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Current use of bisphosphonates in oncology. International Bone and Cancer Study Group.
PURPOSE: The purpose of this article is to review the recent data on bisphosphonate use in oncology and to provide some guidelines on the indications for their use in cancer patients. DESIGN: The group consensus reached by experts on the rationale for the use of bisphosphonates in cancer patients and their current indications for the treatment of tumor-induced hypercalcemia and metastatic bone pain in advanced disease and for the prevention of the complications of multiple myeloma and of metastatic bone disease are reviewed. RESULTS: Bisphosphonates are potent inhibitors of tumor-induced osteoclast-mediated bone resorption. They now constitute the standard treatment for cancer hypercalcemia, for which we recommend a dose of 1,500 mg of clodronate or 90 mg of pamidronate; the latter compound is more potent and has a longer lasting effect. Intravenous bisphosphonates exert clinically relevant analgesic effects in patients with metastatic bone pain. Regular pamidronate infusions can also achieve a partial objective response by conventional International Union Against Cancer criteria and enhance the objective response rate to chemotherapy. In breast cancer, the prolonged administration of oral clodronate 1,600 mg daily reduces the frequency of morbid skeletal events by more than one fourth, whereas monthly pamidronate infusions of 90 mg for only 1 year in addition to chemotherapy reduce by more than one third the frequency of all skeletal-related events. The use of bisphosphonates to prevent bone metastases remains experimental. Last, bisphosphonates in addition to chemotherapy are superior to chemotherapy alone in patients with stages II and III multiple myeloma and can reduce the skeletal morbidity rate by approximately one half. CONCLUSION: Bisphosphonate use is a major therapeutic advance in the management of the skeletal morbidity caused by metastatic breast cancer or multiple myeloma, although many questions remain unanswered, notably regarding the optimal selection of patients and the duration of treatment.
[Supportive care: some definitions and principles].
Supportive care is defined as the totality of medical, nursing, psychosocial and rehabilitative support from the onset of the disease until possible fatal outcome, including all active therapeutic phases. This concept is thus quite large and heterogeneous. The term palliative care is reserved for the approach to the terminal patient. Hospital "Palliative Medicine" should be considered as a subspecialty of Internal Medicine and Medical Oncology. In palliative medicine, symptom control, and no longer prolongation of survival, takes a preponderant place to finally become the only goal to reach. In our mind, a Palliative Care Unit is not necessarily the final stay of a patient where spiritual support will be preponderant. One of our essential goals is always that the patient can come back in his family in collaboration with the family doctor, even for a short time. The ideal situation consists in short stays in the Unit to treat an acute complication before the patient is sent back home or to his Residency. Along this line, a very close collaboration with the family doctor is absolutely essential.
[Treatment of cancer pain: the role of co-analgesics].
Opioid analgesics are widely acknowledged as the most important drugs for the treatment of chronic cancer pain. Although these drugs can in most cases control severe pain, even when they are used appropriately, they may produce new symptoms or exacerbate preexisting symptoms, most notably nausea and somnolence. The combination of severe pain, anorexia, chronic nausea, asthenia, and somnolence is a frequent finding in patient with advanced cancer. An adjuvant drug should meet at least one of the following criteria: 1) to increase the analgesic effect of opioids; 2) to decrease their toxicity; 3) to improve others symptoms associated with terminal cancer. Many drugs, such as nonsteroidal antiinflammatory agents, tricyclic antidepressants, corticosteroids, benzodiazepines, amphetamines, antiemetics, oral local anesthetics and bisphosphonates have been suggested to have adjuvant analgesic effects. Unfortunately, most of the evidence for the effects of these drugs is anedoctal. Controlled clinical trials are badly needed to precise the indications and the risk/benefit ratios of these agents, some of which have significant toxicity and could potentially aggravate narcotics toxicity.
[Nutritional and digestive disorders in palliative care].
The anorexia-cachexia syndrome is a particularly frequent complication of advanced cancer. Parenteral nutrition must remain the exception in palliative medicine but enteral nutrition through feeding tubes or by a gastrostomy is an efficient method to provide an adequate long term nutritional support at home which can improve the quality of life of the palliative care patient. One must never forget all simple means to improve nutritional status. Since the cost benefit ratio of the medications stimulating the appetite, such as the corticosteroids and the progestatives, must still be demonstrated in palliative medicine. Hiccups therapy is essentially based on several non pharmacological means and on the administration of metoclopramide, antacids, haloperidol or chlorpromazine. Chronic nausea is an extremely frequent problem in palliative care, treated most often by metoclopramide, haloperidol and corticosteroids. Constipation is another extremely frequent problem which can lead to serious complication if left untreated. Besides general means, therapeutic means essentially comprise drugs such as lactulose and macrogol, bisacodyl, docusan and prokinetic agents like cipraside.
[Hypodermoclysis, a neglected approach].
Patients with advanced cancer frequently present with chronic nausea, emesis, bowel obstruction, confusional syndromes or dysphagia. All these conditions make it difficult for the patient to take oral medications or to maintain an adequate level of hydration by mouth. Hypodermoclysis is a safe and simple method that allows for cost-effective sucutaneous delivery of fluids and drugs. Hypodermoclysis has some clearcut advantages over the i.v. route. It can be started without need for a physician or a nurse, does not immobilize a limb, can be stopped and restarted at any moment without concern for clotting, and its use sparses nursing time. It also allows for easier and safer home discharge. Potentiel side effects of hypodermoclysis include pain at infusion site, sloughing tissues as a result of insufficient fluid absorption, infection, and puncture of vessels with bleeding. This paper gives some guidelines for the use of hypodermoclysis for fluid, electrolytes and drugs frequently used in a palliative care setting. The controversy surrounding the treatment of dehydration in the terminally ili is also briefly examined.
Clinical research update: zoledronate.
The prolonged administration of bisphosphonates can reduce the frequency of morbid skeletal events in patients with metastatic breast carcinoma or multiple myeloma. The development of more potent bisphosphonates will simplify current therapeutic schemes and could improve the therapeutic effectiveness of bisphosphonate therapy. Zoledronate (CGP-42446) is the most potent of the clinically tested compounds. It is a cyclic third-generation bisphosphonate that is 100-850 times more active than pamidronate in several in vivo and in vitro pharmacological test systems. The first therapeutic trial with zoledronate has been performed in patients with tumor-induced hypercalcemia (corrected calcium [Ca] > 2.75 mmol/L after rehydration). In a Phase I multicenter trial, it was shown that a single infusion was already effective at dose levels of 0.02 and 0.04 mg of zoledronate/kg bodyweight, thus 1.2 and 2.4 mg total dose for an average 60-kg individual. Five of 5 patients became normocalcemic after a dose of 0.02 mg/kg, and 14 of 15 (93%) after a dose of 0.04 mg/kg. The median time to normalization of serum Ca was 2 days and the median duration of action was 33 days, suggesting that zoledronate has a faster onset and a longer duration of action than other clinically tested bisphosphonates. Zoledronate was well tolerated; the only side effect was an increase in body temperature in 30% of the cases, which was probably not drug-related in many patients. A Phase I trial also has been initiated in patients with lytic bone metastases. Zoledronate was given as monthly short infusions (5-30 minutes) at doses between 0.1-8.0 mg. There was an analgesic effect and even at low doses (2 mg and above), the effects on the biochemical markers of bone resorption appeared to be greater than after 90-mg pamidronate infusions. These initial human data suggest that zoledronate can be administered as convenient short intravenous infusions and lead to a more marked and a more prolonged inhibition of bone resorption than is currently possible with available compounds. Future trials will have to determine whether prolonged treatment with this extremely potent bisphosphonate also can have a greater effect on the morbidity of bone metastases.
Retrobulbar optic neuritis after pamidronate administration in a patient with a history of cutaneous porphyria.
We describe the case of a patient who developed reversible retrobulbar optic neuritis after intravenous pamidronate therapy for established osteoporosis. This possible complication has never been previously reported and, since our patient had a history of porphyria, it suggests that bisphosphonates should be administered cautiously in patients with this disease.
Prevention and treatment of postmenopausal osteoporosis. National Consensus of the "Belgian Bone Club", November 1996.
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Regulation of c-fos and c-jun expression by calcitonin in human breast cancer cells.
Breast cancer cells (BCC) have calcitonin (CT) receptors, yet the action of the hormone on these cells is largely unknown. We found that CT produced a strong and transient time- and dose-dependent increase in c-fos mRNA in BCC lines. This event was prevented by a protein kinase A (PKA) inhibitor, H89. CT alone did not influence the expression of c-jun and of the tissue inhibitors of metalloproteases (timp) -1 and -2 mRNAs; however, it reduced the induction of these mRNAs by the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA), without apparent changes in the half-life of the mRNA (measured for c-jun). Along the same line, CT reduced the c-jun induction and T-47D growth stimulation by epidermal growth factor (EGF) and insulin. These effects were mimicked by forskolin and/or prevented by H89, suggesting that PKA activation was involved. These results indicate that CT modulates in BCC the mRNA levels of two important growth-related early response genes (c-fos and c-jun) and of two other genes (timp-1 and -2) involved in the control of metastatic events.
The bone isoenzyme of alkaline phosphatase in hypercalcaemic cancer patients.
Alkaline phosphatase (AP) is the classic marker of bone formation, especially in cancer patients, but the interpretation of its measurement is complicated by the existence of various circulating isoenzymes, especially of liver origin. The introduction of a mass measurement of the bone isoenzyme of AP (BAP) by an immunoradiometric assay has markedly improved the sensitivity and the specificity of the determination. We measured BAP and other markers of bone turnover in 46 patients with tumour-induced hypercalcaemia (TIH), which is an interesting model for evaluating markers of bone formation because of the uncoupling between bone formation and bone resorption found by histomorphometric techniques. The extent of bone metastatic involvement was evaluated by planimetry on bone scintigraphy. Mean (+/- S.D.) BAP concentrations were slightly higher in patients with TIH than in healthy subjects, 15.5 +/- 8.5 versus 12.4 +/- 3.5 micrograms/L (P < 0.05). However, the scatter of the data in TIH patients was quite marked. Increased values (10/46 patients, 22%) occurred only in patients with bone metastases. Total AP, gamma GT and BGP levels, as well as markers of bone resorption, were not significantly different between patients with or without bone metastases. BAP levels were significantly correlated with AP (rs = 0.63; P < 0.01) but not with BGP levels nor with markers of bone resorption. BAP levels were also correlated with the extent of bone uptake at scintigraphy (rs = 0.54; P < 0.01), but this was not the case for total AP or BGP. In the 36 patients re-evaluated when normocalcemic after pamidronate therapy, BAP levels increased from 16.3 +/- 9.2 to 22.2 +/- 21.3 micrograms/L (P < 0.05) but there were no significant changes in AP or BGP concentrations. In summary, our data confirm the existence of an uncoupling in bone turnover in TIH and indicate that cancer hypercalcaemia is another pathological condition characterised by a discordance between BAP and BGP concentrations. BAP levels appear to be a better reflection of bone metastatic involvement than total AP or BGP and their short-term increase after pamidronate therapy could reflect the recently described effects of bisphosphonates on osteoblasts.
Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia.
Hypercalcaemia is an important cause of morbidity in malignant disease. We studied the efficacy and safety of intravenous ibandronate (a new, potent bisphosphonate) in a multicentre study of 147 patients with severe cancer-associated hypercalcaemia which had been resistant to treatment with rehydration alone. Of 131 randomized patients who were eligible for evaluation, 45 were allocated to receive 2 mg ibandronate, 44 patients to receive 4 mg and 42 patients to receive 6 mg. Serum calcium values fell progressively in each group from day 2, reaching a nadir at day 5, and in some patients normocalcaemia was maintained for up to 36 days after treatment. The 2-mg dose was significantly less effective than the 4-mg or 6-mg dose in correcting hypercalcaemia, as the number of patients who achieved serum calcium values below 2.7 mM after treatment was 50% in the 2-mg group compared with 75.6% in the 4-mg group and 77.4% in the 6-mg group (P < 0.05; 2 mg vs others). In a logistic regression analysis, three factors were found to predict response; ibandronate dose (higher doses were more effective), severity of presenting hypercalcaemia (severe hypercalcaemia was associated with less complete response) and tumour type (patients with breast carcinoma and haematological tumours responded better than those with other tumours). Ibandronate was generally well tolerated and no serious drug-related adverse events were observed. We conclude that ibandronate is a safe, well tolerated and effective treatment for cancer-associated hypercalcaemia, which should prove a useful addition to the current range of therapies available to treat this condition.
Comparative evaluation of markers of bone resorption in patients with breast cancer-induced osteolysis before and after bisphosphonate therapy.
The understanding of the pathophysiology and the monitoring of metastatic bone disease remains unsatisfactory. We compared several new markers of bone turnover in normocalcaemic patients with breast cancer-induced osteolysis before and after a single infusion of the bisphosphonate pamidronate. We studied 19 ambulatory patients with advanced breast cancer and extensive bone metastases who did not receive any systemic antineoplastic therapy. Pamidronate was administered at doses of 30, 60, 90 or 120 mg and the patients were followed weekly during a mean of 8 (range 4-10) weeks. Compared with healthy premenopausal women, the percentage of elevated values at baseline was 47% for fasting urinary calcium (uCa), 74% for hydroxyproline, 83% for CrossLaps (a new marker of type I collagen degradation) and 100% for the collagen cross-links (measured by high performance liquid chromatography), namely pyridinoline (Pyr) and deoxyPyr (D-Pyr). Pretreatment levels of uCa did not correlate significantly with any of the four markers of bone matrix resorption, whereas the correlations between these four markers were generally significant (r(s)=0.43-0.71). Alkaline phosphatase correlated significantly with markers of bone matrix resorption (r(s)=0.54-0.74). All parameters, except phosphaturia (uPi) and the bone formation markers (osteocalcin and alkaline phosphatase), fell significantly after pamidronate therapy, up to day 42 for hydroxyproline, D-Pyr and CrossLaps and day 56 for uCa. This longer lasting effect was probably due to the parathyroid hormone (PTH) surge following the decrease in serum calcium, implying that the decrease in uCa can overestimate the effects of bisphophonates on bone resorption. The decrease in bone turnover parameters was most marked for CrossLaps, indicating the potential of this new marker for monitoring therapy. Sequential determinations of markers of bone matrix resorption should be useful in delineating the optimal therapeutic schemes of bisphosphonates and for evaluating treatment effects on bone in cancer patients.
The concept of rehabilitation of cancer patients.
The scope of supportive care and cancer rehabilitation is very wide and heterogeneous. In this review we focus on nutritional aspects, sexual and gonadal function, psychological rehabilitation, treatment of cancer pain, and rehabilitation of patients with bone metastases. The anorexia-cachexia syndrome is a particularly frequent manifestation of cancer that profoundly affects body image and significantly impairs quality of life of cancer patients. However, enteral feeding through nasogastric tubes, gastrostomies, or jejunostomies is an efficient method for providing long-term enteral nutrition at home and for contributing to complete rehabilitation after cancer therapy. Recent effort has focused on nutritional pharmacology and on the optimalization of the use of appetite-stimulating drugs, such as progestational agents. The psychological components of cancer, anticancer therapy, and quality of life have now been widely recognized and studied. Effective pharmacological and psychotherapeutic interventions help patients and their family to better adjust to the chronic stress of cancer, but more specific determinants of psychological morbidity should be developed. In particular, the safe and efficient use of the most recent classes of antidepressants and anxiolytics should be urgently studied. More than 90% of cancer patients present one or more pain syndromes during their illness. The adequate use of drugs is the cornerstone of treatment. The development on new molecules and new routes of administration opens interesting perspectives for cancer pain control. Bone metastases are the source of considerable morbidity. Intravenous bisphosphonates have been successfully used for the treatment of the symptoms of metastatic bone disease, especially bone pain. Moreover, monthly pamidronate infusions in addition to chemotherapy reduce the mean skeletal morbidity rate by more than one third and contribute to the rehabilitation of cancer patients with bone metastases from breast cancer or with multiple myeloma.
Secretory products of breast cancer cells specifically affect human osteoblastic cells: partial characterization of active factors.
The pathogenesis of tumor-induced osteolysis (TIO) following breast cancer metastases in bone remains unclear. We postulated that osteoblasts could be target cells for the secretory products of breast cancer cells. We previously showed that serum-free conditioned medium (CM) of the breast cancer cell line MCF-7 inhibits DNA synthesis by 75% of control values in osteoblast-like cells SaOS-2 and that this effect is only in a minor part due to transforming growth factor beta secretion. To establish the specificity of our observations and to look for other biologically active factors, we have tested the effects of medium conditioned by several cancer and noncancer cell lines (breast, colon, placenta, or fibrosarcoma) on the proliferation of osteoblast-like cells (SaOS-2, MG-63), normal human osteoblasts, human fibrosarcoma cells, and normal human fibroblasts. Culture medium (1:2) of the breast cancer cell lines MCF-7, T-47D, MDA-MB-231, and SK-BR-3 inhibited by 25-50% the proliferation of osteoblast-like cells SaOS-2, MG-63, and normal osteoblasts as evaluated by the MTT survival test or [3H]thymidine incorporation. MCF-7 cells completely inhibited the proliferation of normal human osteoblasts in coculture. This inhibitory effect was reversible and not due to cytotoxicity. Moreover, the cyclic adenosine monophosphate (cAMP) response to parathyroid hormone (PTH) of osteoblast-like cells SaOS-2 was also increased by 100-240% by the same CM. Such activities were, however, not detected in medium from the breast noncancer cell line HBL-100 or in the medium conditioned by non-breast cancer cell lines (COLO 320DM, HT-29, JAR, or HT-1080). Medium from the breast cancer cells had no effect on normal human fibroblasts or fibrosarcoma cells (HT-1080), suggesting the specificity of their action on human osteoblasts. After partial purification by ultrafiltration and size-exclusion chromatography, we found that medium of T-47D cells contained at least three nonprostanoid factors of low molecular weights (apparent MW of 700, 1500, and 4000 D) which affected human osteoblast-like cells. These factors were heat stable and could be peptides without disulfide bonds. In summary, our data show that human breast cancer cells release soluble factors that inhibit osteoblast proliferation and increase their cAMP response to PTH, indicating that osteoblasts could be important target cells for breast cancer cells and could be involved in the process of TIO.
[Bone metastases: pathogenesis and treatment with diphosphonates].
Tumor-induced osteolysis is essentially mediated by the osteoclasts whose number and activity appear to be stimulated under the influence of tumor secretory products. In cases of hypercalcemia, there is also a variable inhibition of the bone formation rate leading to a characteristic "uncoupling" in bone turnover. An analog of parathyroid hormone--"parathyroid hormone-related protein (PTHrP)"--plays an essential role in the pathogenesis of neoplastic hypercalcemia. PTHrP concentrations are not regulated by calcium levels which is in marked contrast for PTH. We have also shown that osteoblasts could be essential target cells in the process of tumor-induced osteolysis leading to an increase in osteoclast function and number. From a therapeutic point of view, we have contributed to the optimalization of the therapeutic schemes for tumor-induced hypercalcemia and tumor-induced osteolysis for which the dose of 90 mg of pamidronate appears to be optimal.
Tumor-induced hypercalcemia in a patient with extensive soft tissue sarcoma: effects of bisphosphonate therapy and surgery.
Tumor-induced hypercalcemia (TIH) is a frequent complication of advanced cancer, but it has been rarely reported in patients with sarcoma. We describe the case of a young female patient with TIH and with an extensive synoviosarcoma of the left lower limb destroying the bony structures. Hypercalcemia was severe (18.3 mg/dl) and accompanied by low serum Pi and suppressed parathyroid hormone (PTH) and 1,25(OH)2 vit D3 serum concentrations. Hypercalcemia was successfully treated with ibandronate, a new third-generation bisphosphonate, and radical surgery was performed when the patient was normocalcemic. Circulating levels of PTH-related protein (PTHrP) were elevated at 22.5 pmol/L (NI < 9). PTHrP levels did not change after successful therapy of TIH, in contrast with PTH, which increased sharply. PTHrP levels were normalized after radical surgery. Moreover, low serum Pi with reduced threshold for phosphate excretion and increased tubular calcium reabsorption supported the notion that PTHrP was indeed the essential mediator of paraneoplastic hypercalcemia in this case despite the extensive bone destruction.
Administration of the bisphosphonate ibandronate (BM 21.0955) by intravenous bolus injection.
Bisphosphonates (BPs) are used for the treatment of both benign and malignant diseases characterized by increased bone resorption. Because of their potential nephrotoxicity, currently available BPs have to be administered by slow intravenous infusion, with conventional doses requiring an infusion time of at least 2 h. In the present investigation, we evaluated the safety and efficacy of the new BP ibandronate as administered by intravenous bolus injection. On day 0, 15 normocalcemic breast cancer patients with bone metastases were treated with 3 mg of ibandronate injected intravenously over 60-120 s. Ibandronate treatment led to significant decreases in serum levels of calcium (p < 0.0001) and phosphate (p < 0.0001) and to subsequent increases in serum concentrations of parathyroid hormone (p <0.0001) and calcitriol (p <0.0001). Moreover, there was a significant reduction in the urinary excretion of calcium (p <0.0001), pyridinoline (p <0.001), and deoxypyridinoline (p < 0.0001). Three serious adverse events were observed: vomiting (WHO grade 3), pulmonary infection (WHO grade 2), and deterioration of a pre-existing impaired glucose tolerance (WHO grade 3). Only vomiting appeared to be related to administration of the drug. The most frequent nonserious adverse events were 10 cases of transient clinically asymptomatic hypocalcemia and 8 cases of asymptomatic hypophosphatemia. Serum levels of creatinine and urea nitrogen did not increase, nor did creatinine clearance deteriorate. When tested with the dipstick method, proteinuria was present in five (33%) patients prior to ibandronate treatment (median protein concentration, 30 mg/dl). Following the BP injection, seven (47%) patients showed slight (highest protein concentration, 30 mg/dl) transient proteinuria at at least one time point, of which six cases appeared in conjunction with leucocyturia and three with microhematuria. Side effects specific to aminosubstituted BPs (fever, reduction in white blood cell counts, and lymphocyte counts) were not seen in these 15 patients. In conclusion, a single intravenous injection of 3 mg of ibandronate significantly inhibited osteoclast activity as reflected by the decrease in serum calcium and in urinary parameters of bone resorption. Serum creatinine levels and estimates of creatinine clearance were not affected by therapy. However, before repeated bolus injections of ibandronate at this dosage can be recommended for further clinical trials, whether a relationship exists between the transient pathological urinary findings and injected ibandronate needs to be determined.