Metronomic chemotherapy may be active in heavily pre-treated patients with metastatic adreno-cortical carcinoma.

OBJECTIVE: The potential benefit of further chemotherapy approaches in patients with adrenocortical carcinoma (ACC) showing progressive disease after 2 chemotherapy lines is actually unknown. This study provides explorative information on the activity of metronomic chemotherapy in heavily pre-treated ACC patients. DESIGN AND METHODS: We tested the activity of cytotoxic treatments administered on a metronomic schedule in metastatic ACC patients showing disease progression after treatment with gemcitabine and capecitabine scheme. RESULTS: Eight patients out of 28 consecutively enrolled in that trial were treated with several metronomic cytotoxic regimens. Six of them showed disease progression, but 2 patients obtained a clear benefit. The first patient was treated with oral etoposide (50 mg daily) as the 6th-line therapy and obtained a partial response lasting 24 months, while the second patient obtained a partial response lasting 10 months with metronomic oral cyclophosphamide (50 mg daily) as the 5th chemotherapy line. Both patients had sex hormone secreting tumors and were bearing a rather indolent ACC. CONCLUSIONS: The administration of several chemotherapy lines in advanced ACC patients cannot be routinely recommended outside prospective clinical trials. Few patients with indolent tumors, however, may benefit from this approach. According to our experience, oral cyclophosphamide and oral etoposide may be used in this setting.

Long term control of luteinized thecoma with sclerosing peritonitis with leuprorelin and tamoxifen treatment.

BACKGROUND: Luteinized thecoma with sclerosing peritonitis (LTSP) is a very rare condition, and its clinical management is not evidence-based. Here we describe a case of long-term disease control achieved with leuprorelin and tamoxifen therapy. CASE PRESENTATION: A 18-year-old woman with acute abdomen underwent surgical removal of an ovarian mass and received diagnosis of LTSP. Treatment plan consisted of leuprorelin and tamoxifen, followed by a good instrumental response. After 5 years, leuprorelin was stopped, and the patient continued tamoxifen alone. Ten years after diagnosis, she is still disease free. CONCLUSION: Even in the absence of solid evidence, the combination of leuprorelin and tamoxifen could be considered as a possible medical treatment of LTSP. Considering the limitations related to the rarity of disease, further studies are needed to improve its management.

Phase II study of vinorelbine with protracted fluorouracil infusion as a second- or third-line approach for advanced breast cancer patients previously treated with anthracyclines.

PURPOSE: To evaluate the feasibility and activity of vinorelbine in association with protracted infusional fluorouracil in patients with advanced breast cancer who were previously treated with anthracycline-containing regimens. PATIENTS AND METHODS: Eighty-three consecutive patients were entered onto the study. Forty-three patients experienced treatment failure or relapse after anthracycline-based, first-line chemotherapy for advanced disease and 29 experienced treatment failure or relapse after first- and second-line approaches; 11 patients experienced progressive disease within 6 months of completion of adjuvant anthracycline therapy. Sites of involvement were as follows: liver involvement, 42 patients (50.6%); lung 24 (28.9%); bone, 49 (59.0%); and skin/lymph nodes, 21 (25.3%). Treatment consisted of vinorelbine 30 mg/m(2) administered on days 1 and 15 every 28 days and fluorouracil 200 mg/m(2)/d given continuously over a 24-hour period. RESULTS: Toxicity was recorded for 441 cycles. The scheme was well tolerated: grade 1/2 nausea/vomiting occurred in 13 patients (15.6%), grade 1/2 diarrhea in nine (10.8%), and grade 2/3 stomatitis in six (7.2%). Three patients (3.6%) experienced grade 3/4 leukopenia and four (4.8%) experienced grade 2/3 anemia. Grade 2/3 neurologic toxicity was observed in three cases (3.6%), and grade 2/3 hand-foot syndrome was observed in three (3.6%). The median relative dose-intensity was 92% and 100% for vinorelbine and fluorouracil, respectively. Six patients (7.2%) attained a complete clinical response and 45 (54.2%) attained a partial response, for an overall response rate of 61.4% (95% confidence interval, 50.9% to 71.9%). Twenty-one patients (25.3%) obtained disease stabilization, and 11 (13.3%) experienced disease progression. Median time to progression in responding patients was 15 months; median overall survival of the entire population was 22 months. CONCLUSION: Vinorelbine associated with protracted infusional fluorouracil is an active and manageable scheme in advanced breast cancer patients previously treated with anthracyclines. The response obtained is durable.

Multimodal management of stages III-IVa malignant thymoma.

PURPOSE: The optimal therapy for locally advanced malignant thymoma is controversial. We review our experience with a multimodal approach in 63 consecutive cases. PATIENTS AND METHODS: Forty-three patients had stage III and 20 stage IVa disease. Surgery with radical intent was initially performed in 30 cases, while 33 cases not amenable to radical surgery underwent neoadjuvant treatment (radiotherapy in 8 and chemotherapy in 25) before surgical reassessment. All patients, whether or not surgically resected, received radiation therapy. RESULTS: Radical resection (RR) was performed in 20 patients ab initio (all stage III) and in 12 patients after neoadjuvant treatment (eight stage III and four stage IVa). With the addition of patients radically operated with neoadjuvant treatment, the radical resection rate increased from 46 to 65% in stage III patients, and from 0 to 20% in those with stage IVa disease, respectively. Radical surgery was associated with longer progression free survival and overall survival according to both univariate analysis ( P< 0.001 and P<0.01, respectively) and multivariate analysis after adjustment for age, gender, histology and disease stage ( P<0.001 and <0.02, respectively). Progression free survival (median 56.9 months) was slightly lower in patients undergoing radical surgery after neoadjuvant approaches than in those radically resected ab initio (median not achieved), but overall survival (median not achieved) was similar in both groups. Subtotal surgical resection promoted complete response to subsequent radiation therapy. This condition significantly correlated with a better outcome. CONCLUSIONS: Complete surgical resection is an independent prognostic parameter in locally advanced thymoma treated with a multimodal approach. Preoperative treatment to increase the complete resection rate could improve the overall survival of these patients.

Osteoblastic flare assessed by serum alkaline phosphatase activity is an index of short duration of response in prostate cancer patients with bone metastases submitted to systemic therapy.Gruppo Onco Urologico Piemontese (G.O.U.P).

A transient rise in serum alkaline phosphatase (ALP) activity (ALP flare) after androgen deprivation in prostate cancer patients with bone metastases has been previously correlated with both response to therapy and poor prognosis. In the present study we analyzed data coming from an Italian multicenter phase III, trial aimed to compare the efficacy of treatment with goserelin alone with that of goserelin plus mitomycin C. Sixty-seven bone metastatic patients were enrolled: 32 were treated with goserelin and 35 with and goserelin plus mitomycin. 58 cases had ALP measured every month; and were considered for flare assessment. Remarkably elevated ALP and PSA levels at baseline were significantly correlated with poor prognosis. The addition of mitomycin to goserelin resulted in a greater percent reduction of PSA values with respect to goserelin alone but did not augment the time to progression and overall survival. The monthly profile of ALP serum levels was superimposable in patients assigned to hormone therapy or chemotherapy plus hormone therapy. Patients showing a flare in ALP activity (transient rise > 15% in ALP values with respect to baseline at the first month) were classified as responders to therapy or as having stable disease upon PSA evaluation and/or at bone pain assessment, but had a shorter time to progression (median 12 months) in comparison to those showing a different ALP pattern (median 23 months). The measurement of flare in ALP activity during androgen suppression with or without concomitant mitomycin administration, may permit the early identification of patients who are likely to progress rapidly, and hence be candidate for more aggressive treatments.

Long-term disease free survival in a patient with metastatic adreno-cortical carcinoma after complete pathological response to chemotherapy plus mitotane.

Adreno-cortical carcinoma (ACC) is a rare cancer with poor prognosis. Complete surgical resection of the primary tumor and, when feasible, of the local and distant metastases offers the best prospects for long-term survival; conversely, the role of systemic therapy in patients developing unresectable metastatic disease is unclear. We describe the case of a young female patient (36 yr) who presented with an androgen-releasing metastatic ACC. Treatment consisted of five courses of chemotherapy with etoposide, doxorubicin and cisplatin (EDP scheme) plus oral mitotane, which caused the complete disappearance of distant metastases and reduction of the primary tumor, as documented by serial computed tomography (CT) scans of the chest and the abdomen. Moreover, during treatment, clinical and biochemical resolution of the hypersecretory status occurred. The left adrenal gland was then removed and histopathological examination showed extensive tumor necrosis and the absence of viable cancer cells. The patient is currently alive without evidence of recurrence 3 yr after surgery. This report shows that chemotherapy plus mitotane could result in complete pathological remission, which may be a surrogate for long-term progression- free survival in metastatic ACC patients.

Prevalence of adrenal incidentaloma in a contemporary computerized tomography series.

Adrenal incidentalomas, defined as masses discovered incidentally during imaging investigation of non-adrenal disorders, have become a rather common finding in clinical practice. The prevalence is not well characterized and varies among studies. The aim of the present study was to perform a prospective evaluation of the prevalence of adrenal incidentalomas among subjects undergoing computerized tomography (CT) scan of the chest in a screening program of lung cancer (Tic TAC study) in Piedmont, a region of Northwestern Italy. This evaluation included 520 subjects (382 males and 138 females, aged between 55-82 yr), referred to our hospital from April to December 2001. Twenty-three patients with adrenal masses were identified: 21 adrenal adenomas, 1 myelolipoma, and 1 metastasis of lung cancer. Therefore, the overall prevalence of adrenal lesions was 4.4%, and that of benign adrenal masses was 4.2%. This prevalence is higher than those found in previous CT scan series reported in the literature, probably because of the use of high-resolution CT scanning technology. Another factor that influenced our results is that subject age is skewed towards the decades characterized by a greater occurrence of adrenal masses. The outcome of this study confirms that we are presently able to identify incidentally discovered adrenal masses more often than in early years and that the prevalence of adrenal incidentalomas on CT images is approaching that of autopsy series. The present study provides a reliable estimate of the prevalence of adrenal incidentaloma with currently used CT scanners. Notwithstanding that our subjects were at increased risk of lung cancer, the rate of adrenal metastases was low. We think that the present results can be generalized even if we may disclose the lack of histological diagnosis.

Three-year findings of an early lung cancer detection feasibility study with low-dose spiral computed tomography in heavy smokers.

BACKGROUND: Low-dose spiral computed tomography (sCT) showed a four-fold increase in the detection rate in high-risk subjects and a higher percentage of stage I lung cancer in comparison with chest X-ray. However, there is a considerable discrepancy among studies in the percentage of lung nodules, overall lung cancer and stage I detection rate. SUBJECTS AND METHODS: From April to December 2001, 520 asymptomatic volunteers aged >or=55 years with a history of cigarette smoking >or=20 pack-years and no previous cancer were enrolled to receive an annual sCT of the chest for five consecutive years. RESULTS: Seventy three per cent were male, median age was 59 years and 91% were current smokers. At baseline, nodules >or=5 mm were detected in 114 (22%) undergoing sCT; the size of lung nodules ranged from 5 to 9.9 mm in 81.5% of the cases. Five (1%) cases of lung cancer were detected. In two additional cases a pathological diagnosis of atypical adenomatous hyperplasia was made. Three new cases of lung cancer were detected in the second and third year of the study. One interval case was detected during the third year. CONCLUSIONS: Despite some promising data, convincing evidence from ongoing randomized trials is needed to support the routine use of sCT as a recommended tool for screening of lung cancer.

Pamidronate administration improves the secondary hyperparathyroidism due to "Bone Hunger Syndrome" in a patient with osteoblastic metastases from prostate cancer.

BACKGROUND: The so-called Bone Hunger Syndrome is a metabolic derangement that sometimes complicates the natural history of prostate cancer patients with osteoblastic bone metastases. An excessive bone formation leads to calcium entrapment in bone and the subsequent increase of parathyroid hormone (PTH) levels, in response to calcium demand. PTH elevation stimulates the osteoclasts in sites distant from those involving the tumor, leading to osteomalacia. METHODS: PTH and markers of bone turnover were monitored every 3 weeks, from the start of pamidronate treatment in a prostate cancer patient with progressive disease, to luteinizing hormone releasing hormone analog (LHRH-A) administration, developing hyperparathyroidism, hypophosphatemia, and albumin corrected serum calcium close to the lower limit of normality. Serum bone alkaline phosphatase (BALP), assessed by two different methods: electrophoretic and immunoradiometric, and urinary levels of markers of bone collagen breakdown were also remarkably elevated. RESULTS: As a consequence of pamidronate infusion (60 mg e.v. every 3 weeks for a total of four times), BALP and PTH decreased consistently, serum calcium and phosphorus returned within the normal range, while markers of collagen resorption showed a significant decrease at the 9th week, preceded by a transient rise. CONCLUSIONS: This case report indicates that bisphosphonates could inhibit both osteoclast activity. The anti-osteoblastic effect is mainly responsible for the improvement of the pretreatment calcium imbalance of our patient towards hypocalcemia and the consequent hyperparathyroidism.

Comparison of assay of total and bone-specific alkaline phosphatase in the assessment of osteoblast activity in patients with metastatic bone disease.

The evaluation of response of osseous metastases to systemic treatments is often low as a consequence of the different radiologic appearances that make objective assessment not only difficult but sometimes impossible. Radiographic evidence of recalcification, the UICC criterion of response, is often evident for 6 months and sometimes may be delayed even more. This accounts for lower response rates in bone with respect to other metastatic sites in clinical trials. A transient rise in bone formation indices may provide an early indication of bone healing and, along with measurement of symptomatic changes, could ameliorate the response evaluation. Among the biochemical markers of bone formation, total alkaline phosphatase (TALP) is widely employed, but it lacks specificity. Estimation of bone isoenzyme (E-BALP) by electrophoretic techniques is time consuming and semiquantitative. The immunoradiometric assay (I-BALP) seems to overcome these limitations. In this study, we compared the two methods of bone isoenzyme estimation with each other and with the levels of bone gla protein (BGP) and carboxyterminal propeptide of type I procollagen (PICP) in a group of 136 cancer patients with bone metastases stratified as having lytic or mixed and blastic lesions at X-ray, and in 62 cancer patients without apparent bone involvement. The same indices were also evaluated prospectively in a patient subset submitted to chemotherapy associated with pamidronate. The aims of the study were to evaluate whether I-BALP is superior to E-BALP and whether both methods of bone isoenzyme estimation are more advantageous than TALP, BGP, and PICP in the assessment of osteoblast activity either in baseline conditions or in response to treatment. In bone metastatic patients with lytic appearances, values above the cut-off limit were observed in 32.1%, 23.3%, 48.9%, 32.9%, and 14% for, TALP, E-BALP, I-BALP, PICP, and BGP, while the corresponding percentages in those with blastic/mixed appearances were 74.0%, 84.8%, 76.9%, 51.9%, and 43.8%, respectively. In the patients without bone involvement, values within the normal range were 90.2%, 98.2%, 89.6%, 71.7%, and 90.2%, respectively. Levels of TALP, E-BALP, and I-BALP were reciprocally correlated in the three groups examined. In bone metastatic patients, however, the degree of correlation of the enzymes with PICP and BGP was weak. Liver isoenzyme of alkaline phosphatase (LALP) was found to correlate with E-BALP, but not with I-BALP, in patients with mixed/blastic lesions. Thirty-eight patients were submitted to pamidronate therapy (60 mg every 3 weeks, administered 4 times) in association with cytotoxic treatment. Osteoblastic markers were determined before any administration. Serum TALP, E-BALP, and I-BALP showed a transient rise in 9 cases, a progressive reduction in 12, no change in 2, and a progressive increase in 6. Changes in E-BALP and I-BALP from baseline were greater than those of TALP. A divergent pattern between TALP and both I-BALP and E-BALP was found in 9 patients, whereas a divergent temporal profile between the two methods of bone isoenzyme estimation was recorded in only 3 patients. Eight out of 38 cases obtained a partial recalcification of lytic and mixed lesions. Seven of them showed the concomitant early increase in TALP, E-BALP, and I-BALP followed by a gradual decline (osteoblastic flare), whereas 1 patient demonstrated the flare of E-BALP and I-BALP but not of TALP. No relationship was found between response and temporal changes in in BGP and PICP serum levels. We conclude that I-BALP is a useful marker for detecting excess osteoblastic activity in patients who have at imaging "pure" lytic bone metastases. In the longitudinal evaluation of patients receiving multiple pamidronate infusions plus chemotherapy, TALP, E-BALP, and I-BALP, but not BGP and PICP, appeared to be useful to identify responders in bone. (ABSTRACT TRUNCATED)