TTFR has been demonstrated to be prognostic in different pediatric tumors,1–5
but it has not been thoroughly studied in neuroblastoma. Some studies have shown that a more chronic course of neuroblastoma after failure of primary therapy seems to be associated with longer times of first remission16
or older age at diagnosis.17–19
Cotterill et al20
identified late relapse in a small subset of high-risk patients; however, this study was unable to predict which factors influence long-term survival given the limited follow-up.
In each of the single-institution studies, the number of patients and data collection were limited. In our analysis of 2,266 patients with relapsed neuroblastoma, we have shown that TTFR is an important factor to predict OS after an event. The relationship of TTFR and OS post relapse is complex; the risk of death was highest for patients who relapsed between 6 and 18 months from diagnosis and then decreased steadily, being lowest in patients who relapsed at 36 months or later. The association of TTFR and OS post relapse was the strongest in stage 3 and 4 patients with MYCN amplified tumors. Surprisingly, in the overall cohort, the risk of death for patients who relapsed between 6 and 18 months after diagnosis was higher than for patients who relapsed within 0 to 6 months, or more than 18 months, after diagnosis. A more intuitive relationship would be linear, where those with the shortest TTFR had the highest risk of death, with decreasing risk of death as TTFR increased. A possible explanation for why the patients with the shortest TTFR did not have the highest risk of death may lie in the more favorable clinical characteristics of the patients who relapsed within 6 months; a significantly larger proportion of patients were younger or had stage 1, 2, 3, or 4S disease in comparison with those who relapsed later. Patients who were younger and had a lower stage of disease may have received little or no therapy before relapse and therefore may have responded well to postrelapse treatment. Another possible explanation for the upward slope of the risk-of-death curve with TTFR of less than 12 months and the downward slope of the risk-of-death curve with TTFR of 12 months or longer () is that patients who are able to make it to transplantation (occurring approximately 10 to 12 months post diagnosis) without relapse/progression realize a benefit in terms of prolonged OS.
Accepted prognostic factors for neuroblastoma include age at diagnosis, MYCN
gene amplification, and histologic features.21
These factors are standard determinants of initial risk stratification, but their prognostic value after an event had not been studied previously. In our analysis, we identified several factors that were independently prognostic of OS after relapse: stage, MYCN
status, age, and TTFR. Many other factors were significantly predictive of poor outcome after relapse in univariate, but not multivariable, analysis. Within the subgroups of patients with MYCN
nonamplified tumors or stage 1, 2, or 4S disease, TTFR was not predictive of OS post relapse; it seems that the patients with INSS stage 3 and 4 MYCN
amplified tumors were driving the association between TTFR and OS.
Two previous single-institution studies in neuroblastoma also showed that shorter time to first relapse was a significant adverse factor for survival.6,16
Lau et al16
reviewed 31 patients with neuroblastoma with relapsed disease and found that patients who relapsed less than 12 months from diagnosis had significantly shorter survival time. The only other significant factor in their analysis for survival post relapse was tumor MYCN
amplification. Santana et al6
addressed the study of disease-control intervals in 91 high-risk patients with neuroblastoma. The estimated median times to disease recurrence were 18.3, 8.7, and 3.8 months for the first, second, and third recurrences, respectively. Patients with longer initial disease control had a significant postrecurrence survival advantage. This study emphasized the importance of knowing the intervals of disease progression as end points for the design of protocols with new agents.6
Other studies in pediatric malignancies have also shown that earlier relapse portends shorter survival. The Italian Off-Therapy Registry published results on 694 patients, including those with neuroblastoma, CNS tumors, sarcoma, Wilm's tumors, and Hodgkin's lymphoma, who had experienced recurrence. They found significantly different HRs for survival by type of diagnosis and found overall that patients relapsing less than 12 months off therapy had worse survival in univariate, but not in multivariable, analysis.22
Risk factors for survival post relapse in neuroblastoma were not evaluated separately. Interestingly, the patients relapsing in the more recent treatment era had shorter survival, perhaps because the relapse may have occurred after more intensive therapy. A similar trend has been reported in childhood leukemia, in which multiple studies have shown that duration of first remission was the most significant predictor of outcome after relapse of acute lymphoblastic leukemia.4,5
In a retrospective study, Garaventa et al23
described 781 children with neuroblastoma experiencing tumor recurrence. Ten-year OS was 6.8% after progression and 14.4% after relapse. Similar to our series, the factors worsening prognosis in univariate analysis were age older than 18 months, advanced stage, high LDH, MYCN
amplification, and abdominal primary (no multivariable analysis). Most relapses occurred early (median interval, 7.8 months), but 86 (24%) occurred late (median, 28 months). Early relapses had a more rapid, unfavorable course, with approximately 80% of deaths occurring within 2 years, whereas survival time was longer for late relapses.
From German protocols NB90, NB97, and NB2004 (n = 493 high-risk patients), Simon et al24
presented data on 254 patients with neuroblastoma who relapsed after autologous bone marrow transplantation as part of initial treatment. MYCN
amplification, early recurrence within 18 to 24 months after diagnosis, bone marrow, and lung/pleura metastasis at relapse were independently predictive of poor survival. The 24 patients who underwent a second autologous stem-cell transplantation had better outcome.
Ultimately, understanding the genetic differences in early versus late relapsing patients will facilitate selection of appropriate targeted therapy. Meanwhile, we propose that stratification of relapsed patients according to the timing of first relapse, as well as stage, age, and MYCN status, is critical in certain types of study designs, such as randomized phase II trials, to maintain a balance of less favorable patients between treatment arms. One might also wish to compare two strata for a given treatment to see which has better outcome. TTFR is a significant, readily available prognostic factor for stratification of patients on retrieval trials. In addition, TTFR may be used in therapy selection. Studies of novel agents using time to progression as an end point could be designed to stratify patients based on TTFR so that the effect of the novel agents can be separated from inherent tumor behavior.
We were not able to establish a single clear TTFR cutoff time point for stratification, perhaps because the INRG series is heterogeneous in relation to era of treatment and initial therapy received or because the true relationship between TTFR and OS post relapse is nonlinear. Our results demonstrate that the period from 6 to 18 months from diagnosis to relapse is associated with the shortest survival of relapsing patients, including the subset of patients with stage 3 and 4 MYCN amplified tumors.
In conclusion, time to first relapse is a significant predictor of death after relapse; the risk of death is higher for patients who relapse between 6 and 18 months after diagnosis than it is for patients who relapse more than 18 months from diagnosis. Stratification of relapsed patients with neuroblastoma according to the timing of first relapse, age, stage, and MYCN status is important in retrieval study designs, especially for patients with stage 3 or 4 MYCN amplified tumors.