The comparison of treatment outcomes between combined chemotherapy-radiation therapy (Chemo-RT) and radiation therapy alone (RT) in intracranial germ cell tumor in adolescent and young adult patients (AYA)

doi:10.21203/rs.3.rs-3952172/v1

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The comparison of treatment outcomes between combined chemotherapy-radiation therapy (Chemo-RT) and radiation therapy alone (RT) in intracranial germ cell tumor in adolescent and young adult patients (AYA)

https://doi.org/10.21203/rs.3.rs-3952172/v1

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Background

The incidence of Intracranial germ cell tumor(iGCT) in adolescents and young adults (AYA) is less common that in pediatric patients. However, the recurrent rate of iGCT in AYA (7.6%) is higher than children (2%). Because iGCT in AYA population are lacking randomized trials to standardize the treatment. Thus, the purpose of this study is to determine the practice patterns and outcomes of iGCT in AYA.

Methods

This is a single-center retrospective cohort study. Patients with IGCT aged 15 to 39 years were managed at Siriraj Hospital, Thailand from 2007 to 2019. The charts were reviewed and compared outcome between who received Chemo-RT and RT alone.

Results

The median follow-up time was 7.6 years. Eighty-four patients were included in this study: 60 germinomas, 24 NGGCT patients. In the case of NGGCT, the 5-year and 10-year EFS/OS were 100% and 100% in RT alone. In RT plus chemotherapy, the 5-year and 10-year EFS were 67.57% and 54.05%. The 5-year and 10-year OS were 68.44% and 68.44%. For germinoma, the 5-year and 10-year EFS were 95.83% and 76.87% in RT alone. The 5-year and 10-year OS were 95.83% and 86.40%. Whereas in RT plus chemotherapy, the 5-year and 10-year EFS were 73.33% and 69.63%. The 5-year and 10-year OS were 85.10% and 69.63%.

Conclusions

We report the outcomes with different approaches of patients in AYA with iGCT to our knowledge. In our series, the patient who received chemotherapy had no survival benefit and probably worsen survival in both NGCCT and pure germinoma.

Intracranial germ cell tumor

adolescence and young adult

chemotherapy

radiotherapy

non-germinomatous germ cell

The role of chemotherapy combined with radiotherapy in intracranial germ cell tumor in adolescent and young adult patients is controversially debated. We aim to explore the risk and benefit of chemotherapy combined with radiation compared to radiotherapy alone. Here, we provide evidence that the EFS and OS for both germinoma and NGGCT with radiation alone seem superior to those with CMT. It might because of treatment-related mortality and lack of the standardize follow-up guideline. It is imperative to pursue further research in this demographic to gather more comprehensive information that can help solidify the treatment approach for AYA patients.

The incidence of Intracranial germ cell tumor (iGCT) in adolescents and young adults (AYA) is less common that in pediatric patients[1] representing 0.5-3% of all primary brain tumors. Mostly iGCT can be found in Asians more than European and North American populations. The prognosis of diseases is based on histology subtype, biomolecular markers, and treatment[2, 3]. iGCT is classified into 2 major groups: germinoma and non-germinomatous germ cell tumors (NGGCT). Furthermore, age is also one essential factor that can affect the survival of patients. The recurrent rate of iGCT in AYA (7.6%) is also higher than pediatric iGCT (2%). The treatment paradigm of pediatric iGCT consists of surgery, chemotherapy, and radiotherapy. In contrast, iGCT in AYA population, defined as age 15 to 39[4] now are lacking randomized trials to standardize the treatment. Prospective studies have shown that using radiation treatment by itself is an effective approach that leads to significant success rates in curing the condition and safety. Considering the favorable outcomes achieved through radiotherapy alone, the use of chemotherapy is not routinely recommended for AYA patients diagnosed with intracranial germinoma[5, 6]. Some trials combining chemotherapeutic schemes with focal radiotherapy did not improve the relapse free survival[1, 6, 7]. In contrast to the pediatric population, AYA can generally tolerate radiotherapy well, whereas the potential for harmful side effects from chemotherapy is more pronounced [1, 8]. Thus, the primary focus of this study is comparing the outcome between combined chemotherapy and radiotherapy (Chemo-RT) vs radiotherapy alone.

Study population

All patients who received RT with iGCT aged between 15 to 39 years at Siriraj Hospital, Thailand from 2007 to 2019 were included in this study. The charts were retrospectively reviewed, and data collected in terms of event-free survival and overall survival based on cell types. Patients who were older than 18 years old were treated by adult medical oncologists, whereas those who were younger treated by pediatric oncologists. Diagnoses were done based on pathologic findings, CT/MRI imaging in both brain and spinal regions, and tumor markers according to the Thai National Protocol for the Treatment of Childhood Cancer 2018 and Children’s Oncology Group (COG) [9]following these criteria.

Germinoma should meet the criteria of pathologic report confirmed with normal tumor markers level (serum and/or cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) ≤ 10 ng/dL, serum and/or CSF beta subunit of human chorionic gonadotrophin(B-HCG) ≤100 IU/L. In contrast, NGGCT must have a pathologic report confirmed of immature teratoma with malignant transformation, yolk sac tumor, embryonal cell carcinoma, choriocarcinoma, and mixed germ cell tumor or serum and/or CSF tumor marker AFP >10 ng/dL or B-HCG >100 IU/L. For baseline investigations for metastasis patients at the time of diagnosed including serum blood chemistry, complete blood count, serum AFP, serum B-HCG, MRI brain and spine, ophthalmologic evaluation, pituitary axis function evaluation, and biopsy if indicated were done.

Treatment

The treatment sequence and protocols of iGCT have varied over the past based on evolving evidence. The patients were treated with various chemotherapy regimens including etoposide and cisplatin with or without bleomycin (BEP), or carboplatin and etoposide with or without ifosfamide (ICE). The factors of elevated tumor marker, NGCCT subtype, and metastasis would be considered CMT treatment. Different chemotherapy protocols were used consisted of SIOP CNS CGT 96[7] ICE: carboplatin (600 mg/m2/day, days 1–3), etoposide (100 mg/m2/day, days 1–3), ifosfamide (1,800 mg/m2/day, days 1–5), COG cycle[9] A: etoposide (150mg/m2/day, days 1–3) and carboplatin (600 mg/m2/day, days 1). Cycle B: Etoposide (100 mg/m2/day, days 1-5) and etoposide (150 mg/m2/day, days 1–3), and UK CCSG[10] (Cisplatin (100mg/m2, day 1), etoposide (120mg/m2/day, days 1–3) and bleomycin (15mg/m2, day 2). After chemotherapy treatment, patients underwent serum tumor marker testing and imaging to evaluate response.

Radiotherapy was delivered at 1.8-2 Gy per fraction. Patients who were diagnosed with germinoma received either whole-ventricular radiotherapy(18-30Gy)[11] with or without focal boost. Diagnosed NGGCT patients could be underwent either craniospinal irradiation 30-36 Gy with or without focal boost, whole brain irradiation, or only focal boost depend on post-chemotherapy tumor responses and clinician decision [3, 9, 11]. For focal boost was done in all patients to cumulative dose to 24-36 Gy in germinoma and 45-54 Gy in NGGCT.

After treatment was complete, patients were observed with clinical examination with serum tumor markers at 3- to 4-month intervals for 2 years then every 6-month intervals after that. MRI brain and screening whole spine was performed every 6-month intervals for 2 years then annually after that. Additional MRI investigations were investigated depending on the patient's symptom suspicious of recurrence.

Study design

The study, approved by the Siriraj Ethical Review Board, is a single-center, retrospective cohort at Siriraj Hospital, Thailand. The primary outcome of the study was overall survival defined as the time interval from the date of completed radiotherapy course to the date of death from any cause, event-free survival defined as the time interval from the date of completed radiotherapy course to the date of recurrence and death events which were divided into 3 subgroups: In-field recurrence, Out-filed recurrence, and systemic recurrence. In-field recurrence was determined as a site of recurrence within 80% of the prescription isodose line, while out-filed recurrence was explained as a site of recurrence out of 80% of the prescription isodose line. Systemic recurrence was defined as any recurrence away from the brain and cerebrospinal axis.

Statistical analysis

The study was calculated by using STATA 16.0. The baseline patient, tumor, and treatment characteristics of the patients were reported by descriptive statistics. The final analysis of overall survival, and event-free survival was calculated by the Kaplan-Meier method and log-rank tests to compare study groups. Univariable & Multivariable Cox regression analysis between both groups. The Results were considered significant if P≤ 0.05.

Patient characteristics are shown in Table 1. The median interval from the start of treatment to the last follow-up time was 7.6 years. Most of NGGCT histology was mixed subtype at 21 of 26 patients, followed by teratoma in 3 of 26 patients, and choriocarcinoma in 2 of 26 patients.

NGGCT

All the patients in this group were diagnosed by tissue pathology. Eleven of 24 patients (46%) got a biopsy, while 13 of 24 patients (54%) got subtotal tumor removal (STR). Median B-HCG level in NGGCT was 37.56 IU/L (0.56-583.20) in serum and 35.63 IU/L (29.64 – 103.4) in the CSF. For AFP, the median value was 35.05 ng/ml (3.82-198.38) in serum and 2.34 ng/ml (0.5-14.22) in the CSF. Metastasis disease had been found in 3 of 24 patients (13%) on MR imaging and/or on CSF cytology. They received chemotherapy followed by CSI to 36Gy. 20 of 24 patients with NGGCT received chemotherapy (83%) including 25% of BEP, 42% of ICE, and 17% of Carboplatin combined with etoposide, Twenty-two of 24 patients received RT (consisting of 50% CSI, 12% WBRT, 32% WVRT, and 6% involved-filed). Two patients who did not receive radiotherapy because one patient lost to follow-up and other patient developed lung fibrosis after chemotherapy. Two patients experienced an interruption in their RT regimen, each receiving a radiation dose below 18Gy. Both patients passed away due to pneumonia before they could complete the course of radiotherapy.

In NGGCT patients, the 5-year and 10-year EFS were 73.33%±9.3% and 61.11%±11.1%. The 5-year and 10-year OS were 75%±10.8% and 67.5% ±12.1%. In RT alone, the 5-year and 10-year EFS and OS were 100% and 100%. In Chemo-RT arm, the 5-year and 10-year EFS were 67.57%±10.88% and 54.05%±12.20%. The 5-year and 10-year OS were 68.44%±10.79% and 68.44%±10.79%. Three of the 9 deaths were related to disease recurrence. One patient who had a multifocal mixed germ cell tumor combined germinoma and immature teratoma received CMT with a stable response. Then, a patient got radiotherapy for 9 sessions, he passed away due to serious pneumonia. Another patient who mixed germ cell tumor with spinal metastasis and paraplegia at presentation received CMT then CSI to 36Gy passed away after 5 months of completing a radiotherapy course because of UTI with sepsis. Three of them had experienced severe sepsis. No documentation was available on the other one.

Five and 10-year OS were 100% and 100% for WBRT, 100% and 75% in CSI plus CMT , 33% and 0% WVRT alone , 66.67%, 66.67% WVRT+CMT. In WBRT plus CMT and focal tumor bed RT plus CMT showed no patients alive at 5-and 10-year. When we compare in terms of OS of CMT and site of RT factors, there were no statistically significant parameter different between OS (P= 0.21) as shown in Figure 1. The pattern of failure was in-field RT 2 of 3 patients. One of 3 patients developed diffuse leptomeningeal involvement and local recurrence at the pineal area as shown in Table2. Another individual developed out-field drop metastases at T5-6 spinal region after WVRT only 6 months. Acute toxicities were reported in Figure 2. Grade 3 toxicity was found in patients who received CMT plus RT more than RT alone in terms of anemia (10%) and thrombocytopenia (5%). Radiotherapy treatment interruption in combined Chemo-RT was found 31.6% (6/19) and 0% in RT alone.

For subgroup patients with elevated tumor markers, there are sixteen patients who received CMT+RT. The 5-year and 10-year EFS were 66.67%±13.93% and 66.67%±13.93%. The 5-year and 10-year OS were 71.38%±12.18% and 71.38%±12.18%. Only one patient received radiotherapy alone because of poor performance status. He underwent WBRT 34Gy in 17 fractions alone. Despite the challenging circumstances, the patient managed to survive for 13 years after completing the radiotherapy course. He passed away due to severe sepsis at the primary hospital.

Germinoma

Fifty-three of 60 patients underwent surgeries, whereas 7 of 60 patients were diagnosed by radiologic finding and tumor marker level. Forty-seven of the 60 patients had biopsies, and 6 had subtotal resections (STR). The median B-HCG was 1.91 IU/L (0.20-17.6) in serum and 22.46 IU/L (2.90-81.70) in CSF. For AFP, the median value was 1.47 ng/ml (0.79-2.59) in serum, and 0.5 ng/ml (0.5 -0.7) in the CSF, respectively. Thirty-six patients (60%) received chemotherapy which is composed of BEP (32%), carboplatin plus etoposide (18%), and cisplatin plus etoposide (32%). Fifty-nine patients (98%) received radiotherapy treatment (consisting of 62% WVRT, 26% CSI, and 12% WBRT). One patient did not proceed with radiotherapy because condition continued to worsen after completing four cycles of BEP treatment then passed away because of obstructive hydrocephalus caused by disease progression at the left basal ganglion. Three of the 60 patients had found radiographic spinal metastases and positive CSF cytology. All three metastases’ patients received combined CSI and chemotherapy.

In germinoma patients, EFS were 82.7%±5% at 5 years and 72%±6.7% at 10 years. 5-year and 10-year OS were 89.30%±4.1% and 77.19%±6.23%, respectively. In RT alone, the 5-year and 10-year EFS were 95.83%±4.08% and 76.87%±9.16%. The 5-year and 10-year OS were 95.83%±4.08% and 86.40%±7.35%. Whereas in Chemo-RT, the 5-year and 10-year EFS were 73.33%±7.69% and 69.63%±9.54%. The 5-year and 10-year OS were 85.10%±6.19% and 69.63%±9.54%. Of the 15 deaths, 6 were related to disease, 1 was related to complications of treatment, 4 were from severe infection, 4 were due to unrelated causes (2 from heart disease, 1 from meningitis, and 1 from OSA-related sequence). Five and 10-year OS were 100% and 100% for WBRT plus CMT and CSI alone, 87.5% and 87.5% in CSI plus CMT , 93% and 87% WVRT alone, 100% and 75% for WBRT alone, 85% and 62% WVRT+CMT. As shown in Table2. The local pattern of failure was in-field RT 3 of 5 patients. To Compare in terms overall survival of pure germinoma patients based on the RT site and CMT, no statistically significant differences in parameters were observed for OS (P=0.41). Corresponding with EFS and OS, hazard ratio of patients who received combined CMT and RT compared to RT alone were 1.61(P=0.308), and 2.74 (P = 0.141) in Table 3. After adjusting by age > 18, primary site, metastasis, type of surgery, field of radiotherapy, gender, serum beta-HCG, serum AFP, the HR for EFS and OS were 2.49(P=0.095), and 2.55 (P = 0.237).

The acute toxicity was found to be lower than that of the non-germinoma group, mainly due to a smaller number of patients who underwent craniospinal irradiation (CSI). The rate of grade 2 and 3 toxicities in terms of anemia, neutropenia, thrombocytopenia, and renal toxicity was observed in patients who received both RT and CMT compared to those who received RT alone, as depicted in Figure 2. Radiotherapy treatment interruption in Chemo-RT was found 17.6% (6/34) and 21.7% (5/23) in radiotherapy alone.

Our study is a retrospective report about outcomes of specific iGCT in AYA group which nowadays had less evidence than the pediatric group to support treatment management[12]. In our institution, patients are treated by adults and pediatric oncologists depending on their ages. Thus, a variety of treatment approaches might be found. To improve knowledge about overall outcomes of AYA patients based on a variety of treatment approaches is excessively essential to standardization of treatment in AYA group. From Wang et al[13]showed that in adult patients, RT alone is most used. Whereas in the pediatric population, CMT plus RT approach is predominant. Additionally, studies have indicated that there is no notable disparity in survival rates between groups that received only RT and those that underwent a combined treatment. In our institution, compared with other research in developed countries[1, 14, 15], seems to be inferior, especially in NGGCT subgroup and at a 10-year period. Prior study in Thailand focused on pediatric populations who are less than 15 years old[16] reported the 5-year EFS and OS at 94.3% and 96.2% respectively which were higher than our study in AYAs groups. One study shows that survival rates of lower-middle-income countries are lower than high-income countries[17]. The factor that might affect the survival outcome is the delayed diagnosis from primary hospital to tertiary hospital. The delay of diagnosis in intracranial germ cell tumor had the potential to increase the risk of disseminated disease[18]. Furthermore, a lack of schedule follow-up protocol especially imaging interval because of time constraints would be factors[19]. Our results showed that 9 of 14 patients (64%) died from severe infection corresponding with a 10-year OS dropped when compared to another study[1, 15]. B S Ehrlich et al[20] reported that treatment-related mortality was inversely related to country income. The most common leading cause of death is sepsis at 71.7%. In the future, we should standardize our cancer follow-up schedule to improve the outcome and minimize treatment-related mortality for AYA population. Moreover, the radiotherapy treatment interruption would be one factor that affect the outcome of local control and overall survival[21]. Patients in the group receiving Chemo-RT experienced higher levels of toxic effects compared to those undergoing radiotherapy alone that would be increased the treatment time interval. As a result, the EFS in the Chemo-RT group may be lower than in the radiotherapy alone group especially in the NGGCT patients who have trend to have a large RT area compared to germinoma.

Radiotherapy

The standard treatment strategy for pediatric patients involves the integration of both chemotherapy and radiation, supported by a substantial body of randomized evidence. Anyway, radiotherapy treatment strategies also differ between SIOP and COG approaches[14]For NGGCT following SIOP protocol[22], employs a treatment plan that includes delivering radiation to the involved-field RT up to a dose of 54 Gy. In contrast, the COG method, as outlined in the ACNS0122 protocol, begins with CSI at a dose of 36 Gy, followed by a subsequent dose boost to 54 Gy because of increasing in a number of patients who experienced relapsed at spinal area compared to from historical data. In case of pure germinoma, for SIOP-CNS-GCT 96[7] the treatment involves delivering WVRT dose of 24 Gy, followed by a focused RT boost to 40 Gy if a complete response (CR) is not achieved. On the other hand, COG follows WVRT dose of 18 Gy, along with a focal RT boost to 30 Gy upon achieving CR. If a complete response is not attained, the COG approach adjusts the treatment to a WVRT dose of 24 Gy, followed by a boost to 36 Gy[23].In contrast, AYA population faces a scarcity of well-established approaches due to a lack of robust evidence so radiotherapy approaches in our institution have a variation among individual patients. In patients with NGGCT who were treated with focal tumor bed and WBRT seem lower OS compared with those treated with WVRT and CSI. Only one patient developed out-field relapse after WVRT. It might support Fonseca et al.[24] that the relapse patterns are not associated with the field of radiation therapy. However, this difference was not statistically significant (P=0.76), possibly due to the limited size of the sample used for analysis. Further study should be focused on this topic.

This study could help the gap in practice patterns and outcomes of AYA iGCT population. Our results showed that germinoma and NGGCT have different responses depending on the multifactor of treatment and prognosis. Although there are many differences in the treatment approaches of iCGT globally, EFS and OS for germinoma without CMT seem superior to those with CMT. It might be from the infection causes more than relapse events. On the other hand, EFS and OS for NGGCT without CMT were not different from the group of patients who received CMT. Treatment-related mortality is an important factor to consider for better long-term outcomes. Because of the rarity of this disease in the AYA population, conducting specific trials tailored to AYAs can be a formidable challenge. It is imperative to pursue further research in this demographic to gather more comprehensive information that can help solidify the treatment approach for AYA patients.

Limitation

The limitation of this study is nonrandomized retrospective design, as well as the possibility of selection bias in treatment approaches. Consequently, it's probable that more severe disease factors could lead physicians to intensify more aggressive treatment options. Additionally, the sample size remains a constraint, especially regarding the limited number of cases involving NGGCTs upon which we base our conclusions.

Author Contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Teeradon Treechairusame, Warissara Rongthong and Kullathorn Thephamongkhol. The first draft of the manuscript was written by Teeradon Treechairusame and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.”

Disclosures: The authors of this manuscript have no financial interest in the subject under discussion. No funding was provided for this study.

Conflict of Interest Statement: None

Funding Statement: None

Data Availability: The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary material. Raw data that support the findings of this study are available from the corresponding author, upon reasonable request. No new data were generated or analyzed in support of this research

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Tables 1 to 3 are available in the Supplementary Files section.

No competing interests reported.

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The comparison of treatment outcomes between combined chemotherapy-radiation therapy (Chemo-RT) and radiation therapy alone (RT) in intracranial germ cell tumor in adolescent and young adult patients (AYA)

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IMPORTANCE OF THE STUDY

Introduction

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Discussion

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Supplementary Files

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