How Far Is Too Far? Cost-Effectiveness Analysis of Regionalized Rectal Cancer Surgery.

BACKGROUND: Regionalized rectal cancer surgery may decrease postoperative and long-term cancer-related mortality. However, the regionalization of care may be an undue burden on patients. OBJECTIVE: This study aimed to assess the cost-effectiveness of regionalized rectal cancer surgery. DESIGN: Tree-based decision analysis. PATIENTS: Patients with stage II/III rectal cancer anatomically suitable for low anterior resection were included. SETTING: Rectal cancer surgery performed at a high-volume regional center rather than the closest hospital available. MAIN OUTCOME MEASURES: Incremental costs ($) and effectiveness (quality-adjusted life year) reflected a societal perspective and were time-discounted at 3%. Costs and benefits were combined to produce the incremental cost-effectiveness ratio ($ per quality-adjusted life year). Multivariable probabilistic sensitivity analysis modeled uncertainty in probabilities, costs, and effectiveness. RESULTS: Regionalized surgery economically dominated local surgery. Regionalized rectal cancer surgery was both less expensive on average ($50,406 versus $65,430 in present-day costs) and produced better long-term outcomes (10.36 versus 9.51 quality-adjusted life years). The total costs and inconvenience of traveling to a regional high-volume center would need to exceed $15,024 per patient to achieve economic breakeven alone or $112,476 per patient to satisfy conventional cost-effectiveness standards. These results were robust on sensitivity analysis and maintained in 94.6% of scenario testing. LIMITATIONS: Decision analysis models are limited to policy level rather than individualized decision-making. CONCLUSIONS: Regionalized rectal cancer surgery improves clinical outcomes and reduces total societal costs compared to local surgical care. Prescriptive measures and patient inducements may be needed to expand the role of regionalized surgery for rectal cancer. See Video Abstract at http://links.lww.com/DCR/C83 . QU TAN LEJOS ES DEMASIADO LEJOS ANLISIS DE COSTOEFECTIVIDAD DE LA CIRUGA DE CNCER DE RECTO REGIONALIZADO: ANTECEDENTES:La cirugía de cáncer de recto regionalizado puede disminuir la mortalidad posoperatoria y a largo plazo relacionada con el cáncer. Sin embargo, la regionalización de la atención puede ser una carga indebida para los pacientes.OBJETIVO:Evaluar la rentabilidad de la cirugía oncológica de recto regionalizada.DISEÑO:Análisis de decisiones basado en árboles.PACIENTES:Pacientes con cáncer de recto en estadio II/III anatómicamente aptos para resección anterior baja.AJUSTE:Cirugía de cáncer rectal realizada en un centro regional de alto volumen en lugar del hospital más cercano disponible.PRINCIPALES MEDIDAS DE RESULTADO:Los costos incrementales ($) y la efectividad (años de vida ajustados por calidad) reflejaron una perspectiva social y se descontaron en el tiempo al 3%. Los costos y los beneficios se combinaron para producir la relación costo-efectividad incremental ($ por año de vida ajustado por calidad). El análisis de sensibilidad probabilístico multivariable modeló la incertidumbre en las probabilidades, los costos y la efectividad.RESULTADOS:La cirugía regionalizada predominó económicamente la cirugía local. La cirugía de cáncer de recto regionalizado fue menos costosa en promedio ($50 406 versus $65 430 en costos actuales) y produjo mejores resultados a largo plazo (10,36 versus 9,51 años de vida ajustados por calidad). Los costos totales y la inconveniencia de viajar a un centro regional de alto volumen necesitarían superar los $15,024 por paciente para alcanzar el punto de equilibrio económico o $112,476 por paciente para satisfacer los estándares convencionales de rentabilidad. Estos resultados fueron sólidos en el análisis de sensibilidad y se mantuvieron en el 94,6% de las pruebas de escenarios.LIMITACIONES:Los modelos de análisis de decisiones se limitan al nivel de políticas en lugar de la toma de decisiones individualizada.CONCLUSIONES:La cirugía de cáncer de recto regionalizada mejora los resultados clínicos y reduce los costos sociales totales en comparación con la atención quirúrgica local. Es posible que se necesiten medidas prescriptivas e incentivos para los pacientes a fin de ampliar el papel de la cirugía regionalizada para el cáncer de recto. Consulte Video Resumen en http://links.lww.com/DCR/C83 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

VcR-CVAD Induction Chemotherapy Followed by Maintenance Rituximab Produces Durable Remissions in Mantle Cell Lymphoma: A Wisconsin Oncology Network Study.

INTRODUCTION: VcR-CVAD was developed as an intermediate-intensity induction regimen with maintenance rituximab (MR) to improve remission durations after first-line therapy for mantle cell lymphoma (MCL) in older and younger patients with MCL. PATIENTS AND METHODS: Patients with previously untreated MCL received VcR-CVAD induction chemotherapy for 6 cycles (21-day cycles). Patients achieving at least a partial response received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary endpoints were overall and complete response (CR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. There was an even distribution of patients < 60 years and ≥ 60 years. Mantle cell lymphoma international prognostic index medium- or high-risk disease was present in 60%. The overall response rate observed was 90% (77% CR/unconfirmed CR). After a median follow-up of 7.8 years, the 6-year PFS and OS were 53% and 70%, respectively. There was no difference in 6-year PFS or OS between the younger (age < 60 years) and older (age ≥ 60 years) subgroups. In a univariate analysis, lactate dehydrogenase, when analyzed for interaction with age, had a significant effect on PFS outcomes at 6 years. There were no pretreatment variables determined to have a significant effect on OS outcomes at 6 years. CONCLUSIONS: Long-term outcomes with VcR-CVAD are comparable with more intensive inductions and consolidation approaches. MCL is biologically heterogeneous, and durable remission can be achieved with intermediate intensity therapy. MR appears to contribute to these excellent outcomes.

Reduction in oral mucositis severity using a topical vasoconstrictor: A case report of three bone marrow transplant patients.

BACKGROUND: Grade 3 oral mucositis (OM) is historically observed in >90% of bone marrow transplant patients who received the cyclophosphamide + total body irradiation (CY+TBI) conditioning regimen. It was previously shown that orotopically applied adrenergic vasoconstrictor prevented up to 100% of radiation-induced oral mucositis in two preclinical animal models. METHODS: Adrenergic vasoconstrictor (i.e., phenylephrine in an aqueous-alcohol NG11-1 formulation) was orotopically applied to three patients (ages 24-29) who received the CY+TBI conditioning regimen; they were compared to five matched controls who received no orotopical vasoconstrictor. All patients received the CY+TBI conditioning regimen for acute lymphoblastic leukemia within the University of Wisconsin Adult Bone Marrow Transplant Program. Over the seven-day Cy+TBI conditioning regimen, 20 min before each treatment, either radiation or chemotherapy, vasoconstrictor was applied topically to the oral cavity, and patients then received either 1.5 Gy whole-body radiation or IV cyclophosphamide. RESULTS: OM severity was scored over a three-week period using: i) physican assessments, ii) daily photos of the oral cavity, iii) oral pain and oral function score sheets, and iv) recorded narcotic consumption. Both "Grade 3 OM" duration and "any OM" duration in vasoconstrictor-treated patients were substantially lower than for the five control patients. Though nasogastric tube or total parenteral nutrition were used in 3 out of 5 control patients, there was no use of these supportive care measures in the three vasoconstrictor-treated patients. CONCLUSION: Orotopically applied NG11-1 vasoconstrictor formulation substantially reduced the incidence and severity of "Grade 3" and "any" oral mucositis when compared to matched control patients, all of whom received the same CY+TBI conditioning regimen. The liquid orotopical formulation was easily tolerated by patients both in its ease of use and lack of side effects.

Retrospective analysis of fluoroquinolone prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Patients undergoing allogeneic hematopoietic stem cell transplant are at a high risk for infection-related mortality in the immediate post-transplantation phase. Prophylaxis with a fluoroquinolone is now recommended to reduce this risk with the stipulation that surveillance for increased fluoroquinolone resistance Clostridium difficile associated diarrhea be conducted. METHODS: We conducted a retrospective chart review of 48 patients who underwent an allogeneic hematopoietic stem cell transplant and received a fluoroquinolone for prophylaxis and 48 patients who underwent an allogeneic hematopoietic stem cell transplant who did not receive a fluoroquinolone for prophylaxis. All patients received the same standard antifungal, antiviral and anti-pneumocystis prophylaxis. RESULTS: Patients receiving fluoroquinolone prophylaxis had a lower incidence of febrile neutropenia than those not receiving prophylaxis, though the difference was not found to be statistically significant (83% vs. 67%, p = 0.098). Similar non-significant improvements in the number of positive cultures recovered during an episode of febrile neutropenia and antimicrobial days were noted. No significant increase in fluoroquinolone resistance, Clostridium difficile associated diarrhea, or in methicillin resistant Staphylococcus aureus infections were noted. CONCLUSION: Our single institution experience with fluoroquinolone prophylaxis for allogeneic hematopoietic stem cell transplant patients supports continuation of this practice. Expansion to autologous hematopoietic stem cell transplant patients may be appropriate based on guideline recommendations and our institution-specific experience with fluoroquinolone prophylaxis.

VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study.

Intensive chemotherapy regimens are not feasible in many adults with mantle cell lymphoma (MCL). We sought to build upon our previous experience with a non-intensive regimen, modified R-hyperCVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) with maintenance rituximab (MR), by the incorporation of bortezomib (VcR-CVAD) and the extension of MR beyond 2 years. Patients with previously untreated MCL received VcR-CVAD chemotherapy every 21 d for six cycles. Patients achieving at least a partial response to induction chemotherapy received rituximab consolidation (375 mg/m(2) × 4 weekly doses) and MR (375 mg/m(2) every 12 weeks × 20 doses). The primary end points were overall and complete response (CR), and secondary endpoints were progression-free (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. All patients had advanced stage disease, and 60% had medium/high MCL International Prognostic Index risk factors. A CR or unconfirmed CR was achieved in 77% of patients. After a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively. The observed 3-year PFS and OS with VcR-CVAD in MCL were comparable to reported outcomes with more intensive regimens. A cooperative group trial (E1405) is attempting to replicate these promising results.

Rituximab and CHOP chemotherapy plus GM-CSF for previously untreated diffuse large B-cell lymphoma in the elderly: a Wisconsin oncology network study.

PURPOSE: Human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) may potentiate rituximab activity by upregulating CD20 expression and activating effector cells necessary for antibody-dependent cellular cytotoxicity. GM-CSF was combined with standard rituximab + CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy (R-CHOP) in the treatment of elderly patients with de novo diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Thirty-eight patients over the age of 60 years with newly diagnosed DLBCL were treated with R-CHOP every 21 days for 6-8 cycles and GM-CSF 250 µg/m2 per day on days 3-10. Patients were evaluated for response after cycles 4, 6, and 8. The primary endpoint was the rate of complete response, and secondary endpoints were progression-free survival (PFS), event-free survival, and overall survival (OS). RESULTS: Thirty-eight patients were enrolled, with a median age of 72 years, and 29% of patients having high-risk disease (International Prognostic Index [IPI] score ≥ 4). A complete or unconfirmed complete response (CR) was achieved in 53% of patients. After a median follow-up of 51.1 months, the 3-year PFS and OS were 78% and 84%. Twenty-one percent of patients discontinued protocol treatment because of chemotherapy-related toxicity and 16% because of GM-CSF toxicity. Dose intensity for planned chemotherapy cycles was 81.1%. CONCLUSION: These data suggest that survival outcomes may be modestly improved when GM-CSF is combined with R-CHOP in the treatment of elderly DLBCL. GM-CSF had toxicity precluding planned administration in 16% of patients, which may limit usefulness of this agent. Further investigation of GM-CSF in combination with rituximab-containing chemotherapy is warranted.

Augmented and standard Berlin-Frankfurt-Munster chemotherapy for treatment of adult acute lymphoblastic leukemia.

The augmented Berlin-Frankfurt-Munster (aBFM) regimen has demonstrated improved outcomes in children with acute lymphomblastic leukemia (ALL), but efficacy in adults is unknown. In this retrospective study, we evaluated clinical outcomes in 29 adult ALL patients (aged 19-70) treated with standard BFM (sBFM) or dose-intensive aBFM. Patients were stratified into risk groups based on age, cytogenetic abnormalities, peripheral leukocytosis and response to induction chemotherapy. Inter-mediate risk patients less than 50 years old and all high-risk patients were assigned to aBFM. Complete remission after induction therapy was achieved in 93% of patients. Fifteen patients completed a full course of BFM chemotherapy, with seven discontinuing because of relapse, three because of toxicity, two because of transplantation and two toxic deaths. Five-year event-free survival (EFS) was 45% (95% CI 30-67%), with 39% and 50% rates of EFS observed in the aBFM and sBFM subgroups at 5 years, respectively. Overall survival at 5 years was 62% (95% CI 46-82%), with 61% and 62% in the aBFM and sBFM subgroups alive at 5 years, respectively. Two toxic deaths were observed, and infections and neuropathy were the most common toxicities. sBFM and aBFM have efficacy and toxicity comparable with other adult ALL regimens.

Thalidomide maintenance following high-dose melphalan with autologous stem cell support in myeloma.

BACKGROUND: Recent experience with thalidomide maintenance after high-dose chemotherapy with autologous stem cell support has demonstrated improvement in progression-free survival (PFS) and overall survival (OS). We further explored the tolerability and efficacy of lower doses of maintenance thalidomide in this single-institution study. PATIENTS AND METHODS: Thirty-eight patients with myeloma were enrolled and treated with melphalan 200 mg/m(2) followed by autologous stem cell transplantation. Thalidomide 50 mg per day was started on day > or = 60 after recovery of blood counts and was escalated to a maximum dose of 200 mg per day. Responses were assessed at 2 months, 1 year, and 2 years after transplantation. RESULTS: Of the 38 enrolled patients, 7 patients never received thalidomide. Among 31 patients receiving thalidomide, complete or very good partial responses were observed in 65% and 42% of patients at 1 and 2 years, respectively. Tolerability was a major issue, with only 17 patients completing 1 year of thalidomide. The goal of dosing 200 mg per day was achieved in just 17 of 31 patients, and the median tolerated thalidomide dose was 100 mg per day. Sensory neuropathy was the primary reason for dose modification and discontinuation. No thromboembolic events were observed. The median PFS was 20.8 months, and the median OS was > 60 months. CONCLUSION: Thalidomide maintenance at a goal dose of 200 mg per day was not feasible in this population, with our data suggesting that 100 mg per day is a more reasonable maintenance dose.

Correlation between rash and a positive drug response associated with bevacizumab in a patient with advanced colorectal cancer.

Bevacizumab is the fi rst vascular endothelial growth factor-targeted agent shown to increase survival in patients receiving first- and second-line intravenous 5-FU-based chemotherapy for the treatment of metastatic colorectal cancer. Bevacizumab is typically well tolerated and its major side effects include hypertension, proteinuria, bleeding, gastrointestinal perforation and arterial thrombotic events. Although exfoliative dermatitis has been described as a side effect in 19% of patients, skin rash (type unspecified) has rarely been described in patients following infusion of bevacizumab. We recently reported the fi rst patient with colon cancer manifesting a correlation between rash and a positive drug response with bevacizumab. A 49-year old male with T3 N1 M1 rectal carcinoma received modified FOLFOX-6/bevacizumab, which he tolerated very well except for grade 2 skin rash related to bevacizumab. The rash continued to progress as the serum carcinoembryonic antigen decreased significantly. Computed tomography and positron emission tomography scan confirmed response to FOLFOX/bevacizumab. We therefore believe that this rash was linked to bevacizumab administration and correlated with response to therapy. Grade 1/2 rash has been described in patients after infusion of bevacizumab in initial phase I and II studies. Skin rash was observed in 34% and 46% of patients in the Kabbinavar's study receiving 5 mg/kg dose and 10 mg/kg respectively but no patient developed > grade 3 rash. This toxicity was not well described in pivotal phase III studies. On the other hand, acneiform rash occurs in > 90% patients who receive cetuximab and panitumumab, severity of which appears to be predictive of response. To our knowledge, this case report is the second report of possible correlation between rash and a positive drug response associated with bevacizumab and warrants further investigation of similar observation.

A 5-drug regimen maximizing the dose of cyclophosphamide is effective therapy for adult Burkitt or Burkitt-like lymphomas.

Burkitt lymphoma (BL) and Burkitt-like lymphomas (BLL) are clinically and biologically aggressive B-cell malignancies. Brief-duration, high intensity multidrug regimens with central nervous system (CNS) prophylaxis have proven to be effective, with published series of adult patients documenting complete response (CR) rates of 80 to 100 percent and 2-year event-free survival (EFS) rates ranging from 60 to 90 percent. Based upon the known sensitivity of BL to cyclophosphamide and favorable results reported from the Dana Farber Cancer Center using high-dose CHOP in diffuse aggressive lymphomas, we tested a regimen designed to maximize the administered dose of cyclophosphamide while eliminating other agents commonly used in BL protocols. Eleven patients with Burkitt or Burkitt-like lymphoma were treated with 4 cycles of a 5-drug regimen, called high-dose CHOP, which contains a cyclophosphamide dose of 4 gm/m2 with each cycle. Intrathecal methotrexate and midcycle high-dose methotrexate were added as CNS prophylaxis. Ten patients achieved a complete response (91 percent) and with a median follow up of 38 months, the 3-year EFS is 64 percent and the 3-year overall survival (OS) is 72 percent. Three patients recurred after the achievement of a CR. Treatment-related toxicities included myelosuppression, neutropenic fevers/infections, and tumor lysis syndrome requiring hemodialysis in 2 patients. There were no treatment-related deaths and none of the patients had to discontinue therapy secondary to toxicity. In conclusion, the high-dose CHOP with midcycle methotrexate regimen produces response rates and EFS rates comparable to other regimens, with an acceptable toxicity profile. Utilization of high dose cyclophosphamide may eliminate the need for several other agents in Burkitt lymphoma regimens.

Excessive toxicity of the high dose thiotepa and etoposide regimen when combined with radiation: Long-term autologous transplantation experience in follicular and mantle cell lymphoma.

We recently described a novel thiotepa plus etoposide high-dose therapy (HDT) conditioning regimen for aggressive histology non-Hodgkin's lymphoma (NHL) that had low regimen-related toxicity (RRT) and an efficacy rate comparable to other NHL HDT regimens. In this report, we describe the UW experience with the addition of total body irradiation (TBI) and pre-transplant involved-field radiation (IFRT) to the thiotepa + etoposide HDT regimen. Between 1992 and 1999, 28 patients with indolent or mantle cell lymphoma were treated on this protocol. With a median follow-up of 64 mo, the median event-free survival (EFS) was 24 months, and the median overall survival (OS) had not been reached. The median number of grade 3 - 4 non-hematologic toxicities was five. There were five deaths (18%) in the first three months after HDT due to RRT. In contrast, the thiotepa + etoposide conditioning regimen (without TBI or IFRT) given to 65 intermediate grade NHL patients resulted in only one treatment-related death and considerably fewer grade 3 - 4 toxicities. Given the relatively short EFS in this cohort of indolent NHL patients, we conclude that the combination of IFRT and TBI plus thiotepa and etoposide resulted in a HDT regimen with excessive toxicity and this protocol was closed at our institution.

Phase II study of weekly low-dose paclitaxel for relapsed and refractory non-Hodgkin's lymphoma: a Wisconsin Oncology Network Study.

This study was performed to determine the clinical activity and safety of weekly low-dose paclitaxel (90 mg/m2) given as a 1-hour infusion in patients with relapsed and refractory non-Hodgkin's lymphoma (NHL). Thirty patients were treated on a phase II protocol conducted at the University of Wisconsin Comprehensive Cancer Center and within the Wisconsin Oncology Network (WON). A cycle of therapy was defined as paclitaxel at 90 mg/m2 weekly for 6 consecutive weeks followed by a 2-week rest period. Cycles were repeated as long as there was no disease progression or unacceptable toxicity. In general, the patients were heavily pretreated with a median of 4 prior therapies (range 2-11), and 73% were refractory to the most recent systemic therapy. The median age was 70 (range 44-97). All NHL histological subtypes were eligible. Of the 30 eligible patients enrolled, 26 were evaluable for response and 28 for toxicity. The overall response rate was 23% (95% confidence interval (CI) 9.0-43.7%). One patient had a complete response, and 5 patients had partial responses. The median response duration was 3.2 months (range 1.4-11.8 months). The median event-free survival was 1.9 months. The major toxicity was neuropathy. Despite the limited marrow reserve in this patient population, myelosuppression was minimal. Paclitaxel given in this dose and schedule has modest activity in previously treated non-Hodgkin's lymphoma. The response rate appears similar to other reports using different doses and schedules. Myelosuppression appears less with this schedule than with other schedules.