Irinotecan plus temozolomide for pediatric relapsed or refractory solid tumors: a retrospective cohort study

Introduction

Solid tumors in children are the main cause of cancer-related morbidity and mortality in China. It is estimated that there are between 120,000 and 160,000 new cases of solid tumors in children each year in China, with more than half of these cases being malignant (1). These malignancies, including neuroblastoma, rhabdomyosarcoma, and hepatoblastoma, are characterized by rapid progression, high invasiveness, and a pronounced tendency for relapse, posing a substantial threat to the survival and health of affected children (2). Despite multimodal treatment strategies based on surgery, combined with chemotherapy and radiotherapy, recurrence remains a major clinical challenge and leading cause of death (3). For instance, the relapse rate approaches approximately 60% in high-risk neuroblastoma (4), 41.8% in rhabdomyosarcoma (5), and around 10% in hepatoblastoma (6). The prognosis for patients after recurrence is generally poor. However, current Chinese pediatric oncology guidelines lack standardized salvage regimens for relapsed/refractory solid tumors, and access to novel targeted or immunotherapies remains limited in many centers. Consequently, there is an urgent need to develop more effective, feasible, and well‑tolerated salvage treatment options.

Chemotherapy remains a cornerstone in the management of pediatric solid tumors, both in primary and recurrent settings (7). However, the development of novel, well-tolerated, and synergistic combination regimens is critical for improving survival in relapsed or refractory disease. The combination of irinotecan and temozolomide (IT) has emerged as a promising therapeutic option based on their complementary mechanisms of action (8,9). Irinotecan, a topoisomerase I inhibitor, induces DNA single-strand breaks, while temozolomide, an alkylating agent, contributes to DNA methylation and double-strand breaks (10-12). This dual action creates a synergistic antitumor effect without overlapping resistance profiles. Furthermore, the combination has demonstrated a relatively manageable safety spectrum in previous studies (13). While this mechanistic synergy is well established in preclinical models, our observational data cannot confirm a synergistic effect in patients; we simply report clinical outcomes associated with the combination.

Several prospective studies have evaluated the IT regimen in pediatric relapsed/refractory solid tumors. In a Children’s Oncology Group phase II study (Bagatell et al., 2011), the overall objective response rate (ORR) was 15% across all assessable patients; among those with MIBG-positive or marrow-evaluable neuroblastoma, the ORR reached 19% (14). Kushner et al. (2006) reported that among 19 patients treated for refractory neuroblastoma, nine (47%) showed evidence of disease regression, including two complete responses (CR) (15). A Spanish multicenter retrospective study (Hernández-Marqués et al., 2013) described an ORR of 33% across various histologies, with an additional 27% of patients achieving stable disease (SD) (16). Despite these encouraging signals, important knowledge gaps remain: (I) efficacy data in non-neuroblastoma subtypes are limited by small sample sizes; (II) real-world evidence from Chinese pediatric populations is lacking; and (III) there is no consensus on prophylactic supportive care (e.g., antibiotic use for diarrhea) in routine practice. The present study addresses these gaps by providing a detailed analysis of 86 consecutive patients treated with IT in a single Chinese center.

Based on the preclinical rationale and positive activity signals from published studies, we conducted a retrospective cohort study to describe the clinical outcomes (efficacy and safety) of the IT regimen in pediatric patients with relapsed/refractory solid tumors treated at our center. Given the observational, single-arm design, our findings cannot definitively establish efficacy or safety comparable to prospective controlled trials; rather, they provide real-world evidence that is inherently subject to selection bias and unmeasured confounding. The goal is to describe our institutional experience and generate hypotheses for future prospective studies. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0280/rc).

Methods

Study design and patient selection

This single-center, observational study enrolled pediatric patients with recurrent or refractory solid tumors who were treated with the IT regimen at Beijing Jingdu Children’s Hospital between March 2021 and March 2025. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This single-center retrospective study was approved by the Independent Ethics Committee of Beijing Jingdu Children’s Hospital (approval number: 24/625-4905). Since this study is a retrospective analysis, informed consent was waived.

Inclusion and exclusion criteria

Patients were identified by searching the hospital’s inpatient medical record system for all patients with a diagnosis of malignant solid tumor who had received at least one dose of IT during the study period. Inclusion criteria were defined as follows: (I) pathologically confirmed malignant solid tumor with evidence of recurrence or progression; (II) normal bone marrow function: hemoglobin >80 g/L, absolute neutrophil count (ANC) >1.0×10⁹/L, platelet count >75×10⁹/L; (III) normal liver function: total bilirubin <1.5× upper limit of normal (ULN), alanine aminotransferase (ALT) <2.5× ULN; (IV) normal renal function; (V) no prior history of irinotecan-temozolomide combination chemotherapy; (VI) no history of severe chronic colitis or chronic diarrhea.

Exclusion criteria included failure to meet any of the above inclusion criteria.

All patients who met the inclusion criteria and received at least one cycle of IT chemotherapy during the study period were consecutively included; no additional selection filters were applied. Patients who received other salvage regimens (e.g., topotecan/cyclophosphamide, gemcitabine/docetaxel) during the same period were not included in this analysis.

Data extraction quality control

Two independent investigators abstracted data from medical records using a standardized case report form. Discrepancies were resolved by consensus or by a third senior investigator Regular cross-checks against source documents (original laboratory reports, radiology reports, and clinical notes) were performed for 20% of randomly selected patients; the concordance rate exceeded 95%.

Treatment regimen

All patients received the following combination chemotherapy regimen: irinotecan (50 mg/m²/day) was administered by intravenous infusion over 90 minutes on days 1 to 5 of each cycle, together with temozolomide (100–150 mg/m²/day) given orally on the same days. Each treatment cycle was repeated every 21 days. Comprehensive supportive care measures were implemented: (I) cefixime was initiated at least 24 hours before the first irinotecan infusion to allow gut bacterial β-glucuronidase inhibition, then continued orally once daily approximately 1 hour prior to each irinotecan infusion on days 1–5 to prevent chemotherapy-related diarrhea. (II) High-volume intravenous fluid replacement (2,000–3,000 mL/m²/day) combined with urine alkalization (using sodium bicarbonate to maintain urine pH >7.0) was administered to prevent tumor lysis syndrome and to ensure adequate renal protection, particularly in patients with bulky disease or pre-existing renal impairment from prior therapies. (III) Standard antiemetics, gastroprotective agents, hepatoprotective agents, and other supportive medications were administered as clinically indicated.

Follow-up and outcome verification

After treatment initiation, patients were followed every 2–3 months through scheduled outpatient visits, which included physical examination, complete blood counts, liver and renal function tests, tumor markers [e.g., neuron-specific enolase (NSE), urinary vanillylmandelic acid (VMA) for neuroblastoma], and cross-sectional imaging [computed tomography (CT) or magnetic resonance imaging (MRI)] as clinically indicated. For patients who missed scheduled visits, survival status was ascertained by telephone contact with the patient, family members, or referring physicians, and further verified against the national death registry when possible. The last follow-up date for all patients was March 31, 2025.

Efficacy and safety assessment

Tumor response was assessed every two cycles of chemotherapy using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Responses were classified as CR, partial response (PR), SD, or progressive disease (PD). In this retrospective study, all radiologic assessments were performed by the treating clinicians (pediatric oncologists and institutional radiologists) as part of routine clinical practice; independent blinded central radiology review was not performed. Confirmation of response after 4 weeks was not mandated, but when confirmatory scans were available they were used.

The primary study endpoints were objective response rate (ORR, defined as CR + PR) and disease control rate (DCR, defined as CR + PR + SD). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and treatment-related toxicity.

Adverse events were monitored throughout treatment and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

Statistical analysis

Categorical variables were expressed as frequencies and percentages, while continuous variables were summarized using median and range. Survival outcomes, including PFS and OS, were evaluated using the Kaplan-Meier method. Statistical significance was defined as a two-sided P value <0.05. All analyses were conducted with SPSS (version 26.0; IBM Corp., Armonk, NY, USA).

Results

Patient’s basic characteristics

A cohort of 86 pediatric patients diagnosed with recurrent or refractory solid tumors was enrolled in this study. The study population consisted of 54 males (62.8%) and 32 females (37.2%), with a median age of 7 years (interquartile range: 4–11 years; range: 1–18 years). At initial diagnosis, among neuroblastoma patients (n=52), 45 (86.5%) had stage IV disease and 7 (13.5%) had stage III disease. For other tumor types, all patients presented with advanced or metastatic disease. The median number of prior therapy lines was 3 (range: 1–7). All 86 patients had received prior chemotherapy (100%), 77 (89.5%) had undergone surgery, 30 (34.9%) had received radiotherapy, 21 (24.4%) had autologous stem cell transplantation, and 10 (11.6%) had received immunotherapy (e.g., dinutuximab). The median Lansky/Karnofsky performance status at IT initiation was 70% (range: 50–90%). The age distribution was as follows: <5 years, 31 patients (36.0%); 5–10 years, 33 patients (38.4%); and 11–18 years, 22 patients (25.6%). The distribution of tumor types was as follows: neuroblastoma (n=52, 60.5%), rhabdomyosarcoma (n=8, 9.3%), hepatoblastoma (n=6, 7.0%), medulloblastoma (n= 5, 5.8%), Ewing’s sarcoma/primary neuroectodermal tumor (PNET; n=4, 4.7%), retinoblastoma (n=3, 3.5%), atypical teratoid/rhabdoid tumor (AT/RT, n=2, 2.3%), Wilms tumor (n=2, 2.3%), and one case each (1.2%) of RT, renal clear cell sarcoma, germ cell tumor, and adrenocortical carcinoma.

Treatment response

According to the RECIST 1.1 standard, all 86 patients met the criteria for the assessment of treatment efficacy. The overall best responses achieved were CR in 6 patients (7.0%), PR in 14 patients (16.3%), SD in 25 patients (29.1%), and PD in 41 patients (47.7%).

The ORR for the entire cohort was 23.3% (20/86), and the DCR was 52.4% (45/86). Descriptively, response rates varied across tumor types. Patients with neuroblastoma (n=52) showed an ORR of 31.0% (16/52) and a DCR of 67.3% (35/52). Among the 8 patients with rhabdomyosarcoma, the ORR and DCR were 25.0% (2/8) and 50.0% (4/8), respectively. No formal statistical comparisons were made between tumor subtypes due to the single-arm, descriptive nature of this study. Conversely, in the medulloblastoma subgroup (n=5), the descriptive ORR and DCR were 20.0% (1/5) and 40.0% (2/5), respectively. Table 1 presents the detailed treatment responses across all tumor subtypes.

Treatment duration

The total number of IT cycles administered was 246 across the 86 patients. The median number of cycles per patient was 4 (range: 1–14). The median treatment duration (from first IT dose to last dose or data cutoff) was 84 days (range: 21–294 days; IQR: 56–126 days). The mean treatment duration was 89.5 days (SD: ±42.3 days). The longest treatment duration was 294 days (14 cycles), observed in a patient with neuroblastoma who remained on treatment with SD at the time of data cutoff.

Survival outcomes

A total of 246 cycles of IT chemotherapy were administered. Disease progression occurred in 41 patients (47.7%) after a median of 5 treatment cycles. The median PFS for the entire study population was 5.5 months. The estimated 1-year OS rate was 36.8% [95% confidence interval (CI): 27.5–49.4%], and the 1-year PFS rate was 22.4% (95% CI: 14.7–34.4%). As this was a single-arm descriptive study, no comparative analyses (e.g., versus historical controls or other regimens) were performed. Survival data are detailed in Figure 1.

Figure 1 Overall survival rate of 86 pediatric patients with recurrent/refractory solid tumors. IT, irinotecan and temozolomide.

Subgroup analysis of neuroblastoma patients (n=52) showed that 17 patients (32.6%) experienced disease progression after a median of 4 treatment cycles. The median PFS in this subgroup was 6.0 months (Figure 2). The 1-year OS and PFS rates for neuroblastoma patients were 53.5% (95% CI: 40.9–70.1%) and 39.6% (95% CI: 27.5–56.9%), respectively. These descriptive estimates should be interpreted with caution given the single-arm design and lack of a control group.

Figure 2 Overall survival rate of 52 children with neuroblastoma. IT, irinotecan and temozolomide.

Reasons for treatment discontinuation

Based on medical record review, the reasons for stopping the IT regimen were as follows: PD in 41 patients (47.7%), unacceptable toxicity in 2 patients (2.3%; both due to recurrent Grade IV neutropenia despite G-CSF support), patient or guardian decision in 3 patients (3.5%), and death while on treatment in 5 patients (5.8%; all due to disease progression). The remaining 35 patients (40.7%) completed their planned cycles or were still receiving treatment at the data cutoff date (March 31, 2025).

Treatment-related toxicity

Treatment safety was assessed across all 246 treatment cycles. The most frequently observed treatment-related toxicities were hematologic events, among which Grade III–IV neutropenia (25.2%) and thrombocytopenia (26.0%) occurred per treatment cycle.

Non-hematologic toxicities were generally manageable. Diarrhea of any grade occurred in 17.8% of treatment cycles, with Grade III–IV events occurring in 3.6% of cycles. Notably, three cases of Grade IV diarrhea were successfully managed with supportive care without dose reduction. Hepatic function abnormalities occurred in 26.9% of treatment cycles, with Grade III–IV events occurring in 4.0% of cycles. One patient experienced Grade IV hepatic toxicity in consecutive treatment cycles, necessitating a reduction in temozolomide dose.

Other notable toxicities included febrile neutropenia (5.7% of treatment cycles) and seizures (0.4% of treatment cycles). No treatment-related deaths were observed (Table 2).

Per-patient worst‑grade adverse events

To complement the per-cycle safety data presented in Table 2, we also analyzed the worst grade of adverse event experienced by each patient. Among 86 patients, Grade III–IV neutropenia occurred in 28 patients (32.6%), Grade III–IV thrombocytopenia in 26 patients (30.2%), Grade III–IV diarrhea in 4 patients (4.7%), and Grade III–IV liver dysfunction in 5 patients (5.8%). No treatment-related deaths occurred. These per-patient data are provided in Table 3.

Seizures were recorded in 5 patients (5.8%) during treatment. All five patients had documented CNS involvement (brain metastases or leptomeningeal disease) prior to IT initiation. In four cases, seizures were attributed to progressive CNS disease rather than the IT regimen; in one case, the cause could not be definitively determined. All seizures were managed with antiepileptic medications (levetiracetam or benzodiazepines), and no patient required discontinuation of IT therapy due to seizures.

Discussion

The management of relapsed or refractory pediatric solid tumors remains a formidable challenge in oncology, with salvage chemotherapy representing a critical line of intervention. In this single-arm, retrospective cohort study, we observed a descriptive ORR of 23.3% and a DCR of 52.4% among 86 heavily pretreated patients. While these results indicate that the IT regimen was associated with tumor response and disease stabilization in a subset of patients, the absence of a control group precludes any claims of efficacy or comparative effectiveness. The following discussion should be interpreted as hypothesis-generating rather than confirmatory.

The mechanistic rationale for combining IT is well-founded on their complementary antitumor activities. Irinotecan is administered as a prodrug and is metabolized in vivo to its active form, SN-38, which acts as a potent inhibitor of topoisomerase I. By stabilizing the transient cleavage complex formed between topoisomerase I and DNA, SN-38 causes irreversible single-strand breaks. Critically, O6-methylguanine adducts, if not repaired by O6-methylguanine-DNA methyltransferase (MGMT), can mispair with thymine during replication, triggering futile mismatch repair cycles that generate long-lived single-strand gaps. These gaps are converted to double-strand breaks and also potentiate the cytotoxic effect of irinotecan by increasing the collision of replication forks with topoisomerase I-DNA complexes, thereby enhancing S-phase-dependent lethality. This synergistic mechanism provides a strong rationale for the combination. These lesions ultimately lead to lethal DNA damage during DNA replication (17). This action is particularly effective against multidrug-resistant tumors (18,19). Temozolomide, an orally administered alkylating agent, exhibits excellent blood-brain barrier penetration. It induces DNA methylation primarily at the O6-position of guanine, resulting in mismatched base pairing and ultimately triggering double-strand DNA breaks. This mechanism contributes to its synergistic cytotoxicity when combined with other antineoplastic agents (20). Preclinical evidence suggests that temozolomide may also attenuate DNA repair mechanisms, potentially mitigating irinotecan-induced toxicity and enhancing therapeutic efficacy (21). The absence of pharmacokinetic interactions further supports the clinical combinability of these agents.

Although we did not measure MGMT expression or other resistance biomarkers in this retrospective study, their potential impact on response to the IT regimen deserves discussion. MGMT is a DNA repair protein that removes O6-alkylguanine adducts, directly counteracting temozolomide-induced damage (22,23). High MGMT expression has been associated with resistance to temozolomide in gliomas and may also influence outcomes in pediatric solid tumors (24,25). Preclinical studies suggest that downregulation of MGMT could enhance IT sensitivity, but clinical data in neuroblastoma and other childhood cancers are lacking (26). Future prospective studies should incorporate MGMT promoter methylation status or protein expression to identify patients most likely to benefit from IT therapy. Other putative resistance mechanisms, such as alterations in topoisomerase I activity or drug efflux pumps (e.g., ABCG2), were not assessed in our study and represent additional unexplored variables.

Our findings indicate an ORR of 23.3% and a DCR of 52.4% in the entire cohort, with particularly promising activity observed in neuroblastoma patients (ORR 31.0%, DCR 67.3%). These results are generally consistent with previously reported data. International studies have documented ORRs ranging from 14% to 33% and DCRs from 62.5% to 75% for neuroblastoma patients treated with IT therapy (14-16,27). A previous domestic study involving 58 patients showed an ORR of 31.0% and a DCR of 60.3%. Group analysis indicated that the response rate for neuroblastoma patients was 39.3%, and that for rhabdomyosarcoma patients was 25.0%. Although the DCR observed in our study seemed slightly lower than those in this literature, this difference might be attributed to the severe pre-treatment conditions of our study subjects. Specifically, patients had received a median of 15 prior chemotherapy cycles, and more than 60% exhibited disease progression at the initiation of the IT regimen. These factors likely contributed to the development of chemoresistance and more aggressive tumor biology.

Despite these challenges, among patients receiving the IT regimen, 25 achieved SD, 14 PR, and 6 CR. The median PFS of 5.5 months and a 1-year OS rate of 36.8% are encouraging in this refractory population. These outcomes suggest that IT chemotherapy may be associated with disease stabilization and, in a subset of patients who have exhausted conventional therapies, potentially longer survival.

The observed safety features are consistent with the known toxicological characteristics of each component drug. The hematological adverse reactions were the most common toxic manifestations, among which Grade III–IV neutropenia and thrombocytopenia accounted for 25.2% and 26.0% respectively during the treatment period. These were effectively managed with growth factor support and transfusion support. Non-hematologic toxicities, including diarrhea (17.8% all-grade, 3.6% Grade III–IV) and transaminase elevation (23.8% all-grade, 4% Grade III–IV), were generally controllable with prophylactic and supportive measures. The low incidence of severe diarrhea may be attributed to our prophylactic use of cefixime, which inhibits bacterial β-glucuronidase activity in the gut, thereby reducing reconversion of SN-38G to the enterotoxin SN-38 (28). This strategy likely contributed to the regimen’s tolerability and low rate of treatment discontinuation.

Several limitations of our study should be acknowledged. First, the single-center, retrospective, single-arm design lacks a positive control group (e.g., patients receiving alternative salvage therapies or best supportive care). Therefore, no causal or comparative efficacy claims can be made; all reported outcomes are descriptive and hypothesis-generating. Second, selection bias is inherent to retrospective studies; although we attempted to consecutively include all eligible patients, unmeasured confounders (e.g., MYCN status, specific genetic alterations, physician’s choice of salvage regimen) may have influenced outcomes. Third, the heterogeneity of tumor types and differences in prior treatment histories (median 3 prior lines, range 1–7) may affect the generalizability of our findings. Fourth, tumor response assessments were not centrally reviewed, and the absence of independent blinded radiology review may introduce measurement bias. Fifth, we did not perform formal statistical comparisons between subgroups (e.g., neuroblastoma vs. other tumors) because the sample sizes were too small for meaningful inference in non-neuroblastoma histologies; any descriptive differences should be considered exploratory. Sixth, the distinction between relapsed and refractory disease could not be reliably ascertained from retrospective records, and we did not analyze these subgroups separately. Given these limitations, our results should be interpreted as descriptive and hypothesis-generating, requiring confirmation in prospective, controlled, multi-institutional studies.

Conclusions

In conclusion, the IT regimen demonstrated clinical activity and was found to be tolerable in this cohort. These descriptive findings are hypothesis-generating and suggest that the IT regimen may have modest antitumor activity in this population, particularly in neuroblastoma (ORR 31.0%). However, due to the absence of a control group and the inherent limitations of a retrospective, single-arm design, no definitive claims of efficacy or comparative effectiveness can be made. Prospective, controlled studies are required to validate these observations.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0280/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0280/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0280/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0280/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This single-center retrospective study was approved by the Independent Ethics Committee of Beijing Jingdu Children’s Hospital (approval number: 24/625-4905). Since this study is a retrospective analysis, informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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