Clinical-practice recommendations for the management of bowel obstruction in patients with end-stage cancer.

The paper highlights a series of questions that doctors need to consider when faced with end-stage cancer patients with bowel obstruction: Is the patient fit for surgery? Is there a place for stenting? Is it necessary to use a venting nasogastric tube (NGT) in inoperable patients? What drugs are indicated for symptom control, what is the proper route for their administration and which can be administered in association? When should a venting gastrostomy be considered? What is the role of total parenteral nutrition (TPN) and parenteral hydration (PH)? A working group was established to review issues relating to bowel obstruction in end-stage cancer and to make recommendations for management. A steering group was established by the (multidisciplinary) Board of Directors of the European Association for Palliative Care (EAPC) to select members of the expert panel, who were required to have specific clinical and research interests relating to the topic and to have published significant papers on advanced cancer patients in the last 5 years, or to have particular clinical expertise that is recognised internationally. The final constitution of this group was approved by the Board of the EAPC. This Working Group was made up of English, French and Italian physicians involved in the field of palliative care for advanced and terminal cancer patients; and of English, American and Italian surgeons who also specialized in artificial nutrition (Dr. Bozzetti) and a professor of health economics. We applied a systematic review methodology that showed the relative lack of RCTs in this area and the importance of retrospective and clinical reports from different authors in different countries. The brief was to review published data but also to provide clinical opinion where data were lacking. The recommendations reflect specialist clinical practice in the countries represented. Each member of the group was allocated a specific question and briefed to review the literature and produce a position paper on the indications, advantages and disadvantages of each symptomatic treatment. The position papers were circulated and then debated at a meeting held in Athens and attended by all panel members. The group reviewed all the available data, discussed the evidence and discussed what practical recommendations could be derived from it. An initial outline of the results of the review and recommendations was produced. Where there were gaps in the evidence, consensus was achieved by debate. Only unanimous conclusions have been incorporated. Subsequently the recommendations were drawn together by Carla Ripamonti (Chairperson) and Robert Twycross (Co-Chair) and refined with input from all panel members. The recommendations have been endorsed by the Board of Directors of the EAPC. It was concluded that surgery should not be undertaken routinely in patients with poor prognostic criteria, such as intra-abdominal carcinomatosis, poor performance status and massive ascites. A nasogastric tube should be used only as a temporary measure. Medical measures such as analgesics, anti-secretory drugs and anti-emetics should be used alone or in combination to relieve symptoms. A venting gastrostomy should be considered if drugs fail to reduce vomiting to an acceptable level. TPN should be considered only for patients who may die of starvation rather than from tumour spread. PH is sometimes indicated to correct nausea, whereas regular mouth care is the treatment of choice for dry mouth. A collaborative approach involving both surgeons and physicians can offer patients an individualized and appropriate symptom management plan.

Techniques and complications of ileostomy takedown.

OBJECTIVE: We use a loop ileostomy for temporary fecal diversion because of ease of technical construction and assumed low complication rate. Here, we review our complications of loop ileostomy and takedown using three techniques of closure. METHODS: We reviewed charts of all patients who had temporary ileostomies constructed during 1987 to 1995 (n = 366). Ileostomy takedown was performed in 339 patients using one of three closure techniques: enterotomy suture (65%), resection with handsewn anastomosis (20%), and stapled anastomosis (15%). Complications were recorded for pre-takedown and 30-day post-takedown intervals. RESULTS: Overall complication rate was 28%. Pre-takedown complications occurred in 21 patients (5.7%), including small bowel obstruction (2.5%) and dehydration/electrolyte derangement (2.2%). Post-takedown complications occurred in 83 patients (24.5%), including wound infection (14.2%), small bowel obstruction (5%), anastomotic leak (2.9%), and 1 death from a cardiac event. Post-takedown obstruction was higher for closure using resection with sutured anastomosis (12%) compared with enterotomy suture (2.3%), P < or = 0.003. Stapled anastomosis had an intermediate rate of obstruction (7.7%). Anastomotic leak was similar between closure techniques. CONCLUSIONS: Loop ileostomy and takedown are associated with low rates of serious complications (5% or less). As such, we continue to advocate use of loop ileostomy as a diversion procedure. Closure by enterotomy suture is preferred over resection. However, if resection is required, closure by stapled anastomosis is preferred over suture anastomosis.

Should patients with combined colonic inertia and nonrelaxing pelvic floor undergo subtotal colectomy?

PURPOSE: Treatment of severe constipation caused by combined colonic inertia and nonrelaxing pelvic floor is controversial. This study is designed to evaluate the outcome of preoperative biofeedback and subtotal colectomy for patients with combined colonic inertia and nonrelaxing pelvic floor. METHODS: One hundred six patients who underwent subtotal colectomy for intractable constipation from 1982 through 1995 answered a detailed questionnaire regarding postoperative bowel function, symptoms of abdominal pain and bloating, and degree of satisfaction after the operation. Sixteen of these patients had a combination of colonic inertia and nonrelaxing pelvic floor diagnosed by transit marker study, electromyography, and defecography. These patients completed preoperative biofeedback training. RESULTS: Electromyographic relaxation of pelvic floor musculature was demonstrated after the biofeedback treatment in all patients, but symptoms of difficult evacuation persisted. Postoperatively, seven patients (43 percent) had complete resolution of symptoms of constipation or difficult evacuation. Six patients still complained of incomplete evacuation that was severe in two and unresponsive to postoperative biofeedback. Three patients (18 percent) complained of diarrhea (>5 bowel movements per day) and incontinence of liquid stools (at least one episode a week). Nine patients (56 percent) were satisfied despite persistent symptoms. CONCLUSIONS: Subtotal colectomy can improve some symptoms in patients with slow transit constipation and nonrelaxing pelvic floor. However, incomplete evacuation persists in a significant number of patients and almost one-half of patients are dissatisfied with their surgery.

Role of enteral nutrition in advanced cancer patients: indications and contraindications of the different techniques employed.

Over the last 20 years there has been great progress regarding total parenteral nutrition and enteral nutrition for patients who cannot take food by mouth or cannot swallow, or so that controlled feeding can be established in anorexic and malnourished patients. The use and the role of artificial nutrition is still controversial in advanced cancer patients. Such controversies often are due to the fact that these patients have a survival expectancy that varies from one to several months. The present review describes the most frequent techniques used for enteral nutrition (nasoenteral tubes, gastrostomy and jejunostomy), their indications, contraindications and complications, and gives an indication regarding which patients may really benefit from enteral nutrition taking into consideration not only the potential advantages but also the discomfort and distress related to enteral nutrition and the different techniques that are employed.

Functional assessment of ileal pouch-anal anastomotic techniques.

BACKGROUND: Recent advances in ileal pouch-anal anastomotic (IPAA) technique include the substitution of a double stapled anastomosis for a mucosectomy and hand-sewn pouch-anal anastomosis, and the use of staples to construct a "J" shaped pouch rather than a hand-sewn "S" pouch in most cases. METHOD: To determine the impact these technical changes have had on pouch function, 235 IPAA patients with 15 to 155 months of follow-up (mean 70 months) were interviewed by telephone concerning pouch function and quality of life. Categorical responses were then evaluated by contingency table analysis to detect differences between mucosectomy (n = 157) and nonmucosectomy (n = 80) groups, and between J pouch (n = 50), S pouch with mucosectomy (n = 137), and S pouch nonmucosectomy (n = 30) subgroups. An index encompassing nine functional measures was used to quantify the overall impact of technique changes (optimal score 100). RESULTS: Stool frequency for mucosectomy patients was 7.2 movements/24 hours, compared to 7.1 for nonmucosectomy patients. Elimination of a mucosectomy dramatically reduced nocturnal major incontinence (P < 0.001), nocturnal minor incontinence (P < 0.001), daytime minor incontinence (P = 0.03), and day-time pad use (P = 0.002). Nonmucosectomy patients had a better functional index score than had patients with an S pouch, even when only data from nonmucosectomy patients were analyzed (J = 95.5, S = 91.8, P = 0.009). CONCLUSIONS: Avoidance of a mucosectomy in the performance of an ileal pouch-anal anastomosis does not influence stool frequency but does significantly improve fecal continence and introduces no detectable morbidity associated with the retained rectal mucosa.

Ileal pouch-anal anastomosis. Patterns of failure.

During the period from 1980 through 1990, our institution constructed 253 ileoanal reservoirs in 253 patients, of whom 25 (9.9%) experienced pouch failure. A poor functional result was the most common cause of pouch failure (seven [28%] of 25 patients). Unsuspected Crohn's disease became manifest in 13 (5%) of the 253 patients, resulting in pouch loss due to perianal sepsis or pouch fistulas in six patients (24% of 25 failures), and resulted in a significantly increased risk of pouch failure compared with that of the non-Crohn's population. Pouchitis occurred in 78 patients (31%) and accounted for four (16%) of 25 failures, but patients with pouchitis were not at higher risk for pouch failure than were patients who did not have pouchitis (failure rates of 6.4% vs 10.4%, respectively; not significant). Significant pelvic sepsis in the absence of Crohn's disease developed in 13 patients, five (38%) of whom lost their pouches. Poor functional results, pelvic sepsis, and unsuspected Crohn's disease were the major causes of pouch failure, while pouchitis was not.

Ileal pouch-anal anastomosis: state of the art.

IPAA surgery has evolved to assume a major role in the operative management of CUC and FAP. In experienced centres, the safety of performing this somewhat complex procedure, often in gravely ill patients, has been confirmed. A significant decrease in morbidity has accompanied increased experience and simplification of the operative techniques. Two major issues await resolution. The first has to do with the less than totally predictable functional results of IPAA surgery. While many patients do well, others, for no apparent reason, do poorly with excess frequency, urgency and incontinence. Whether operative modifications or preoperative testing can alter this outcome is at this time unclear. The second issue has to do with the potential long-term sequelae of IPAA surgery. Pouchitis and nutritional and metabolic consequences, including the potential for malignant transformation of ileal mucosa or of retained rectal mucosa, cannot be ignored. At present, these risks seem remote but only long-term follow-up will determine whether IPAA surgery deserves its current enthusiasm.

Circulating cytokines in patients with metastatic cancer treated with recombinant interleukin 2 and lymphokine-activated killer cells.

Treatment with recombinant interleukin 2 and lymphokine-activated killer cells (rIL-2/LAK) has produced a clinical antitumor effect in preliminary human trials. The cytokines gamma-interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and tumor necrosis factor beta (TNF-beta, lymphotoxin) have potent in vitro antitumor activity and some clinical toxicities similar to interleukin 2 (IL-2)/LAK. This study sought to determine whether these cytokines were detectable in sera of IL-2/LAK-treated patients. Ten patients were treated with a protocol of 5-day i.v. rIL-2 bolus priming (10(5) units/kg, every 8 h), followed by 5 daily phereses with harvested lymphocytes cultured in vitro to generate LAK, and 5 days of rIL-2 bolus with infusion of LAK cells. Five patients were treated with a protocol modified to a 3-day rIL-2 prime and 6-day continuous infusion rIL-2 (3 x 10(6) units/m2/day) with infusion of LAK cells. Serum specimens were obtained prior to and 0.5, 2, 3, and 5 h after IL-2 or LAK cell administrations. IFN-gamma was detected by enzyme-linked immunosorbent assay, TNF-alpha by WEHI 164 bioassay or enzyme-linked immunosorbent assay, and TNF-beta by WEHI 164 cell bioassay. During the prime, few patients manifested in vivo detectable serum cytokines: IFN-gamma, three of ten, 5-day prime (1.03 +/- 0.46 ng/ml), and zero of five, 3-day prime; TNF-alpha, one of ten, 5-day prime, and one of three, 3-day prime; TNF-beta, one of ten, 5-day prime. The supernatants of in vitro LAK generation cultures had detectable levels of cytokines at 24 h which increased progressively until culture harvest at Day 4 (IFN-gamma, 2.56 +/- 0.34 ng/ml; TNF-alpha, 356 +/- 110 pg/ml; TNF-beta, 8.2 +/- 4.4 units/ml). The highest levels of in vivo serum cytokines occurred following LAK cell infusion and were more often elevated in patients receiving rIL-2 by bolus than by continuous infusion: IFN-gamma, four of six bolus, zero of three continuous infusion; TNF-alpha, six of six bolus (maximum 679 pg/ml) versus two of three continuous infusion (maximum, 106 pg/ml). LAK cells in vitro responded with cytokine release on stimulation by tumor cell lines (IFN-gamma, 0.88 +/- 0.06 ng/ml; TNF-alpha, 426 +/- 16 pg/ml; TNF-beta, 0.64 +/- 0.06 units/ml). In summary, this preliminary study has detected circulating cytokines in sera of patients receiving IL-2/LAK therapy. The greatest cytokine elevations followed LAK cell infusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans.

Adoptive immunotherapy with interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells (IL-2/LAK) is a technically demanding cancer therapy dependent upon large scale isolation and culture of lymphocytes. An important question is whether this technology can be accomplished routinely outside of highly specialized centers. In addition, no systematic examination of laboratory correlates of IL-2/LAK therapy in humans has been reported to date. The objectives of this report are to address two issues relevant to IL-2/LAK therapy. (a) Can IL-2/LAK therapy be accomplished outside of previously identified centers of expertise? (b) What are the relevant laboratory/clinical parameter correlations? The six institutions in the National Cancer Institute extramural trial treated 83 evaluable patients with renal cancer, malignant melanoma, or colon cancer with IL-2/LAK by a uniform protocol. Patients received 5 days of IL-2 priming, then daily leukaphereses for 5 days starting 48 h after IL-2 to harvest cells. Mononuclear cells were isolated, then cultured in roller bottles in 1-liter aliquots for 3 to 4 days at a cell density of 1.5 x 10(6) per ml with recombinant IL-2, 1500 units per ml. Cells were harvested and administered to patients with additional IL-2. Administration of IL-2 regularly induced lymphopenia and rebound lymphocytosis. Leukapheresis yields and numbers of LAK cells generated in culture and reinfused into patients correlated directly with peak lymphocyte counts achieved by IL-2 administration. Mean mononuclear cell recovery per 5 days of leukapheresis (+/- SEM) was 14.3 +/- 0.8 x 10(10). Average volume of cells cultured per patient was 95 liters (range, 41 to 235). Mean yield of cells harvested from cultures was 53%. Mean total number of LAK cells infused per patient was 7.6 +/- 0.4 x 10(10) (range, 2 to 15.2 x 10(10]. LAK activity was measured in vitro by lysis of 51Cr-labeled natural killer-resistant Daudi and fresh tumor targets. LAK effector cells regularly lysed these targets in vitro. Neither tumor reduction nor clinical toxicity correlated with dose or with cytolytic activity of LAK cells, or with other laboratory parameters including base-line lymphocyte count and IL-2-induced lymphocytosis. We conclude: (a) large quantities of LAK effector cells with tumoricidal activity can be generated routinely at different centers; (b) neither in vitro LAK activity nor numbers of LAK cells infused were predictive of clinical efficacy or toxicity. There is a need to identify other laboratory or clinical parameters more predictive of IL-2/LAK therapeutic efficacy or toxicity.

Extravasation. A serious complication of the split-sheath introducer technique for venous access.

The use of split-sheath introducers to place venous access catheters results in the potential for subcutaneous extravasation and tissue injury or necrosis. We present six cases that demonstrate this complication and illustrate the probable mechanism. The safe use of these catheters requires verification that blood can be aspirated from the catheter and a high index of suspicion for extravasation when symptoms develop.

In vivo and in vitro activation of natural killer cells in advanced cancer patients undergoing combined recombinant interleukin-2 and LAK cell therapy.

Patients with advanced metastatic cancer were given combined autologous lymphokine activated killer (LAK) cell and recombinant interleukin-2 (rIL-2) therapy on a National Cancer Institute extramural phase II trial. Systemic administration of rIL-2 resulted in pronounced lymphocytopenia. Within two days after completion of in vivo rIL-2 therapy, there was a dramatic increase in absolute numbers of circulating lymphocytes, and cytotoxic activity against tumor cell targets was mediated by peripheral blood lymphocytes, indicating in vivo generation of LAK activity. Patients were leukapheresed and cells cultured for three to four days in rIL-2. rIL-2 cultured cells from all patients demonstrated cytotoxic activity. In order to characterize the effector cell, T cells and natural killer (NK) cells were isolated to greater than 95% purity by flow cytometry. Cytotoxic activity was mediated by rIL-2--activated NK cells, whereas T cells demonstrated no substantial activity. The circulating in vivo cytotoxic effectors detected after in vivo rIL-2 therapy were also shown to be rIL-2--activated NK cells. Results from these studies demonstrate that all patients were capable of generating a cytotoxic response, and that the cytotoxic effector cells were rIL-2--activated NK cells, identified by the phenotype CD3--, Leu 19+.

Evidence that the T cell antigen receptor may not be involved in cytotoxicity mediated by gamma/delta and alpha/beta thymic cell lines.

After culture in IL-2, thymocytes expressing either TCR-alpha/beta or -gamma/delta acquired the ability to lyse hematopoietic and solid tumor cell targets without deliberate immunization or apparent restriction by the MHC. Moreover, TCR-alpha/beta- and TCR-gamma/delta-bearing thymic cell lines demonstrated an essentially identical spectrum of cytolysis against several tumor cell targets. Cytotoxicity was not inhibited by antibodies against CD3 or CD2 and modulation of the CD3/TCR complex also failed to affect cytotoxicity. Thus, non-MHC-restricted cytotoxicity can be mediated by thymocytes with either TCR-alpha/beta or TCR-gamma/delta, but the TCR may not be responsible for target recognition.

Home support of patients with end-stage malignant bowel obstruction using hydration and venting gastrostomy.

Palliative terminal care of patients with malignant bowel obstruction is a major clinical and ethical challenge. These patients are often mentally alert and ambulatory, but are kept in the hospital for hydration, nasogastric suction, and pain control. Parenteral nutrition requires frequent metabolic monitoring, is expensive, and is ethically questionable. We have used an alternative method of home management for 27 patients who met the following criteria: inoperable bowel obstruction due to untreatable cancer, an estimated life expectancy of between 2 weeks and 3 months, and understanding of the goals and limits of therapy. Hydration was provided by 10 percent dextrose and electrolyte solutions administered as overnight infusions through long-term central venous catheters. Thirteen patients with complete bowel obstruction required a venting gastrostomy which, when connected to passive drainage, relieved nausea and vomiting. The mean duration of survival was 64 days (range 9 to 223 days). Acceptance by patients and families was excellent, although most acknowledged increased costs due to limited insurance coverage for outpatient care. Seven patients returned to the hospital for terminal care (average stay 3.2 days), and 20 chose to die at home. The mean daily expense for fluids and supplies was +73.50, with an overall cost decrease of $900,000 compared with inpatient care. Home support with fluids and gastric venting is a humane, cost-effective alternative to in-hospital care for selected patients.