Carlo Ratto

Infusional 5-fluorouracil and ZD1839 (Gefitinib-Iressa) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: a phase I and II Trial (1839IL/0092)

PURPOSEnTo report the final data of a Phase I and II study (1839IL/0092) on the combination of an anti-epidermal growth factor receptor drug (gefitinib), infusional 5-fluorouracil, and preoperative radiotherapy in locally advanced, resectable rectal cancer.nnnMETHODS AND MATERIALSnPatients received 45 Gy in the posterior pelvis plus a boost of 5.4 Gy on the tumor and corresponding mesorectum. Infusional 5-fluorouracil (5-FU) and gefitinib (250 and 500 mg/day) were delivered during all radiotherapy course. An IORT boost of 10 Gy was allowed. The main endpoints of the study were to establish dose-limiting toxicity (DLT) and to evaluate the rate of pathologic response according to the tumor regression grade (TRG) Mandard score.nnnRESULTSnA total of 41 patients were enrolled. The DLT was not reached in the 6 patients enrolled in the dose-escalation part of the study. Of the 33 patients in the Phase II, TRG 1 was recorded in 10 patients (30.3%) and TRG 2 in 7 patients (21.2 %); overall 17 of 33 patients (51.5%) had a favorable endpoint. Overall, Grade 3+ toxicity was recorded in 16 patients (41%); these included Grade 3+ gastrointestinal toxicity in 8 patients (20.5%), Grade 3+ skin toxicity in 6 (15.3%), and Grade 3+ genitourinary toxicity in 4 (10.2%). A dose reduction of gefitinib was necessary in 24 patients (61.5%).nnnCONCLUSIONSnGefitinib can be associated with 5-FU-based preoperative chemoradiation at the dose of 500 mg without any life-threatening toxicity and with a high pCR (30.3%). The relevant rate of Grade 3 gastrointestinal toxicity suggests that 250 mg would be more tolerable dose in a neaoadjuvant approach with radiotherapy and infusional 5-FU.

Outcomes of clinical T4M0 extra-peritoneal rectal cancer treated with preoperative radiochemotherapy and surgery: A prospective evaluation of a single institutional experience

BACKGROUNDnOur objective was evaluate the outcome of primary clinical T4M0 extraperitoneal rectal cancer treated by neoadjuvant radiochemotherapy. Prognosis of clinical T4 rectal cancer is poor. Preoperative chemoradiation therapy may be beneficial. The results obtained are unclear due to lack of objective and strictly applied staging methods.nnnMETHODSnPatients with primary, clinical, T4MO, extraperitoneal rectal cancer, defined by transrectal ultrasonography, computed tomography or magnetic resonance imaging, were considered. Intraoperative radiotherapy and adjuvant chemotherapy were employed in some patients after curative resection (R0). Variables influencing the possibility to perform an R0 resection and a sphincter-saving procedure were investigated as predictors of outcome.nnnRESULTSn100 patients were included. R0 resection was performed in 78 patients. R0 resection rate was greater in females (93% vs 67%) and in responders to neoadjuvant chemoradiation (94% vs 60%). The ability to perform a sphincter-saving procedure was 57%, greater in middle rectal location (85% vs 51%) and in responders to the chemoradiation (70% vs 47%). Median follow-up was 31 months (range, 4-136). Local recurrences were found in 7 patients (10%). Five-year local control in R0 patients was 90% and better in the IORT group (100%). Distant relapse occurred in 24 patients (30%). Five-year overall survival was 59%, and was better after an R0 versus an R1 or R2 resection (68% vs 22%). Overall and disease free survival in R0 patients improved after overall downstaging. Adjuvant chemotherapy given in addition to the neoadjuvant therapy did not appear to offer benefit in improving survival.nnnCONCLUSIONnA multimodal approach enabled us to obtain a 5-year overall survival of about 60%. IORT increased local control. The role of adjuvant chemotherapy needs to be further investigated.

Influence of anterior subdiaphragmatic vagotomy and TPN on rat feeding behavior

Total parenteral nutrition (TPN) inhibits food intake and feeding behavior. Whether caloric sensory function of the liver contributes to this food intake and feeding behavior regulation via vagal-afferent innervation was tested after performing anterior hepatic vagotomy or sham operation in rats infused with a TPN solution providing 100% of daily energy needs, given continuously for 4 days. Food intake, meal number, size, duration, meal and intermeal sniffs, and eating activity were measured using an automated computerized rat eater meter (ACREM). TPN infusion resulted in a significant decrease of food intake and feeding indexes in both groups. The vagotomized rats showed a significantly higher food consumption, achieved by greater meal frequency, larger meal size, and longer meal duration. Thus, vagotomized rats consumed more than their controls by eating larger meals more often and of longer duration. Data suggest that anterior hepatic vagotomy interrupts hepatic caloric sensory feedback loop, diminishing inhibitory vagal effects on food intake with TPN, leading to an overall increase in food intake.

Preoperative chemoradiation with raltitrexed ('Tomudex') for T2/N+ and T3/N+ rectal cancers: a phase I study.

The use of raltitrexed (Tomudex) as concomitant chemotherapy during preoperative radiotherapy in chemonaïve patients with stage II/III rectal cancer has been examined in this study and its recommended dose in conjunction with radiotherapy investigated. Forty-five Gray (Gy) of radiotherapy (1.8 Gy daily, 5 days per week) was delivered to the posterior pelvis, followed by a 5.4 Gy boost. Single doses of raltitrexed (2.0, 2.5 and 3.0 mg/m(2)) were administered on days 1, 19 and 38. Only 1 of the 15 patients entered experienced a dose limiting toxicity (DLT) (grade 3 leucopenia) at the 3.0 mg/m(2) dose level. The overall response rate was 80% (five complete responses, seven partial responses). These preliminary data suggest that raltitrexed is a well tolerated and effective treatment when combined with preoperative radiotherapy in patients with stage II/III rectal cancer. The recommended dose of raltitrexed for future phase II studies will be 3.0 mg/m(2).

Dynamics of oral intake resumption after general anesthesia and operation in rats

The influence of general anesthesia and operation on dynamics of postoperative food intake resumption was investigated in eight rats. A laparotomy was performed on each rat under anesthesia induced by intraperitoneally injected chloral hydrate. Spontaneous food intake and feeding indexes were continuously measured using an Automated Computerized Rat Eater Meter (ACREM) before and after operation. Although spontaneous food intake and all feeding indexes were depressed immediately following anesthesia and operation, each feeding index was depressed to a greater degree during the dark vs. the light cycle. Initially, rats fully capable of eating ate fewer, smaller, and shorter meals. The return to normal of each feeding index differed temporally. Thus, although meal number normalized by the third postoperative day, meal size by the sixth postoperative day, and meal duration by the fourth postoperative day, normalization of meal number during the light cycle occurred sooner than during the dark cycle, while the converse occurred with meal size and meal duration.

SPHINCTER PRESERVATION IN FOUR CONSECUTIVE PHASE II STUDIES OF PREOPERATIVE CHEMORADIATION: ANALYSIS OF 247 T3 RECTAL CANCER PATIENTS

AIMS AND BACKGROUNDnTo evaluate the impact of preoperative chemoradiation on sphincter preservation in patients with low-medium locally advanced resectable rectal cancer treated by four chemoradiation schedules.nnnMATERIALS AND METHODSnBetween 1990 and 2002, 247 patients were treated according to four schedules of chemoradiotherapy: FUMIR (5-fluorouracil, mitomycin, external beam radiotherapy 37.8 Gy), PLAFUR (cisplatinum, 5-fluorouracil, external beam radiotherapy 50.4 Gy),TOMRT (raltitrexed, external beam radiotherapy 50.4 Gy), and TOMOXRT (raltitrexed, oxaliplatin, external beam radiotherapy 50.4 Gy). Four to five weeks after chemoradiation, patients were restaged and surgery was performed 2-3 weeks later.nnnRESULTSnOverall, the sphincter-saving surgery was performed in 82.5% of patients. In patients candidate to an abdominoperineal resection before chemoradiaton (distance tumor-anorectal ring, < 30 mm) a sphincter-saving surgery was possible in 58% of cases: 44% (FUMIR), 52% (PLAFUR), 63% (TOMRT), 76% (TOMOXRT) (P < 0.017). The involved surgeons kept the same surgical criteria in performing sphincter-saving surgery. After chemoradiation, patients with tumor location still between 0 and 30 mm received sphincter-saving surgery according to the protocols: 33% (FUMIR), 42% (PLAFUR), 50% (TOMRT), 64% (TOMOXRT) (P = 0.066).nnnCONCLUSIONSnEven though the surgeons skill in performing sphincter-saving surgery could be improved with time, the high rate of this procedure in the latest schedules suggests an impact of the new drugs in promoting tumor downsizing and therefore sphincter-saving surgery.

5-Fluorouracil (FU) with folinic acid (FA) and mitomycin c (MMC) in the adjuvant treatment of colorectal carcinoma. part i. evaluation of toxicity

Ninety-six patients with colorectal cancer (stage B2-C) were randomized to the control arm or to receive adjuvant chemotherapy with folinic acid, FU and MMC. Ninety-three patients are evaluable. The median follow up is 12 months. The average time between surgery and the start of therapy is 28 days. Toxicity is evaluable in 36 of 41 treated patients. Four patients (10%) failed to complete the projected treatment due to toxicity. Toxicity observed in 208 courses of therapy was mostly gastrointestinal and hematological. No cases of treatment related death or cancer-associated hemolytic uremic syndrome (C-HUS) were reported. The average relative dose intensity (rDI) of the projected treatment was 82.6%. Our study is ongoing and further patients are required to achieve statistically significant results.

Diagnostic workup in incontinent patients: An integrated approach

Anal continence is assured by the activity of complex anatomical and physiological structures (anal sphincters, pelvic floor musculature, rectal curvatures, transverse rectal folds, rectal reservoir, rectal sensation). It is dependent also on numerous other factors, such as stool consistency, patient’s mental faculties and mobility, and social convenience. Only if there is an effective, coordinated integration between these elements can defecation proceed normally. On the other hand, fecal incontinence (FI) is the result of disruption of one or several of these different entities: frequently, it can be due to a multifactorial pathogenesis, and in many cases, it is not secondary to sphincter tears. The disruption could lie in alterations intrinsic to the anorectal neuromuscular structures of continence control or be extrinsic to them, involving extrapelvic control mechanisms. The primary aim of an effective therapeutic approach must be the improvement-better, the resolution-of this distressing condition. Different forms of therapy are now available so that physicians must select the best option for each patient.

Medical Treatment of Fecal Incontinence

Management of fecal incontinence (FI) should be based on a meticulous assessment of pathophysiology through both clinical and physiological diagnostic workup. There are cases with prevalently altered diet and hygiene. Very frequently, diarrhea and constipation can be found involved in the development and maintenance of FI [1-3], both in the presence or absence of other traumatic or nontraumatic causes. Consequently, in those cases, treatment must be directed toward cure of these dysfunctions, either as single-line or combined treatment. Little evidence exists in the available literature about medical therapy for FI; recently, a Cochrane Database Review high-lighted that “there is little evidence with which to assess the use of drug therapies for the management of fecal incontinence” [4]. Therefore, medical treatment in FI is debatable and often pragmatic.

Social Aspects and Economics of Fecal Incontinence

Health care expenditure in the most economically advanced countries seems to have spiraled out of control over the last few decades. There are three main reasons accounting for this situation: ageing of the population has led to an increase in the numbers requiring health care services, the accelerating pace of technological development has given rise to new techniques that have improved the quality of treatment, and with the introduction of new, increasingly costly, products, patient expectations have changed and patients thus demand better medical treatment. The combination of these three factors has resulted in health care spending becoming increasingly difficult to control.