Children's Neuroblastoma Cancer Foundation

Introduction
Most of the current treatments of neuroblastoma and other cancers target the tumor cell itself. For example, chemotherapy agents like cyclophosphamide and cisplatin kill rapidly dividing cells (i.e. tumor cells), radiation is beamed directly at tumors, and the surgeon removes visible masses. Although targeting the cancer cells with these methods has been beneficial, the success rate for curing neuroblastoma is nowhere near where we would like to be. We must continue to look in new directions for effective treatments.

Metastatic tumors are tumor cells that spread from the original tumor to distant sites of the body, their presence signifies an aggressive tumor. The sites of metastatic spread are not random. Neuroblastoma most commonly spreads to the bone marrow (70%) and bone (56%), and less commonly to the lymph nodes, liver, or soft covering of the brain [1]. Bone metastases, the focus of this article, cause problems for children because they are painful, they weaken the bone leading to fractures, and they are a common place for recurrent tumors.

In the late 1800’s, a forward thinking surgeon named Stephen Paget introduced his hypothesis of why tumors spread in set patterns. He recognized that tumor cells (seeds) need the body to survive and that they will grow best in those sites where the normal environment (soil) is the most fertile for them[2]. This theory is known as the seed and soil hypothesis and provides the rationale behind a new direction for fighting tumors: changing the soil so the seeds don’t grow. In this article I hope to explain the environment of the bone, how neuroblastoma tumor cells grow there, and a new trial to interrupt their interactions.

Normal Bone
Bones provide form and structure to our limbs and protection to our heart, lungs and brain. The bone, or cortical bone, is the hard outer layer surrounding the bone marrow, the site of production of blood cells. It is important to understand that bone and bone marrow are separate organs; although they are located close together, the cells that reside in each and the functions each serves in day-to-day activities are different. Although bone appears solid and seemingly immovable, it is actually quite dynamic. It grows as the child grows, strengthens areas that are weak, and heals after breaks.

Three key players maintain cortical bone: the bony matrix, osteoclasts and osteoblasts. The bony matrix is a hard concrete-like structure that is mostly made of calcium. To make it stronger collagen is woven throughout, similar to rebar-reinforced block of concrete. Embedded within this structure are numerous chemicals that act as growth factors, encouraging the cells whose job it is to maintain the matrix. (Figure 1)

Osteoclasts dissolve and destroy old matrix so that it can be replaced. These cells use acids and enzymes to break down the calcium and collagen structure and then absorb some of the waste products into themselves. As they work, they form physical cavities within the bone matrix. These cavities need to be filled with new matrix, a function performed by osteoblasts. Osteoblasts are also important for bone growth so are very busy in growing children. Osteoclasts and osteoblasts talk back and forth through chemical signals. It is important that they balance one another. If osteoblasts become too active, the bone may become too thick or misshaped. Overactive osteoclasts can weaken the bone leading to breaks.

Neuroblastoma Metastases to Bone
Almost all children with neuroblastoma have a primary tumor mass. This is where the neuroblastoma began and grew to form an actual tumor. These primary masses are usually found in the adrenal gland or along the nervous system. For about half of these children, tumor cells will be detected elsewhere as well. These other sites of disease are called metastases and are the oncologist’s initial predictor of how aggressive the tumor will be. The mechanisms behind the cause of metastases are beyond the scope of this article, but some general points can aid understanding bone metastatses. In order for a metastasis to occur, tumor cells must break free of the primary mass and circulate around the body, frequently via the blood stream or lymphatic system. While circulating, they are looking for other areas that would provide them with a good growth environment.

Neuroblastoma cells are attracted to the bone. Once there they need a physical space to survive so they signal the osteoclasts to come near and dissolve a hole in the matrix[3]. In the process, the tumor cells take in some of the growth factors within the matrix which makes them even more active, divide more, and recruit even more osteoclasts[4]. This process continues until the bone is destroyed. (Fig 2)

Bisphosphonates
Bisphosphonates were originally used to fight osteoporosis. These drugs work by killing osteoclasts. Once in the blood stream, bisphosphonates rapidly attach to the bone matrix. Osteoclasts absorb the bisphosphonates as they destroy and absorb the matrix[5]. The end product is less osteoclast activity, less bone destruction, less growth factors encouraging tumor growth and less physical space for the tumor cells to live. Clinical trials in adults with breast or prostate cancers have shown that bisphosphonates can prevent or slow down bone metastases in some patients[6,7]. Dr DeClerk and colleagues have successfully used bisphosphonates to slow down neuroblastoma bone tumors in mice[3].

Because bone metastatses from neuroblastoma are common, bisphosphonates seem worthy of study. Zometa, the most recent bisphosphonate to be released and the most effective in adult studies, is the focus of a new NANT (New Approaches to Neuroblastoma Therapy) phase I study opening this spring. Zometa has not been studied in children before but other bisphosphonates have been used for a variety of reasons and seem to be well tolerated. Symptoms such as fever, body aches, nausea, and low calcium levels were common but manageable. A small subset of patients develop kidney problems that appear to go away if the drug is stopped[6,7]. This current study is a phase I clinical trial meaning it will serve to find a safe dose for further study. Zometa is given once a month through an IV, the dose will take about 15 minutes. Because Zometa does little to target tumor cells outside of the bone, this study will give an oral daily dose of cyclophosphamide as well. Children on the study will be evaluated for side effects and effects on the tumor. This study will also look at how we best measure bone tumors. We will be using standard imaging studies (radiographs, bone scans, MIBG scans) and specialized urine and blood studies to help us define how we study these tumors in the future.

The purpose of this study is to begin to understand whether bisphosphonates can help in the fight against neuroblastoma. It will help us to define safe doses for future studies, clearer ways to measure bone tumors, and a better understanding of how tumors and bone interact. It is unlikely that one new drug or one new idea will solve the entire problem of neuroblastoma. It does, however, provide hope that there are new agents on the horizon and stimulates us to continue to ask questions and look for the answers.

Reference List

1. DuBois, SG, Kalika, Y, Lukens, JN et al. Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol 1999;21:181-189.

2. Fidler, IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 2003;3:453-458.

3. Sohara Y, Shimada, H, Scadeng M et al. Lytic bone lesions in Human Neuroblastoma xenograft involve osteoclast recruitment and are inhibited by bisphosphonate. Cancer Res 2003;63:3026-3031.

4. Mastro AM, Gay CV, and Welch DR. The skeleton as a unique environment for breast cancer cells. Clinical and Experimental Metastasis 2003;20:275-284.

5. Dunford, JE, Thompson, K, Coxon, FP et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 2001;296:235-242.

6. Coleman, MP. Efficacy of zoledronic acid and pamidronate in breast cancer patients: a comparative analysis of randomized phase III trials. Am J Clin Oncol 2002;25:S25-S31.

7. Saad, F, Gleason, DM, Murray, R et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458-1468.