Neuroblastoma Relapse Treatment Rationale

Your doctor will take into consideration many factors when recommending treatment for relapse:
Age of child:
  • less than one year
  • 1-21 years
  • over 21
How long the child was in remission after treatment:
  • less than one year
  • 1-2 years
  • long remission
Where disease is located:
  • at primary site
  • lung; liver
  • central nervous system (CNS)
  • distant sites (bone, marrow)
How much disease (tumor burden):
  • minimal or trace disease
  • many bone metastases or loaded bone marrow
  • bulky disease (soft tissue); many lymph nodes
Rate of tumor growth:
  • rapid progression
  • slow or stable disease
Prior treatment history
  • induction regimen (agents used)
  • number of stem cell transplants (SCTs)
  • local, targeted, or total body irradiation
  • antibodies
Organ function:
  • impaired kidney, liver, bone marrow function, hearing, etc
Available stem cells:
  • number of rescues stored
  • length of storage time
  • potential of another collection
Changing characteristics of the child’s NB:
  • no longer MIBG-avid
  • chemo-resistance (loss of p53 function)
Goals of treatment:
  • cure
  • prolonging life
  • quality of life
  • palliative care
Your child’s specific situation may present options and/or limitations for certain treatments. A key factor is whether or not the neuroblastoma still responds to chemotherapy. Having already been down that road, many parents want something new for their child, but the fact remains that chemo-sensitive neuroblastoma will commonly be treated most successfully first with chemotherapy. However, the specific facts will be carefully considered. If a child had a certain chemo combination during induction, the oncologist may choose a different combination at relapse. If a child has recently undergone stem cell transplant, it is less likely high-dose chemo would be recommended due to the threat to bone marrow recovery and organ function; in contrast, a “late” relapse often allows for options of more aggressive therapy similar to frontline treatment. If, however, the neuroblastoma is not responding to chemotherapy, then the oncologist will consider other treatment possibilities. Some children with very minimal bone marrow disease detected early may be a candidate for antibody therapy and/or retinoids. There is a treatment specifically for isolated CNS or brain relapse at MSKCC in New York City, using an antibody called 8H9 and surgery in addition to chemo. Surgery may be recommended for certain local tumor recurrences, but some cases are not ideal for surgery, such as multiple masses in the liver.

Treatments for relapse vary in approach and intensity. Some or all of the elements of frontline treatment for high-risk neuroblastoma --chemotherapy, surgery, radiation, Accutane, or antibodies -- can potentially be used in the relapse setting, depending on the individual situation. Each of these treatments attack NB in a different way and with varying intensity.

The variety of intensity in treatment means there are weighty decisions to be made regarding treatments allowing good quality of life versus harsh treatments with potential to bring about cure or long term survival. There may be a sequence that starts out with harsh treatment, and then depending on the disease response, the child may move onto less aggressive treatments, or conversely, a child may respond to something lower dose at first, and then require harsher treatment later to elicit a response. Your child’s oncologist must help you navigate this difficult dynamic, but sometimes the decisions to be made are very personal. See discussion below regarding “maximizing your options” and “quality of life” considerations.

It is advisable to ask your oncologist about collecting stem cells (new or to add to your current supply) during the planning stage of relapse treatment, since the availability of stem cells can allow for treatments not otherwise possible.

Can we know what will actually work against my child’s neuroblastoma? The truth is, no one knows for certain. Neuroblastoma cells can change and lose functions that make them chemo-sensitive. It also appears that every child’s neuroblastoma disease is unique. Research is ongoing of “individualized medicine,” with the long-term goal of someday being able to determine the most effective treatment for each child (understanding and use of these technologies is limited thus far). One such effort is underway at the University of Texas in Houston. Analysis of a child’s tumor characteristics (“morphoproteomics” or “Molecular Tumor Profiling Using Morphoproteomic Analysis by Immunohistochemistry”) is being done to identify certain predominant weaknesses of the neuroblastoma cells in a child’s tumor sample.

There are no hard and fast rules, and currently relapse treatment relies on educated trial-and-error to see what works in each child. To reiterate, oncologists will recommend certain treatment options depending on all the variables in your child’s specific case. The treatments mentioned below are merely examples to illustrate how varied the choices can be; furthermore, treatment for relapsed children is an ever-changing landscape. The guidance of an experienced oncologist through this complex landscape is crucial.

High-Dose Chemotherapy and Radiation

Some treatments include high doses of chemotherapy or targeted radiation therapy, or a combination of the two, which may require stem cells for rescue. A current example of a high dose chemotherapy combination is known as ICE (ifosfamide, carboplatin, and etoposide). High-dose choices can require potentially long inpatient stays. MIBG radiation therapy, a type of “targeted” radiation using the radioactive iodine isotope 131-I, has been used to treat relapse and refractory neuroblastoma since the mid-1980s. The child must be MIBG-avid – i.e., neuroblastoma shows up on the child’s MIBG scan. See “MIBG Treatment” for more information on treatment issues surrounding MIBG. “Hot antibodies” (3F8 antibodies with radioactive isotope131-I attached, currently given in conjunction with avastin) is another approach to high-dose, targeted radiation. Allogeneic (donor) or cord blood transplants, albeit less common, are additional aggressive possible treatment options considered for relapse.

Medium-Dose Chemotherapy

Outpatient chemotherapy that is relatively easy on the blood counts is often chosen for certain relapse scenarios. One combination used frequently is topotecan and cyclophosphamide, which is usually administered IV at a clinic daily for one week out of every three or four weeks. Topotecan with etoposide has been studied as a relapse regimen in Germany. Another commonly used combination is irinotecan and temozolomide. Irinotecan can be administered as an IV infusion daily for one or two weeks or taken orally, and temozolomide is an oral chemo taken in pill form daily for five days out of a three or four week cycle.

Low-Dose Chemotherapy

Low-dose oral agents in pill form, such as topotecan, Cytoxan, temozolomide, or etoposide, may be used in some cases. These regimens are much easier on blood counts than high dose chemo so often transfusions and neutropenic fevers can be avoided. Occasionally combinations of oral chemos are used.

Timing, dosage and form of the various chemotherapy regimens can vary per patient based on the specific medical and personal factors.

Targeted Drugs (“Small Molecules”) and Biologics

These drugs employ different mechanisms from chemo to destroy NB and sometimes are used in conjunction with medium- or low-dose chemo. Targeted drugs currently being tested in clinical trials for relapsed (or refractory) neuroblastoma include inhibitors of certain NB cell functions and signals such as CEP-701 ; inhibitors of blood vessels that support NB tumors— “anti-angiogenic” agents, such as ABT-751 ; and stimulators of “differentiation” or apoptosis of NB cells (to mature or cause their death) such as the retinoids fenretinide or Accutane. Nifurtimox, an anti-protozoal drug, is being administered to patients along with chemotherapy in a trial to determine if it enhances the effectiveness of chemotherapy. Some new drugs are attractive for their low toxicity profile and may cause relatively minor side effects, but toleration does vary. From the child’s perspective, the main advantage of low-dose regimens (chemo or targeted drugs) is allowing for near-normal activity.

Immunological Treatments

Monoclonal antibodies may be an option for some relapsed children, generally those with minimal disease. For example, MSKCC has been treating children with 3F8 antibodies since the mid-1980s as part of frontline treatment. There are currently several different trials using the 3F8 antibody for certain refractory and relapse cases. This antibody, made in mice, generally must be preceded by high-dose chemo to prevent premature formation of an ultimately desirable immune response known as human anti-mouse antibody, or “HAMA.” St. Jude’s is producing a new “humanized” antibody hu14.18 to use with cytokines (immune stimulators). The ch14.18 antibody (chimeric refers to its part mouse and part human derivation) is not currently available to relapsed patients, but some refractory cases with minimal detectable disease may be eligible immediately after stem cell transplant. Efforts are underway at several institutions to produce various vaccines against NB, intended primarily for those with minimal disease or in second remission.

Clinical trials sometimes open and close, and then open again, so contacting the investigators is the best way to know the status of a specific trial. See discussion of research into clinical trials, below.

Second Remission Treatment Issues

With advances in treating relapsed neuroblastoma, more children are able to reach NED (no evidence of disease) again. While this is very good news of course, it poses a unique treatment dilemma. Once a child relapses, the likelihood of another relapse is very high, and therefore continued treatment of some sort is usually advised. However, there is no consensus on what agents should be used or for what length of time, and few drugs are available for an oncologist to prescribe beyond low-dose oral chemo. The problem is that almost all clinical trials of new treatments for relapsed NB require evidence of disease. Possible options for relapsed children in second remission include Acctuane, low-dose oral chemo in pill form (such as topotecan, Cytoxan, etoposide, temozolomide, thalidomide, Celebrex—separately or in various combinations), 3F8 antibody (requires high-dose chemo), and vaccines. As more studies are planned to treat minimal residual disease (MRD) occasionally eligibility for “second or greater response” is included, such as the CEP-701 NANT Phase I trial. Some treatments may be available for “NED after relapse” via “compassionate use” such as ABT-751. This is an important item for discussion with your child’s doctor.