Personalising docetaxel and G-CSF schedules in cancer patients by a clinically validated computational model.

BACKGROUND: This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia. METHODS: Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules. RESULTS: The combined model accurately predicted observed nadir timing (r=0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients (r=0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 µg m(-2) tri-weekly, is G-CSF, 300 µg, Q1D × 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m(-2), is optimally supported by the slightly less cost-effective G-CSF 300 µg, Q1D × 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per µl) under Doc, 100-150 mg m(-2) tri-weekly. CONCLUSIONS: The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted.

Retrospective comparison of two different schedules of irinotecan, 5-fluorouracil and folinic acid in previously untreated patients with advanced colorectal carcinoma: a single institution experience.

PURPOSE: To compare efficacy and tolerability of weekly irinotecan combined with 5-fluorouracil (5-FU) bolus and folinic acid (FA) regimen (IFL) versus biweekly irinotecan with infusional 5-FU and FA (FOLFIRI) in patients (pts) with advanced stage colorectal cancer. PATIENTS AND METHODS: Treatments outcome of 86 pts (IFL - 38 pts, FOLFIRI - 48 pts) was evaluated. Chemotherapy regimens were as follows: IFL - intravenous (i.v.) infusion irinotecan 125 mg/m(2) over 90 min and 5-FU 500 mg/m(2) preceded by FA 20 mg/m(2) both given by i.v. bolus injection, all repeated on days 1, 8, 15 and 22 every 6 weeks; FOLFIRI - i.v. irinotecan 180 mg/ m(2) on days 1 and 15 with subsequent FA 200 mg/m(2) administered as a 2-hour infusion and i.v. bolus injection of 400 mg/m(2) 5-FU immediately followed by 22-hour i.v. infusion of 600 mg/m(2) 5-FU on days 1, 2, 15 and 16 every 4 weeks. Treatment continued until disease progression or unacceptable toxicity. RESULTS: A total of 152 (mean - 4) IFL cycles and 328 (mean - 6) FOLFIRI cycles were administered. Average dose intensity was 0.8 and 0.78 respectively. Toxicities were mild and manageable for both regimens evaluated. Overall response rate was 36.8% in IFL arm and 44.7% in FOLFIRI arm. At the median follow-up of 16 months in IFL arm and 14 months in FOPFIRI arm the two year survival was 38% and 45%, the median survival was 18 months and 21.5 months, and the median progression free survival was 6 months and 9.4 months respectively. CONCLUSIONS: In our experience, both IFL and FOLFIRI regimens have acceptable toxicity at a similar level of dose intensity. Compared to IFL, FOLFIRI seems to improve progression-free survival.

Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastases-analysis of an international multicenter database.

BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment. METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate cancer (CRPC) patients treated with radium-223, in eight centers in three countries. RESULTS: A total of 130 patients were included, the majority (n=84, 65%) received radium-223 post docetaxel. Thirty-four of 99 patients with available data (34%) received concomitant abiraterone or enzalutamide. A total of 54% (n=70) patients completed the planned six injections of radium-223. In patients with available data, a transient increase in bone metastases-related pain was observed in 27% (n=33/124) and an improvement of bone metastases-related pain on treatment with radium-223 was noted in 49% of patients (n=61/124). At 3 and 6 months of treatment with radium-223, bone imaging showed stable disease in 74% (n=84/113) and 94% of patients (n=93/99) with available data, respectively. An increase in the number of bone lesions was documented at 3 months compared with baseline in 26% (n=29/113) and at 6 months compared with 3 months in 6% of patients (n=6/99), respectively. Radiological extraskeletal disease progression occurred in 46% of patients (n=57/124) with available CT data at 3 and/or 6 months. CONCLUSIONS: Progression of bone metastases during radium-223 therapy is uncommon. A bone flare (pain and/or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression.

Cutaneous photosensitivity induced by paclitaxel and trastuzumab therapy associated with aberrations in the biosynthesis of porphyrins.

BACKGROUND: Paclitaxel and trastuzumab are new treatments for patients with metastatic breast cancer. CASE REPORT: We describe here a 40-year-old female patient with metastatic breast cancer who developed a photosensitive rash 1 month after initiation of paclitaxel and trastuzumab therapy. The eruption appeared on the dorsal aspect of her hands, forearms, legs and face and consisted of erythema, edema and vesicles, and was associated with distal onycholysis. Aberrations in various parameters of the metabolism of porphyrins were observed in urine and erythrocytes. Sun avoidance and withdrawal of paclitaxel was followed by resolution of the rash and a return to the normal pattern of porphyrins biosynthesis. CONCLUSION: The combination of paclitaxel and trastuzumab treatment and sun exposure may induce a photosensitive reaction, associated with changes in various parameters of porphyrins biosynthesis.

Primary malignant lymphoma of the prostate--a report of three cases.

We report the clinical, morphological and immunohistochemical findings in 3 cases of primary non-Hodgkins malignant lymphoma of the prostate. After treatment with doxorubicin-based chemotherapy, two patients achieved a complete remission, and 1 died of infective endocarditis three months after diagnosis. Until a consensus has been reached regarding the optimal treatment of prostatic lymphoma, therapy should be determined by the histologic type diagnosed and stage of the lymphoma.

Metastatic angiosarcoma of the spleen after accidental radiation exposure: a case report.

Angiosarcoma is a rare malignant tumor arising from endothelial cells of blood vessels or lymphatic channels. Therapeutic irradiation, thoriumdioxide administration, pyothorax, and polyvinyl chloride exposure have been shown to be predisposing factors for developing angiosarcoma. Accidental radiation exposure has not been associated with angiosarcoma. We present an unusual case of angiosarcoma of the spleen, with metastases to bone, liver, breast, and bone marrow, in a woman who lived near the Chernobyl nuclear facility in the former Soviet Union at the time of the reactor accident in 1986. To the best of our knowledge, this is the first report of metastatic angiosarcoma after accidental radiation exposure.

Primary bilateral adrenal lymphoma relapsing as a solid cerebral mass after complete clinical remission: a case report.

Primary adrenal lymphoma is extremely rare. Only 75 cases have been reported in the medical literature. A case of non-Hodgkin's lymphoma originating in both adrenal glands is presented. Combination chemotherapy apparently produced complete disappearance of the primary lymphomatous lesions, but subsequently a cerebral relapse was discovered 6 months later, in the form of a solid brain mass. Cranial extension of primary adrenal lymphoma is extremely unusual, and the presentation as a solid mass seems to be unique.

Phase II study of weekly high dose fluorouracil in previously treated patients with metastatic colorectal cancer.

UNLABELLED: The purpose of this study was to evaluate the efficacy, toxicity, and safety of outpatient chemotherapy with weekly high-dose 5-fluorouracil (HD-5FU) in previously treated patients (pts) with metastatic colorectal cancer. Previously treated and failed pts with histologically confirmed, measurable metastatic colorectal cancer, performance status (WHO) 0-2 and adequate bone marrow function were eligible for treatment. Patients received 5FU (2.6 g/m2) as a 24-hour continuous infusion. Treatment was repeated weekly. A total of 202 cycles were given. Eighteen pts were enrolled. No pts achieved objective response. In 6 pts (33%), after 4 weeks of treatments, CEA level decreased 25% or more, and after 8 weekly treatments it rose again. Mild myelosuppression rarely occurred. Grade I nausea and vomiting occurred in 2 pts and Grade I diarrhea occurred in 2 pts. Mucositis was not observed. CONCLUSION: In our experience single agent, weekly, high dose 5-FU is well tolerated, but is ineffective as second-line treatment for metastatic colorectal cancer, and has only a marginal effect on CEA level.

Acute myocardial infarction in a young man receiving chemotherapy for testicular cancer: case report.

The authors report on a case of treatment-related myocardial infarction in a young man receiving chemotherapy (BEP) for testicular cancer and discuss the implications of the case.

Retrospective comparison of single-agent chemotherapy with weekly 5-fluorouracil or weekly irinotecan in previously treated patients with metastatic colorectal cancer.

UNLABELLED: This study is a retrospective analysis of response, toxicity and freedom from progression of two single-agent chemotherapy regimens in patients with previously treated metastatic colorectal cancer. Thirty-five patients with histologically confirmed measurable metastatic colorectal cancer received chemotherapy after failure of first-line 5-fluorouracil (5-FU) and leucovorin treatment. The median age was 61 years. Twenty-seven patients had liver metastases, 6 had local recurrence, 1 had retroperitoneal lymph node metastases and 1 had lung metastases. Eighteen patients received weekly 2600 mg/m2 5-FU and 17 patients received weekly 125 mg/m2 irinotecan (CPT-11). Treatment was given until disease progression. Total number of cycles was 202 for 5-FU and 248 for CPT-11. The relative dose intensity was 1.0 for 5-FU and 0.84 for CPT-11. No grade 3-4 toxicity was registered in patients who received 5-FU. Grade 3-4 toxicity rates were as follows in those who received CPT-11: vomiting 1 (5.9%) patient in 1 cycle, diarrhea 3 (17.7%) patients in 3 cycles and neutropenia in 3 (17.7%) patients in 3 cycles. No patients manifested febrile neutropenia. Two patients (11.8%) needed hospital admission because of toxicity: 1 for vomiting and 1 for diarrhea. No objective responses were observed in the 5-FU group of patients. Three patients (17.6%) who received CPT-11, achieved partial response with a median duration of 8 months. Stable disease was registered in 3 (17.6%) and 9 (52.9%) patients in 5-FU and CPT-11 groups respectively (p=0.05). Median time to progression was 3.3 months for patients who received 5-FU and 4.2 months for those treated with CPT-11 (not significant). One-year survival was 22.2% and 54.3% respectively (p=0.05). CONCLUSION: Weekly chemotherapy with CPT-11 is tolerated with acceptable toxicity and leads to a better response rate than weekly high dose 5-FU. It also significantly improves survival but does not prolong freedom from progression.

Toxic epidermal necrolysis associated with gemcitabine therapy in a patient with metastatic transitional cell carcinoma of the bladder.

The authors report on a case of treatment-related toxic epidermal necrolysis in an elderly man receiving chemotherapy (gemcitabine) for transitional cell carcinoma of bladder and discuss the implications of the case.

Massive cavitation of solid pulmonary metastatic lesions in a breast cancer patient: a case report.

A 40-year-old female with metastatic breast cancer developed multiple lung nodules some of them with cavitations. Following treatment with Taxol/Herceptin most of the lesions disappeared and in many cavity lesions appeared. There was no further change in the appearance of lung lesions.

Influence of age on the prognosis of patients with renal cell carcinoma (RCC).

OBJECTIVE: Aim of this study was to analyze the prognostic value of age in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: A group of 15 patients (age < or = 40 years, group I) and a group of 103 patients (age > or = 50 years, group II) with sporadic RCC who underwent radical nephrectomy between 1985 and 1997 were compared. The two groups were analyzed with respect to histologic cell type, tumor grade, stage and outcome. RESULTS: In group I low-stage tumors (stage I and II) were diagnosed in 93% of patients and in group II in 65% of the patients (p = 0.017). High-grade tumors (stage III and IV) were diagnosed in 7% and 35% of patients in group I and group II, respectively (p < 0.01). In group I only one patient (7%) with stage II disease died of cancer. In group II the distribution of cancer-specific mortality was as follows: 6 patients (100%) with stage IV, 13 patients (42%) with stage III, and 12 patients (17%) with stage I and II died of disease. The 5-year-survival in group I was 93% and in group II was 77% (p = 0.05). CONCLUSION: According to our data we conclude that RCC is diagnosed at a lower stage in young patients than in the older patient group. RCC may exhibit a more favorable prognosis in young patients, possible due to the lower stage at time of diagnosis.

Granulocyte-colony stimulating factor for the prevention of chemotherapy-induced febrile neutropenia in the adult cancer patient population of Southern Israel.

To evaluate the efficacy of granulocyte-colony stimulating factor (G-CSF) prophylaxis in preventing chemotherapy-induced febrile neutropenia in the heterogeneous population of adult cancer patients treated in our institution, all adult cancer patients with either a solid tumor or lymphoma who were admitted for chemotherapy in our institution between 1 January 1994 and 31 July 1995 were retrospectively studied. We compared the characteristics of chemotherapy cycles in which G-CSF was given as prophylaxis and of those with no prophylaxis. In all, 1,079 chemotherapy cycles given to 209 patients were analyzed. Prophylaxis with G-CSF was given in 66 cycles (6%). Patients receiving G-CSF were significantly younger and were more likely to have lymphomas. Febrile neutropenia developed in 40 cycles (4%). There was no difference in the rates of febrile neutropenia, infection, hospitalization or mortality between the study groups in general, and cycles administered to patients being treated for lymphomas in particular. The routine use of prophylactic G-CSF in a mixed cancer patient population with a low incidence of febrile neutropenia is not justified and should be reserved for individual patients with a high likelihood of developing febrile neutropenia.