Ifosfamide, carboplatin, and etoposide for neuroblastoma
A high-dose salvage regimen and review of the literature
The authors report a retrospective analysis of high-dose ifosfamide, carboplatin, and etoposide (HD-ICE) for patients with refractory or relapsed neuroblastoma (NB). A major reason for using this regimen was the long time since patients received previous treatment with a platinum compound. The authors also summarized the published experience on ICE in patients with NB.
Treatment comprised ifosfamide (2000 mg/m2 daily for 5 days), carboplatin (500 mg/m2 daily for 2 days), and etoposide (100 mg/m2 daily for 5 days). Patients who had poor hematologic reserve (platelet count <100,000/μL) from previous therapy received peripheral blood stem cells (PBSCs) after HD-ICE. Disease status before and after HD-ICE was defined according to International Neuroblastoma Response Criteria (expanded to include 123I-metaiodobenzylguanidine findings). Publications that were informative about ICE for NB were reviewed.
Seventy-four patients received 92 cycles of ICE, including 37 patients who received PBSC rescue. Grade 3 toxicities were rare: 1–3 patients had encephalopathy, mucositis, or gastroenteritis. Bacteremia was documented in 24 of 92 cycles (26%). The absolute neutrophil count reached 500/μL on day 17–30 (median, day 22) in patients who had satisfactory hematologic reserve. Disease regressions (major and minor responses) were achieved by 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory NB, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy (P = .005). In the literature, patients received ICE at lower dosages and achieved major response rates >36% in phase 1 and 2 studies (in which less comprehensive staging evaluations were used) that involved resistant NB and >70% in induction for newly diagnosed NB.
HD-ICE is appealing as salvage treatment or consolidative therapy because of its anti-NB activity and the low risk of major nonhematologic toxicity. PBSC support is unnecessary for patients who had intact hematologic reserve. Cancer 2013. © 2012 American Cancer Society.
Standard chemotherapy for high-risk neuroblastoma (NB) includes dose-dense or dose-intensive and myeloablative regimens using alkylators, platinum compounds, topoisomerase-II inhibitors, and, most recently, the topoisomerase-I inhibitor topotecan.1 The most common salvage regimens for resistant NB combine topoisomerase-I inhibitors (topotecan, irinotecan) with alkylators (cyclophosphamide, temozolomide),2-4 topoisomerase-II inhibitors (doxorubicin, etoposide),5,6 or both classes of drugs.7 For salvage purposes, in addition to regimens that combine a topoisomerase-I inhibitor and an alkylator,8-11 we have used high-dose ifosfamide, carboplatin, and etoposide (HD-ICE).
The development of HD-ICE was based on several considerations. Most important, in patients with resistant NB, a prolonged period has often passed since prior exposure to platinum compounds (which have excellent anti-NB activity); this time gap is attributable to common use of the above-mentioned salvage regimens. Second, the combination's lack of cardiotoxicity, hepatotoxicity, and gastrointestinal toxicity is appealing, and there is little risk of undue morbidity (eg, mucositis or nephrotoxicity).12-14 Third, ototoxicity is a concern in this patient population, but hearing is minimally affected by carboplatin in nonmyeloablative doses. Finally, risks from myelosuppression were deemed acceptable with a) standard supportive measures in patients who have adequate bone marrow (BM) reserve, or b) infusion of peripheral blood stem cells (PBSCs) in patients who have poor hematologic reserve because of prior therapy. The overall toxicity profile supported the feasibility of high dosing, which carried promise of overcoming chemoresistance.15,16 In the current report, we address the use of ICE for NB by presenting a large experience with a high-dose salvage regimen and a literature review.
MATERIALS AND METHODS
This retrospective study covered all patients at Memorial Sloan-Kettering Cancer Center (MSKCC) who received HD-ICE for resistant, high-risk NB between October 2004 and March 2012 (Table 1). Like other MSKCC retrieval regimens,3,8-11 toxicity of major organs had to be grade ≤2 (National Cancer Institute Common Toxicity Criteria). In accordance with MSKCC rules, informed written consents for treatment were obtained from guardians who understood each agent's toxicities, the certainty of pancytopenia with possible infection or hemorrhage, and the risks of unforeseen toxicities. The guardians were uniformly well versed in toxicity issues, given the prior intensive therapy received by all patients. An institutional review board waiver was obtained for patient records.
Table 1. Clinical Profiles of Patients Who Received High-Dose Ifosfamide, Carboplatin, and Etoposide
|Age at diagnosis, y||4.0 [0.2–8.5]||3.8 [0.9–25.5]||3.8 [0.1–13.8]||6.2 [1.8–7.9]|
|Years from diagnosis||2.4 [0.9–6.7]||2.3 [0.6–8.7]||3.0 [0.7–16.5]||4.6 [1.3–5.2]|
|Age when treated, y||5.9 [4.6–12.0]||6.9 [1.7–15.5]||7.5 [1.3–24.8]||8.9 [6.3–13.1]|
|Prior therapy|| || || || |
| HD-CDV||14 (82)||25 (96)||33 (97)||6 (100)|
| HD cisplatin||14 (82)||21 (81)||32 (94)||6 (100)|
| Topotecan||13 (76)||26 (100)||34 (100)||6 (100)|
| Irinotecan||10 (59)||18 (69)||31 (91)||3 (50)|
| Temozolomide||7 (41)||13 (50)||30 (88)||3 (50)|
| Myeloablative therapyc||5 (29)||10 (38)||12 (35)||1 (17)|
| 131I-MIBG||0 (0)||10 (38)||10 (29)||1 (17)|
|No. of prior relapses|| || || || |
Reasons for treating a given patient with HD-ICE included: 1) extensive prior exposure to, and/or NB persistent or progressing after, cyclophosphamide-topotecan or irinotecan-temozolomide; and 2) no recent (>6 months) treatment with a platinum compound (and avoiding the toxicities of cisplatin). The patients were grouped according to standard clinical subsets of chemoresistant disease (Table 1). Thus, the patients received HD-ICE as treatment for: 1) a new relapse detected when the patient was in remission and was not receiving chemotherapy; 2) refractory disease, including a) NB that responded incompletely to induction (primary refractory NB) but no prior progressive disease (PD) and b) relapsed NB that responded incompletely to salvage therapy (secondary refractory NB); 3) PD detected while the patient was receiving chemotherapy; and 4) consolidating a second or later complete response/very good partial remission (CR/VGPR).
HD-ICE comprised ifosfamide 2000 mg/m2 (2-hour infusion), with the same dosage of mesna (24-hour infusion) on days 1 through 5; carboplatin 500 mg/m2 (1-hour infusion) on days 1 and 2; and etoposide 100 mg/m2 (1-hour infusion) on days 1 through 5. Thus, the total dosages were ifosfamide 10,000 mg/m2, carboplatin 1000 mg/m2, and etoposide 500 mg/m2.
Patients with poor hematologic reserve, defined (like in other MSKCC studies9-11) as a persistent platelet count <100,000/μL, received PBSCs as outpatients 72 hours after HD-ICE. Granulocyte–colony-stimulating factor commenced 24 hours after either PBSC rescue or completion of HD-ICE (in patients who did not require PBSCs).
Staging studies included 123I-metaiodobenzylguanidine (123I-MIBG) scans and BM histology (aspirates and biopsies from bilateral posterior and anterior iliac crests). The International Neuroblastoma Response Criteria17 were expanded to include 123I-MIBG findings: CR indicated no evidence of NB in all studies; VGPR, primary mass reduced >90%, no evidence of distant disease, and normal catecholamines; partial response (PR), a decrease >50% in measurable disease, an improved 123I-MIBG scan in all lesions, and ≤1 positive BM site; mixed response (MR), a decrease >50% in any lesion with a decrease <50% in any other lesion and an 123I-MIBG scan improved in some but not all sites; stable disease (SD), a decrease <50% but an increase <25% in any existing lesion; and PD, new lesion or an increase >25% in a known lesion.
Standard search methods were used to identify publications that were informative about ICE for patients with NB.
The 74 patients (62% males) included 8 patients who received treatment at 2 (n = 7) or 3 (n = 1) separate time points (Table 1). All 74 patients had previously been treated on group-wide or single-institutional high-risk protocols. Prior treatment included ifosfamide in 7 patients (9%), high-dose cyclophosphamide (140 mg/kg per cycle or 4200 mg/m2 per cycle) in 74 patients (100%), high-dose carboplatin (>1000 mg/m2 per cycle) and/or cisplatin (200 mg/m2 per cycle) in 69 patients (93%; the other 5 patients received lower dose cisplatin or carboplatin), and etoposide in 74 patients (100%).
Comparison of Response Rates by Group
Major responses (CR, VGPR, and PR) occurred in 9 of 17 patients (53%; 95% confidence interval [CI], 28%-77%) who were treated for a new relapse versus 4 of 26 patients (15%; 95% CI, 4%-35%) who were treated for refractory NB and 1 of 34 patients (3%; 95% CI, from <1% to 15%) who were treated for PD that developed on chemotherapy (P < .0005; exact test) (Table 2). Disease regression (major responses and MRs) was documented in 14 of 17 patients (82%; 95% CI, 57%–96%) with a new relapse versus 13 of 26 patients (50%; 95% CI, 30%–70%) with refractory NB and in 12 of 34 patients (35%; 95% CI, 20%–54%) with PD who were receiving chemotherapy (P = .005; exact test).
Table 2. Responses to High-Dose Ifosfamide, Carboplatin, and Etoposide
|Refractory|| || || || || || |
|PD during therapy||34c||0||1d||12e||9||12f|
|Second or later CR||6||NA||NA||NA||NA||NA|
Details of Responses by Group
Among the 17 patients who were treated for new relapses that occurred off chemotherapy (Table 1), the time from prior chemotherapy to relapse was <12 months in 14 patients. The 9 major responses involved BM alone (n = 3), bones (MIBG scan; n = 1), soft tissue alone (n = 4), and soft tissue plus BM (n = 1). Four MRs involved soft tissue masses, and 1 MR included CR in BM (Table 2).
Patients who were treated for refractory NB (Table 1) included 4 with NB that was resistant to induction (primary refractory disease); the others received HD-ICE for relapsed NB that was resistant to salvage (secondary refractory disease). The 4 major responses (Table 2) included 1 CR of NB in BM (by histology and MIBG scan); 1 CR by MIBG scan; 1 PR with a CR in BM by histology and MIBG scan but an incomplete response of soft tissue disease; and 1 PR with CR in BM and PR by MIBG scan. The 9 MRs involved CR or PR in BM but unchanged/improved MIBG scans (n = 5), improved MIBG scans (n = 2), a decrease in soft tissue disease (n = 1), and a decrease >90% in catecholamines (n = 1). SD was seen in the 1 patient in this group who previously received HD-ICE for PD on chemotherapy (with an MR). Two patients in this group received HD-ICE twice at separate time points for refractory disease: 1 patient had SD of primary refractory disease and secondary refractory disease (treated 12 months apart); and 1 patient had SD and a PR, respectively, of secondary refractory disease (treated 13 months apart).
All patients who received treatment for PD that occurred on chemotherapy had a history of multiple relapses except for 2 who had poor responses to induction (Table 1). Evidence of anti-NB activity included 1 PR (CR in BM, PR by MIBG scan); 12 MRs involving bone/BM alone (n = 6), bone/BM plus soft tissue (n = 4), and soft tissue alone (n = 2); and stabilization of NB in bone/BM alone (n = 2), bone/BM plus soft tissue (n = 4), and soft tissue alone (n = 3) (Table 2). In this group, 5 patients had received HD-ICE 12 to 24 months before receiving it for PD; responses of their PD were MR (n = 3), SD, and continuing PD. One patient was treated twice for PD on chemotherapy (6 months apart) and had an MR and continuing PD, respectively.
Of 6 patients who received treatment to consolidate a second CR or greater, 3 patients remained relapse-free (and received other therapy) at 18 to 25 months.
Ninety-two cycles were administered: Patients routinely received 1 cycle, but 5 patients received 2 cycles, and 2 patients received 3 consecutive cycles of HD-ICE. The multiple cycles caused no cumulative nonhematologic toxicity.
Modest acute toxicity (eg, grade 1-2 nausea) allowed outpatient treatment, but only 4 cycles (1 with and 3 without PBSC rescue) did not involve an eventual hospitalization for infection (see below) or febrile neutropenia. No cycle was truncated for metabolic reasons. Grade 3 toxicities involved encephalopathy that was self-limited but prompted discontinuation of a cycle (n = 2), mucositis (n = 3), liver enzymes (n = 3), and gastroenteritis (n = 1). Cardiac and renal function remained intact. There was no hemorrhagic cystitis.
Myelosuppression was prolonged grade 4. Without PBSC support, absolute neutrophil counts reached 500/μL on day 17–30 (median, day 22), and platelets were transfused through day 15–32 (median, day 22). With the 37 cycles followed by infusions of PBSCs (>0.8 million CD34-positive cells/kg), hematologic recovery was uncomplicated: absolute neutrophil counts were 500/μL by postinfusion day 8–19 (median, day 11), and the last platelet transfusion was on postinfusion day 3–32 (median, day 13). Blood-borne bacterial infections were documented in 24 of 92 cycles (26%), including in 11 of 37 cycles (30%) with PBSC rescue. One patient had grade 3 respiratory impairment from metapneumovirus.
Literature Review: Ifosfamide, Carboplatin, and Etoposide for Neuroblastoma
Pediatric phase 1 trials of ICE18-21 were based on promising antitumor activity and tolerable toxicity of each agent and the antitumor synergism of carboplatin plus etoposide12 and ifosfamide plus etoposide (Table 3).13 One group studied carboplatin dose escalation with fixed dosing of ifosfamide plus etoposide.18,19,21 Granulocyte-macrophage–colony-stimulating factor (GM-CSF) did not ameliorate myelosuppression.22 Major responses of resistant NB exceeded 50%. Similar encouraging results were seen in the Pediatric Oncology Group experience, first, with a phase 1 trial that also investigated carboplatin dose escalation with fixed dosing of ifosfamide plus etoposide and, subsequently, with a phase 2 trial of ifosfamide 6000 mg/m2, carboplatin 635 mg/m2, and etoposide 300 mg/m2.20 That dosing was used in a phase 1 study of amifostine, but this chemoprotectant caused grade 3 and 4 toxicities.23 The studies described above did not specify whether NB responses included MIBG scans or BM findings.
Table 3. Review of the Literature on Ifosfamide, Carboplatin, and Etoposide for Neuroblastoma
|Upfront experience|| || || || || || |
| Marina 199419||Phase 1||6000 (2000×3)||AUC 6 or 8 (single dose)||300 (100×3)||4, 6||2/2 (100%)|
| Donfrancesca 200429||Induction||7500 (1500×5)||800 (400×2)||500 (100×5)||2||12/16 (75%)|
| Sung 200730||Induction||6000 (1200×5)||800 (400×2)||500 (100×5)||3–5||NS|
| De Ioris 201131||Induction||9000 (1800×5)||800 (400×2)||500 (100×5)||2||11/14 (79%)|
|Retrieval experience|| || || || || || |
| Marina 199318||Phase 1||4000 or 6000 (2000×2 or ×3)||AUC 3–8 (single dose)||200 or 300 (100×2 or ×3)||1–8 (Median, 5)||5/10 (50%)|
| Marina 199422||Phase 2, ±GM-CSF||6000 (2000×3)||AUC 8 (single dose)||300 (100×3)||NS||3/4 (75%)|
| Kung 199520||Phase 1&2||4500 (1500×3)||300–700 (single dose)||300 (100×3)||NS||7/12 (58%)|
| Pratt 199621||Phase 1&2, ±GM-CSF||4000 or 6000 (2000×2 or ×3)||AUC 3–8 (single dose)||200 or 300 (100×2 or ×3)||NS||14/24 (58%)|
| Fouladi 200123||Phase 1, amifostine||6000 (3000×2)||635 (single dose)||300 (150×2)||4||2/4 (50%)|
| Rahman 201128||Salvage||9000 (1800×5)||450 (single dose)||500 (100×5)||2–8 (Median, 4)||24/64 (36%)|
In Children's Cancer Group studies that used higher dosing than previously reported in children (ifosfamide, 9000 mg/m2; carboplatin, 800 mg/m2; etoposide 500 mg/m2), GM-CSF/interleukin-3 fusion protein,24 G-CSF,25 and interleukin-6 plus G-CSF,26 produced no hematologic benefit; and the large patient population included only 2 cases of NB.27 The studies pointed to a better response rate of refractory or recurrent sarcomas to this ICE regimen compared with lower dose ICE or 2-drug carboplatin-etoposide or ifosfamide-etoposide regimens.27
Recently, ICE at dosages higher than in preceding phase 1 studies a) was used as salvage, with major responses in 24/64 (36%) patients treated for primary refractory or progressive NB28; and b) was included in induction regimens for patients with newly diagnosed NB with responses defined according to International Neuroblastoma Response Criteria29-31 (Table 3). In previously untreated patients, ICE achieved a >70% major response rate.19,29 Elsewhere, ICE was incorporated into induction after other combinations had been administered.30,31 Thus, Sung et al initially reserved ICE for NB that was resistant to combined cisplatin, etoposide, doxorubicin, and cyclophosphamide (CEDC) for 5 cycles.30 Encouraging results (not detailed) prompted a change to alternating cycles of CEDC and ICE in induction. The report covered 52 patients; induction was followed by tandem transplantation, and the 5-year event-free survival rate was 62.1% ± 13.7%.
De Ioris et al enrolled 35 patients with newly diagnosed NB on a study with induction comprising high-dose cyclophosphamide/topotecan (HD-Cy/To) for 2 cycles followed by ICE for 2 cycles (Table 3).31 Responses were assessed immediately pre-ICE and post-ICE. Anti-NB activity of ICE was evident by the following changes compared with findings at diagnosis: The BM response rate rose from 40% post-HD-Cy/To to 67% post-ICE; tumor volume decreased from a mean of 57% ± 23% post-HD-Cy/To to 74% ± 22% post-ICE; and the overall major response rate improved from 58% post-HD-Cy/To to 90% post-ICE. Among the 14 patients with metastatic NB who had not achieved a major response post-HD-Cy/To, 11 (79%) did so with ICE.
The large experience reported herein resulted from our turning to HD-ICE in a variety of difficult clinical situations among the many NB patients who were referred to MSKCC for salvage therapy. These patients typically have relapsed on clinical trials or are ineligible for investigative studies because of clinical problems, such as thrombocytopenia. In many of these patients, the long time gap from prior exposure to a platinum agent, often because of salvage therapies that include topoisomerase-I inhibitors (topotecan, irinotecan), supports integrating HD-ICE into an aggressive treatment plan aimed at ablating refractory NB or controlling progressing NB.
ICE in lower dosages has activity against various solid tumors,18-31 but it may be particularly suitable for treating NB. Thus, NB is sensitive to all 3 components, whereas other major pediatric solid tumors (eg, Ewing sarcoma) are relatively resistant to platinum compounds. Combinations of 2 components of ICE (carboplatin plus etoposide12 and ifosfamide plus etoposide13) have well established anti-NB activity. The same holds for 2-drug combinations of related agents, namely, cyclophosphamide plus carboplatin,32 cyclophosphamide plus etoposide,33 and cisplatin plus etoposide.34 Indeed, a literature review (Table 3) amply documents the activity of ICE against newly diagnosed as well as resistant NB and provides a broader context for this synergistically interacting 3-drug combination than our single-institution experience with HD-ICE. Comparisons of response rates between HD-ICE versus lower dose ICE regimens in published reports are of limited value, because the latter do not specify whether patients underwent BM tests and MIBG scans.18,20-23
We previously reported that response to salvage chemotherapy is significantly more likely in patients with NB who are treated for a new relapse that occurs off therapy than in patients who are treated for NB that is persistent (ie, refractory) or progressing on treatment.9 Results with HD-ICE are consistent with that observation as regards major responses (CR/VGPR/PR; P < .0005) as well as disease regressions overall (major responses and MRs; P = .005). These statistical analyses were possible because of the large study population (Table 1) and make it clear that anti-NB activity may be erroneously overlooked if a novel treatment is assessed in subsets of patients who are unlikely to respond to any therapy. However, even in patients who were treated for PD on therapy, HD-ICE demonstrated anti-NB effects, with SD or better in 22 of 34 patients (65%) (Table 2), including 3 patients who received a second or third cycle of HD-ICE. Four other patients also received 2 or 3 consecutive cycles (Table 2). Because administering 2 or 3 consecutive cycles of HD-ICE entailed no cumulative toxicity, multiple cycles may be warranted in patients who have a response.
In devising HD-ICE, high dosing was chosen to exploit the dose-response relation of NB and other tumors to alkylators, including ifosfamide.15,16,27 Furthermore, prior experience with lower dose ICE,18-30 or comparable dosages of 2 components of ICE,12,13 confirmed that the common extramedullary toxicities of ICE (hemorrhagic cystitis and renal dysfunction) could be prevented or readily managed. Indeed, HD-ICE had modest nonhematologic side effects and produced no unforeseen toxicities in our large series of patients who had NB that was resistant to intensive and long-term therapy. Encephalopathy, which is a well described toxicity of ifosfamide,35 aborted only 2 of 92 cycles (2%) and was reversible with no sequelae. The absence of nephrotoxicity justified both the substitution of carboplatin for cisplatin and the use of carboplatin with ifosfamide. An outpatient setting was feasible because the manageable emetogenicity of each agent plus the use of portable pumps for overnight hydration/mesna.
The dose-limiting toxicity of ICE in past reports was prolonged myelosuppression with no benefit from hematopoietic cytokines.22,24-26 The pancytopenia from HD-ICE engendered no major clinical complications, infectious or otherwise. That welcome finding was attributable in part to the rarity of mucositis and other nonhematologic toxicities. Bacteremia in 26% of the cycles is comparable to rates with similarly myelosuppressive regimens.36,37
In patients who, when treated with HD-ICE, had poor hematologic reserve (evidenced by thrombocytopenia) because of extensive prior treatment, including stem cell transplantation after myeloablative chemotherapy or recent 131I-MIBG therapy, PBSC rescue was received in the outpatient clinic. Engraftment was uncomplicated, and full hematologic recovery enabled patients to meet eligibility criteria for formal clinical trials. Collecting abundant PBSCs during induction has been recommended,38 because PBSC availability expands the range of salvage options if NB proves resistant to standard treatments. This point is evident in our current and prior reports on salvage chemotherapy for NB8-11 as well as in experience with 131I-MIBG therapy.39 PBSC support also has allowed the investigation of novel submyeloablative induction chemotherapy regimens against NB37,40 and other solid tumors in children.36,41
We conclude that, in patients with high-risk NB, turning to HD-ICE for salvage or consolidative therapy is an attractive option because of noncross-resistance with widely used retrieval regimens.2-7 The risk of excessive morbidity from nonhematologic toxicity is low and therefore acceptable. PBSC support is unnecessary when hematologic reserve is intact.
This work was supported in part by grants from the National Institutes of Health (New York, NY; CA10450), the Robert Steel Foundation (New York, NY), and Katie's Find A Cure Fund (New York, NY).
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.