Analysis of Early Postoperative Morbidity Among Patients with Rectal Cancer Treated with and without Neoadjuvant Chemoradiotherapy

Background: The impact of neoadjuvant treatment and their subsequent early complications in the treatment of rectal cancer has not been adequately assessed. The aim of this prospective study was to evaluate early postoperative morbidity and mortality among patients with rectal cancer treated with adjuvant radiotherapy and chemotherapy followed by surgery, compared with patients treated with surgery alone. We also identified independent risk factors associated with early major complications. Methods: Between 1995 and 2004, 273 consecutive patients underwent treatment for rectal cancer. A total of 170 patients (group A) received preoperative radiotherapy with a total of 45–50.4 Gy (180 cGy per day) and 5-fluorouracil-based chemotherapy, followed by surgery; 103 patients (group B) were treated with surgery alone. Dependent variables related to patients, treatment, radiotherapy, and tumor were analyzed. Results: Both groups were similar with regard to age, sex, body mass index, American Society of Anesthesiologists (ASA) score, and tumor location but not for ileostomy (27% in group A vs. 6.8% in group B). The number of complications was similar in both groups (43.1% in group A vs. 44.6% in group B). No differences in wound infection (8.2% vs. 7.8%), intraabdominal abscess (4.7% vs. 4.9%), anastomotic dehiscence (4.2% vs. 3.8%), postoperative hemorrhage (3.5% vs. 3.9%), urinary complications (6.5% vs. 4.9%), paralytic ileus (8.9% vs. 9.7%), or general complications (7.1% vs. 9.6%) were found. The global mortality in the first 30 days after surgery was .7%. An ASA score of III–IV and surgery duration longer than 3 hours were identified as independent prognostic factors for early complications. Conclusions: Preoperative chemoradiation in patients with rectal cancer treated with surgery is not associated with a higher incidence of early postoperative complications. The patient~s preoperative clinical condition and lengthy surgery time are prognostic factors for early complications

Analysis of POSSUM score and postoperative morbidity in patients with rectal cancer undergoing surgery

The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) and later modifications (P-POSSUM y CR-POSSUM) have been used to predict morbidity and mortality rates among patients with rectal cancer undergoing surgery. These calculations need some adjustment, however. The aim of this study was to assess the applicability of POSSUM to a group of patients with rectal cancer undergoing surgery, analysing surgical morbidity by means of several variables. METHODS: between January 1995 and December 2004, 273 consecutive patients underwent surgery for rectal cancer. Information was gathered about the patients, tumour and therapy. To assess the prediction capacity of POSSUM, subgroups for analysis were created according to variables related to operative morbidity and mortality. RESULTS: The global morbidity rate was 23.6% (31.2% predicted by POSSUM). The mortality rate was 0.7% (6.64, 1.95 and 2.08 predicted by POSSUM, P-POSSUM and CR-POSSUM respectively). POSSUM predictions may be more accurate for patients younger than 51 years, older than 70 years, with low anaesthetic risk (ASA I/II), DUKES stage C and D, surgery duration of less than 180 minutes and for those receiving neoadjuvant therapy. CONCLUSION: POSSUM is a good instrument to make results between different institutions and publication comparable. We found prediction errors for some variables related to morbidity. Modifications of surgical variables and specifications for neoadjuvant therapy as well as physiological variables including life style may improve future prediction of surgical risk. More research is needed to identify further potential risk factors for surgical complications

Presence of Activated (Phosphorylated) STAT3 in Radiation Necrosis Following Stereotactic Radiosurgery for Brain Metastases

Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs. Given that the pathophysiological mechanisms behind RN are not fully understood, we sought to investigate the role of STAT3 among other inflammatory markers in RN development. A mouse model of RN using clinical LINAC-based SRS was designed to induce brain necrosis with the administration of 50 Gy in a single fraction to the left hemisphere using a circular collimator of 5 mm diameter. Immunohis- tochemistry and multiplex staining for CD4, CD8, CD68, GFAP, and STAT3 were performed. For validation, eleven patients with BMs treated with SRS who developed symptomatic RN and required surgery were identified to perform staining for CD68, GFAP, and STAT3. In the mouse model, the RN and perinecrotic areas showed significantly higher staining for F4/80+ and GFAP+ cells, with a high infiltration of CD4 and CD8 T-lymphocytes, when compared to the non-irradiated cerebral hemisphere. A high number of GFAP+pSTAT3+ and F4/80+pSTAT3+ cells was found in the RN areas and the rest of the irradiated hemisphere. The analysis of human brain specimens showed that astrocytes and microglia were actively phosphorylating STAT3 in the areas of RN and gliosis. Phosphorylated STAT3 is highly expressed in the microglia and RA pertaining to the areas of brain RN. Targeting STAT3 via inhibition represents a promising strategy to ameliorate symptomatic RN in BM patients undergoing SRS

Analysis of Early Postoperative Morbidity Among Patients with Rectal Cancer Treated with and without Neoadjuvant Chemoradiotherapy

Background: The impact of neoadjuvant treatment and their subsequent early complications in the treatment of rectal cancer has not been adequately assessed. The aim of this prospective study was to evaluate early postoperative morbidity and mortality among patients with rectal cancer treated with adjuvant radiotherapy and chemotherapy followed by surgery, compared with patients treated with surgery alone. We also identified independent risk factors associated with early major complications. Methods: Between 1995 and 2004, 273 consecutive patients underwent treatment for rectal cancer. A total of 170 patients (group A) received preoperative radiotherapy with a total of 45–50.4 Gy (180 cGy per day) and 5-fluorouracil-based chemotherapy, followed by surgery; 103 patients (group B) were treated with surgery alone. Dependent variables related to patients, treatment, radiotherapy, and tumor were analyzed. Results: Both groups were similar with regard to age, sex, body mass index, American Society of Anesthesiologists (ASA) score, and tumor location but not for ileostomy (27% in group A vs. 6.8% in group B). The number of complications was similar in both groups (43.1% in group A vs. 44.6% in group B). No differences in wound infection (8.2% vs. 7.8%), intraabdominal abscess (4.7% vs. 4.9%), anastomotic dehiscence (4.2% vs. 3.8%), postoperative hemorrhage (3.5% vs. 3.9%), urinary complications (6.5% vs. 4.9%), paralytic ileus (8.9% vs. 9.7%), or general complications (7.1% vs. 9.6%) were found. The global mortality in the first 30 days after surgery was .7%. An ASA score of III–IV and surgery duration longer than 3 hours were identified as independent prognostic factors for early complications. Conclusions: Preoperative chemoradiation in patients with rectal cancer treated with surgery is not associated with a higher incidence of early postoperative complications. The patient~s preoperative clinical condition and lengthy surgery time are prognostic factors for early complications

Immune mechanisms mediating abscopal effects in radioimmunotherapy

Radiotherapy of cancer has been traditionally considered as a local therapy without noticeable effects outside the irradiated fields. However, ionizing radiation exerts multiple biological effects on both malignant and stromal cells that account for a complex spectrum of mechanisms beyond simple termination of cancer cells. In the era of immunotherapy, interest in radiation-induced inflammation and cell death has considerably risen, since these mechanisms lead to profound changes in the systemic immune response against cancer antigens. Immuno- therapies such as immunomodulatory monoclonal antibodies (anti-PD-1, anti-CTLA-4, anti-CD137, anti-OX40, anti-CD40, anti-TGFβ), TLR-agonists, and adoptive T-cell therapy have been synergistically combined with radio- therapy in mouse models. Importantly, radiation and immunotherapy combinations do not only act against the irradiated tumor but also against distant non-irradiated metastases (abscopal effects). A series of clinical trials are exploring the beneficial effects of radioimmunotherapy combinations. The concepts of crosspriming of tumor neoantigens and immunogenic cell death are key elements underlying this combination efficacy. Proinflamatory changes in the vasculature of the irradiated lesions and in the cellular composition of the leukocyte infiltrates in the tumor microenvironment contribute to raise or dampen cancer immunogenicity. It should be stressed that not all effects of radiotherapy favor antitumor immunity as there are counterbalancing mechanisms such as TGFβ, and VEGFs that inhibit the efficacy of the antitumor immune response, hence offering additional therapeu- tic targets to suppress. All in all, radiotherapy and immunotherapy are compatible and often synergistic approaches against cancer that jointly target irradiated and non-irradiated malignant lesions in the same patient

High-dose BCNU and autologous progenitor cell transplantation given with intra-arterial cisplatinum and simultaneous radiotherapy in the treatment of high-grade gliomas: benefit for selected patients

A phase II study of postoperative high-dose carmustine (HDBCNU), intracarotid cisplatin (CDDP), and radical radiotherapy in patients with high-grade glioma was performed. Patients underwent 4-6 consecutive days of blood hematopoietic progenitor cell (HPC) apheresis without prior mobilization. Chemotherapy included intracarotid CDDP, 60 mg/m2, and BCNU, 900 mg/m2. HPC were infused 48 h after HDBCNU. Whole brain irradiation, up to 50 Gy, was started on the 8th day after HPC infusion. With a median follow-up time of 44 months, median overall survival was 15.5 months. Eight patients (23.5%) are alive free of disease 2-6 years after treatment (seven out of 25 patients with glioblastoma multiforme and one out of nine patients with anaplastic astrocytoma). Survival was influenced by young age, good performance and complete surgical resection. Two patients (5.8%) died of therapy-related complications. Acute hematological toxicity of HDBCNU was moderate, with a full recovery on day 26. No acute pulmonary or hepatic toxicity was found. Late severe neurological toxicity was observed in one third of patients surviving beyond 2 years. We conclude that HDBCNU, 900 mg/m2, intracarotid CDDP and radical radiotherapy appear to benefit some patients with high-grade gliomas, and phase III studies should preferentially select young patients with resectable tumors