Cyclic Metronomic Chemotherapy for Pediatric Tumors: Six Case Reports and a Review of the Literature

Abstract

We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the kidney, one ependymoma, two medulloblastomas, one neuroblastoma, and a type II neurocytoma of the spine. Treatment included oral cyclophosphamide daily for 21 days alternating with oral etoposide daily for 21 days in a backbone of daily valproic acid and celecoxib. In one case, celecoxib was substituted with sulindac. Of the six patients, three showed complete responses, and all patients showed some response to metronomic therapy with only minor hematologic toxicity. One patient had hemorrhagic gastritis likely associated with NSAIDs while off prophylactic antacids. These data add to a growing body of evidence suggesting that continuous doses of valproic acid and celecoxib coupled with alternating metronomic chemotherapy of agents such as etoposide and cyclophosphamide can produce responses in pediatric tumors relapsing to conventional dose chemotherapy.

Keywords: cyclophosphamide; etoposide; metronomic chemotherapy; pediatric tumors; valproic acid.

Figure 1

Patient 1: CT with contrast shows a large 11 × 7 cm left renal tumor with retroperitoneal infiltration, regional metastatic retroperitoneal adenopathy, and extension to renal vein and inferior vena cava. The patient also had innumerable solid circumscribed masses throughout the lung parenchyma bilaterally (not shown).

Figure 2

Patient 2: MRI shows confluent encephalomalacia gliosis in the left temporal and occipital lobes. There was no evidence of mass or pathologic enhancement 8 years from diagnosis and 4 years off therapy.

Figure 3

Patient 4: (A) image shows and enhancing tumor in the anterior horn of the left ventricle when she presented with first relapse of medulloblastoma. She achieved complete remission with salvage therapy; (B) image shows an enhancing tumor involving the anterior aspect and floor of the fourth ventricle (arrows) when she presented with second relapse; (C) image shows response to 3 months of metronomic therapy with decreased size and intensity of enhancing lesions; (D) image shows interval progression of the tumor seen in T2 FLAIR resulting in a change from temozolomide to etoposide at 4 months of treatment; (E) image shows resolution of the tumor mass and T2 FLAIR changes at 8 months of metronomic therapy; (F) image shows progressive disease at 10 months of treatment.

Figure 3

Patient 4: (A) image shows and enhancing tumor in the anterior horn of the left ventricle when she presented with first relapse of medulloblastoma. She achieved complete remission with salvage therapy; (B) image shows an enhancing tumor involving the anterior aspect and floor of the fourth ventricle (arrows) when she presented with second relapse; (C) image shows response to 3 months of metronomic therapy with decreased size and intensity of enhancing lesions; (D) image shows interval progression of the tumor seen in T2 FLAIR resulting in a change from temozolomide to etoposide at 4 months of treatment; (E) image shows resolution of the tumor mass and T2 FLAIR changes at 8 months of metronomic therapy; (F) image shows progressive disease at 10 months of treatment.

Figure 3

Patient 4: (A) image shows and enhancing tumor in the anterior horn of the left ventricle when she presented with first relapse of medulloblastoma. She achieved complete remission with salvage therapy; (B) image shows an enhancing tumor involving the anterior aspect and floor of the fourth ventricle (arrows) when she presented with second relapse; (C) image shows response to 3 months of metronomic therapy with decreased size and intensity of enhancing lesions; (D) image shows interval progression of the tumor seen in T2 FLAIR resulting in a change from temozolomide to etoposide at 4 months of treatment; (E) image shows resolution of the tumor mass and T2 FLAIR changes at 8 months of metronomic therapy; (F) image shows progressive disease at 10 months of treatment.

Figure 4

Patient 6: (A) MRI shows a 4.5 cm homogeneously enhancing expansile intramedullary tumor involving the medulla and upper cervical cord down to the level of C3–C4 (arrow) with an elongated syrinx extending inferiorly to the T3–T4 level; (B) the tumor was removed and treated with radiation but came back, for which it was treated with nine cycles of topotecan–ifosfamide–carboplatin with no significant change in tumor size (arrow) but significant toxicity, for which treatment was changed to metronomic chemotherapy; (C) after 3 months on metronomic chemotherapy, the patient recovered from toxicity and the tumor was slightly decreased; (D) the tumor was stable at the end of 4 years of metronomic chemotherapy.

Figure 4

Patient 6: (A) MRI shows a 4.5 cm homogeneously enhancing expansile intramedullary tumor involving the medulla and upper cervical cord down to the level of C3–C4 (arrow) with an elongated syrinx extending inferiorly to the T3–T4 level; (B) the tumor was removed and treated with radiation but came back, for which it was treated with nine cycles of topotecan–ifosfamide–carboplatin with no significant change in tumor size (arrow) but significant toxicity, for which treatment was changed to metronomic chemotherapy; (C) after 3 months on metronomic chemotherapy, the patient recovered from toxicity and the tumor was slightly decreased; (D) the tumor was stable at the end of 4 years of metronomic chemotherapy.

Figure 5

Schematic of future planned studies for pediatric cases eligible for metronomic chemotherapy. Proteomic and metabolic pathway analysis, where feasible, will be used to determine eligibility of patients to receive specific tyrosine kinase inhibitor (TKI) therapy coupled with metronomic chemotherapy, which involves alternating cycles of metronomic etoposide with metronomic cyclophosphamide. Patients not selected or not eligible for TKI-based therapies will receive valproic acid (VA) and celecoxib with metronomic chemotherapy as outlined in this manuscript.