We reviewed the medical records of all patients with solid tumors who experienced relapse/progression during or after first-line treatment at Samsung Medical Center between 1996 and 2016. The subjects were retrospectively identified through a survey of our institutional database. Patients whose tumor relapsed after surgery alone (without previous history of chemotherapy), those with low-grade glial tumors, those who were transferred to our center during salvage treatment, and those who refused salvage treatment were excluded from the analysis. During the study period, patients except those with unilateral retinoblastoma or initially low-risk tumors and those with organ dysfunction were recommended to undergo HDCT/auto-SCT if they remained progression-free during salvage treatment. For patients who failed tandem HDCT/auto-SCT, allogeneic stem cell transplantation (allo-SCT) was recommended if they remained progression-free during salvage treatment. Conventional chemotherapy was administered in order to reduce the tumor burden as much as possible prior to SCT. Salvage chemotherapy regimens were selected, and changed if necessary, depending on the regimens used prior to relapse/progression, tolerability to first-line salvage chemotherapy, and response to first-line salvage chemotherapy. Surgery was conducted to reduce the tumor burden whenever possible. Radiotherapy (RT) was also administered to relapsed or metastatic sites whenever possible. RT dose and volume were determined according to previous RT prior to relapse/progression.67 A detailed review of the clinical data was performed to ascertain the presenting features, degree of surgical resection, pathology, chemotherapy regimen, RT, the response to salvage treatment, and any events (relapse/progression, second malignancy, treatment-related mortality, and death).

We evaluated the treatment response using computed tomography, magnetic resonance imaging, various radioisotope scans, and bone marrow examination. We categorized the disease response as follows: 1) progressive disease (PD): greater than 25% increase in tumor size or the appearance of a new tumor; 2) stable disease (SD): less than 50% reduction in tumor size or less than 25% increase in tumor size; 3) partial response (PR): greater than 50% decrease in tumor size; and 4) complete response (CR): complete disappearance of all previously measurable tumors. For neuroblastomas, the international response criteria for neuroblastoma were used to evaluate the treatment response.8

PFS was calculated from the date of first relapse/progression until the occurrence of second relapse/progression or last contact if the patient remained progression-free. OS was calculated from the date of initial relapse/progression until death from any cause or last contact if the patient remained alive. Survival rates and standard errors were estimated using the Kaplan-Meier method, and comparison of survival rates among groups were performed through the log-rank test. Multivariate analysis for survival was performed with Cox proportional hazards model. P values less than 0.05 were considered significant.

The study protocol was approved by the Institutional Review Board at Samsung Medical Center (IRB No. 2017-12-067). The need for informed consent was waived by the board.

Table 1 lists the clinical characteristics of 258 patients (148 boys and 110 girls) who met the inclusion criteria. Sixty-one (23.6%) patients had brain tumors, 64 (24.8%) had neuroblastomas, 74 (28.7%) had bone and soft tissue sarcomas, 12 (4.7%) had Wilms tumor, 15 (5.8%) had retinoblastoma, and the remaining 32 (12.4%) had other tumors. The median age at the time of initial diagnosis and at the time of first relapse/progression was 5.6 years (range, 0.0−27.1) and 8.1 years (range, 0.7−27.7), respectively. The median interval between the initial diagnosis and first relapse/progression was 1.3 years (range, 0.1–7.8). Of the total 258 patients, 80 (31.0%) patients had a previous history of HDCT/auto-SCT during initial treatment course.

With regard to the type of salvage therapy, 227 (88.0%) of the 258 patients received salvage chemotherapy, 106 (41.1%) underwent surgery, and 100 (38.8%) received RT. A schematic flowchart of the total 258 patients is shown in Fig. 1. Of the 60 patients who remained progression-free during first-line salvage treatment, 26 went off therapy without HDCT/auto-SCT, 26 proceeded to HDCT/auto-SCT (1 of them underwent allo-SCT following HDCT/auto-SCT), and 8 proceeded to allo-SCT. Of the 198 patients who experienced relapse/progression again during first-line salvage treatment, 49 gave up further treatment and the remaining 149 received second-line salvage treatment. Of these 149 patients, 10 went off therapy without subsequent HDCT/auto-SCT, 58 experienced relapse/progression again and gave up further treatment, 50 proceeded to HDCT/auto-SCT (4 of them underwent allo-SCT following HDCT/auto-SCT), and 31 proceeded to allo-SCT, regardless of the response to second-line salvage treatment. Therefore, 76 (29.5%) of 258 patients underwent HDCT/auto-SCT and 44 (17.1%) underwent allo-SCT. As a result, 56 of the 258 patients remained progression-free and 71 patients survived during a median follow-up of 5.9 years (range, 1.7–19.8) from first relapse/progression. The 10-year OS and PFS for the total 258 patients were 24.5% ± 3.0% and 18.4% ± 2.7%, respectively (Fig. 2A).

We analyzed the outcomes according to the findings at first relapse/progression: timing of relapse/progression, patterns of relapse/progression, and previous history of HDCT/auto-SCT. Patients who experienced relapse/progression during follow-up after off-therapy showed significantly higher PFS and OS than those who experienced relapse/progression during initial treatment (10-year PFS: 21.8% ± 3.6% vs. 14.0% ± 3.7%, P < 0.001, Fig. 2B; 10-year OS: 28.4% ± 4.2% vs. 19.0% ± 4.0%, P < 0.001). Patients with local relapse/progression alone showed significantly higher PFS and OS than those with metastatic relapse/progression (10-year PFS: 28.8% ± 4.9% vs. 12.1% ± 3.0%, P = 0.006, Fig. 2C; 10-year OS: 37.2% ± 5.5% vs. 17.0% ± 3.3%, P < 0.001). However, no significant difference in the PFS and OS was noted between patients who had a previous history of HDCT/auto-SCT and those who did not (10-year PFS: 19.6% ± 3.2% vs. 16.1% ± 4.4%, P = 0.969, Fig. 2D; 10-year OS: 26.6% ± 3.6% vs. 21.2% ± 5.0%, P = 0.199).

PFS and OS rates according to the histologic diagnosis were summarized in Tables 2 and 3, respectively. We classified the 258 patients into six tumor groups according to histologic diagnosis: brain tumors, neuroblastoma, bone and soft tissue sarcomas, Wilms tumor, retinoblastoma and other tumors. Fig. 3 shows survival rates in each histologic group and subgroup. When brain tumors were further classified into six subgroups according to the histologic diagnosis, survival rates were relatively higher in patients with anaplastic ependymoma (10-year PFS: 50.0% ± 15.8%, Fig. 3B; 10-year OS: 28.0% ± 21.6%). No patients with primitive neuroectodermal tumors (PNETs) or high-grade gliomas remained progression-free. When neuroblastomas were classified into two subgroups, i.e., initially non-high-risk and initially high-risk tumors, patients with initially non-high-risk neuroblastomas showed higher PFS and OS than those with initially high-risk neuroblastomas (10-year PFS: 62.5% ± 21.4% vs. 9.7% ± 4.3%, P < 0.001, Fig. 3D; 10-year OS: 45.0% ± 18.8% vs. 14.5% ± 4.9%, P = 0.009). When bone and soft tissue sarcomas were divided into four subgroups — osteosarcoma, Ewing sarcoma family of tumors (ESFTs), rhabdomyosarcoma, and non-rhabdomyosarcoma soft tissue sarcomas (NRSTSs) — PFS and OS were highest among patients with osteosarcomas (10-year PFS: 25.0% ± 10.6% Fig. 3F; 10-year OS: 29.0% ± 10.9%). No patients with ESFTs remained progression-free after first relapse/progression. Survival rates in patients with Wilms tumor were encouraging (10-year PFS: 58.3% ± 14.2% Fig. 3G; 10-year OS: 65.6% ± 14.0%). PFS in patients with retinoblastoma was not satisfactory; however, many patients remain alive after enucleation of involved eye (10-year PFS: 22.2% ± 12.2% and 10-year OS: 78.3% ± 11.2%, Fig. 3H). When the ‘other tumors’ were classified into three subgroups — hepatoblastoma, extracranial germ cell tumors, and the remaining rare tumors — there was no significant difference in survival rates (Fig. 3I and J).

Outcomes according to the type of salvage treatment provided after relapse/progression were analyzed. The PFS and OS of the 106 patients who underwent debulking surgeries were higher than those who did not (10-year PFS: 31.6% ± 4.7% vs. 8.8% ± 2.7%, P < 0.001, Fig. 4A; 10-year OS: 38.7% ± 5.3% vs. 14.5% ± 3.2%, P < 0.001). Surgery was a significant prognostic factor for PFS in patients with anaplastic ependymoma, osteosarcoma, Wilms tumor, or hepatoblastoma (Table 2). Surgery was also a significant prognostic factor for OS in patients with medulloblastoma, osteosarcoma, NRSTS, Wilms tumor, hepatoblastoma, or extracranial germ cell tumors (Table 3). The PFS of the 100 patients who received RT after the first relapse/progression was higher than that of patients who did not (10-year PFS: 23.0% ± 4.5% vs. 15.3% ± 3.2%, P = 0.019, Fig. 4B). However, there was no difference in OS between groups (10-year OS: 24.8% ± 4.7% vs. 24.3% ± 3.8%, P = 0.942). RT was a significant prognostic factor for PFS in patients with atypical teratoid/rhabdoid tumor or high-risk neuroblastoma (Table 2). RT was also a significant prognostic factor for OS in patients with atypical teratoid/rhabdoid tumor or NRSTS (Table 3).

The 10-year PFS and OS from SCT in 115 patients who underwent SCT were 20.2% ± 5.7% and 24.3% ± 6.1%, respectively. The 10-year PFS from HDCT/auto-SCT (n = 76) and allo-SCT (n = 44) were 30.9% ± 5.8% and 16.1% ± 6.8%, respectively. The 10-year OS from HDCT/auto-SCT and allo-SCT were 34.8% ± 5.8% and 14.4% ± 5.8%, respectively (Fig. 5A). Patients who were in CR/PR before SCT showed higher survival than those who were in SD/PD (10-year PFS: 52.1% ± 7.6% vs. 6.7% ± 3.7%, P < 0.001; 10-year OS: 54.8% ± 7.0% vs. 7.0% ± 3.5%, P < 0.001, Fig. 5B). When the data were analyzed separately according to the type of SCT, tumor status before SCT was important for both types of SCT. Patients in CR/PR before HDCT/auto-SCT showed higher survival than those in SD/PD (10-year PFS: 62.7% ± 9.2% vs. 8.5% ± 4.6%, P < 0.001; 10-year OS: 66.5% ± 8.2% vs. 7.3% ± 4.5%, P < 0.001). Patients in CR/PR before allo-SCT also showed higher survival than those in SD/PD (10-year PFS: 31.3% ± 11.6% vs. 0.0%, P = 0.256; 10-year OS: 31.6% ± 10.7% vs. 4.4% ± 4.3%, P = 0.024).

The multivariate analysis for PFS showed that relapse/progression during treatment, metastatic relapse/progression, impossible debulking surgery, and impossible RT were independent risk factors for poor prognosis. In multivariate analysis for OS, all factors mentioned above except impossible RT after relapse/progression retained poor prognostic significance (Table 4). In addition, histologic diagnosis was also an independent factor for OS and Wilms tumor and retinoblastoma showed favorable outcome as compared to brain tumors.