regarding relapse-free survival. Currently, there is
no agreement between the use of one or two cycles of BEP. At first glance at the number
of relapses reported in Tables 5 and 6, two cycles of BEP seem to provide better results,
although the difference is not obvious. The only two studies that made a direct comparison
with one cycle of BEP obtained a lower number of relapses with two cycles but with
no survival benefit reported [23,26]. Meanwhile, the debate is centered on the issues of
dose-related toxicities from BEP. Table 7 summarizes adverse events from BEP, grouped
by dose and non-dose related [39]. The acute toxicities reported in the trials mentioned in
this paper were mainly hematological and gastrointestinal (nausea, vomiting). Bleomycine-
induced lung injury is a well-known dose-limiting toxicity. Lung function was analyzed
before and after chemotherapy describing a discreet decrease in respiratory parameters
but with no symptomatic respiratory dysfunction 32 or pneumonitis reported in any of the
studies selected for this paper. Perhaps one of the most concerning dose-related toxicity
is infertility. Most of the studies reviewed for this article reported outcomes on fertility
with the majority of the patients being able to conceive one or two years after the treatment.
This was applicable not only to the patients that performed one cycle of BEP but also
for those who performed two cycles of BEP with minimal toxicity on fertility [34]. This
is in accordance with the results obtained by Bujan et al. [40] regarding the impact of
chemotherapy and radiotherapy on spermatogenesis. The authors concluded that after two
or fewer cycles of BEP sperm count returns to pretreatment levels after twelve months, but
not after radiotherapy or more then two cycles of BEP.

Table 7. Toxicities of BEP chemotherapy [39].

Dose-Related Non-Dose Related

Infertility
Fatigue
Pneumonitis or lung fibrosis
Renal damage Neutropenia
AnaemiaPeripheral neuropathy Alopecia
Ototoxicity Nausea andvomiting
Skin toxicity
Reynaud’s phenomena
Avascular necrosis hip
BEP—Bleomycin, Cisplatin, Etoposid.

5. Conclusions
Taking into account the fact that the data we currently have, we suggest that all
treatment options for clinical stage I testicular cancer provide similar survival outcomes
and considering the potential dose-related toxicity associated with chemotherapy, we can
Medicina 2023, 59, 916 9 of 11

conclude that at the moment there is not enough evidence to support the superiority of two
cycles of chemotherapy instead of one.

Funding: This research received no external funding.

Institutional Review Board Statement: Ethical review and approval were waived for this study due
the format of the article.
Informed Consent Statement: Patient consent was waived due to the format of the article.
Data Availability Statement: The data analyzed in this systematic review were obtained from
Pubmed electronic database.
Conflicts of Interest: The authors declare no conflict of interest.

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