High Risk Neuroblastoma Treatment

All treatments for newly diagnosed high risk neuroblastoma share many components, but differences in protocols do exist, due to continued efforts to increase survival rates using various approaches. Currently, each of the national and international cooperative pediatric oncology groups, such as the Children’s Oncology Group (COG), the International Society of Pediatric Oncology (SIOP), and the German Society for Pediatric Oncology and Hematology (GPOH), have clinical trials for newly diagnosed NB cases. In addition, some institutions treating a large number of NB cases, such as Memorial Sloan-Kettering Cancer Center (MSKCC), Baylor/Texas Children’s, and St. Jude’s Children’s Research Hospital, have their own single-institution or multi-institution frontline protocol. The chemotherapy agents (and their administration and dose), number of induction cycles, timing of stem cell collection, timing of surgery, type of radiation therapy, use (or not) of transplant, conditioning regimen for transplant, timing of Accutane, and use (or not) of antibodies – all of these components differ somewhat in the various frontline protocols.

The following summary has been prepared by NB parents in the hope it will help you have a more meaningful dialogue with your NB team – who is always the ultimate source of information about NB treatments and their relevance to your child’s specific case.

The induction phase is the initial phase of treatment aimed at ridding the body of all detectable NB using chemotherapy and surgery. During induction the child will have a central venous line placed, then undergo chemotherapy, surgery to remove the primary tumor and affected lymph nodes, stem cell harvest, and tests, scans, and bone marrow biopsies to monitor response to treatment. If the child responds with a “complete response” (CR) or in some cases “very good partial response” (VGPR), he or she moves on to next phase called “consolidation.”


Central Venous Line (CVL)
Chemotherapy
Growth Factor
Stem Cell Harvest
Surgery
Neuroblastoma Consolidation Phase
Stem Cell Transplant: 1, 2, 3 or 0
Radiation
Treating Minimal Residual Disease
Accutane
Monoclonal Antibodies
Vaccines

Central Venous Line (CVL)

Children undergoing chemotherapy have some type of central venous access device placed before chemotherapy begins.  Usually a single or double Broviac™ or Hickman™ central line will be placed, although some children receive a single or double “port”—a device implanted under the skin that is accessed by a special needle.  Some type of venous access is necessary because in addition to chemotherapy treatments, the child will need blood and platelet transfusions, IV medications, and fluids for hydration. Double lines are required for stem cell transplant.  In addition, blood samples are needed quite frequently, and these can be easily obtained through a central line or port with minimal trauma to the child.  For additional information, see Chapter 3, “Central Venous Lines: Broviacs, Hickmans, & Ports.”

Chemotherapy

Various combinations of high-dose chemotherapy are administered intravenously for a few days out of approximately every 21 days (or 10 days in Europe), for five to eight cycles, usually inpatient. The table below lists the agents used in various protocols, but the dosages are not all the same.  (This is not an exhaustive list of current protocols.)


Chemotherapy Agents used in Selected High-Risk Induction Protocols

Study group

COG[1]

SIOP[2]

GPOH[3]

MSK[4]

TXCCC[5]

Phase

III

III

III

II (pilot)

II (pilot)

Accrual

495

1000

360

<100

30

Cycles

6

8

6/8*

5

5

length of cycle, days

21

10

21

21

21

CHEMOTHERAPY AGENTS

Cisplatin

X

X

X

x

X

Carboplatin

 

X

 

 

 

cyclophosphamide/Cytoxan

X

X

X

x

X

doxorubicin/Adriamyacin

X

 

X

x

X

etoposide/VP-16

X

X

X

x

x**

Vincristine

X

X

X

x

 

Topotecan

X

 

x*

 

 

Vindesine

 

 

X

 

 

Dacarbazine

 

 

X

 

 

Ifosfamide

 

 

X

 

 

*GPOH randomizes half enrolled to extra two cycles containing topotecan.
**Both low dose oral and high dose IV etoposide used.
COG Children’s Oncology Group; SIOP International Society of Pediatric Oncology; GPOH German Pediatric Hematology Oncology Group; MSK Memorial Sloan-Kettering Cancer Center, New York; TXCCC Texas Children’s Cancer Center, Houston/Baylor

For example, the COG protocol uses six cycles, the German protocol uses either six or eight cycles (half are randomized to two extra cycles of topotecan), and the European SIOP protocol uses eight 10-day cycles of a rapid chemotherapy administration (termed “Rapid COJEC”). MSKCC’s protocol uses five cycles of induction chemo. Baylor/Texas Children’s pilot protocol also uses five cycles, but includes low-dose etoposide and high-dose cisplatin in the first two cycles to determine if an improved response rate will result from a high-dose/low-dose mix (called “chemo-switching”).

Growth Factor

A growth factor (granulocyte colony stimulating factor or G-CSF) is administered in most protocols after each cycle of chemotherapy to boost white cell count recovery. G-CSF is usually given as daily injections until the white cell count reaches a prescribed level.  The use of G-CSF is randomized in the current SIOP protocol in Europe (see appendix below).

Stem Cell Harvest

All high-risk NB treatment protocols currently include a collection of peripheral blood stem cells, ideally as soon as the bone marrow is clear of NB. Early collection minimizes the stem cell exposure to chemotherapy and clear bone marrow minimizes the chance for contamination with NB tumor cells.  Whether or not the collected stem cells should be “purged” (i.e., subjected to a laboratory process to remove any NB cells)  was answered by the recent (2000-2006) randomized study COG-A3973, which showed purging stem cells did not increase survival rates.  The advantage to not purging is that some of the stem cells could be damaged or lost in the expensive purging process.

The harvest may be done as early as after the second round of induction chemotherapy (COG, MSKCC, and GPOH) or as late as after the last round (SIOP). Stem cells are boosted after a cycle of chemotherapy by administering daily G-CSF shots for a week or more, until white blood count is high enough to begin collection. This stimulates the bone marrow to push stem cells out into the peripheral blood.

The collection is performed through a process known as “apheresis.” Blood is drawn and passed into a machine that spins the blood to remove certain stem cells (those identified as “CD34+”), and then the blood is returned to the child. Apheresis may be scheduled on an outpatient basis in the blood bank, or your child may be admitted to the hospital, depending on the institution’s practice.  Your child may or may not require placement of a special apheresis line or catheter to collect stem cells. This process is usually done over a few consecutive days to collect enough stem cells.

At least 2 million cells per kilogram (child’s weight) are required for one rescue. The stem cells are tested for the presence of NB cells with very sensitive methods (RT-PCR immunocytohistochemistry) and used only if no NB cells are detected (i.e., no NB cells detected per 500,000 stem cells). The stem cells are divided into “rescue” doses and frozen with a preservative called DMSO (dimethyl sulfoxide; this causes the distinct smell of “creamed corn” when thawed and reinfused in the child during “rescue”).  The cells will be tested for viability before use, and have been used successfully as long as 8 to 10 years after collection.

Most protocols use the collected stem cells for autologous stem cell transplant (ASCT) in the consolidation phase of treatment.  However, even children that do not undergo ASCT may have need for stem cells later, as some NB treatments may be damaging to the bone marrow and a stem cell “boost” may be given to help rejuvenate bone marrow. 

In the event a child’s disease is deemed refractory (resistant to treatment) or relapses (recurs), having stem cells on hand can make the difference between qualifying for a promising new treatment or being ineligible. For this reason, it is advisable to discuss with your doctor the quantity of stem cells that will be collected, with an eye toward any necessary long-term treatment. Most neuroblastoma patients are small at diagnosis (average age of 2), so it is also important to consider the potential growth of a child who might double or triple in size, thus requiring a much larger amount of cells for a future rescue.

Surgery

All high-risk NB patients undergo tumor resection, usually after receiving at least 3 cycles of chemotherapy. In some cases, a surgeon may be able to remove the primary NB tumor at biopsy, but this is rarely the case, because high-risk NB tumors are invasive and notorious for growing around major blood networks and organs. The surgeon carefully plans the surgery to remove the primary tumor as well as all suspicious lymph nodes while aiming to spare organs. Chemotherapy helps shrink the tumor and makes removal less difficult, although resection of a high-risk NB is still considered a difficult and major surgery. Parents should expect their children to be in the operating room at least five hours and sometimes as long as 12 hours or more.  The timing varies according to different protocols. Surgery may be done after the second (TXCCC), third (MSKCC), fourth (GPOH), fifth (COG), or eighth cycle (SIOP) of induction chemotherapy. 

The necessity of full removal (gross total resection) in high-risk cases remains a subject of controversy among some NB specialists. Some oncologists believe that total removal of the primary tumor, though desirable, is not a necessity because chemotherapy and radiation given subsequent to surgery will destroy any remaining disease, and cite complications in difficult surgeries. Others have concluded that complete resection is related to increased survival. 

For example, referring to this controversy, Dr. Michael LaQuaglia, author of “The Role of Surgery in the Treatment of Neuroblastoma” in the 2005 pediatric oncology text Neuroblastoma (Cheung & Cohn, eds.), says:
“Despite doubts as to the feasibility, safety, and efficacy of surgical resection in high-risk neuroblastoma, the present consensus in the Children’s Oncology Group (COG), and European and Japanese cooperative groups is that an aggressive resection of loco-regional disease should be attempted. Surgery has an even more important role in low- and intermediate-risk disease.” [13]

Parents with children who have tumors deemed to be unresectable often decide to seek another opinion from an experienced NB surgeon who routinely removes difficult tumors, such as Dr. Michael LaQuaglia in New York City, Dr. Robert Shamberger in Boston, Dr. Andrew Davidoff in Memphis, or Dr.  Jed Nuchtern in Houston, among others.  See Chapter 1, U.S. Neuroblastoma Specialists.

Neuroblastoma Consolidation Phase

Consolidation therapy is anti-cancer treatment given when a child is in complete remission (CR) or very good partial remission (VGPR), aimed at killing any remaining cancer cells. Consolidation therapy varies according to different protocols.

Stem Cell Transplant: 1, 2, 3 or 0?

Stem cell transplant (also referred to as myeloblative therapy) is currently the most frequently used form of consolidation. Terminology surrounding stem cell transplant can be confusing, as many terms used are synonymous.  Autologous means the stem cells are one’s own, and allogeneic means the source of stem cells is a donor. Most NB treatments use autologous stem cells collected from the patient’s peripheral blood. Peripheral blood stem cells engraft much faster than cells surgically removed from the bone marrow, so “bone marrow transplants” are much less common in NB treatment today.[14]  You will see the synonymous terms peripheral blood stem cell transplant (PBSCT), stem cell transplant (SCT), autologous stem cell transplant (ASCT), hematopoietic stem cell transplant (HSCT), and high-dose chemotherapy with stem cell rescue (HDC/SCR) all used interchangeably.

Stem cell transplant is high-dose chemotherapy or other treatment so severely suppressing the bone marrow that a subsequent “transplant” or “rescue” infusion of stem cells is required. Transplant has been frequently used since the 1980s for consolidation for high-risk NB.  Three randomized studies of patients accrued since the 1980s -- most notably the phase III study CCG-3891 conducted by the Children’s Cancer Group and published in 1999 -- have suggested that survival is improved with transplant.
Subsequently, autologous stem cell transplant has been widely adopted for treatment of high-risk NB. Double and triple autologous tandem transplants have also been tested in pilot studies, as well as allogeneic transplants.

The recent phase III study COG-A3973, as noted above, showed no need for purging stem cells used for rescue at transplant, and other important changes in treatment adopted for that study included the use of higher dose induction chemotherapy, using stem cells from peripheral blood rather than bone marrow, and local radiation rather than TBI. The current COG phase III transplant study, ANBL0532, began accruing patients in December 2007 and randomizes them to either a single or double (tandem) autologous stem cell transplant with local radiation (no TBI).

Some institutions offer their own unique regimens for transplant, such as using donor or cord blood for the source of stem cells, or using a new combination of chemotherapy, or using triple tandem transplants, and some institutions use protocols from closed trials. Most conditioning regimens use mega-doses of chemotherapeutic agents—usually drugs not used in the induction phase—while less common regimens use chemo with total body irradiation (TBI) or MIBG radiation therapy. In the current European SIOP trial, children are randomized to one of two different chemo combinations.

A notable exception to the use of transplant for high-risk NB cases is MSKCC, whose frontline protocols have not included stem cell transplant since 2004 and instead use antibody treatment for consolidation. Doctors at MSKCC say they have not observed myeloablative consolidation treatments to have a significant impact on survival rates in their studies over the past 15 years.[22]  After successful response to induction chemotherapy and surgery, patients on MSKCC’s current protocol move on to local radiation, 3F8 antibodies, and Accutane.

Radiation

Children diagnosed with high-risk disease routinely undergo radiation therapy after induction chemotherapy and surgery. In protocols that include stem cell transplant, radiation therapy usually begins after the patient is released from the hospital.
Even children whose tumors have been completely removed receive radiation to the primary site of disease.  Some institutions also radiate bone sites where NB was present at diagnosis, even if those tumors have completely responded to chemotherapy; other places radiate only the spots still showing before transplant. At least one protocol includes MIBG radiation therapy if remaining disease is detected by MIBG scan before transplant.

Neuroblastoma is generally responsive to radiation, but because intensive radiation treatment poses a significant risk of causing secondary cancers and other health issues, doctors try to use the minimum effective dose. Also, radiation beams must be carefully pinpointed to avoid damaging nearby organs, so children undergo a planning session with three-dimensional CT scan simulation before treatment starts.  They may receive tiny pinpoint tattoos that are used to align the radiation beams.  For children receiving radiation to the head or orbits, a mask is made that can be fastened to the radiation table, so the child does not move during the treatments.  Similar “forms” may be made to hold a child’s arm or leg in position, if treatment to those areas is necessary.
External beam, MIBG radiation therapy, total marrow irradiation (TMI or TomoTherapy), proton beam, radiosurgery (Gamma knife), intraoperative radiation therapy (IORT), and intensity-modulated radiation therapy (IMRT) are various ways radiation can be delivered, depending on the protocol and the patient’s circumstances.

Treating Minimal Residual Disease

One of the things that makes NB so difficult to cure is the fact that even when it cannot be found through scans, lab tests, or bone marrow biopsies, the disease can still be present in very small amounts in the body.  Doctors believe that this undetectable disease can sometimes smolder and grow, eventually coming back as relapsed NB, which is much harder to cure.  Accutane and antibodies are two strategies that have been developed to help eradicate undetectable disease, but the two work in very different ways. Much research on vaccines against NB has been accomplished, but use after frontline therapy is a new development.

Accutane

Accutane, or 13-cis retinoic acid, is a synthetic vitamin A derivative that has been shown to stop the growth of NB cells.  Accutane can cause some NB cells to mature (differentiate) into non-cancerous cells.  A five-year (1991-1996) randomized study (CCG-3891) concluded that high doses of Accutane improved the event-free survival for children in remission.  Since those findings were published in 1999, the use of Accutane has become widely accepted for high-risk NB.

Accutane is given by mouth in capsule form in two-week on/off cycles—the medicine is taken twice a day for two weeks, then children take no medication for two weeks.  Typically, children receive Accutane over six months. In the German NB2004 protocol it is given for six months with a three-month break, and then three more months.

Accutane has many side effects, but most are mild, including dry skin, moodiness and sun sensitivity. Because some of Accutane’s side effects can be more serious, children are monitored during their Accutane treatment with regular check-ups and blood draws (particularly for calcium levels and triglycerides). 

It is extremely important that pregnant women, and those who may become pregnant, follow strict safety precautions when handling Accutane, because ingestion of the drug (which can be absorbed through the skin) poses a risk of serious birth defects and deformities.

Monoclonal Antibodies

Our bodies manufacture antibodies that create an immune response to bacteria, viruses, and other foreign substances to help keep us healthy.  Ordinarily, a child’s immune system will not attack NB because the cancer is a part of the child’s body.  Monoclonal antibody therapy (monoclonal refers to development from one clone) uses mouse antibodies produced in the laboratory from plasma (myeloma) cells. The antibodies used in NB treatment attach to a ganglioside (a fat-sugar complex molecule) on the NB cell called GD2. Because the antibody alerts the child’s own immune system to attack the NB cell the antibody is attached to, the cancer cell is destroyed. Long-term immune response may be initiated by antibody treatments in some cases.

COG currently offers a phase III study (COG-ANBL0032) of the monoclonal antibody ch14.18 (administered with “cytokines” to augment the immune response to the antibody) to patients following completion of frontline treatment protocols that include stem cell transplant. After an early review of 226 children enrolled determined significantly higher survival with antibodies, the study was amended in April 2009 to stop randomization and allow all patients subsequently enrolled to receive the antibody.  The study will continue until final accrual goal of 423 is met, and it is anticipated that ch14.18 will be part of standard treatment for all COG protocols.  The ch prefix indicates the antibody is “chimeric” or part human (75%) and part mouse (25%) in its formulation. In the current European SIOP trial the use of the same antibody ch14.18 is randomized (but without the use of cytokines).  Note that the similar protocol number of COG-ANBL0322 using a different but similarly named antibody, hu14.18-IL2, is a closed phase II study which was open only to children with relapsed or refractory NB. The hu prefix means the antibody is completely humanized.

MSKCC uses a 100% mouse-derived 3F8 antibody treatment for high-risk patients who complete induction therapy with a good response. GM-CSF (granulocyte-macrophage colony-stimulating factor—a “cytokine” that stimulates the immune system) is usually given with 3F8. This antibody has been in use for two decades. MSKCC reports that their studies have shown improved survival among their patients who successfully complete at least four cycles of 3F8 antibody therapy.

Vaccines

Various vaccines against neuroblastoma have been created and tried in relapsed and refractory children, but recently the CHESAT vaccine became available in a trial in Houston TX for children who have successfully completed frontline therapy with a single transplant.

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