Introduction

This meeting was sponsored by the Paget Foundation and involved more that 20 researchers and clinicians from the U.S. and four other countries. Extensive evidence was presented on the use of bisphosphonates for treating all cancers that metastasize to the bone. These are lecture notes from one of the attendees of this meeting.

Studies presented at this meeting showed that bisphosphonates reduced pain, slowed the growth and spread of bone metastases, reduced tumors and kept patients alive longer. The bisphosphonates do this in a dose-dependent fashion. In addition, when these compounds are given earlier in the course of illness the overall prognosis of the patient appears improved. There was other evidence that bisphosphonates could cause the death of myeloma cells. And a prominent myeloma specialist said his group had found a viral cause for multiple myeloma.

Symposium Chairman Greg Mundy told the group that studies by his group at the University of Texas Health Science Center, show there now is clear evidence that bisphosphonates inhibit the growth and spread of bone lesions and reduce the number of tumors. Other doctors echoed these findings in their presentations and several said bisphosphonates in sufficient doses actually cause tumor cells to die. Throughout the two-day seminar presentations of the effects of bisphosphonates showed:

• Bisphosphonates ease pain and slow the spread and growth of metastatic cancers.

• Present doses are sub-optimal.

 In the U.S. the standard dose for Aredia is now 90 mg once a month. But the doctors who supervised FDA studies for this protocol are now starting trials at much high doses. Dr. James Berenson (NEJM Feb. 21, 1996) is starting trials at 180 mg every 14 days. Symposium Co-chairman Dr. Alan Lipton of the Hershey Medical Center, Pa. (NEJM Dec. 12, 1996) is doing a trial in which he "pre-loads" breast cancer patients with 150 mg. a day for three days and then gives monthly infusions from 90 mg to 150 mg a month. Dr. Robert Coleman reported "significant beneficial effect" by giving metastatic cancer patients 120 mg infusions "on demand." Most of the patients reported less pain and their markers from bone resorption dropped as did markers for tumor growth.

 Toxicity from Bisphosphonates

The bisphosphonates were all reported to be well tolerated. But about 30 per cent of patients report a transient increase in pain during early infusions. There were some reports of anemia, but not greater than in control groups and very rare reports of eye inflammation that can be effectively treated with local or if necessary systemic steroids.

Bone resorption may be linked to cancer cell growth

Physicians reported success with virtually all IV bisphosphonates in treating of a variety of bone cancer including myeloma, breast, prostate and other cancers that metastasize to the bone.

The success of the bisphosphonates was in their ability to prevent tumors from dissolving bone thus stopping the cancers use of the byproducts of bone resorption. Cancer cells stimulate bone destruction which in turn releases cytokines or growth factors that stimulate cancer cell activity and growth. Bisphosphonates interrupt that activity, slowing metastatic bone cancer growth and spread and causing cell death of some cancer cells. In multiple myeloma, tumor deposits stimulate IL-6 production and other factors to increase bone resorption. In breast and prostate cancers tumors produced parathyroid hormone related peptide (PTH-rP) which initiates bone resorption. Bone resorption then stimulates prodigious quantities of IL-1, IL-6, TGF-beta, TNF-alpha, prostaglandin and lymphotoxins which are used by cancer cells for growth.

Dr. Theresa A. Guise form the University of Texas Health Center reported high dose dexamethasone inhibits PTH-rP in animals and has a synergistic effect when used with bisphosphonates in reducing tumor growth in mice. PTH-rP production can be suppressed with high-dose bisphosphonates in animals although proper design for humans has yet to be worked out.

Osteoblastic tumors are most evident in prostate cancer. But Dr. Silvano Adami, Professor of Rheumatology at the University of Verona, Italy, and John A. Kanas, in separate presentations, explained that osteoclasts first prepare sites by destroying bone surfaces, thus providing a foundation for osteoblasts (bone building cells) to construct tumors.

The effectiveness of bisphosphonates in reducing pain, and markers of bone destruction were confirmed by other researchers in the U.S. and England.

Reports of newer, more potent bisphosphonates were available from researchers in Europe. there was general agreement of the potency of the various bisphosphonates:

 The more powerful the drug, the less that was needed for infusion and the more dramatic and long lasting were the effects. There was general agreement among the researchers that the more potent the dose, the earlier that the patient began bisphosphonate therapy, the better the outcome. A 2 mg infusion of Zolendronate was more effective than 90 mg of Pamidronate in reducing pain and markers related to bone destruction and tumor growth. Zolendronate had a faster onset and longer duration of action of all the bisphosphonates. Dr. Berenson is about to publish studies of the phase 1 reports on Zolendronate given as a three minute injection.

No one is sure exactly how the bisphosphonates work other than they are absorbed mostly at the sites of cancer-caused bone damage, coat the surface of the bone there and inhibit osteoclasts from destroying bone. There are some theories that bisphosphonates are absorbed by the osteoclasts resulting in direct damage to osteoclast function. There have been other studies that indicate bisphosphonates are absorbed by osteoblasts too; this may inhibit their destructive instructions to the osteoclast.

Gallium Nitrate

Dr. Raymond Warrell Jr. of Sloan Kettering , New York showed that gallium nitrate infusions inhibited pain, produced apoptosis and reduced markers associated with metastases. Its mechanism is different from bisphosphonates in that it probably inhibits the osteoclast ATPase-dependent proton pump. But it appears to be as effective as Pamidronate. A trial of 40 mg subcutaneous injections for 14 consecutive days of every month for six months is underway to confirm these findings.

Pain Can Make You Sicker

In a presentation on pain management Dr. Richard Payne of the MD Anderson cancer center urged doctors to treat pain early and aggressively. He said that cancer-caused pain stimulated a series of factors that, if not treated quickly, produce a vicious cycle of pain, muscle spasms and more pain resulting in increasing agony to patients. Some of the byproducts of this syndrome-- prostaglandin in particular -- are implicated as growth factors for cancer cells.

The above helped explain the unusual nature of some bone cancer pain, particularly the stiffness and soreness that patients feel. Doctors may dismiss general stiffness and soreness among cancer patients as "non-specific" specific pain. But according to Dr. Payne it can be directly related to the by-products of cancer-caused bone resorption. Growth factors for cancer stimulate chemical pain signals in areas of cancer growth without mechanical stimulation (cracks, crushes or breaks). Dr. Paynes's presentation provided a possible explanation for other pain suffered by some patients following bisphosphonate treatment. Several researchers at the seminar explained that some markers for bone destruction increased or flared for up to three days after bisphosphonate treatment. These growth factors then dropped dramatically for several weeks. The increase in bone resorption factors could account for the flare or phase reaction pain reported in some patients. One doctor talked about success in relieving pamidronate reactions with steroids.

Dr. Lance Liotta of the National Institute of Health told the group that cancers that destroy the bone result from a ten-year history of genetic changes in cells. That means that destroying the myeloma itself will not destroy the disease because precursor cells are there to reestablish it. But he said researchers are already ahead of schedule on establishing a genome library and that laser and computer technology now allows researchers to microdissect precursor and cancer cells to detect the changes at the genetic level and then develop strategies to prevent cancer development.

If you are not getting an IV bisphosphonate treatment for bone cancer at any stage, you are not getting good treatment. If you are getting 90 mg. a month, you are probably not getting enough.

These notes were provided to me by a patient attendee of this meeting.