Development of syndrome of inappropriate secretion of antidiuretic hormone during progression of metastatic breast cancer

A patient who developed syndrome of inappropriate secretion of antidiuretic hormone (SIADH) during progression of metastatic breast cancer is described. The classic criteria for SIADH as defined by Bartter and Schwartz were fulfilled and conditions other than malignant disease were excluded as causes of the syndrome. To the knowledge of the authors SIADH has never been reported to develop during the course of malignant disease in a patient with metastatic breast cancer. It should be borne in mind that SIADH may occur in patients with malignant disease and hyponatraemia, even in the absence of small-cell lung cancer, which is the classic tumour type to develop SIADH.     

Vinorelbine: a new promising drug in Hodgkin's disease

Vinorelbine is a new semisynthetic vinca alkaloid that differs chemically from vinblastine by a substitution of the catharanthine moiety. The powerful cytostatic activity of vinorelbine against murine tumors, human malignant cell lines and human tumor xenografts in nude mice has been demonstrated. Phase I-II studies of intravenous vinorelbine, administered weekly as single agent or in combination chemotherapy have been conducted since 1986. Results suggest that vinorelbine has high activity in non-small cell lung cancer, breast cancer and cisplatin-resistant ovarian cancer with mild toxicity, being neutropenia the major treatment related complication. In this paper we critically review the activity of vinorelbine in pretreated Hodgkin's patients. Available results strongly suggest the inclusion of this drug in first or second line chemotherapy regimens in Hodgkin's disease.     

Efficacy and tolerance of vinorelbine and fluorouracil combination as first-line chemotherapy of advanced breast cancer: results of a phase II study using a sequential group method

PURPOSE: To assess the antitumor efficacy and safety profile of the combination of Fluorouracil (5FU) and vinorelbine given as first-line therapy to patients with advanced breast cancer. PATIENTS AND METHODS: As defined in the seven consecutive steps of a phase II group sequential design, 63 patients received 5FU 750 mg/m2/d for 5 consecutive days as a continuous infusion and vinorelbine 30 mg/ m2 on days 1 and 5 as a short intravenous (I/V) infusion every 3 weeks. RESULTS: Forty-one of 63 patients achieved an objective response, which allowed us to discontinue the study and reject a response rate less than 50% with a statistical power of 90%. The unbiased estimate of the response rate was 61.6%. Response rate did not differ significantly according to the following: (1) type of prior adjuvant therapy (none, n = 23; without anthracycline, n = 6; with anthracyline, n = 34); (2) site of metastatic disease; and (3) number of metastatic sites. The median time to progression was 8.4 months. The median response duration was 12.3 months, and the median duration of complete response (CR), from the first assessment of CR, was 7.3 months. The median overall survival time was 23 months (28.1 months for patients with a CR). The main toxicities (grades 3 and 4) were neutropenia (90% of patients), infection (12.7%), mucositis (37%), and constipation (9.5%). Nevertheless, treatment could be given on an outpatient basis to the majority of patients, and the median relative dose-intensity was 86%. CONCLUSION: This phase II study, which used a group-sequential design, shows that the combination of 5FU and vinorelbine is an active and tolerable regimen for the treatment of first metastatic progression of breast cancer. It provides an alternative regimen for patients who have previously received anthracycline-based adjuvant chemotherapy or in whom anthracyclines cannot be used.     

Squamous cell carcinoma of the thoracic esophagus following radiation therapy for breast cancer

Between 1981 and 1995, 4 patients (3 females, 1 male; aged 48-80) were diagnosed with squamous cell carcinoma of the esophagus, following mediastinal irradiation for breast cancer. The interval between irradiation and the presentation of esophageal cancer was 10.75 years on average (7-19). The treatment consisted of: radiotherapy only; a partial esophagectomy with proximal gastrectomy without post-operative radiotherapy; laser photocoagulation for a superficial tumor; and, palliative treatment including gastrostomy, tracheal photocoagulation and chemotherapy for 1 patient suffering from advanced stage cancer with tracheal invasion, respectively. Radiotherapy of the esophageal cancer (exclusive or adjuvant) should take into account previous esophageal radiation therapy. The indications of curative excision surgery are the same as for other types of esophageal cancer, but the anastomoses should be performed in a non-irradiated area. Excision by esophageal stripping without thoracotomy is contraindicated because of the presence of peri-esophageal sclerosis. Preventive measures in radiation therapy for breast cancer are suggested.     

Hyponatremia related to medical anticancer treatment

Hyponatremia is a common potential complication in cancer patients. It can be related to anticancer medical therapy. Vincristine, vinblastine, cisplatin and cyclophosphamide are the chemotherapeutic agents most frequently associated with hyponatremia. More recently, analogs such as carboplatin and ifosfamide have also been incriminated. Hyponatremia is also associated with new immunomodulators (interferon, interleukin-2 and levamisole) and monoclonal antibodies. The mechanism by which all these drugs act on the sodium steady state is only partially known. The syndrome of inappropriate antidiuretic hormone secretion is described secondary to vinca alkaloids and cisplatin and possibly with alkylating agents. Renal salt wasting is described with platinum compounds.     

Symptomatic syndrome of inappropriate antidiuretic hormone secretion associated with azithromycin

OBJECTIVE: To report a case of symptomatic syndrome of inappropriate antidiuretic hormone (SIADH) secretion associated with azithromycin and review the literature related to this adverse drug reaction. DATA SOURCES: Review articles identified by a computerized (MEDLINE) (1966-April 1996) and manual (Index Medicus) search. DATA SYNTHESIS: Azithromycin is a well-tolerated broad-spectrum macrolide antibiotic. We report a symptomatic case of SIADH secretion associated with azithromycin. The patient received two doses of azithromycin before the development of sudden mental status changes associated with severe hyponatremia. All other potential causes were ruled out. No previous reports exist in the literature. CONCLUSIONS: Azithromycin may be associated with symptomatic SIADH secretion. Awareness and attention are required if patients develop mental status changes or hyponatremia while receiving azithromycin so that appropriate diagnostic and therapeutic actions can be implemented.     

Eradication project for poliomyelitis and surveillance of acute paralysis

We report three lymphoma patients in whom the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was observed during the course of lymphoma-associated hemophagocytic syndrome (LAHS). The clinical course was devoid of any known mechanism for SIADH which could be attributable to lymphoma or antineoplastic treatment. Alternatively, high serum levels of interleukin-1 beta and tumor necrosis factor-alpha, which stimulate the secretion of antidiuretic hormone, may have contributed to the development of SIADH in our patients, who were receiving glucocorticoids. In conclusion, LAHS patients should be considered to be at high risk for SIADH.     

High-dose therapy with cytostatic agents as primary treatment of advanced breast cancer

Thousands of women with breast cancer have received high dose chemotherapy prior to the results from controlled clinical trials being known. As one of these patients the author reviews and discusses the results of the first randomised study from South Africa. High dose therapy with autologous stem cell support was compared with conventional chemotherapy in 90 young women with metastatic aggressive breast cancer. Though survival was short in both groups the disease free survival was doubled in the high dose group. A significant increase was found in response rate, duration of response and survival. Data from America show the cost effectiveness of this treatment to be comparable to that of other life-saving therapies. A comparison is made with the absolute and relative survival benefit of simvastatin treatment. A Norwegian White Paper on high dose therapy does not include advanced breast cancer in the planned trial protocols. It is argued that future health planning should give high priority to the treatment of advanced breast cancer in young women.     

The NLM and Grateful Med: promise, public health, and policy

OBJECTIVE: To characterize a clinical syndrome that occurs in some women who have undergone breast or axillary lymph node biopsy or partial mastectomy. MATERIAL AND METHODS: Six case reports are presented, the clinical and histopathologic findings are described, and the implications for recognition of this entity are discussed. RESULTS: Patients who had undergone partial mastectomy, breast biopsy, or axillary lymph node excision shortly thereafter had clinical signs (most notably, erythema and edema) suggestive of infectious mastitis or inflammatory breast cancer. Representative histologic sections of involved skin revealed dilated dermal vessels without specific evidence of infection or cancer. Although antibiotic therapy was generally ineffective, the clinical findings resolved with time (from 2 months to 1 year). This condition should be considered in the differential diagnosis when this circumscribed patient population has such intervention-related symptoms. CONCLUSION: This clinical syndrome may mimic an infectious or neoplastic process, but we hypothesize that it is due to interruption of lymphatic vessels. Appropriate recognition may alter the use of antibiotic therapy or surgical intervention.     

Thrombosis of tibial arteries in a patient receiving tamoxifen therapy

BACKGROUND: Tamoxifen has been used extensively as adjuvant therapy in the treatment of pre- and post-menopausal patients with breast cancer. One of its known complications is venous thromboembolism. However, arterial thrombosis has been reported rarely. METHODS: A 49-year-old patient with breast cancer had had a total mastectomy 3 years earlier. She was receiving tamoxifen therapy when she developed a sudden onset of pain and numbness of the left foot and calf. An arteriogram showed thrombosis of her tibial arteries. RESULTS: This thrombosis was lysed successfully with urokinase therapy, and tamoxifen therapy was discontinued. At follow-up 4 months later, the patient had normal circulation to both legs. CONCLUSIONS: Patients receiving tamoxifen should be monitored closely for the development of venous or arterial thromboembolism.     

Tamoxifen (antiestrogen) therapy in advanced breast cancer

Fifty-nine postmenopausal women with advanced breast cancer were treated with tamoxifen (antiestrogen), 20 mg orally twice a day for at least 2 months. They had been previously treated with other types of hormonal therapy or intensive chemotherapies, or both. Nineteen of the 59 patients (32%) had either a complete response (seven patients) or partial response (12 patients). The median duration of response was 9+ months. Tumors containing estrogen receptors and those that responded to previous hormonal manipulation tended to respond to tamoxifen (60% and 69%, respectively). Patients with receptor-negative tumor or with a history of failure of previous hormonal treatments did not respond to tamoxifen therapy. Tamoxifen is effective against advanced breast cancer. Side effects of the treatment were mild.     

Paclitaxel (Taxol)

The paclitaxel (TAXOL); Bristol-Myers Squibb Company) represents first agent from novel class of antineoplastic drugs--taxanes to enter routine clinical practice. Paclitaxel interferes with microtubular polymerization by promoting abnormal assembly of microtubules and inhibiting their subsequent disassembly. Pharmacokinetics of paclitaxel has been intensively studied. There are indications for nonlinear pharmacokinetics when paclitaxel is administered as a short infusion and at higher doses. Neurotoxicity, mucositis, and leukopenia correlate with some pharmacokinetic parameters. The clinical development of paclitaxel was initially hampered by hypersensitivity reactions. Current dosage regiments with premedication reduced the incidence of these events to 3%. The major dose-limiting adverse effect of paclitaxel is neutropenia. Significant activities were reported especially in patients with advanced ovarian, breast, non-small cell lung cancer (NSCLC), head and neck cancer and in other types of tumours. Long-term follow-up will also allow the effects of the drug on patient survival to be determined. At present combination of Taxol (paclitaxel) with cisplatin clearly improves the duration of progression-free survival and of overall survival compared with cyclophosphamide and cisplatin in women ovarian cancer. Recently was TAXOL (paclitaxel) registered in Czech republic for treatment of patients with advanced metastatic ovarian carcinoma and in patients with metastatic breast cancer after failure of the standard therapy.     

Neo-adjuvant chemotherapy +/- immunotherapy with s.c. IL 2 in advanced squamous cell carcinoma of the head and neck: a pilot study

We carried out a pilot nonrandomized phase II study to compare the neo-adjuvant chemotherapic regimen with cisplatin, 5-FU and vinorelbine with the same combination plus s.c. IL 2 in advanced head and neck squamous cell carcinoma (HNSCC). The primary goals of the trial were to evaluate the feasibility and response rates of the two regimens. The study design consisted of a patient's assignment to either of the two following arms: Arm A: Cisplatin 80 mg/m2 i.v. on day 1; 5-FU 600 mg/m2 i.v. on days 2-5; and vinorelbine 20 mg/m2 i.v. on days 2 and 8, Arm B: the same chemotherapic regimen plus recombinant IL 2 (Proleukin, Eurocetus) 9 MIU s.c. daily from day 9 to 13 and from day 16 to 20 for every cycle. From March 1993 to November 1993 twenty three patients with Stage III-IV HNSCC were enrolled in the study. Patients could be evaluated for response to treatment if they had received at least 2 complete cycles of therapy. The overall response rate (ORR) was 63% in Arm A and 100% in Arm B. The differences for ORR and CR rates were statistically significant in favor of Arm B. The analysis for each of the three drugs included in the chemotherapy schedule shows that both the actually received average dose-intensity and the actually delivered average cumulative doses/patient were higher for Arm B (chemo-plus IL 2 therapy) (approximately 80% of programmed dose-intensity) than for Arm A (approximately 70% of programmed dose-intensity). Both the actually received average dose-intensity and the actually delivered average cumulative doses/patient for IL 2 were more than 80%. In both arms the most frequent side effects were myelosuppression, phlebitis and electrolyte disturbances. There were 2 toxic deaths, 1 in Arm A and 1 in Arm B, both for hematologic toxicity. Our "pilot" study suggests that the combination of cisplatin, 5-FU, vinorelbine plus IL 2 is a highly active, but rather toxic, neo-adjuvant treatment in advanced HNSCC with very high ORR and CR rates.     

Pearson marrow pancreas syndrome: a molecular study and clinical management

Breast cancer is the commonest malignancy in women and although identification of this multi-system disease has increased, the survival rates have not dramatically altered over the past four decades. Optimium treatment of patients with breast cancer is a subject of great debate and traditionally may be divided into surgery, radiotherapy, chemotherapy and hormone manipulation. Halsted's radical mastectomy, although initially superseded by more mutilating surgery involving removal of tumour, breast, pectoral muscles and axillary contents, has given way to more conservative surgery and breast conservation, so now removal of the tumour with a marginal of healthy tissue is possible. Additional loco-regional radiotherapy has added to the increasing number of treatment options available to both doctor and patient. Systemic adjuvant therapy, primarily hormonal therapy, is used with the aim of decreasing the incidence of recurrence and distant tumour development. Through the process of randomized controlled trials these new therapeutic treatments have shown to be effective in the treatment of locoregional disease. Surgery in patients with advanced systemic disease is limited, however radiotherapy is of considerable importance and can be used to treat or palliate sites of metastases. In recent years trials have assessed chemotherapeutic regimens. However, limited number of patients and adequate randomization have hindered the confident acceptance of these results. Cyclophosphamide, methotrexate and 5 fluorouracil still remain the standard chemotherapeutic regimen, however many new drugs are currently undergoing trials and these or combinations of these may prove to be of future clinical use. Dramatic advances in cell and molecular biology have allowed the development of novel breast cancer therapies. Specific oncogenes and loss of tumour suppressor genes have been associated with decrease patient survival, with the presence of lymph node metastases and with decreased relapse free survival. Growth factor receptor blockers and tyrosine kinase inhibitors may be developed to specifically eradicate breast cancer cells. Immunotherapy and gene therapy may produce effective therapies. Trials utilizing cytokines and trials increasing the immunogenicity of tumours have already reported promising results. Surgery, chemotherapy, radiotherapy and hormone manipulation are the major treatment arms of breast cancer therapy. However, breast cancer still accounts for 20 percent of all female cancer deaths and the overall survival of patients has remained relatively static over the past forty years. From our increasing understanding of the pathological processes involved in the development and spread of breast cancer, new pharmaceutical, immunological and gene therapies may dramatically increase the cure rate of this serious disease.     

Significance of full-thickness chest wall resection as a local treatment for sternum metastasis of breast cancer

Bone metastasis of breast cancer generally tends to be multiple. However, breast cancer frequently metastasizes to the sternum as solitary metastasis. Resection of the sternum was reported to be an effective surgical technique for sternum metastasis which could not be remarkably improved by chemo-endocrine therapy and locoregional recurrent breast cancer invading the skin. A first patient was diagnosed with sternum metastasis invading the skin 44 months after radical mastectomy for breast cancer of stage II. A second patient had breast cancer of stage IV simultaneously with metastases to the sternum and the lung. Only the lung metastasis was successfully controlled by chemo-endocrine therapy, but the sternum metastasis was progressive, following radical mastectomy. Both patients manifested solitary bone metastases and underwent full-thickness chest wall resection. The defect of the chest wall was reconstructed with the mucocutaneous flap using the dorsal latissimus muscle in case 1 and with the abdominal rectus muscle in case 2. Twenty months after the resection of the sternum, the first patient suffered from supraclavicular lymph node metastasis, and the multidisciplinary treatment including radiation therapy was indicated. This therapeutic procedure was effective, and the patient survived for 63 months after resection of the sternum. The second patient has made good progress for six months in maintaining complete remission with chemo-endocrine therapy. These findings suggested that surgical resection was a useful local treatment for solitary sternum metastasis.     

Insurance coverage of patients with breast cancer in the 1991 commission on cancer patient care evaluation study

BACKGROUND: Trends in the care of patients with cancer are monitored annually by the Commission on Cancer of the American College of Surgeons. In 1991 a patient care evaluation study of breast cancer was conducted, which among other questions examined the correlation of health insurance with type or quality of care delivered for breast cancer on a national basis. METHODS: The tumor registry system of the American College of Surgeons was used to obtain data on patients with breast cancer diagnosed in 1983 and 1990. Trends in diagnosis and treatment were correlated with the type of insurance or lack of insurance. RESULTS: Data were obtained from hospitals in 50 states on a total of 41,651 patients. The largest number of patients were covered by Medicare. Fewer than 5% were considered medically indigent. Medically indigent patients presented with higher stage disease and did not participate in a trend toward downstaging, which occurred between the two study years. The treatment of medically indigent patients appeared to be appropriate and comparable with better insured patients. Insurance type (health maintenance organization vs. private) did not affect stage, treatment, or outcome. Decisions to use controversial therapies, such as chemotherapy for stage I disease, did not appear to be financially driven. CONCLUSION: A nationwide pattern of care study for breast cancer indicates that medically indigent patients present with more advanced disease compared with better insured patients, but once the diagnosis is made, treatment and outcome have little to do with insurance type.     

Ifosfamide and etoposide in previously treated patients with advanced breast cancer

AIMS AND BACKGROUND: Ifosfamide is an active alkylating agent in the treatment of breast cancer, as a first-line therapy and in advanced disease. Since the combination of etoposide with an alkylating agent produces a synergistic and tolerable activity in various malignancies, in the present study, ifosfamide and etoposide were administered to patients with advanced breast cancer to evaluate the response characteristics and the toxicity profile. STUDY DESIGN: The combination of ifosfamide, mesna and etoposide was prospectively administered to 41 previously treated patients with stage IV breast carcinoma. The treatment schedule consisted of ifosfamide, 1500 mg/m2, infused over 24 hrs with 1500 mg/m2 mesna on days 1 to 5 and 120 mg/m2 etoposide, infused over 1 hr on days 1 to 3, to be repeated every 4th week. RESULTS: After a median follow-up of 10 months, an objective response rate of 23% (overall 2.5% complete remission and 20.5% partial remission) and a median response duration of 5.3 months were obtained in 39 assessable patients. The non-responder group consisted of 28.3% stable disease and 48.7% progressive disease. The prior status of chemotherapy was the only significant prognostic factor with an impact on the response rate. The overall toxicity was generally mild, with grade 3 myelotoxicity encountered in 25.7% of patients. CONCLUSIONS: The tolerable side effect profile of the ifosfamide and etoposide combination might be advantageous as regards the quality of life. To improve the rate and/or the duration of response and to clarify the precise role of the ifosfamide-etoposide combination in previously treated advanced breast cancer, further trials are warranted.     

Neuropathies associated with malignancy

Patients with malignancy can develop peripheral neuropathies as (1) a direct effect of the cancer by invasion or compression of nerves, (2) a remote or paraneoplastic effect, or (3) an iatrogenic effect of treatment. Focal or multifocal cranial neuropathies, radiculopathies, and plexopathies typically result from tumor infiltration, herpes zoster infection, or radiation-induced injury. Sensorimotor polyneuropathies are the most frequently encountered peripheral nerve syndromes, but motor neuropathies, sensory neuronopathies, polyradiculoneuropathies, and autonomic neuropathies can also occur. Although uncommon, paraneoplastic mechanisms should be considered in a patient with malignancy and an associated peripheral nerve disorder, especially in the setting of small-cell lung cancer or lymphoproliferative cancer. Toxic neuropathies occur with exposure to several chemotherapeutic agents, including the vinca alkaloids, cisplatin, taxanes, and suramin. These neuropathies are usually dose-related, sensory-predominant, and at least partially reversible, with an axonopathic or ganglionopathic mechanism. Suramin is unique in causing subacute, demyelinating polyradiculoneuropathy.     

Economic and policy implications of adopting paclitaxel as first-line therapy for advanced ovarian cancer: an Ontario perspective

PURPOSE: To determine the potential economic and policy implications that result from incorporating paclitaxel into first-line therapy for stage 3 and 4 ovarian cancer patients in the province of Ontario, Canada. METHODS: A cost-effectiveness analysis was conducted to compare cisplatin/cyclophosphamide (CC), a standard therapy, with cisplatin/paclitaxel (CT). Based on survival curves from a clinical trial, mean costs and survival were calculated. Sensitivity analyses were conducted based on altering the duration of paclitaxel infusion, discount rates, and efficacy of paclitaxel. RESULTS: The mean survival duration is prolonged from 2.06 years with the standard therapy to 2.44 years with the paclitaxel combination. The paclitaxel therapy is more expensive, with a mean cost of $17,469 (Canadian) per patient treated with CT compared with $5,228 per patient with CC. The incremental cost-effectiveness ratio is $32,213 per year gained. Sensitivity analyses show that the conclusions remain unchanged. The use of CT as first-line treatment for advanced ovarian cancer patients in Ontario requires an additional $9 million per year over and above the present costs to treat this patient population. CONCLUSION: Although paclitaxel-based therapy prolongs survival, it comes at an increased cost. It may not be possible to fund paclitaxel treatment using resources presently allocated to first-line chemotherapy for advanced ovarian cancer. The policy implications for absorbing the cost of paclitaxel in the context of a publicly funded health care system are discussed.