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Competing Interests: Disclosures RC has received consulting and/or speaker fees from Amgen, Astellas, Eisai, Genomic Health, Inbiomotion and Scancell, he is a patent holder for a biomarker developed by Inbiomotion and a former employee of prIME Oncology; PH has received consulting and speaker fees from Amgen, Pfizer, AstraZeneca, Eli Lilly, Gedeon-Richter, Janssen, Roche and Novartis and given expert testimony on behalf of Novartis; J-JB has received consulting and/or speaker fees from Amgen, Bayer and Sandoz; DS has received consulting and/or speaker fees from Amgen, Astellas, Novartis, Janssen, Roche, Bayer, Pfizer, Boehringer, Servier, Merck, Bristol-Myers Squibb and Merck Sharp & Dohme; EC has received speaker fees from Purdue; ET has received consulting and/or speaker fees from Amgen, Janssen, Celgene, Takeda and Novartis; SO has received consultant fees from Novartis, Pfizer, Astellas, Janssen, Sanofi, MSD, Bristol-Myers Squibb, Bayer, Ipsen and Roche; PF has received consulting and/or speaker fees from Algeta, Bayer, Sirtex, Ipsen, Novartis and AAA; CVP has received royalties from UpToDate and research funding from Bayer; MA has received consulting and/or speaker fees from Amgen, Bayer, Celgene, Roche and Novartis; KJ has received advisory board and/or honoraria for presentations for Merck Sharp & Dohme, Merck, Amgen, Hexal, Riemser, Helsinn, Tesaro, Kreussler, Voluntis, Pfizer, POMME-med, PharmaMar, Prime Oncology and Onko Update; OB and AK have declared no potential conflicts of interest.

In the past decades, new cancer treatment approaches for children and adolescents have led to a decrease in recurrence rates and an increase in long-term survival. Recent studies have focused on the evaluation of the late effects on bone of pediatric cancer-related treatments, such as chemotherapy, radiation and surgery. Treatment of childhood cancer can impair the attainment of peak bone mass, predisposing to premature onset of low bone mineral density, or causing other bone side-effects, such as bone quality impairment or avascular necrosis of bone. Lower bone mineral density and microarchitectural deterioration can persist during adulthood, thereby increasing fracture risk. Overall, long-term follow-up of childhood cancer survivors is essential to define specific groups at higher risk of long-term bone complications, identify unrecognized long-term adverse effects, and improve patient care. Children and adolescents with a cancer history should be carefully monitored, and patients should be informed of possible late complications of their previous medical treatment. The International Osteoporosis Foundation convened a working group to review the bone complications of pediatric cancer survivors, outlining recommendations for the management of bone health, in order to prevent and treat these complications., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

There are three distinct areas of cancer management that make bone health in cancer patients of increasing clinical importance. First, bone metastases are common in many solid tumours, notably those arising from the breast, prostate and lung, as well as multiple myeloma, and may cause major morbidity including fractures, severe pain, nerve compression and hypercalcaemia. Through optimum multidisciplinary management of patients with bone metastases, including the use of bone-targeted treatments such as potent bisphosphonates or denosumab, it has been possible to transform the course of advanced cancer for many patients resulting in a major reduction in skeletal complications, reduced bone pain and improved quality of life. Secondly, many of the treatments we use to treat cancer patients have effects on reproductive hormones, which are critical for the maintenance of normal bone remodelling. This endocrine disturbance results in accelerated bone loss and an increased risk of osteoporosis and fractures that can have a significant negative impact on the lives of the rapidly expanding number of long-term cancer survivors. Finally, the bone marrow micro-environment is also intimately involved in the metastatic processes required for cancer dissemination, and there are emerging data showing that, at least in some clinical situations, the use of bone-targeted treatments can reduce metastasis to bone and has potential impact on patient survival., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations., Competing Interests: René Rizzoli has received speaker or advisory board fees from Amgen, MSD, GSK, Servier, Danone and Takeda. Jean-Jacques Body has received speaker and consulting fees from Amgen and Novartis. Jorge B. Cannata-Andía has received research grants and speaker or advisory board fees from Amgen, Abbott, Servier and Shire. David Kendler has received honoraria for speaking, consulting and/or research grants from Amgen, Novartis, GSK, Eli Lily, Merck, Johnson&Johnson, Pfizer and Roche. Alexandra Papaioannou has been a consultant, or on a speaker’s bureau, or received unrestricted grants from Amgen, Eli Lilly, Merck Canada Inc., Novartis, Pfizer and Warner Chilcott. Tobias J de Villiers has received speaker or advisory board fees from Amgen, Merck, Adcock Ingram and Pfizer. Catherine Van Poznak has received research support from Amgen and Novartis. Ghada El-Hajj Fuleihan has received grants to support courses on osteoporosis from Novartis Pharmaceuticals and Les Laboratoires Servier. Abdellah El Maghraoui, Nicola Napoli, Dominique D Pierroz and Maria Rahme have no conflict of interest.

Purpose: Hypercalcemia is a frequent finding in cancer patients and can be observed in any type of cancer. The physician in charge of cancer patients often ignores non-malignant causes of hypercalcemia. Our objective was to review the causes of hypercalcemia in a large series of cancer patients., Methods: We have retrospectively studied in a Cancer Centre all consecutive hypercalcemic (Ca> 10.5 mg/dl) patients over an 8-year period. Of 699 evaluated patients, 642 were analyzed after exclusion of patients whose hypercalcemia resolved after rehydration or who had a normal Ca level after correction for protein concentrations. Clinical information was gathered on the type of cancer, its histology, whether the disease was active or in complete remission, and on the presence of bone metastases. Biochemical data included serum Ca, P(i), proteins in all patients, PTH in most patients, and PTHrP, 25OH-Vitamin D, 1,25(OH)(2)-Vitamin D, TSH, and T4 in selected cases., Results: By order of decreasing frequency, the main causes of hypercalcemia were cancer (69.0 %), primary hyperparathyroidism (24.6 %), hyperthyroidism (2.2 %), milk alkali syndrome (0.9 %), and sarcoidosis (0.45 %). In cancer-related causes, bone metastases accounted for 53.0 % of the cases, humoral hypercalcemia of malignancy (HHM) for 35.3 % while there were 11.7 % of cases apparently due to both HHM and bone metastases. Hypercalcemia was not due to cancer in 97 % (84/87) of the patients who were in complete remission. Even in patients with active neoplastic disease, the number of patients whose hypercalcemia was not due to cancer remained clinically relevant (115/555 = 20.5 %). In the 158 patients with primary hyperparathyroidism, 92 patients were in complete remission and 66 patients had active neoplastic disease., Conclusions: In this large series of hypercalcemia in cancer patients, the cause was not due to cancer in almost one third of the cases. Most patients considered to be in complete remission had hypercalcemia due to a benign condition. In that perspective, serum PTH determination is essential in the approach of hypercalcemic cancer patients since primary hyperparathyroidism is by far the first non-malignant cause of hypercalcemia.

Current clinical treatment guidelines recommend cytotoxic chemotherapy, endocrine therapy, or both (with targeted therapy if indicated) for premenopausal women with early-stage breast cancer, depending on the biologic characteristics of the primary tumor. Some of these therapies can induce premature menopause or are specifically designed to suppress ovarian function and reduce circulating estrogen levels. In addition to bone loss associated with low estrogen levels, cytotoxic chemotherapy may have a direct negative effect on bone metabolism. As a result, cancer treatment-induced bone loss poses a significant threat to bone health in premenopausal women with breast cancer. Clinical trials of antiresorptive therapies, such as bisphosphonates, have demonstrated the ability to slow or prevent bone loss in this setting. Current fracture risk assessment tools are based on data from healthy postmenopausal women and do not adequately address the risks associated with breast cancer therapy, especially in younger premenopausal women. We therefore recommend that all premenopausal women with breast cancer be informed about the potential risk of bone loss prior to beginning anticancer therapy. Women who experience amenorrhea should have bone mineral density assessed by dual-energy X-ray absorptiometry and receive regular follow-up to monitor bone health. Regular exercise and daily calcium and vitamin D supplementation are recommended. Women with a Z-score <-2.0 or Z-score ≤-1.0 and/or a 5-10% annual decrease in bone mineral density should be considered for bisphosphonate therapy in addition to calcium and vitamin D supplements., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3-4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.

The Supportive and Palliative Care Unit of the Institut Jules Bordet officially started its activities in February 1999. Our Unit comprises eight beds (four rooms with one bed each and two rooms with two beds each). We admit advanced cancer patients presenting with severe symptoms whose control is going to require all the expertise of a multidisciplinary team. Whilst these eight beds are identified geographically in the hospital, the team's mobility assures continuity of care for patients who wish to stay in another department. The infrastructure of the Unit and its rooms allow close family members who wish to sleep close to the patients to do so. Otherwise, visits are allowed round the clock, though always with due consideration for patients' comfort. Patients are referred either by a physician working in our Institution (medical oncologist, surgeon, or radiotherapist) or by their family physicians. Less frequently, patients themselves specifically ask to be admitted to our Unit. The activity of the Unit itself during its first year of functioning can be summarized as follows. We admitted 155 advanced cancer patients, for a total number of 210 hospitalizations. Patients were admitted a median of 35 months after their diagnosis and a median of 20 days before death. Stays were generally short (median 11 days). We systematically used quantitative assessment tools (MMSQ, MDAS,EFAT and various VAS) to detect and monitor their symptoms and any complications. The main symptoms on admission were pain, anorexia, asthenia, dyspnea and anxiety/depression. Pain, nausea/vomiting, constipation and cough were controlled in almost all patients, whereas control of asthenia and anorexia was most often insufficient. In 51% of our cases the patients could be discharged home; 40% died in the unit; 4% were transferred to long-term palliative care units and 1% to other units within our Institution (4% were still hospitalized at the time of this analysis).

Background: Tumor-induced hypercalcemia (TIH) is essentially due to a marked stimulation of osteoclast-mediated bone resorption. An inhibition of bone formation and an enhanced tubular reabsorption of calcium play an important contributory role. These factors explain why serum calcium often rises rapidly in cancer patients and why high doses of bisphosphonates are needed to normalize bone resorption and to overcome the contributory role of the kidney., Methods: The author provides a short review of clinical trials in hypercalcemic cancer patients, with an emphasis on the most recent trials., Results: Rehydration and bisphosphonates now constitute the standard treatment of TIH. A single-day 1500-mg infusion of clodronate achieves normocalcemia in approximately 80% of the cases. Clodronate also can be given by subcutaneous infusion that can be particularly useful in the palliative setting. A dose of 90 mg of pamidronate achieves normocalcemia in more than 90% of the patients and has a longer-lasting effect than clodronate. Newer more potent bisphosphonates, such as ibandronate and zoledronate, may improve these results, and they certainly will simplify the therapeutic schemes. Ibandronate at the dose of 6 mg normalizes serum calcium in more than 75% of the patients with moderate or severe hypercalcemia. Of note, the same doses of pamidronate and ibandronate, repeated monthly for 1-2 years, have been shown to substantially reduce the skeletal morbidity rate in normocalcemic patients with tumor bone disease. Even lower doses of zoledronate, the most potent bisphosphonate tested so far, are able to correct TIH when administered as a 30-minute infusion., Conclusions: Bisphosphonates have become the standard treatment for cancer hypercalcemia. Success is achieved in more than 90% of the cases. Other classes of compounds are being tested for their antiosteoclastic activity, and animal studies suggest that osteoprotegerin could be as efficient and act faster than bisphosphonates.

The frequency of hyponatraemia varies from less than 1% to more than 40% in series reported from general hospitals. We performed a prospective study to evaluate its incidence and to determine the types of hyponatraemia in a dedicated cancer hospital. All patients admitted to the Department of Medicine were prospectively studied over 11 months. Hyponatraemia was defined as a serum Na level < or =130 mEq/l. Urine and blood samples were collected at baseline, and all consecutive hyponatraemic episodes were studied. One hundred and six patients developed 123 episodes of hyponatraemia. The observed incidence of hyponatraemia was 3.7%. Sodium depletion and syndrome of inappropriate antidiuretic hormone secretion (SIADH) each accounted for almost one third of all aetiologies. Serum urea and uric acid, urinary Na and fractional excretions of Na and urea were most useful for the differential diagnosis. The percentage of deaths observed in the hyponatraemic group, 19.5%, was higher than in the whole cancer population (6.3%) although no death was apparently due directly to hyponatraemia. Hyponatraemia is regularly diagnosed in cancer patients, but it was related to SIADH in only about one third of the cases. A higher mortality was observed in hyponatraemic patients than in normonatraemic patients.

The pathogenesis of hypercalcemia of malignancy comprises increased net bone resorption and enhanced renal tubular reabsorption of calcium (Ca). To evaluate the prevalence of an increased renal tubular reabsorption of Ca index [tubular reabsorption of calcium index (TRCaI)] in cancer patients with hypercalcemia and of elevated circulating levels of PTH-related protein (PTHrP), which is recognized as a major mediator of this syndrome, we investigated 315 well rehydrated patients, aged 58.1 +/- 0.7 yr (mean +/- SEM), with hypercalcemia [albumin-corrected plasma Ca (pCa), >2.7 mmol/L] secondary to histologically proven malignancy. Changes in pCa and, therefore, various Ca filtered loads were obtained by different degrees of bone resorption inhibition achieved with a single infusion of the bisphosphonate ibandronate, given at various doses on a randomized, double blind basis. PTHrP was determined at baseline in 147 of the patients and 7 days after bisphosphonate therapy in 73. Before ibandronate therapy, pCa was 3.36 +/- 0.02 mmol/L, mean TRCaI was increased at 3.09 +/- 0.03 mmol/L glomerular filtration rate (GFR; normal, 2.40-2.90), and 65% of patients had TRCaI above 2.90 mmol/L GFR. Mean serum PTHrP levels were 4.9 +/- 0.5 pmol/L (normal, <2.5) and values above the normal range were found in 53% of the patients (76% in lung and upper respiratory tract malignancies). By 7 days after the infusion of ibandronate, a decrease in pCa of 0.69 +/- 0.03 mmol/L (20.0 +/- 0.7%; P < 0.001) and in bone resorption [mean change in fasting urinary Ca, 0.09 +/- 0.04 mmol/L GFR (47.6 +/- 8.6%; P < 0.001) and 14.4 +/- 1.7 nmol/mmol (27.6 +/- 10.6%; P < 0.01) in deoxypyridinoline] was observed. TRCaI was slightly lowered by 0.30 +/- 0.09 mmol/L GFR. Mean changes in PTHrP, 1,25-dihydroxyvitamin D3, and PTH were +0.7 +/- 0.4 (P = NS), +27.6 +/- 3.0 (P < 0.001), and +2.9 +/- 0.8 (P < 0.005) pmol/L, respectively. After ibandronate treatment, the relative risk of relapsing hypercalcemia was particularly increased (3.43-fold) in lung and upper respiratory tract malignancies. These results obtained in a large cohort of patients indicate a significant prevalence of an increased renal tubular reabsorption of calcium index in hypercalcemia of malignancy and a substantial proportion of patients with detectable PTHrP.

Zoledronate is a new heterocyclic imidazole bisphosphonate that is the most potent bisphosphonate administered in humans because it is 100-850 times more potent than pamidronate, according to in vitro or animal models of bone resorption. We conducted an open-label, dose-finding, single-dose phase I study in tumor-induced hypercalcemia (TIH), which has been similarly used as a model to determine the active doses of other bisphosphonates. The primary objective was to determine, with a dose escalation schedule, two nontoxic dose levels of zoledronate able to induce normocalcemia in at least 80% of patients with TIH after rehydration (corrected Ca for albumin levels >/=2.75 mmol/l). Based on estimates of potency, the starting dose was 0.002 mg/kg, and further tested doses were 0. 005, 0.01, 0.02, and 0.04 mg/kg. To obtain a more precise estimate of the response rate, we treated 10 more patients at the highest of the two effective dose levels. The median infusion time of zoledronate was 30 minutes. Thirty out of the 33 treated patients were evaluable for efficacy. Thirty percent of the patients had breast cancer and 54% had metastatic bone involvement. For all groups combined, mean Ca levels at baseline was 3.0 mmol/l. The two effective dose levels were 0.02 mg/kg and 0.04 mg/kg. Five out of five patients became normocalcemic after 0.02 mg of zoledronate/kg and 14 out of 15 after 0.04 mg of zoledronate/kg. The success rate of the latter dose was thus 93% (95% confidence interval [CI] 68-100%). At this dose, the first day of normocalcemia was day 2 or 3 for all but one patient. The duration of normocalcemia for the two effective doses could be assessed in nine patients; seven patients remained normocalcemic throughout the trial (32-39 days). The fall in serum Ca was accompanied by a marked fall in fasting urinary Ca excretion. Zoledronate was well tolerated: 7 out of 33 patients developed transient hypophosphatemia, and 3 developed transient hypocalcemia. The only clinically detectable side effect was an increase in body temperature occurring in 10 (30%) patients. In summary, very low doses of zoledronate (0.02 mg/kg and 0.04 mg/kg, i. e., 1.2 mg and 2.4 mg for a 60-kg individual, respectively) administered by a short-time infusion effectively treated patients with TIH. The fall in serum Ca was rapid, and normocalcemia was often maintained for several weeks. Zoledronate was well tolerated. Future trials will determine whether prolonged treatment with this potent compound can have greater effects on the skeletal morbidity rate in patients with tumor bone disease than can be achieved with currently available bisphosphonates.

The pathogenesis of cancer anorexia/cachexia is still unclear, partly explaining why its treatment remains disappointing. Anorexia plays a central role but cancer cachexia is more complex than chronic starvation. One of the key differences is the preferential mobilization of fat and the sparing of skeletal muscle in simple starvation compared to an equal mobilization of fat and skeletal muscle in cancer patients. An increase in basal energy expenditure also appears to play a contributory role in many patients. Cytokines, essentially but not exclusively tumor necrosis factor-alpha, play an essential pathogenic role and the syndrome can be compared to a low grade chronic inflammatory state. Parenteral nutrition could facilitate the administration of complete doses of chemotherapy or radiotherapy but no significant survival benefit or decrease in treatment-induced toxicity have been demonstrated in prospective randomized trials. The gut should have the preference for nutritional support. Percutaneous endoscopic gastrostomy is used more and more often in patients with a functionally intact gastrointestinal tract, especially in patients with head and neck cancer. Progestational drugs can to some extent stimulate appetite, food intake, energy level, increase weight and decrease the severity of nausea and vomiting. However, pharmacological treatment of cancer cachexia remains disappointing and more trials with anticytokine drugs, anabolic agents or polyunsaturated fatty acids should be conducted.

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.

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.

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.

Purpose: To evaluate the hypocalcemic effect and safety of three different doses of the bisphosphonate ibandronate in tumor-associated hypercalcemia, and to identify factors predicting response., Patients and Methods: One hundred seventy-four cancer patients with a serum calcium level greater than 2.7 mmol/L (10.8 mg/dL) were enrolled onto the trial. If hypercalcemia persisted after fluid repletion, patients were randomly assigned to treatment with 0.6 mg, 1.1 mg, and 2.0 mg of ibandronate. Response, defined as restoration of normocalcemia, was evaluated by an intent-to-treat analysis., Results: One hundred seventy-three (99%) patients were assessable for toxicity and 151 (87%) for efficacy. The administration of 0.6 mg (group A), 1.1 mg (group B), or 2.0 mg (group C) of ibandronate led to response rates of 44%, 52%, and 67%, respectively. Significantly more patients in group C responded than in group A (P = .0276). Of the various parameters examined, only the initial serum calcium level (P < .0001; odds ratio, 0.083) and the dose of ibandronate (P = .0162; odds ratio, 2.094) correlated with response. One hundred ninety-five adverse events (AEs) were reported, 99 classified as serious and 96 as nonserious. Three serious and sixteen nonserious AEs were considered related to ibandronate treatment. The three serious AEs were one case with thrombocytopenia, one with nausea, and one with fever., Conclusion: Ibandronate therapy led to a dose-dependent reduction in serum calcium levels. The response to ibandronate treatment correlated negatively with the initial serum calcium level and positively with the dose administered. A dose of 2 mg was necessary to achieve a response rate comparable to that in previous studies with the bisphosphonates pamidronate and clodronate. Because the incidence of drug-associated AEs was low, a dose escalation of ibandronate can be recommended for further clinical trials.

Circulating interleukin-6 (IL-6) concentrations correlate with disease activity in severe inflammatory conditions, in sepsis and in some hematological malignancies. On the other hand, IL-6 is a potent stimulator of osteoclastogenesis and has been implicated as a contributory factor in the genesis of osteopenic conditions. We measured circulating IL-6 levels by a sensitive (detection limit of 10 U/ml) and specific bioassay in 103 patients with advanced cancer, including 41 with tumor-induced hypercalcemia before any specific hypocalcemic therapy. We related IL-6 concentrations to clinical features and to biochemical parameters of bone metabolism, including blood Ca, Ca2+, Pi, intact parathyroid hormone, parathyroid hormone-related protein, osteocalcin, 1,25-(OH)2-vitamin D and, as markers of bone resorption, the fasting urinary excretion of calcium (Ca/creatinine) and hydroxyproline. IL-6 levels were increased, i.e. detectable, in 23% of the patients, 8/41 (20%) hypercalcemic and 16/62 (26%) normocalcemic patients (NS); the distribution of the values was similar in the two groups. The presence of increased IL-6 concentrations was not related to any clinical characteristic, notably not to the survival nor to the existence of bone metastases, whether in hypercalcemic or normocalcemic patients; e.g., only 3/12 (25%) hypercalcemic subjects without bone metastases had elevated IL-6 levels. We found no significant correlations between IL-6 concentrations and any of the biochemical parameters studied. Hypercalcemic subjects with increased IL-6 had higher urinary Ca/creatinine levels than patients with normal IL-6 levels (P < 0.005) but this was not the case in normocalcemic subjects. Mean concentrations of inflammatory or other bone metabolism markers were not significantly different between patients with normal or with elevated IL-6 levels. In summary, circulating IL-6 levels were increased in 23% of 103 patients with advanced cancer, but the frequency of increased IL-6 concentrations was not related to the presence of hypercalcemia or to any marker of calcium metabolism or bone turnover. The pathogenic importance of circulating IL-6 in patients with solid tumors remains to be demonstrated and our data indicate that increased circulating levels of IL-6, possibly reflecting the activation of the immune system, only contribute in a minor way to the osteolytic process in patients with tumor-induced hypercalcemia.

Background: Patients with humoral hypercalcaemia of malignancy appear to respond less well to biphosphonate therapy than hypercalcaemic patients with osteolytic metastases. On the other hand, pamidronate is currently the most potent of the commercially available biphosphonates and it is recommended that its dose be increased as a function of pretreatment calcium levels., Patients and Methods: We reviewed our experience with pamidronate in 160 patients with tumour-induced hypercalcemia (TIH) persisting after rehydration, particularly the influence of the dose administered, the tumour type and the presence of bone metastatic involvement on the calcaemic and calciuric response to pamidronate therapy., Results: Serum Ca was normalized in 92% of the cases (87% when Ca was corrected for protein levels). After therapy, 59% of the patients developed asymptomatic hypocalcaemia (30% for Corr. Ca levels). A multiparameter regression analysis revealed that the response to pamidronate was significantly (P < 0.01) influenced by initial Ca levels up to days 5-7 and, thereafter, only by the dose received. To confirm the dose effect, we divided the patients into three groups according to the median dose received, namely 0.5 mg/kg (n = 35), 1.0 mg/kg (n = 52), and 1.5 mg/kg (n = 73). The differences among the three groups became significant (P < 0.05) from days 5-7 until the end of the evaluation (days 22-26). Similarly, the success rate, considering Corr. Ca levels, was 80% for the 0.5 and 1.0 mg/kg groups combined, compared to 94% for the 1.5 mg/kg group (P < 0.05). The duration of normocalcaemia was similarly more prolonged in the high-dose group. There was a dose-response relationship only in patients with Ca levels above 3.0 mmol/L and in patients with an elevated index of tubular calcium reabsorption. By contrast, the decrease in Ca levels and in fasting urinary calcium excretion, a sensitive index of bone resorption, were not significantly influenced by the primary tumour site or by the presence of bone metastatic involvement., Conclusions: Our data demonstrate a dose-response relationship for pamidronate in TIH over an efficient hypocalcaemic dose range, at least in patients with an elevated tubular calcium reabsorption, which helps to resolve conflicting data in the literature. We suggest that a dose of around 1.5 mg of pamidronate/kg is optimal for the treatment of TIH, except in patients with mild hypercalcaemia, for whom a dose of 1 mg/kg appears to be sufficient. At these dose levels, the efficacy of pamidronate is not significantly influenced by the tumour type or the degree of metastatic bone involvement.

We studied the influence of circulating parathyroid hormone-related protein (PTHrP) concentrations on the response of hypercalcemic cancer patients to bisphosphonate therapy. We also examined the changes in circulating PTHrP levels during the normalization of serum Ca to determine if part of the increase in PTHrP concentrations is not secondary to hypercalcemia itself, as suggested by some in vitro data. We sequentially measured in 45 hypercalcemic cancer patients treated by pamidronate the circulating concentrations of PTHrP (by an amino-terminal RIA; normal values < 9 pmol/liter), Ca, Ca2+, Pi, intact PTH, and the fasting urinary excretion of Ca (Ca/Cr) and cyclic AMP (cAMP). Mean +/- SEM baseline PTHrP levels were 9.5 +/- 1.3, with a median (range) value of 6.0 (< 3.4-43) pmol/liter. PTHrP levels were elevated in 18 of 45 patients, more often in epidermoid than in glandular carcinomas (P < 0.05), and they were significantly (P < 0.05) correlated with the concentrations of Pi (r = -0.46), Ca/Cr (r = -0.31), and urinary cAMP (r = 0.47). Mean pretreatment Ca levels were not significantly different between patients with elevated and patients with normal PTHrP levels, 13.3 +/- 0.4 versus 12.9 +/- 0.4 mg/dl, but the concentrations became significantly different (P < 0.005) 4 days after therapy, 10.2 +/- 0.3 versus 9.2 +/- 0.1 mg/dl, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor-induced hypercalcemia (TIH) and tumor-induced osteolysis (TIO) are essentially due to a marked increase in osteoclast-mediated bone resorption. Parathyroid-hormone-like protein plays an essential role in TIH, and maybe in TIO, but other substances, such as growth factors or cytokines, could contribute to the osteoclast activation and osteoblast inhibition secondary to the neoplastic infiltration of the skeleton. Treatment of TIH essentially consists of volume repletion and administration of potent anti-osteolytic drugs. Intravenous administration of the bisphosphonate clodronate or pamidronate is particularly useful for this. Pamidronate at a dose of 1.0-1.5 mg/kg as a single 4- to 24-h infusion can normalize serum calcium in about 90% of hypercalcemic cancer patients. The apparently low response rate of bone metastases to systemic antineoplastic therapy seems essentially to reflect the relative insensitivity of our current methods for assessing response in TIO. Quantitative evaluation of pain and of newly developed biochemical markers of bone turnover could be particularly useful for early assessment of response. Prolonged administration of oral pamidronate could reduce by almost one-half the complications of TIO, and iterative bisphosphonate infusions could induce a dramatic relief of bone pain in one-third and a sclerosis of lytic lesions in one-fourth of the cases. These data must, however, be confirmed in randomized blind trials and many questions remain unanswered concerning the optimal therapeutic schemes. Despite these limitations, medical therapy of TIO by non-cytotoxic means has already become a reality.

Spontaneous recovery of parathyroid secretion during correction of tumor-associated hypercalcemia by bisphosphonates provides a unique clinical opportunity to further unravel the complex relationship between Ca and PTH levels. We measured plasma ionised Ca (Ca2+) and serum intact PTH concentrations in 31 hypercalcemic cancer patients every 2 (range, 1-3) days over a period of 3-21 (median, 7) days after pamidronate therapy. The mean (+/- SD) initial Ca2+ concentration was 1.64 +/- 0.20 mmol/L (normal, 1.05-1.26 mmol/L), with a corresponding PTH level of 4.9 +/- 2.6 (median, 4.5; range, less than 2.0-14.7) ng/L. PTH levels were subnormal in 30 of 31 patients. During correction of hypercalcemia, the relationship between Ca2+ and PTH concentrations was best described by a polynomial regression (r = 0.89; P less than 0.001). The curve of the regression entered the normal range of PTH levels (10.5 ng/L) for a Ca2+ concentration of 1.21 mmol/L. Similarly, the mean Ca2+ level that caused a reproducible increase in PTH levels compared to baseline values was 1.21 +/- 0.12 (median, 1.17; range, 1.00-1.45) mmol/L. Comparable values were obtained when day to day variations in PTH levels were considered; the mean Ca2+ threshold level was 1.24 +/- 0.12 (median, 1.25; range, 1.00-1.43) mmol/L. This PTH secretory threshold was not significantly influenced by several factors, including the type of cancer hypercalcemia, the day to day variations in Ca2+ levels, various biochemical parameters of calcium metabolism, or the number of days to obtain a normal Ca2+ concentration. In summary, contrary to previous reports, our data show that the PTH secretory threshold during correction of tumor-associated hypercalcemia lies in the upper part of the normal range of Ca2+ concentrations and is not significantly influenced by the rate of change in Ca2+ levels.

Osteoclastic activity is increased in tumor-associated hypercalcemia, which, thus, constitutes an excellent opportunity to assess new markers of the bone resorption rate. We have measured the fasting urinary excretion of the pyridinium cross-links pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) in 36 hypercalcemic cancer patients (mean +/- SD, 3.2 +/- 0.4 mmol/L for total serum Ca and 1.66 +/- 0.24 mmol/L for Ca2+). Thirty-two of them were reevaluated after treatment with iv bisphosphonates. Urinary Pyr and D-Pyr levels were higher than those in healthy controls (130 +/- 62 vs. 40 +/- 19 nmol/mmol creatinine for Pyr and 20 +/- 15 vs. 6 +/- 3 nmol/mmol creatinine for D-Pyr; P less than 0.001 for both). This represented a mean 3.3-fold increase over the normal mean compared to 5.8- and 3.4-fold increases for fasting urinary Ca and hydroxyproline, respectively. Individual values were elevated in 83% and 75% of the cases for Pyr and D-Pyr compared to 97% and 83% for urinary Ca and hydroxyproline, respectively. The levels of Pyr and D-Pyr tended to be higher in patients with head and neck tumors than in patients with breast cancer. Urinary Pyr and D-Pyr correlated with each other (r = 0.72; P less than 0.001) and were highly correlated with hydroxyproline (r = 0.68 and 0.83, respectively; P less than 0.001 for both), but poorly correlated with urinary Ca (r = 0.21; P = NS and r = 0.42; P = 0.01, respectively), suggesting that these markers reflect different events of bone resorption. Similarly, after bisphosphonate therapy, urinary Pyr and D-Pyr levels fell by 31% and 50%, respectively, compared to 38% for hydroxyproline and 76% for urinary Ca. There was a significant correlation between posttreatment D-Pyr and serum Ca levels (r = 0.43; P less than 0.05). In summary, we found that the urinary excretion of Pyr and D-Pyr was markedly increased in hypercalcemic cancer patients and was adequately lowered by bisphosphonate therapy. The urinary excretion of the pyridinium cross-links, especially D-Pyr, should be helpful to specifically quantitate bone matrix resorption and monitor the inhibition of bone resorption in cancer patients receiving antiosteolytic drugs.

Tiludronate is a new bisphosphonate whose efficacy has already been reported for the prevention of postmenopausal bone loss. We have evaluated its efficacy and tolerance by a dose-finding study in 19 hypercalcemic cancer patients after adequate intravenous (iv) rehydration. Treatment consisted of 3 days of iv tiludronate given at doses of 3.0 mg/kg/day (n = 3), 4.5 mg/kg/day (n = 3), or 6.0 mg/kg/day (n = 13); this iv therapy was followed by 17 days of oral tiludronate, 400 mg (n = 13) or 800 mg (n = 6) daily. Treatment had to be discontinued in 9 patients, including 3 because of evident treatment failure and 1 because of severe toxicity. After iv tiludronate, 13/18 patients had a normal Ca level, including 10/12 who had received 6.0 mg/kg/day, but Ca2+ levels were fully normalized in only 4/18 and 3/12 patients, respectively. After 6.0 mg/kg/day, Ca levels had fallen from 12.1 +/- 0.3 to 10.0 +/- 0.4 mg/dl (P less than 0.0005), whereas fasting urinary calcium excretion went from 0.639 +/- 0.099 to 0.272 +/- 0.054 mg Ca/mg creatinine on d4 (P less than 0.001). On the other hand, oral tiludronate was unable to normalize Ca in patients who were still hypercalcemic after the iv course, although the daily administration of 800 mg appeared to be more efficient than the 400 mg daily dosage. The administration of tiludronate caused an increase in serum phosphate levels, from 2.9 +/- 0.2 to 3.7 +/- 0.2 mg/dl after the iv course, probably through an increase in the TmP/GFR index, which went from 2.3 +/- 0.2 to 3.6 +/- 0.4 mg/dl (P less than 0.05). Three patients had an increase in serum creatinine levels after the iv course, one obese patient developing an acute renal insufficiency; during oral tiludronate therapy, 5 other patients also presented an increase in serum creatinine levels. Oral tiludronate administration was also associated with occasional nausea and vomiting. In summary, compared with aminobisphosphonates, tiludronate is not indicated for the treatment of tumor-associated hypercalcemia because of the need for high iv doses which are potentially nephrotoxic.

We studied the pharmacokinetics of recombinant methionyl human interleukin-2 alanine (r-met-Hu IL-2 [ala 125]) given at high doses by i.v. bolus according to Rosenberg's initial schedule in seven patients with advanced cancer. Serum concentrations of IL-2 were measured by radio-immunoassay. The drug followed second-order kinetics. During the administration of repeated high doses of IL-2, we noted a progressive increase in the volume of distribution (from 5,984 +/- 1,850 to 9,084 +/- 4,345 ml) and a progressive decrease in the AUC (from 32,643 +/- 3,817 to 22,397 +/- 511 IU min ml-1) and beta-half-life (from 61 +/- 14 to 48 +/- 6 min); the peak serum IL-2 concentrations also decreased significantly. We attribute these findings to an expansion of the extracellular fluid space and an increase in the number of IL-2 target cells during the treatment.

Intravenous aminohydroxypropylidene bisphosphonate (APD) normalizes serum calcium in most hypercalcemic cancer patients, however the optimal therapeutic scheme has not been established. We compared in a randomized prospective trial the efficacy and the tolerance of APD given as a 3-day treatment of daily 2-h infusions of 0.5 mg/k.d in 250 ml of saline (group A) with single 24-h infusions of 1.5 mg/kg (group B) or of 0.5 mg/kg in 1 liter of saline (group C). Thirty-three cancer patients remaining hypercalcemic after a 48-h rehydration period were included and monitored daily until normocalcemia or treatment failure was documented. Serum calcium became normal in all but 1 patient (in group C) but remained normal for only 1 or 2 days in 4 other patients (1 in A, 1 in B, 2 in C). The decline in total or ionized serum calcium was slightly less marked in group C than in the two other groups, but the differences were not significant. The fall of fasting urinary calcium excretion was however significantly less rapid in group C (p less than 0.05 from day 1 to day 4). Serum concentrations of iPTH and 1,25-dihydroxyvitamin D [1,25-(OH)2D] increased significantly in the three groups. Serum magnesium concentrations fell slightly from 1.41 +/- 0.05 to 1.28 +/- 0.04 mEq/liter (p less than 0.001) after rehydration but returned to normal after APD administration (day 5, 1.52 +/- 0.04 mEq/liter, p less than 0.001 versus day 0).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum osteocalcin (BGP) is a new marker of bone turnover that reportedly evaluates bone formation. Thus, its measurement could assess the bone formation rate in tumor-associated hypercalcemia. We measured concentrations of BGP and other parameters of bone metabolism in 54 untreated hypercalcemic cancer patients as compared to 109 healthy subjects. Primary tumor sites were breast (19), lung (11), head and neck (6), multiple myeloma (3), kidney (2), and various (11) or multiple (2). Mean BGP levels were higher in the hypercalcemic subjects, 4.6 +/- 0.4 (SEM) ng/ml, than in the normal subjects, 3.6 +/- 0.1 ng/ml (p less than .05), and were normalized in the 22 patients who could be reevaluated after successful treatment of hypercalcemia with intravenous aminohydroxypropylidene diphosphonate (APD). There was no correlation of BGP levels with age, sex, or renal function. Compared with the Gaussian distribution in the normal subjects, there was a considerable scatter of the data in hypercalcemic patients, suggesting the existence of defined subgroups with abnormally low or abnormally high values. However, we found no significant relationship of BGP concentrations with tumor site or histology or with bone metastatic involvement. We found also no significant correlation between concentrations of serum BGP and total or ionized calcium, alkaline phosphatase, parameters of bone resorption, and indices of parathyroid function. In summary, serum BGP levels were slightly elevated in tumor-associated hypercalcemia and were normalized after successful treatment of hypercalcemia. More importantly, BGP concentrations varied widely even in the subgroups of patients with hypercalcemia accompanying massive bone metastatic involvement or in the patients without detectable skeletal metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy of intravenous aminohydroxypropylidene bisphosphonate as treatment for the hypercalcemia of malignancy was examined in a phase II multicenter study in 132 patients with a large variety of primary tumors. This provided an opportunity for an analysis of the separate influences of bone resorption and renal calcium handling on the genesis and maintenance of hypercalcemia. The results demonstrated that increased bone resorption is the major contributory factor and that inhibition with bisphosphonate normalizes the serum calcium concentration within five days in more than 90 percent of patients. Hypercalcemia is sustained by an inability of the kidney to deal efficiently with a chronically increased calcium load. This is influenced by the requirements of volume regulation in the presence of a sodium diuretic effect of hypercalcemia and is very sensitive to induced variations of sodium load. In addition, in a minority of patients, direct renal actions of tumor-derived humoral factors adversely reduce the ability to excrete calcium. For optimal treatment of tumor-induced hypercalcemia, bisphosphonate treatment should be combined with intravenous administration of saline solution.

Bisphosphonates (or diphosphonates) constitute a major advance in the treatment of tumor-associated hypercalcemia and also have the potential to prevent or reverse osteolysis in normocalcemic patients. Available information on adequate therapeutic doses and potential toxicity is, however, very fragmentary. This report describes a phase I study of one of the most promising bisphosphonates currently available, aminohydroxypropylidene bisphosphonate (AHPrBP or APD), in tumor-associated hypercalcemia. Only patients remaining hypercalcemic after 48 hours of rehydration were evaluated, and antineoplastic therapy was delayed at least until a normal serum calcium level was reached. AHPrBP was given as two-hour daily infusions for three days, and three different patients were treated at each of the six following dosage levels: 0.01, 0.05, 0.25, 0.75, 1.5, and 3.0 mg/kg per day. The two lowest dosages levels were insufficient to normalize serum and urinary calcium levels, but the efficacy of the four other dosages was very similar. Plasma immunoreactive parathyroid hormone levels increased as a function of calcium levels, whereas urinary hydroxyproline levels did not prove to be a very useful measure of AHPrBP's effects on bone resorption. The drug was generally very well tolerated: only six patients had transient fever and/or decreases in lymphocyte count that were not clearly related to AHPrBP dosage. The only real problem was observed at the highest dosage of 3.0 mg/kg per day in an obese woman in whom high fever and hypotension developed. Efficacy and tolerance in dehydrated patients were verified by treating seven other patients, not previously rehydrated, at 1.0 mg/kg per day for three days. In summary, the therapeutic range of AHPrBP, given for three days as a two-hour infusion daily, lies between 0.25 and 1.5 mg/kg per day. Fasting urinary calcium levels are probably the most reliable and easily measured parameter to monitor AHPrBP's inhibition of bone resorption in normocalcemic patients.