Evidence Based Questions Flashcards

1
Q

What is the Tx paradigm for low-risk stage 4S NB, and which study supports this approach?

A

Low-risk stage 4S NB Tx paradigm: Bx → supportive care. Chemo and/or RT are reserved for rapidly growing or symptomatic Dz. A subgroup analysis of CCG 3881 showed that supportive care is sufficient for 57% of pts. The protocol resulted in a 5-yr EFS of 86% and an OS of 92%. (Nickerson HJ et al., JCO 2000)

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2
Q

Which studies support the use of observation (without resection) in infants with localized NB without N-myc amplification?

A

The use of observation (without resection) in infants with localized NB without N-myc amplification was evaluated in the German GPOH trials NB95-S and NB97. Of 93 pts with gross Dz, 44 had spontaneous regression. OS and DMFS were no different from outcomes of pts treated with Sg or chemo in these trials. (3-yr OS 99%, DMFS 94%). (Hero B et al., JCO 2008)

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3
Q

What is the role of RT in the Tx of intermediate-risk NB?

A

In intermediate-risk pts, RT is typically reserved for those who are symptomatic d/t tumor bulk and are not responding to initial chemo, such as pts with respiratory distress d/t hepatomegaly or with neurologic compromise d/t cord compression. RT is not indicated as a consolidative therapy even with persistent Dz. Indications for RT based on A3961: Symptomatic palliation, viable residual Dz in Tx-refractory pts, and recurrent Dz.

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4
Q

What is the Tx for unfavorable stage 4S (intermediate-risk) Dz?

A

The Tx is chemo × 8 cycles.

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5
Q

Which targeted agent has recently been demonstrated as promising new adj therapy for high-risk NB?

A

Promising results have been observed with immunotherapy targeting the surface glycolipid molecule disialoganglioside (GD2). A recent phase III randomized trial showed a significant improvement in EFS and OS for children with high-risk NB receiving chimeric anti-GD2 (ch14.18) combined with cytokines (IL2 and GM-CSF) and isotretinoin after myeloablative consolidation therapy. (Yu AL et al., NEJM 2010)

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6
Q

In low-risk and intermediate-risk NB, what dose of RT is generally used?

A

In low-risk NB, RT to 21 Gy at 1.5 Gy/fx can be used for Sx that do not respond to chemo. In intermediate-risk NB, if PR to chemo and viable residual Dz after 2nd-look Sg, then RT can be given locally to the primary + 2-cm margin to 24 Gy at 1.5 Gy/fx.

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7
Q

In high-risk NB, what tissues are targeted during RT and to what dose?

A

Per current COG ANBL0532, high-risk NB pts are treated with RT to their postchemo, preop tumor bed to a total dose of 21.6 Gy in 1.8 Gy/fx if GTR and 36.0 Gy (21.6 Gy to preop GTV → 14.4 Gy boost) if gross residual. Based on pts with residual Dz treated on CCG 3891, 21.6 Gy is also acceptable for high-risk Dz. (Haas-Kogan D et al., IJROBP 2003)

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8
Q

In high-risk NB, should elective nodal RT be given?

A

No. In high-risk NB, only clinically+ or pathologically+ LN regions are covered in the RT volumes.

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9
Q

What study indirectly demonstrated an RT dose–response in high-risk NB?

A

A secondary analysis of CCG 3891 found that high-risk NB pts who rcvd 10 Gy local EBRT + 10 Gy TBI as part of a transplant preparation regimen had better LC than pts who did not get TBI (or a transplant) (5-yr LR rate was 22% vs. 52%). These results support the current use of 21.6 Gy in high-risk protocols. (Haas-Kogan D et al., IJROBP 2003)

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10
Q

What study demonstrated the benefits of high-dose chemo → BMT as well as adj cis-retinoic acid in high-risk NB?

A

In CCG 3891, 379 high-risk NB pts were treated with induction chemo → Sg and 10 Gy to gross residual. Pts were then randomized to 3 cycles of nonmyeloablative chemo vs. myeloablative chemo, TBI, and BMT. Pts underwent secondary randomization to observation vs. cis-retinoic acid × 6 mos. Both the myeloablative chemo and cis-retinoic acid improved OS. 5-yr OS for pts who rcvd both was 59%. (Matthay KK et al., JCO 2009)

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11
Q

What is the appropriate Tx for NB pts with cord compression?

A

Consider chemo initially for NB-related cord compression. Unresponsive Dz can be treated with Sg or RT.

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12
Q

What is the RT dose and dose/fx used for NB pts being treated for symptomatic cord compression?

A

For symptomatic cord compression:

  1. If pt is <3 yo, treat to 9 Gy (1.8 Gy/fx)
  2. If pt is ≥3 yo, treat to 21.6 Gy (1.8 Gy/fx)
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13
Q

What is the RT dose and dose/fx used for NB pts being treated for symptomatic hepatomegaly?

A

Symptomatic hepatomegaly is treated to 4.5 Gy (1.5 Gy × 3).

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14
Q

Can the vertebral body be split during RT planning?

A

No. It is necessary to always cover the full width of the vertebrae to avoid scoliosis.

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15
Q

What is the role of I-131 MIBG in NB?

A

I-131 MIBG can be used for refractory NB, based on a promising phase II study showing a 36% response rate. (Matthay KK et al., JCO 2007)

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16
Q

What is the treatment paradigm for low-risk disease?

A

Low-risk disease is the most common presentation of neuroblastoma. Surgery is the mainstay of therapy if the tumor is deemed resectable. Residual disease may be observed if pts are ≤18 months and have favorable risk factors (favorable histology and nondiploid tumors). CHT is reserved for unresectable, unfavorable, symptomatic, or progressive/recurrent disease. This is supported by COG P9641, which stratified postoperative CHT based on risk factors. This study found a higher risk of recurrence in pts with stage 1 N-myc amplified disease or stage 2b ≥18 months or have unfavorable histology or diploid tumors if pts were observed after surgery. There is no role for routine adjuvant RT in low-risk pts given the outcomes with salvage therapy.

17
Q

What are the outcomes for stage 4S disease?

A

Pts less than 1 year of age presenting with abdominal tumors can still have excellent outcomes (3-yr EFS and OS >95%) if observed closely. Katzenstein et al. showed that pts who may require intervention are those symptomatic from their disease (hepatomegaly), very young (<2 months), or have unfavorable histology. The concern with very young pts is that they have a higher risk of rapid clinical decline without intervention. If CHT is given for symptomatic disease, it is generally given until cessation of symptoms. Early results of COG-ANBL0531 for pts with 4S disappointingly showed a lower 2-yr OS of 81%, which was thought to be due to inclusion of pts who could not undergo biopsy due to poor clinical factors previously excluded from prior trials (see intermediate risk later).

18
Q

Is RT beneficial for intermediate-risk disease?

A

RT was shown to increase both EFS and OS when added to adjuvant CHT in the Castleberry study of POG C pts. However, in the modern era, additional genetic/biologic risk-stratification factors (such as N-myc status) are used to better risk-stratify pts. Thus, the current intermediate-risk pts (in whom RT is not a standard component of first-line therapy), are not the same pts as those in the Castleberry study (as a group). As in low-risk pts, RT is typically reserved for pts with residual disease refractory to CHT, recurrent disease, or those who remain symptomatic.

19
Q

What is the role of autologous SCT and adjuvant isotretinoin in high-risk disease?

A

Matthay, CCG 3891 (NEJM 1999, PMID 10519894, Update Matthay JCO 2009, PMID 19171716):Prospective study of 539 pts with high-risk NB. Induction CHT consisted of cisplatin, doxorubicin, etoposide, and cyclophosphamide x five cycles. After induction CHT, pts without progression underwent delayed primary surgery with nodal assessment followed by RT to gross residual disease. RT dose was 20 Gy/10 fx to extra-abdominal disease and 10 Gy/5 fx to mediastinal and intra-abdominal tumors. Pts were subsequently randomized to receive consolidation CHT or myeloablative CHT + TBI with SCT. Consolidation CHT consisted of three cycles of cisplatin, etoposide, doxorubicin, ifosfamide. Myeloablative CHT was carboplatin and etoposide. TBI was 10 Gy/3 fx daily. Following SCT or consolidation CHT, pts without disease progression were randomized to six cycles of 13-cis-retinoic acid (isotretinoin) or no further therapy. 5-yr EFS and OS for all pts were 26% and 36%, respectively. The 5-yr LRR was 51% for pts treated with CHT versus 33% for pts treated with SCT (p = .0044). 3-yr EFS with CHT was 22% versus 34% with SCT. 3-yr EFS after the second randomization was 46% among the 130 pts who received 13-cis-retinoic acid versus 29% among the 128 who received no further therapy (p= .027). 2009 update demonstrated 5-yr EFS of 19% for pts treated with consolidation CHT versus 30% for pts treated with SMT (p = .04). 5-yr EFS from second randomization was higher for isotretinoin than no further therapy, although not significant (42% vs. 31%). Conclusions: This study set the standard treatment regimen for high-risk neuroblastoma, which includes both autologous SCT and isotretinoin.

20
Q

Why are doses above 20 Gy recommended to control gross disease?

A

There appeared to be a benefit to the addition of TBI when only 10 Gy was used.

21
Q

Is there a benefit to tandem stem cell transplants?

A

Park, COG ANBL 0532 (ASCO 2016, Abstract LBA3): PRT of children with high-risk neuroblastoma randomized to either single autologous SCT versus tandem SCT. 652 pts, median 3.1 years of age. Tandem SCT improved 3-yr EFS from 48.8% to 61.8% (p = .008) with a nonsignificant improvement in OS (69.0%–73.8%, p = .256). 249 pts received postconsolidation immunotherapy, which also improved both EFS and OS (EFS 55.4% vs. 73.7%, p < .001; OS 75.7% vs. 86.3%, p = .016). Conclusion: Tandem SCT improves EFS in pts with high-risk neuroblastoma.

22
Q

Is there a benefit to targeted immunotherapy in high-risk pts?

A

Ch14.18, a chimeric anti-GD2 antibody improves overall survival but at the cost of high acute toxicity in the form of pain and capillary leak syndrome.

Yu, COG ANBL0032 (NEJM 2010, PMID 20879881): PRT 226 pts randomized to immunotherapy versus standard therapy after myeloablative therapy and stem cell rescue. The immunotherapy arm was ch14.18 with alternating GM-CSF and IL2 (to stimulate Ab-dependent cell-mediated cytotoxicity) plus isotretinoin versus isotretinoin alone (standard arm). Ch14.18 is a chimeric anti-GD2 monoclonal Ab; GD2 is a surface protein on tissues of neuroectodermal origin.46 Immunotherapy improved 2-yr EFS (66% vs. 46%, p = .01) and improved 2-yr OS (86% vs. 75%, p = .02). Grade 3-4 pain was higher in the immunotherapy arm, with 52% of pts having grade 3 or 4 pain. Additionally, 23% and 25% of pts in that arm had capillary leak syndrome and hypersensitivity reaction, respectively. Early in the study, two pts were inadvertently given an overdose of IL-2 (>20 times the intended dose), with one of these pts consequently experiencing grade 5 toxicity in the form of capillary leak with pulmonary edema. Conclusion: Immunotherapy with anti GD-2 monoclonal antibodies shows improved outcomes compared to standard therapy. Comment: Closed early due to highly favorable results. FDA approved h14.18 (dinutuximab) in 2015 for use in combination with GM-CSF, IL-2, and isotretinoin for high-risk neuroblastoma pts who achieve at least a partial response to standard multimodality therapy.

23
Q

Is there a benefit to MIBG with I-131 or crizotinib in high-risk neuroblastoma?

A

This is the question of the ongoing study COG ANBL1531. Iobenguane I-131 is essentially therapeutic MIBG including I-131 (diagnostic MIBG includes I-123) and has shown dramatic responses in relapsed/refractory cases. Crizotinib is active against ALK mutated tumors

24
Q

When is radiotherapy used for intermediate-risk neuroblastoma patients?

A

Intermediate-risk patients are expected to have a survival of greater than 80% after primary tumor resection and chemotherapy. Radiation therapy is reserved for symptomatic palliation (4.5 Gy/3 fx for hepatomegaly), viable residual disease in chemo-refractory patients or recurrent disease.

Matthay, K, Haas-Kogan, D, Constine, L. Neuroblastoma. In: Halperin, E, Constine, L, Tarbell, N, et al., eds. Pediatric Radiation Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:108-136.

25
Q

What is the 3-year EFS for high-risk disease and what is the appropriate therapy?

A

The expected 3-year EFS for high-risk neuroblastoma patients is 30% to 40%. Treatment consists of induction chemotherapy, surgery, myeloablative chemotherapy followed by hematopoietic cell transplant, consolidative RT, oral isotretinoin + anti GD2 antibody. RT is delivered to the postchemo, presurgery tumor volume (21.6 Gy at 1.8 Gy/fx for GTR and consider boost to residual for total 36 Gy as per current COG 0532) and any persistent metastatic sites.