Pediatrics - Evidence-based radiation oncology PDF

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XI: PEDIATRIC

52: MEDULLOBLASTOMA Camille A. Berriochoa, Bindu V. Manyam, and Erin S. Murphy

QUICK HIT: Medulloblastoma (MB) is the most common malignant pediatric CNS

tumor, accounting for 20% of all childhood brain cancers.1 MB typically arises in the cerebellum, most commonly in the cerebellar vermis, leading to obstruction of CSF flow and hydrocephalus. Presenting symptoms are related to increased intracranial pressure (ICP): irritability, nausea, vomiting, increased head circumference in young infants, headaches, diplopia, ataxia, and papilledema.2 Surgery alone leads to poor outcomes with multiple studies showing an improvement with the use of RT and CHT.3,4 Attempts to reduce CSI dose and its associated growth and neurocognitive toxicities have been facilitated by optimized CHT regimens.5 The recommended treatment paradigm is determined by patients’ risk status, with average-risk patients meeting the following criteria: age ≥3 years, GTR/NTR (1.5 cm2 residual disease post-op • Poor histology (large cell; anaplastic)

36 Gy/20 fx with weekly concurrent vincristine

Boost PF to 54–55.8 Gy**

CDDP/VCR/CYC

60%

*Infants 10% in the past 6 months). May see Pel–Ebstein fevers (cyclical spiking fevers up to 40°C, last ~1 week and remit for ~1 week; due to cytokine release), generalized pruritus or alcohol-induced pain in tissues infiltrated by HD. Generally, Hodgkin’s disease is unifocal and 90% present with contiguous sites of involvement. >80% originate above the diaphragm. Visceral involvement may be due to direct extension or hematogenous spread (liver or bone). Mechanism of spread to spleen is unclear; however, is likely hematogenous. TABLE 60.3: Comparison of Pediatric and Adolescent/Young Adult Hodgkin’s Disease Pediatric (age £4 y/o)

AYA (age 15–35 y/o)

Gender (M:F)

2–3: 1

1.1–1.3:1

Site of Disease

More commonly have cervical More commonly have (80%) LAD. Many also have mediastinal disease (75%) mediastinal disease. Rare to have isolated mediastinal or subdiaphragmatic disease (94%

90%

65%–80% 10%–25% 1%–5% 2%–8%

Source: From Ref. (21).

WORKUP: H&P with particular attention to LN regions (detailed earlier).

Labs: CBC, ESR, BMP, LFTs, LDH, hCG, PFTs. Imaging: CXR, CT with contrast of chest, abdomen, and pelvis. PET/CT once diagnosis is established. Echocardiogram prior to CHT. Pathology: Excisional biopsy is required to evaluate lymphoid architecture. Bone marrow biopsy if PET+, stage III/IV or B symptoms.

570 XI: PEDIATRIC

STAGING: See Chapter 48 for Ann Arbor staging system. PROGNOSTIC FACTORS: Poor prognostic factors include advanced stage, large medias-

tinal adenopathy, >4 subsites, B symptoms, poor histology, age (20 y/o), male sex, slow response to CHT. Risk stratification for pediatric Hodgkin’s lymphoma is as per Table 60.4. CHIPS prognostic score for pts with COG Intermediate Risk (based on AHOD0031).6 Includes stage IV disease, large mediastinal mass, albumin (90%); however, have significant associated toxicity. Initial trials focused on testing whether less-intensive CHT would lead to equivalent outcomes with improved toxicity. German HD-90 trial and French MDH-90 trial demonstrated excellent outcomes with CHT deintensification + ISRT. TABLE 60.6: Deintensification Trials in Early Pediatric Hodgkin’s Disease Study

N

Years

Arms

EFS

MDH-82 (French)9

238

1982–1988

ABVD x4 + 20 Gy (CR/PR) 40 Gy (non-CR/PR) IFRT

90% 92%

ABVD X2/MOPP X2 + same RT

87%

VBVP x4 + 20 Gy IFRT (good responders) VBVP x4 + OPPA x2 + 40 Gy (poor responders)

91% 97.5% (all)

MDH-90 (French)10

HD-90 (German)

202

267

1990–1996

OS

MFU Prognostic Factors/ (yr) Comment 6

97% CR/PR rate

6

Hb 25% residual disease or >50 mL residual. See Table 60.6 (early stage) and the following (intermediate and advanced stage). Conclusion: OEPA

572 XI: PEDIATRIC

is a satisfactory alternative to OPPA. RT can be confi ned to involved sites when combined with appropriate CHT. Is it possible to omit RT in patients who have a complete response (CR) to CHT? This question was evaluated in HD-95, POG 8625, and CCG 5942. HD-95 suggested that in pts who achieve CR after two cycles, RT can be omitted. However, POG 8625 showed that to omit RT, two additional cycles of CHT are required. When CHT is further de-escalated from MOPP/ ABVD, CCG 5942 showed that RT cannot be omitted (trial closed early). Therefore, omitting RT in the setting of de-escalated CHT is not recommended. TABLE 60.7: Risk-Adapted Trials Omitting RT in Early Pediatric Hodgkin’s Study

N

Years

Arms

HD-95 (German)

281

1995–2001

POG 862511

78

CCG 594212

294

EFS

OS

MFU Prognostic (Yrs) Factors/ Comment

OPPA(♀)/ OEPA(♂) X2, then 97% CR → No RT PR → 20–35 Gy 92.2% IFRT

98.8%

10

Comment: EFS for low-risk pts with CR and no RT same as PR with RT.

1986–1992

MOPP x3/ABVD x3 (no RT) MOPP x2/ABVD x2 + 25.5 IFRT

83% 91% (NS)

94% 97%

8

Laparotomy staged. Two cycles of MOPP/ABVD equivalent to 25.5 Gy IFRT.

1995–1998

CR pts randomized to IFRT CR pts randomized to no RT

100% 97.1% 89.1% (SS) 95.1% p = .5

10

Clinically staged pts. Trial stopped early as IFRT was superior. Updated numbers reflect 10-yr EFS and OS.

St. Jude

88

2000–2008

VAMPx2 CR no RT 75%, IFRT to 25 Gy; those with residual tumors >50 cc (considered bulky), IFRT to 25 Gy with 10 to 15 Gy boost. See Table 60.7 (early stage) and Table 60.9 (intermediate and advanced stage). IFRT was given to pts with poor CHT response; however, it was associated significantly with better EFS among intermediate- and high-risk pts but not among low-risk pts. No difference in OS. On QA, 2/17 relapses on RT arm due to poor quality RT. 4/14 pts with stage IIA who failed, had prolonged delay between CHT and RT. Conclusion: The omission of RT after CR results in increased risk of treatment failures, most notably in advanced-stage pts (note: a nonrandomized obser vation). May omit RT after CR in early-stage (low-risk) pts because no EFS benefi t seen in this group.

60: PEDIATRIC HODGKIN’S LYMPHOMA 573

Donaldson, St. Jude, Favorable Risk (JCO 2007, PMID 17235049): Phase II trial of 110 children with low-risk HD were treated with four cycles of VAMP (vincristine, Adriamycin, methotrexate, prednisone). Pts with CR received 15 Gy IFRT and those with PR received 25.5 Gy. After MFU of 9.6 yrs, 10-yr EFS and OS were 89.4% and 96.1%, respectively. Early CR, absence of B symptoms, lymphocyte predominant histology, and 50% PPD) receive IFRT 21 Gy/14 fx. Any pt who failed after initial CR, if failed as stage I/II, would receive IV/DECA (dexamethasone, etoposide, cisplatin, cytarabine) + IFRT 21 Gy. If pts failed as advanced stage, they will receive highdose CHT with autologous SCT. Study closed early due to higher risk for relapse in pts with CR who were PET+ after one cycle. CR after three cycles was achieved in 63.6%, PR in 34.5%, and stable disease in 1.8%. See Table 60.8 for additional results. Pts with mixed cellularity had significantly improved EFS compared to pts with nodular sclerosis histology (95.1% vs. 75.6%, p = .01). Conclusion: Rapid response as defi ned in this trial does not adequately defi ne a population in which RT can be avoided. PET response after one cycle is highly predictive of outcomes. TABLE 60.8: Early Results of AHOD 0431 2-year FU

EFS

EFS (-PET vs. +PET after 1c)

CR

80%

87% vs. 65% (p = .005)

PR (+ RT)

88%

96% vs. 82% (p = .047)

p value

.21

.001 (across 4 groups)

Intermediate-high risk/advanced/favorable pediatric Hodgkin’s Can RT be avoided in patients with CR after CHT? Several trials have evaluated whether RT can be eliminated for pts who have a CR to induction CHT. HD-95 and CCG 5942 studies showed that IFRT improved EFS, but no difference in OS. TATA Memorial from India suggested that there was an OS benefit to IFRT after CR (caveat was

574 XI: PEDIATRIC

that ~50% were AYA or adult HD). However, POG 8725 trial (STNI) and CCG 521 (EFRT), both of which utilized large RT volumes, did not show an EFS or OS benefi t to RT. These trials together suggested that there may be pts in whom RT could be avoided without impacting oncologic outcome; however, it was unclear who those pts are. TABLE 60.9: Trials Omitting RT in Intermediate/High-Risk Pediatric Hodgkin’s Lymphoma Study

N

Years

Arms

EFS

OS

MFU Prognostic (yr) Factors

POG 872513

179

1987–1992

MOPP X4 + ABVD x4 (CR) + 21 Gy STNI MOPP X4 + ABVD x4 (CR) alone

80%

96%

5

79% (NS)

87% (NS)

CR after 3 cycles; age...