Pediatric Hematology and Oncology, 23:81–86, 2006Copyright C© Taylor and Francis Inc.ISSN: 0888-0018 print / 1521-0669 onlineDOI: 10.1080/08880010500313629

COLLINS’ LAW REVISITED: Can We Reliably Predict the Time

to Recurrence in Common Pediatric Tumors?

Arnold C. Paulino, MD � Department of Radiology, Section of Radiation Oncology,Baylor College of Medicine, Texas Children’s Hospital and the Methodist Hospital, Houston,Texas, USA

� Collins’ law states that the period of risk for tumor recurrence is the age of the child at diagnosisplus 9 months. The purpose of this study is to validate this rule through a retrospective review ofcommon pediatric tumors seen at 1 institution. Inclusion criteria for this study included an age atdiagnosis of <16 years old, minimum follow-up time of the Collins risk period (CRP) if child didnot relapse and treatment with curative intent. The records of 424 children seen and treated forneuroblastoma (n = 98), Wilms tumor (n = 86), rhabdomyosarcoma (n = 82), medulloblastoma(n = 59), Ewing sarcoma (n = 43), ependymoma (n = 25), supratentorial PNET (n = 22), andsynovial sarcoma (n = 9) from 1960 to 2001 were reviewed. CRP was calculated using the ageof child at initial diagnosis plus 9 months. The median follow-up time was 164 months (range,11–484 months), while the median follow-up/CRP ratio was 4.89 (range, 1.0–48.0). A total of 183of 424 (43.2%) patients relapsed, with 180 (98.4%) relapses occurring during the CRP. Relapsesbeyond the CRP were seen in 3 young children (ages 7 months, 24 months, and 2 weeks at initialdiagnosis) with a diagnosis of Wilms tumor (n = 2) and supratentorial PNET (n = 1) at 1, 3, and26 months post-CRP. Collins’ law is a useful and simple way of predicting risk period for relapse inthe tumor types studied.

Keywords brain tumor, childhood cancer, Collins’ Law, relapse, sarcoma

In 1955, Collins first reported his observations regarding the risk periodfor recurrence in children with Wilms tumor [1]. He concluded that a tumorat birth had to develop within a period of 9 months or less. He also noted thatthe time of diagnosis depends on the growth rate of the tumor, which shouldbe the same at the time of diagnosis and recurrence. These “embryonic” tu-mors may manifest themselves at different times, depending on growth rate,such that a fast-growing tumor will be discovered shortly after birth, while aslower-growing tumor may manifest itself later in childhood. Although quite

Received 21 June 2005; accepted 8 August 2005.Presented in part at the 87th Annual Meeting of the American Radium Society, 30 April to 4 May,

2005, at Barcelona, Spain.Address correspondence to Arnold C. Paulino, MD, Methodist Hospital, Radiation Oncology, 6565

Fannin St., DB1-077, Houston, TX 77030, USA. E-mail: apaulino@tmh.tmc.edu

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82 A. C. Paulino

simplistic and not entirely true, these observations have given rise to Collins’law, which states that the age of the child at initial diagnosis plus 9 monthsis the risk period for recurrence after which the child is considered cured.There have subsequently been few reports in other childhood tumors suchas medulloblastoma, ependymoma, and neuroblastoma regarding the appli-cability of Collins’ law [2–5]. The purpose of this study is to validate thisrule through a retrospective study of common pediatric tumors seen at oneinstitution.

PATIENTS AND METHODS

Inclusion criteria for this study included an age at diagnosis of <16 yearsold, minimum follow-up time of the Collins risk period (CRP) if the childdid not relapse, and treatment with curative intent. From 1960 to 2001,497 children were seen and treated at the University of Iowa Hospitals andClinics with a diagnosis of neuroblastoma (n = 110), rhabdomyosarcoma(n = 97), Wilms tumor (n = 91), medulloblastoma (n = 76), Ewing sarcoma(n = 58), ependymoma (n = 28), supratentorial primitive neuroectodermaltumor (PNET) (n = 23), and synovial sarcoma (n = 14). Of the 489, 424children met the inclusion criteria. Table 1 shows the number of cases andmedian follow-up for each tumor type. The median follow-up time for the424 children satisfying the eligibility criteria was 164 months (range, 11–484months).

CRP was calculated using the age of child at initial diagnosis plus 9months. For each patient who did not relapse, a ratio of median follow-upand CRP in months was calculated. The median follow-up/CRP ratio for eachtumor type is presented in Table 2. The median follow-up/CRP ratio for allrelapse-free patients was 4.89 (range, 1.0 to 48.0). As expected, children withneuroblastoma, rhabdomyosarcoma, and Wilms tumor who were youngerhad larger median ratios from 3.66 to 10.32 compared to other tumors such

TABLE 1 Number of Cases and Follow-Up Period According to Tumor Type

Eligible Median follow-up RangeTumor type cases (N) (months) (months)

Neuroblastoma 98 174 11–484Rhabdomyosarcoma 82 234 26–469Wilms’ tumor 86 140 28–306Medulloblastoma 59 156 32–341Ewing’s Sarcoma 43 175 52–396Ependymoma 25 134 36–295Supratentorial PNET 22 138 27–240Synovial sarcoma 9 209 105–312Total 424 164 11–469

Note. N = number; PNET, primitive neuroectodermal tumor.

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Collins’ Law Revisited 83

TABLE 2 Median Follow-Up/Collins Risk Period Ratio According to Tumor Type

Median follow-up/Tumor type Collins risk period ratio Range

Neuroblastoma 10.32 1.0–48.0Rhabdomyosarcoma 3.66 1.13–10.23Wilms tumor 4.1 1.02–17.69Medulloblastoma 1.86 1.0–11.76Ewing sarcoma 1.24 1.0–3.31Ependymoma 1.69 1.02–5.97Supratentorial PNET 1.57 1.03–7.77Synovial sarcoma 1.97 1.52–2.42Total 4.89 1.0–48.0

Note. PNET, primitive neuroectodermal tumor.

as Ewing sarcoma and synovial sarcoma, which occurred in older patientswith ratios from 1.24 to 1.97.

RESULTS

A total of 183 of 424 (43.2%) patients relapsed. Of the 183 relapsed pa-tients, 180 (98.4%) relapses occurred during the CRP. Relapses beyond theCRP were seen in 2 children with Wilms tumor and 1 child with supraten-torial PNET. The characteristics of these children and their treatment andpattern of relapse are presented in Table 3. Relapses as related to the CRPare presented in Table 4 and show that all relapses occurred during the CRPin all but 2 tumor types. For children with Wilms tumor, 14 of 16 relapses(87.5%) occurred during the CRP, while for supratentorial PNET, 14 of 15(93.3%) were within the CRP. With regard to age at initial diagnosis, for age≥24 months, 32 of 35 relapses (91.4%) were within the CRP, whereas for age>24 months, all 148 relapses occurred during the CRP.

DISCUSSION

Collins’ law states that children with embryonic tumors who survive,disease-free, for a period of time equal to the age at diagnosis plus 9 monthscan be declared cured. Our experience validates this law, as 98.4% of relapsesoccurred during the CRP. In fact, of the 3 relapses that occurred after theCRP, 2 were documented to occur within 3 months past the risk period. Itis possible that a delay in diagnosis was responsible, and earlier studies mayhave detected relapses earlier.

Other studies have also supported the validity of Collins’ law. A study ofbrain tumors in 39 children under 3 years of age showed that there wereno exceptions to Collins’ law [6]. For medulloblastoma, multiple publica-tions have supported the reliability of this method to predict recurrence[2, 3, 7, 8]. A study from the Childhood Brain Tumor Consortium showed

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TABLE 3 Characteristics of Patients Who Relapsed Beyond the Collins Risk Period

Time to Month(s)Age at relapse and beyond

Patient diagnosis, Tumor type, location of Collinsno. gender stage Treatment relapse risk period

1 7 monthsmale

Wilms tumorFH, stage II

Left nephrectomyfollowed by 15 monthsof vincristine anddactinomycin

17 months,mediastinalnodalmetastases

1

2 24 monthsmale

SupratentorialPNET, M0

Subtotal resectionfollowed by “8 in 1”chemotherapy and 36Gy craniospinal RTfollowed by 23.4 Gyboost

36 months, localrecurrence

3

3 2 weeksmale

Wilms tumorFH, stage V

Vincristine anddactinomycin for 4months followed byright nephrectomy andleft partialnephrectomy.Postoperative 10.5 GyRT to lefthemiabdomen

36 months, leftkidney

26

Note. FH, favorable histology; RT, radiation therapy.

that less than 4% of medulloblastoma patients were exceptions to Collins’law [3]. A critical review by Latchaw and colleagues showed that cases vi-olating Collins’ law constitute less than 2% of all medulloblastomas [7]. Ahigher rate of relapses beyond the CRP was reported by Belza et al. whereCollins’ law was applicable in only 83% of cases [9]. In our study, there wereno medulloblastoma patients who relapsed after the CRP, with a medianfollow-up of 1.86 times the CRP.

TABLE 4 Relapses Within the Collins Risk PeriodAccording to Tumor Type

Relapses within theTumor type Collins risk period

Neuroblastoma 38/38 (100%)Rhabdomyosarcoma 34/34 (100%)Wilms tumor 14/16 (87.5%)Medulloblastoma 31/31 (100%)Ewing sarcoma 30/30 (100%)Ependymoma 12/12 (100%)Supratentorial PNET 14/15 (93.3%)Synovial sarcoma 7/7 (100%)Total 180/183 (98.3%)

Note. PNET, primitive neuroectodermal tumor.

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Collins’ Law Revisited 85

With regard to other brain tumors, Brown et al. showed that Collins’law was applicable not only to medulloblastoma but also to ependymoma,pineoblastoma, malignant astrocytoma, and germinoma; Collins’ law wasnot found to be useful for craniopharyngioma, oligodendroglioma, or low-grade astrocytoma [2]. In both ependymoma, and supratentorial PNET, wefound the usefulness of this method to predict recurrence with only 1 relapseoccurring beyond the CRP.

For children with sarcomas, there have not been any reports, to ourknowledge, regarding the applicability of Collins’ law. For rhabdomyosar-coma, Ewing sarcoma, and synovial sarcoma, relapses all occurred duringthe CRP. This is despite the fact that in children with rhabdomyosarcoma,the median follow-up is 3.66 times the CRP. For children with Ewing sarcomaand synovial sarcoma, the median follow-up/CRP ratios were 1.24 and 1.97,respectively. Although the follow-up/CRP ratios were smaller for these tu-mors secondary to the older age of these children at initial diagnosis, themedian follow-up times were 175 and 209 months, respectively.

One interesting observation in our study is the young age of those who vi-olated Collins’ law. All were ≤24 months at initial diagnosis. In the ChildhoodBrain Tumor Consortium study, all the patients who violated Collins’ law were<6 years of age [3]. Reports of exceptions to Collins’ law have also been de-scribed notably in children ≤5 years of age [10–13]. In a Japanese study ofchildren with ependymoma diagnosed within the first year of life, approx-imately half of the cases violated Collins’ law [11]. It is possible that theseviolations have been reported in younger children, as older children may nothave long follow-up to determine if they have passed the risk period. Ourstudy, however, found that even in older children, Collins’ law was validated.We did not find any violations in the 148 relapses that occurred in patients>2 years of age.

This study validates the applicability of Collins’ law in medulloblastomaand Wilms tumor. It also shows the applicability of this method of determin-ing risk period in tumors not widely or never reported before such as supra-tentorial PNET, ependymoma, Ewing sarcoma, rhabdomyosarcoma, and neu-roblastoma. Compared to other reported studies, our median follow-up of164 months is quite long and gives credibility to the applicability of this modelin older children. Some limitations of the study include the small number ofpatients with synovial sarcoma, which makes it difficult to make a conclusionas to whether Collins’ law is applicable in this particular tumor. In addition,about 15% of patients seen initially were not evaluable as they were eithertreated with palliative intent or had follow-up less than the CRP.

In summary, Collins’ law was found to be applicable in more than 98%of relapses in this study. It is a useful tool in estimating the risk period asdemonstrated in this report. Exceptions to Collins’ rule seem to occur morein young children, as seen in our analysis where the 3 exceptions to the ruleoccurred in patients ≤24 months.

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