Towards a comprehensive treatment of repetitions, periodicity and temporal constraints in clinical guidelines

OBJECTIVE: In this paper, we define a principled approach to represent temporal constraints in clinical guidelines and to reason (i.e., perform inferences in the form of constraint propagation) on them. We consider different types of constraints, including composite and repeated actions, and propose different types of temporal functionalities (e.g., temporal consistency checking). BACKGROUND: Constraints about actions, durations, delays and periodic repetitions of actions are an intrinsic part of most clinical guidelines. Although several approaches provide expressive temporal formalisms, only few of them deal with the related temporal reasoning issues. METHODOLOGY: We first propose a temporal representation formalism and two temporal reasoning algorithms. Then, we consider the trade-off between the expressiveness of the formalism and the computational complexity of the algorithms, in order to devise a correct, complete and tractable approach. Finally, we show how the algorithms can be exploited to provide clinical guideline systems with different types of temporal facilities. RESULTS: Our approach offers several advantages. During the guideline acquisition phase, it enables to represent temporal constraints, and to check their consistency. In the execution phase, it checks the consistency between the execution times of the actions and the constraints in the guidelines, and provides query answering and simulation facilities.     

High response rate to cisplatin/etoposide regimen in childhood low-grade glioma.

PURPOSE: The aim of this study was to avoid radiotherapy and to induce an objective response in children with low-grade glioma (LGG) using a simple chemotherapy regimen based on cisplatin and etoposide. PATIENTS AND METHODS: Thirty-four children (median age, 45 months) with unresectable LGG were treated with 10 monthly cycles of cisplatin (30 mg/m(2)/d on days 1 to 3) and etoposide (150 mg/m(2)/d on days 1 to 3). Tumor originated in the visual pathway in 29 patients, in the temporal lobe in two, in the frontal lobe in two, and in the spine in one. Eight children were affected by neurofibromatosis type 1. Objective tumor response and toxicity were evaluated by magnetic resonance imaging and neurologic and functional tests at 3-month intervals. RESULTS: An objective response was obtained in 24 (70%) of 34 patients, whereas the others had stable disease. None of the children were electively irradiated. In 31 previously untreated children, overall survival was 100% and progression-free survival was 78% at 3 years, with a median follow-up of 44 months. Acute toxicity was unremarkable; 28% patients evaluated for acoustic neurotoxicity revealed a loss of perception of high frequencies. CONCLUSION: Cisplatin and etoposide combined treatment is one of the most active regimens for LGG in children and allows avoidance of radiotherapy in the vast majority of patients.     

Clinical experience with psychological aspects in pediatric patients amputated for malignancies

AIMS AND BACKGROUND: Amputation surgery in pediatric patients suffering from malignant tumors is less common than in the past, but has a great emotional impact on patients and their families as well as on the medical team. Studies addressing the psychological aspects of limb amputation in childhood cancer are still relatively limited, and the results have sometimes been contradictory. METHODS: At the Pediatric Oncology Unit of the Istituto Nazionale Tumori of Milan psychological support was provided to candidates for amputation and their families, involving medical oncologists, a clinical psychologist, and social assistants. Twenty-two patients were analyzed and 16 underwent mutilating surgery. RESULTS: Different emotional reactions were observed. Surgery proved to be easier to accept when the tumor caused pain and functional loss. Specialist medical psychological support was needed in case of defense mechanisms (eg, splitting and projection) and depressive reactions evolving into isolation or intolerance. CONCLUSIONS: The reported experience could be helpful in providing adequate support to children with tumors requiring mutilating surgery.     

Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment

The aim of the present study was to evaluate the effectiveness of two consecutive nonrandomised treatment programs applied between 1989 and 1999 at the Istituto Nazionale Tumori of Milan in an unselected cohort of 59 children over the age of one with stage 4 neuroblastoma. Both treatment programs consisted of two phases, the induction of the remission phase and the consolidation phase. The induction of the remission phase consisted of intensive chemotherapy, and remained the same throughout the study period. The consolidation phase consisted of sequential hemi-body irradiation (HBI) (10 Gy per session, 6 weeks apart) in the first period (1988-June 1994) and sequential high-dose cyclophosphamide, etoposide, mitoxantrone+L-PAM and autologous haemopoietic stem cell transplantation in the second (July 1994-1999). Intention-to-treat analysis revealed a significantly better outcome for patients treated with the second program, the 5-year event-free survival probability being 0.12 for program 1 and 0.31 for program 2 (P=0.03). This finding led us to conclude that sequential HBI is useless as consolidation treatment. The high-dose chemotherapy adopted in the second program enabled a proportion of patients to obtain long-term survival but, since the clinical results remain unsatisfactory, new treatment strategies are warranted.     

Five-day infusion fluorouracil plus vinorelbine i.v. in metastatic pretreated breast cancer patients

The aim of the present study was to evaluate the clinical activity and side effects of a combination chemotherapy consisting of a five-day continuous infusion of fluorouracil and i.v. vinorelbine in metastatic previously treated breast cancer patients. The patient population was represented by 28 women with evaluable disease, previously subjected to chemotherapy, including anthracycline-containing regimens in 89% of patients. Treatment consisted of five-day infusion of 700 mg/m²/day of fluorouracil and vinorelbine, 20 mg/m² iv bolus on day 1 and 6. In the absence of Grade > 3 leukopenia and stomatitis, cycles were repeated every three weeks, for a total of six cycles. Four complete and thirteen partial responses were documented, accounting for a response rate of 61% (95% CI: 40.5–78.5); the clinical efficacy was high even in patients unresponsive to prior anthracycline treatment. The median response duration calculated from the first drug injection was 8 months (range 4–11). Treatment was well tolerated, with 4% Grade 4 stomatitis and 20% Grade 3 leukopenia as the main toxic reactions. This drug combination is active in metastatic previously treated breast cancer patients, is devoid of severe side effects, and warrants further testing.     

Evolving treatment strategies for parameningeal rhabdomyosarcoma: the experience of the Istituto Nazionale Tumori of Milan

BACKGROUND: Ninety pediatric patients with parameningeal rhabdomyosarcoma (PM-RMS) were treated between 1970 and 2002 at the Istituto Nazionale Tumori, Milan. METHODS: Combined treatment was implemented in high-risk patients with whole-brain irradiation and intrathecal chemotherapy between 1978 and 1981 and intrathecal methotrexate alone between 1982 and 1987. Radiotherapy was given with conventional fractionation until 1988 and hyperfractionated accelerated radiotherapy (HART) thereafter. RESULTS: The 5-year disease-free survival was 41.3%, increasing from 15.4% (1970-1977) to 55.9% (1989-2002) for localized cases. Local failure rates were 41% and 24% with conventional fractionation and HART, respectively. In patients treated with HART, acute toxicities were more pronounced, but the treatment compliance was better. Severe radiation-related late sequelae were observed. CONCLUSIONS: The outcome for patients with PM-RMS has improved over the years but is still not as satisfactory as that for patients with RMS of other sites. Thanks to improvements in radiotherapy techniques and chemotherapy efficacy, meningeal prophylaxis is no longer necessary. Although more evidence is needed to confirm our data, the results obtained with twice-daily HART seem promising.     

Vinorelbine in previously treated advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma

BACKGROUND: Vinca alkaloids have proved active against a number of pediatric malignancies. The aim of this study was to assess the feasibility and effectiveness of using vinorelbine in previously treated pediatric patients with advanced sarcomas. METHODS: From September 1998 to August 2001, 33 previously treated patients with progressive sarcoma were treated: 13 had rhabdomyosarcomas, 5 had other soft tissue sarcomas, 9 had Ewing sarcomas, and 6 had osteosarcomas. Vinorelbine was given intravenously on Days 1 and 8 of a 21-day treatment cycle. Four patients with uncontrolled pain or central nervous system invasion received concurrent radiotherapy and were only evaluated for toxicity. RESULTS: One hundred seventy-eight treatment cycles were administered (median of four per patient, range 1-20). Grade 3 to 4 neutropenia occurred in 63% of patients, Grade 3 anemia in 9%, and Grade 3 thrombocytopenia in 3%. Nonhematological toxicity was mild or moderate, i.e., always lower than Grade 3, with the exception of one child who experienced paralytic ileus. Twenty-eight patients were assessable for response. Eight patients had a partial response, one patient had a minor response, and nine patients had stable disease. Objective responses were observed in 6 of 12 patients with rhadbomyosarcomas (five of six of the alveolar subtype), in one of five patients with osteosarcomas, and in one of seven patients with Ewing sarcomas. The median duration of response was 10 months (range, 3+ to 20). CONCLUSIONS: Vinorelbine has a favorable toxicity profile with evidence of biological activity in already heavily treated pediatric patients with sarcomas. In particular, the objective response rate obtained for patients with alveolar rhabdomyosarcoma seems very promising. Due to the few cases considered here, further Phase II studies are needed to establish a potential role of vinorelbine in the treatment of these tumors.