Children's Doctor

Oncology - Winter 2013

High-Risk Neuroblastoma: Using Proton Therapy as Part of Multi-modality Treatment

Christine Hill-Kayser, MD, and Naomi Balamuth, MD

A 3-year-old girl presents with difficulty sleeping, increased crying, and abdominal pain. She is the product of a normal full-term delivery and has no significant past medical history. Her parents note that she was healthy until approximately a month ago, when she began waking at night complaining of pain. They also note that she has been increasingly irritable and less willing to walk over the past 2 to 3 weeks. They deny fever, vomiting, diarrhea, and constipation. She has not lost any weight that they have noticed, although her appetite has been dwindling.

On examination, the patient is in no acute distress, although appears somewhat quiet and clingy. An abdominal mass is palpable in the region above the umbilicus. Her lungs are clear, and the remainder of her exam is within normal limits. CT scan of the chest, abdomen, and pelvis shows a large mass in the central abdomen, extending cranially to the mid-thorax along the right paraspinous region. Bone marrow biopsy demonstrates small round blue cells. Urine catecholamines are somewhat elevated above normal.

Discussion: The diagnosis is neuroblastoma, a malignancy that arises from embryonic neural crest cells of the peripheral nervous system and is the most common extra-cranial solid tumor of childhood. The presentation and stage at diagnosis, as well as the associated prognosis, may be very heterogeneous. Several diagnostic elements factor into risk stratification, including patient age, disease stage, tumor cell ploidy, histopathology, MYCN gene copy number, and other genetic aspects of the tumor. Select patients who are very young (less than 1 year of age) may have disease designated stage 4S that is expected to spontaneously regress and have an excellent prognosis. Patients with lowor intermediate-risk (stage 1 or 2) disease have an excellent prognosis after treatment with surgical resection with or without chemotherapy. Unfortunately, however, about half of patients have high-risk disease (stage 3 or 4, depending on other diagnostic factors) at diagnosis. Although the prognosis for such children is guarded, with aggressive treatment, long-term survival rates approach 50%. The current treatment paradigm for children with high-risk neuroblastoma is intensive multi-agent induction chemotherapy followed by surgical resection of the primary tumor, high-dose chemotherapy followed by autologous stem cell transplant (ASCT), radiation therapy, and immunotherapy.

The patient described above was ultimately diagnosed with highrisk neuroblastoma. She underwent induction chemotherapy that included topotecan, cyclophosphamide, cisplatin, etoposide, vincristine, and doxorubicin. Surgical resection of her abdominothoracic mass was undertaken; the abdominal component was completely resected although the chest mass could not be entirely removed.

Following ASCT, the patient received radiation therapy. Historically, X-ray therapy has been used to deliver this treatment for neuroblastoma patients; in most centers worldwide, either 3D conformal X-ray therapy or intensity-modulated X-ray therapy would have been employed. Proton therapy is a radiation technology that has been available since the 1970s and has become more widespread over the past 1 to 2 decades. Proton therapy differs from X-ray therapy in that protons can be made to stop within tissue. Compared to X-rays, which traverse the patient depositing both entrance and exit dose, protons, with their ability to target smaller areas, allow considerable sparing of normal tissues. Proton therapy for neuroblastoma is a relatively new approach.

For this patient, the use of proton therapy compared to X-ray therapy allowed a100-fold reduction in radiation dose delivered to the patient’s normal liver, lungs, and heart (see Figure 1). This was particularly important as it reduced her risk of pulmonary toxicity that was increased previously by her chemotherapy. It also reduced her risk of liver and kidney toxicity, allowing her to quickly receive the needed immunotherapy following completion of her radiation. The patient tolerated radiation with no clinical toxicity and is currently disease-free.


Figure 1: Radiation treatment plans for delivery of radiation to the tumor bed in the abdomen and chest using protons (left) versus x-ray therapy (right). Note the relative sparing of the liver and lungs when proton therapy is employed.

Proton therapy shows great promise for patients such as the one described here, and is available to many patients with solid and brain tumors who travel from around the world to receive treatment at The Children’s Hospital of Philadelphia/Roberts Proton Therapy Center.

References and Suggested Readings

Yu AL, Gilman AL, Ozkaynak MF, et al; Children’s Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324-1334.

Hill-Kayser CE, Both S, Tochner Z. Proton therapy: ever shifting sands and the opportunities and obligations within. Front Oncol. 2011;1:24.

Hattangadi JA, Rombi B, Yock TI, et al. Proton radiotherapy for high-risk pediatric neuroblastoma: early outcomes and dose comparison. Int J Radiat Oncol Biol Phys. 2012;83(3):1015-1022.

All in the Family

Kristin Zelley, MS, CGC, and Kim E. Nichols, MD

CL is a previously healthy 15-year-old girl who presents with a 2-week history of left-sided knee pain and progressive swelling. There is no history of fever or trauma. Physical examination reveals swelling of the left knee, but no redness, warmth, tenderness to palpation, or limitation in range of motion. A left knee X-ray reveals a lytic lesion in the distal femur, later confirmed by MRI (see Figure 2). The mass is biopsied and found to be an osteosarcoma.

Upon further knee mriFigure 2: MRI of the left knee demonstrates an enhancing lesion of the distal femur with edema of the surrounding soft tissues.questioning, CL’s mother notes that her husband died recently from acute myeloid leukemia following treatment for rhabdomyosarcoma. His sister has a history of breast cancer. Based on the family history of cancer, it was questioned whether CL might have Li-Fraumeni syndrome (LFS). She and her mother were counseled, and subsequently CL chose to undergo genetic testing. Test results returned positive for a mutation in TP53, the causative gene in LFS.

Discussion: CL has LFS, a rare cancer predisposing condition first described by Frederick Pei Li, MD, MA, and Joseph Fraumeni, MD, MSc, in 1969. Families with LFS are at greatest risk to develop six tumor types, including sarcomas of the muscle or bone, breast cancer, brain tumors, adrenocortical tumors, and acute leukemia. Since the original description, recent reports suggest that there are excess rates of many other cancer types. LFS is a highly penetrant syndrome, with more than 90% of affected individuals developing cancer by age 80. There is a significant risk for tumor development in childhood, with up to 20% of patients developing cancer during the first 2 decades of life. Affected individuals are at increased risk to develop multiple primary tumors, as in the case of CL’s father, and may be at increased risk for radiation- or therapy-induced cancers.

CL had a highly suspicious family cancer history, which is a strong indicator of a possible underlying predisposition syndrome (see Table 1). Family histories concerning for hereditary predisposition to cancer typically include: 1) multiple members on the same side of the family with the same or similar types of cancer, or distinct cancer types that group together in specific syndromes (such as the rhabdomyosarcoma, osteosarcoma, leukemia and breast cancer in this case); 2) relatives with early onset, multiple or bilateral cancers; and 3) a pattern suggestive of autosomal dominant inheritance. Therefore, when gathering a family history, clinicians should collect information on the age of cancer onset, type of cancer, and laterality in at least first- (parents and siblings), second- (grandparents, aunts, and uncles), and third- (cousins and great-grandparents) degree relatives. They should consider referral to a genetic counselor, oncologist, or geneticist with expertise in cancer predisposition if any of the features described below are identified.

Table 1: Features suggestive of an underlying cancer syndrome
Clinical manifestation Indicator suggesting underlying predisposition
Family history
  • Individuals on same side with early, bilateral or multi-focal cancers
  • Distinct cancer patterns
  • Autosomal dominant inheritance
Syndromic features
  • Dysmorphic features, including hemihypertrophy
  • Developmental delay, intellectual disabilities, autism spectrum disorder
  • Skin findings (café au lait, freckling, epidermoid cysts)
  • Macrocephaly
  • Skeletal abnormalities
  • Dental abnormalities (extra/missing teeth)
  • Eye findings (Lisch nodules, congenital hypertrophy of the pigmented retinal epithelium)
Specific tumor types
  • Adrenocortical carcinoma, bone and soft tissue sarcomas, breast cancer, brain tumors, leukemia (Li-Fraumeni syndrome)
  • Atypical teratoid/rhabdoid tumor (rhabdoid tumor syndrome)
  • Desmoid tumor, hepatoblastoma, medulloblastoma (familial adenomatous polyposis)
  • Hepatoblastoma, Wilms tumor (Beckwith-Wiedemann syndrome/idiopathic hemihypertrophy)
  • Medullary thyroid cancer (multiple endocrine neoplasia, Type 2)
  • Optic pathway tumor (neurofibromatosis)
  • Retinoblastoma (hereditary retinoblastoma)
  • Pleuropulmonary blastoma, cystic nephroma, ovarian sex cord stromal or Sertoli-Leydig cell tumors (DICER1 tumor predisposition syndrome)
  • Wilms tumor (hereditary Wilms tumor syndromes)

It is important to recognize a hereditary cancer syndrome because identification of affected children allows for appropriate surveillance and cancer management. In pre-symptomatic children, the primary goal of surveillance is to detect cancers at the earliest stages, when they are small, more easily resected and require treatment with less intensive or even no chemotherapy. As a result, the chances for cure are maximized and risks of side effects reduced. In certain cases, children may also undergo prophylactic removal of at-risk organs, a procedure that eliminates or significantly lowers the lifetime risk for cancer. For those children already affected with cancer, genetic information can guide the choice of surgical approach or medical regimen. Finally, identification of affected children enables the testing of other family members who may or may not require similar surveillance, preventive, or treatment measures.

At CHOP, the Pediatric Hereditary Cancer Predisposition Program evaluates and manages children who have or are suspected of having a cancer-predisposing genetic condition. A pediatric oncologist, geneticist, genetic counselor, and psychologist work to address the needs of children who are at increased risk for cancer. Our team provides comprehensive medical management, recommends and reviews the results of screening tests, and offers supportive counseling. Each member of our team is dedicated to providing the most skilled, compassionate care available in an environment that focuses on children and their families. Also key to the program are community physicians, who are often the most likely to spot signs of predisposition in families, particularly among siblings and other relatives.

References and Suggested Readings

Strahm B, Malkin D. Hereditaty cancer predisposition in children: genetic basis and clinical implications. Int J Cancer. 2006;119(9):2001-2006.

Rao A, Rothman JE, Nichols KE. Genetic testing and tumor surveillance for children with cancer predisposition syndromes. Cun Opinion Pediatr. 2008;20(1):1-7.

Teplick A, Kowalski M, Biegel JA, Nichols KE. Screening in cancer predisposition syndromes: guidelines for the general pediatrician. Eur J Pediatr. 2011;170(3):285-94.

Knapke S, Zelley K, Nichols KE, Kohlman W, Schiffman J. Considerations for the identification, management, and genetic evaluation of children with cancer predisposing conditions. 2012. Am So Clin Oncol Educ Program.

Caring for Pediatric Cancer Survivors: Partnership Is Essential

Jill P. Ginsberg, MD

The news about childhood cancer survivors continues to improve. Through organized clinical trials, pediatric oncologists have discovered treatments that can now cure almost 80% of children who are diagnosed with cancer. Currently, there are more than 270,000 pediatric cancer survivors living in the United States. These numbers will continue to grow, making it more and more likely that primary care providers (PCPs) will encounter cancer survivors in their daily practice. It is important for oncologists and PCPs to work together to care for this special population of patients.

When Therapy Ends

Families often struggle with the initial transition back to primary care after therapy ends. While they still have routine follow-up for their cancer, not every medical issue requires attention from their oncologist. Patients are encouraged and may need to be redirected to contact their pediatrician’s office for routine medical care.

As time passes, the number and intensity of oncology follow-up visits diminish and some sense of normalcy settles in. This chapter of the after-therapy experience for pediatric cancer survivors varies, depending on the intensity of treatments used to cure their disease. Most survivors will do quite well long-term, with minimal health issues related to their cancer or treatment. Other patients may experience more longterm effects and require closer medical monitoring throughout their lifespan. At The Children’s Hospital of Philadelphia, we understand there is a need for specialized care in a clinic that focuses specifically on the needs of survivors. The Cancer Survivorship Program at CHOP helps patients and family members navigate life after cancer, including both the physical and emotional issues they may face. Once a patient is at least 5 years from diagnosis and 2 years from his or her last cancer therapy, a visit to the Survivorship Clinic can occur. A typical visit involves:

Key Components of a Successful Partnership

No matter where the patient may fall on this survivorship continuum, partnership between the CHOP oncologist and the PCP is paramount. There are several key components to this partnership:

Correspondence: This begins with the initial referral to the Cancer Center and should include details on the recent history, reason for referral and any diagnostic studies already performed. Similarly, it is the specialist’s duty to send information back to the primary care physician on diagnosis, planned treatment and the patient’s progress over time. Once a patient is off therapy, then correspondence from oncology to the primary’s practice should include a treatment summary and recommendations for risk-based surveillance for late effects of therapy over the patient’s lifetime.

Communication: Open lines of communication between the oncologist and the PCP are important. Someone at CHOP is always available to discuss patient issues should concerns arise.

COG Guidelines: The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers are helpful for healthcare professionals who do not regularly care for survivors of pediatric malignancies.

Consistency of Message: It is important patients and parents hear from both their oncologist and PCP that, now that therapy is complete, a visit to the pediatrician/primary care physician should be the first stop for their medical needs.

Community: It is not an “us versus them” scenario when caring for our cancer survivors. While CHOP’s Cancer Center oncologistsprovided the treatments to help cure the child’s cancer, we are only one part of the team. It is a community of healthcare providers, with the primary care physician at the hub, that will provide ongoing follow-up these survivors will need as they move through their lives. Fostering this sense of community with our patients and families will help them to eventually make the transition from on therapy to survivorship.

Referral Information

For physician-to-physician questions and guidance regarding pediatric cancer, call CHOP’s Physician-Only line at 1-888-ONC-CHOP (1-888 662-2467) or email

To reach the specific programs highlighted in this issue, call 215-615-5678 for Proton Therapy; 267-426-5877 for the Pediatric Hereditary Cancer Predisposition Program; and 215-590-0432 for the Cancer Survivorship Program.

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