# Radiation Oncology/Neuroblastoma

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Neuroblastoma

## Epidemiology

* A spectrum of tumors arising from primitive sympathetic ganglion cells
* Third most common childhood cancer (8-10%), after leukemia and brain tumors
** Most common extracranial solid malignancy of childhood
** Most common malignancy of infants (1/2 of all cases)
* Incidence 9/1,000,000 -> ~650 children per year in U.S.
* Median age at diagnosis 17 months
** 75% <2 years
** 90% <5 years
* Majority is sporadic, although 1-2% appear autosomal dominant and present earlier
* Olfactory neuroblastoma, also known as esthesioneuroblastoma, may be a related diagnosis

## Presentation

* Has a broad spectrum of clinical presentations and paraneoplastic syndromes.
* "Quirky natural history" from benign localized lesions to spontaneous remission of metastatic disease to aggressive widely disseminated tumors
* May arise in any portion of the sympathetic nervous system
** Adrenal gland 40%
** Abdominal ganglia 25%
** Thoracic ganglia 15%
** Cervical ganglia 5%
** Pelvic ganglia 5%
* Metastatic ~60% at presentation
** "Favorable" typically to liver, skin
** "Unfavorable" typically to bone marrow, bones (orbits, skull)
* Typical symptoms abdominal swelling or pain, diarrhea/constipation, bone pain, periorbital swelling
* Paraneoplastic syndromes (rare)
** Vasoactive intenstinal polypeptide secretion: intractable diarrhea
** Opsoclonus-myoclonus-ataxia syndrome (1-3%): dancing eye, rhythmic jerking, ataxia
* Spinal cord compression (7-15%) is an oncologic emergency
* Normal sympathetic tissues secrete catecholamines, VMA or HVA noted in urine 90% of patients, but VMA or HVA screening no value

## Workup

* History: diarrhea/constipation, ataxia
* Physical exam: neurologic function, skin mets (reddish-purple raised lesions), periorbital ecchimoses
* Labs: urine catecholamines (epinephrine, norepinephrine, VMA and HVA)
* Imaging: Abdominal ultrasound, CT/MRI to define extent, bone scan, meta-iodobenzyl-guanidine (MIBG, chemical analog of norepinephrine) scan
* Bone marrow biopsy

## Pathology

* Spectrum of tumors arising from primitive sympathetic ganglion cells (least to more differentiated):
** Neuroblastoma (~85%)
** Ganglioneuroblastoma (~10%)
** Ganglioneuroma (~1%) - considered a benign tumor
* Classification based on balance between neural-type cells (primitive neuroblasts, maturing neuroblasts, ganglion cells) and stromal Schwann-type cells (Schwannian blasts, mature Schwann cells)
* Most undifferentiated neuroblastomas are composed entirely of neuroblasts with scant Schwannian (stromal) cells (small, round, blue cells)
* Positive for: neuron-specific enolase, synaptophysin, chromogranin A, neuronal filaments, S100, NB84
* Shimada system ("favorable" vs. "unfavorable") - based on patient age, rich or poor stroma, nodularity, degree of differentiation, mitosis-karyorrhexis index (MKI)
* International Neuroblastoma Pathology Classification System (PMID 10421273, 1999)
** Favorable:
*** Neuroblastoma, <1.5 years old, poorly differentiated or differentiating with low/intermediate MKI tumor
*** Neuroblastoma, 1.5-5 years old, differentiating and low MKI tumor
*** Ganglioneuroblastoma, intermixed
*** Ganglioneuroma
** Unfavorable:
*** <1.5 years old, undifferentiated or high MKI tumor
*** 1.5-5 years old, undifferentiated/poorly differentiated tumor or intermediate/high MKI tumor
*** >5 years old, any tumor
*** Ganglioneuroblastoma, nodular

## Molecular biology

* More aggressive
** MYCN gene amplification (5-400x) in ~25%. MYCN is a DNA binding transcription factor known to cause malignant transformation. Infants 4S with MYCN 3-year OS <50% vs. without MYCN >90%
** Chromosomal deletions 1p (in 23%) and 11q (in 35%)
** Chromosomal gains 17q (in ~50%)
* Less aggressive:
** DNA ploidy. 2-year EFS triploid 94% vs. diploid MYCN- 45% vs. diploid MYCN+ 11%

## Staging
### International Neuroblastoma Risk Groups Staging System (INRGSS)

Staging System; 2009 (PMID 19047290)
* Developed because INSS staging system is based on degree of surgical resection, and therefore is not suitable for induction approaches. This system allows for worldwide comparisons of outcomes based on pretreatment characteristics
* Stage L1 - Localized tumor not involving vital structures as defined by the list of image-defined risk factors and confined to one body component
* Stage L2 - Locoregional tumor with presence of one or more image-defined risk factors
** Extension across two body compartments: Neck-chest; chest-abdomen; abdomen-pelvis
** Neck: Tumor encasing carotid and/or vertebral artery and/or internal jugular vein, tumor extending to base of skull, tumor compressing the trachea
** Cervico-thoracic junction: Tumor encasing brachial plexus roots; tumor encasing subclavian vessels and/or vertebral and/or carotid artery; tumor compressing the trachea
** Thorax: Tumor encasing the aorta and/or major branches; tumor compressing the trachea and/or principal bronchi; lower mediastinal tumor, infiltrating the costo-vertebral junction between T9 and T12
** Thoraco-abdominal: Tumor encasing the aorta and/or vena cava
** Abdomen/pelvis: Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament; tumor encasing branches of the superior mesenteric artery at the mesenteric root; tumor encasing the origin of the coeliac axis, and/or of the superior mesenteric artery; tumor invading one or both renal pedicles; tumor encasing the aorta and/or vena cava; tumor encasing the iliac vessels; pelvic tumor crossing the sciatic notch
** Intraspinal tumor extension whatever the location provided that: More than one third of the spinal canal in the axial plane is invaded and/or the perimedullary leptomeningeal spaces are not visible and/or the spinal cord signal is abnormal
** Infiltration of adjacent organs/structures: Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery
** Conditions to be recorded, but not considered IDRFs: Multifocal primary tumors; pleural effusion, with or without malignant cells; ascites, with or without malignant cells
* Stage M - Distant metastatic disease (except stage MS)
* Stage MS - Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow

### International Neuroblastoma Staging System (INSS)

Revised; 1993 (PMID 8336186)
* Stage 1 - Localized tumor. Complete gross excision, with or without microscopic residual disease. Representative ipsilateral lymph nodes negative microscopically (nodes attached and removed with the primary tumor may be positive)
* Stage 2A - Localized tumor with incomplete gross excision. Representative ipsilateral nonadherent lymph nodes negative microscopically
* Stage 2B - Localized tumor with or without incomplete gross excision. Positive nonadherent ipsilateral lymph nodes. Enlarged contralateral lymph nodes negative microscopically
* Stage 3 - Unresectable tumor infiltrating across the midline with or without regional lymph node involvement. Unilateral tumor with contralateral regional lymph node involvement. Midline tumor with bilateral extension by infiltration (unresectable) or by regional lymph node involvement
* Stage 4 - Dissemination of tumor to distant lymph nodes, bone, bone marrow, liver, and/or other organs (except as defined for stage 4S)
* Stage 4S - Localized primary tumor as defined for Stage 1, 2A or 2B. Dissemination limited to liver, skin and/or <10% of bone marrow (in infants <1 year of age)
Original; 1988 (PMID 8336186)
* Stage 1 - Localized tumor confined to the area of origin. Complete gross excision, with or without microscopic residual disease. Identifiable ipsilateral and contralateral lymph nodes negative microscopically
* Stage 2A - Unilateral tumor with incomplete gross excision. Identifiable ipsilateral and contralateral lymph nodes negative microscopically
* Stage 2B - Unilateral tumor with incomplete gross excision. Positive ipsilateral lymph nodes. Identifiable contralateral lymph nodes negative microscopically
* Stage 3 - Tumor infiltrating across the midline with or without regional lymph node involvement. Unilateral tumor with contralateral regional lymph nodes involvement. Midline tumor with bilateral regional lymph node involvement
* Stage 4 - Dissemination of tumor to distant lymph nodes, bone, bone marrow, liver, and/or other organs (except as defined in stage 4S)
* Stage 4B - Localized primary tumor as defined for Stage 1 or 2. Dissemination limited to liver, skin and/or bone marrow

### Previous staging systems

* St. Jude / POG; 1983 - PMID 6848729 (1983)
** Surgicalpathologic staging
** POG A: Complete gross resection of primary, lymph nodes not adherent to primary tumor are negative, liver is histologically negative
** POG B: Grossly unresected primary tumor, LN -, liver –
** POG C: Complete or incomplete resection, LN+, liver –
** POG D: Distant LN, bone, bone marrow, liver or skin
** POG DS: Infants< 1yr with stage IV-S
* Children's Cancer Study Group (CCSG); 1971 (Evans, 1971, PMID 5100400; Evans, 1980, PMID 7370930)
** Clinical staging
** Evans I: Tumor confined to organ or structure
** Evans II: Tumor extending in continuity beyond organ but not crossing midline or involved ipsilateral lymph nodes
** Evans III: Tumor extending beyond midline or involved bilateral lymph nodes
** Evans IV: Remote disease involving bone, bone marrow, soft tissue or distant lymph nodes
** Evans IV-S: Stage I or II except for presence of mets to liver, skin marrow.

## Risk groups

INRG Risk Groups; 2009 (PMID 19047291)
* Prognostic factors: INRG Stage (see above), Age, Histology, Grade, MYCN, 11q aberration, Ploidy
* Pretreatment categories: 16 (A-R)
* Pretreatment risk groups: Very low, Low, Intermediate, High
| INRG Stage | Age | Histology | Grade | MYCN | 11q | Ploidy | Risk Group | Risk |
| L1/L2 | | GN maturing GNB intermixed | | | | | A | Very low |
| L1 | | any except Risk Group A | | No | | | B | Very low |
| L1 | | any except Risk Group A | | Amp | | | K | High |
| L2 | <1.5 | any except Risk Group A | | No | No | | D | Low |
| L2 | <1.5 | any except Risk Group A | | No | Yes | | G | Intermediate |
| L2 | ≥ 1.5 | GNB nodular NB | Differentiating | No | No | | E | Low |
| L2 | ≥ 1.5 | GNB nodular NB | Differentiating | No | Yes | | H | Intermediate |
| L2 | ≥ 1.5 | GNB nodular NB | Poorly differentiated | No | | | H | Intermediate |
| L2 | ≥ 1.5 | GNB nodular NB | | Amp | | | N | High |
| M | < 1.5 | | | No | | Hyperdiploid | F | Low |
| M | < 1 | | | No | | Diploid | I | Intermediate |
| M | 1-1.5 | | | No | | Diploid | J | Intermediate |
| M | < 1.5 | | | Amp | | Diploid | O | High |
| M | ≥ 1.5 | | | | | | P | High |
| MS | < 1.5 | | | No | No | | C | Very low |
| MS | < 1.5 | | | No | Yes | | Q | High |
| MS | < 1.5 | | | Amp | | | R | High |
| Blank field = "any"; diploid = (DNA index ≤ 1.0); hyperdiploid = (DNA index > 1.0 and includes near-triploid and near-tetraploid tumors); GN = ganglioneuroma; GNB = ganglioneuroblastoma; Amp = amplified; L1 = localized tumor confined to one body compartment and with absence of image-defined risk factors (IDRFs); L2 = locoregional tumor with presence of one or more IDRFs; M = distant metastatic disease (except stage MS); MS = metastatic disease confined to skin, liver and/or bone marrow in children < 18 months of age. Very Low Risk = 5y EFS > 85%; Low Risk = 5y EFS ≥ 75% to 85%; Intermediate Risk = 5y EFS ≥ 50% to 75%; High Risk = 5y EFS < 50%. EFS = eventfree survival. |||||||||
POG Risk Groups:
| Risk group | INSS stage | Age | N-Myc amplified | Histology | Shimada ploidy |
| Low | Stage 1 | any | any | any | any |
| Low | Stage 2A/B | any except as below | any | any | any |
| Low | Stage 4S | Infant | No | any | >1 |
| Intermediate | Stage 3 | Infant | No | any | any |
| Intermediate | Stage 3 | >1 yr | No | Favorable | any |
| Intermediate | Stage 4 | Infant | No | any | any |
| Intermediate | Stage 4S | Infant | No | Unfavorable | any |
| Intermediate | Stage 4S | Infant | No | any | =1 |
| High | Stage 2A/2B | >1 yr | Yes | Unfavorable | any |
| High | Stage 3 | Infant | Yes | any | any |
| High | Stage 3 | >1 yr | Amp or Unfavorable | Amp or Unfavorable | any |
| High | Stage 4 | Infant | Yes | any | any |
| High | Stage 4 | >1 yr | any | any | any |
| High | Stage 4S | Infant | Yes | any | any |
* Stage 1-2 - always low risk
* Stage 3 - intermediate or high risk
* Stage 4 - intermediate or high risk
* Stage 4S - can be low, int, or high risk

## Studies

Risk-related therapy:
* POG 8743 - PMID 9060959 — "Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study." Bowman LC et al. J Natl Cancer Inst. 1997 Mar 5;89(5):373-80.
    Infants. Treated with standard chemotherapy. Showed that pts who were hyperdiploid had more favorable responses compared to diploid pts. NYMC gene amplification and elevated LDH were predictive for worse outcome.
* POG 9243 -
* POG 8742 and POG 9244 - PMID 9516866 — "Event-free survival of children with biologically favorable neuroblastoma based on the degree of initial tumor resection: results from the Pediatric Oncology Group." Strother D et al. Eur J Cancer. 1997 Oct;33(12):2121-5.
    Pts > 1 yr old, INSS Stages 2B and 3.

### Low-risk

* POG 9641 NCT00003119
** Purpose: supportive-care only for low risk disease
** Results: For all 915 eligible patients, 5-year event-free survival (EFS) and OS were 89% ± 1% and 97% ± 1%, respectively. For patients with asymptomatic stage 2a or 2b disease, 5-year EFS and OS were 87% ± 2% and 96% ± 1%, respectively. Among patients with stage 2b disease, EFS and OS were significantly lower for those with unfavorable histology or diploid tumors, and OS was significantly lower for those ≥ 18 months old. For patients with stage 1 and 4s NBL, 5-year OS rates were 99% ± 1% and 91% ± 1%, respectively. Patients who required chemotherapy at diagnosis achieved 5-year OS of 98% ± 1%. Of all patients observed after surgery, 11.1% experienced recurrence or progression of disease.
** Conclusion: Excellent survival rates can be achieved in asymptomatic low-risk patients with stages 2a and 2b NBL after surgery alone. Immediate use of chemotherapy may be restricted to a minority of patients with low-risk NBL. Patients with stage 2b disease who are older or have diploid or unfavorable histology tumors fare less well. Future studies will seek to refine risk classification.
* GPOH NB95-S and NB97 (Germany)(1995-2004)
** Prospective. 340 infants, age <1 year, with Stage 1-3, and MYCN-. Surgery if risk of operation was low (56%); chemotherapy only if threatening symptoms (17%). 93 patients (27%) observed with U/S q6 weeks and MRI q3 months.
** 2008 PMID 18349403 -- "Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97." (Hero B, J Clin Oncol. 2008 Mar 20;26(9):1504-10.)
*** Subset analysis of 93 patients who were observed only.
*** Outcome: spontaneous regression 47%, no change 11%, local progression/stage 4S progression 38%, stage 4 progression 4%. Time-to-regression variable, 1-18 months after diagnosis, in 34% patients >1 year. Median OS, 3-year OS and MDFS not different from patients treated with surgery or chemotherapy
*** Conclusion: Spontaneous regression seen regularly in infants with localized neuroblastoma, and not limited to first year of life. Wait-and-see strategy justified

### Stage 1-2

Surgery alone:
* POG 8104 / POG 8441 (1981-86)
** Prospective. 101 pts with POG / St Jude Stage A (same as INSS 1 but allows for lymph nodes adherent to tumor but removed in resection). Protocol allowed all stages, but this report focuses on Stage A.
*** Treatment: Surgical excision alone.
** PMID 3411339, 1988 — "Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study." Nitschke R et al. J Clin Oncol. 1988 Aug;6(8):1271-9.
*** 2-yr DFS 89%
** Conclusion: surgery is sufficient treatment for Stage A (equivalent to Stage 1).

### Stage 3-4

High risk:
* CCG 3891 (1991-96)
** Randomized. 539 pts. High-risk, Evans Stage IV, or Stage III with MYCN amplification, elevated ferritin, or unfavorable histology.
*** Initial chemotherapy: 5 cycles of cisplatin, doxorubicin, etoposide, and cyclophosphamide. Surgery and RT: given between cycles 4+5 for gross residual disease.
*** Randomized to: 1) Myeloablative therapy and ABMT with TBI vs. 2) intensive nonmyeloablative chemo (cisplatin, etoposide, doxorubicin, ifosfamide x 3 cycles)
*** 2nd randomization: +/- 6 cycles of 13-cis-retinoic acid (isotretinoin)
** PMID 10519894, 1999 — "Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group." Matthay KK et al. N Engl J Med. 1999 Oct 14;341(16):1165-73.
*** 3-yr EFS 34% (ABMT) vs 22%, 46% (retinoic acid) vs 29%.
** Conclusion: survival benefit for ABMT and 13-cis-retinoic acid in high risk pts.

### Stage 4S

* CCG 3881 (1989-95)
** Prospective. 80 pts. Evans Stage IV-S (concordant with INSS 4S). Surgical staging in 49. Trial enrolled good, intermediate, and selected poor-risk neuroblastoma, but report focuses on Stage IV-S pts only.
*** Treatment: supportive care only. 31 pts had resection. Chemo +/- RT was given for rapid tumor growth and compromise of vital organs.
** PMID 10653863, 2000 — "Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study." Nickerson HJ et al. J Clin Oncol. 2000 Feb;18(3):477-86.
*** Median f/u 43 mos. 5-yr EFS was 86%, OS 92%. Supportive care alone was possible in 57% of pts. EFS worse for infants < 2 months age. Favorable histology in 96%, no pts had MYCN amplification.
** Conclusion: many pts with Stage 4S have excellent survival with no therapy.

### Abdominal neuroblastoma

* Emory; 2005 PMID 16302219 -- "Comparison of conventional to intensity modulated radiation therapy for abdominal neuroblastoma." (Paulino AC, Pediatr Blood Cancer. 2005 Nov 21; [Epub ahead of print])
** Retrospective. 6 children, 3 different RT techniques compared
*** Technique A: parallel-opposed AP/PA fields to midline
*** Technique B: IMRT, CTV = tumor after chemo + 1.5 cm margin; PTV = CTV + 0.5 cm margin
*** Technique C: as B + vertebral bodies included in PTV
** Conclusion: "Dose to the PTV and CTV were not significantly different using the three techniques. Although Technique C was the best method of RT delivery in midline tumors with respect to kidney doses, this was at a cost of a higher mean dose to the liver, stomach, and spleen. This, together with the theoretical increase in secondary malignancies, should be considered when treating a child with IMRT techniques. IMRT was not found to be better than the conventional AP/PA field for lateralized tumors."

## Treatment Overview

* Low-risk:
** Surgery alone
** Chemotherapy for persistence or recurrence (carbo/etoposide or carbo/cyclophosphamide/doxorubicin)
** RT for recurrence salvage
* Intermediate-risk:
** Surgery followed by chemotherapy
** Chemotherapy: Short course of chemotherapy (4 courses) if favorable histology. Longer course (8 courses) if unfavorable histology.
** RT (18 to 30 Gy) for local persistence or recurrence of disease
* High-risk:
** Initial resection or biopsy
** Aggressive induction chemotherapy
** Maximal surgical resection to achieve a complete response or debulk tumor
** Myeloablative therapy and ABMT (may use total body irradiation)
** Consolidative RT to post-induction primary and metastatic sites with persistent MIBG avidity on pretransplant scans
* 4S:
** If acute respiratory or abdominal compartment syndrome due to massive liver enlargement

## Radiation technique

* Fields (per Perez 8th edition)
** Primary tumor + 2cm margin to block edge
** Regional lymph nodes if they were radiographically or pathologically involved at any time during disease course
** Elective mediastinal irradiation is typically not recommended due to significant morbidity
* Dose
** Children < 18 months: 15 Gy + 5-10 Gy boost
** Older children: 15-20 Gy + 5-10 Gy boost
** Stage 4S: 4.5 Gy in 3 fractions (1.5 Gy/fx) for liver.

## External links

* medhelp.org - Good resource with staging, etc.