Wiki-based clinical practice guidelines for the management of adult onset sarcoma: a new paradigm in sarcoma evidence.

In 2013 Australia introduced Wiki-based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma. These guidelines utilized a customized MediaWiki software application for guideline development and are the first evidence-based guidelines for clinical management of sarcoma. This paper presents our experience with developing and implementing web-based interactive guidelines and reviews some of the challenges and lessons from adopting an evidence-based (rather than consensus-based) approach to clinical sarcoma guidelines. Digital guidelines can be easily updated with new evidence, continuously reviewed and widely disseminated. They provide an accessible method of enabling clinicians and consumers to access evidence-based clinical practice recommendations and, as evidenced by over 2000 views in the first four months after release, with 49% of those visits being from countries outside of Australia. The lessons learned have relevance to other rare cancers in addition to the international sarcoma community.

Treatment and outcome of radiation-induced soft-tissue sarcomas at a specialist institution.

BACKGROUND: Radiation-induced sarcoma (RIS) is a rare late complication of therapeutic irradiation with a reputation for aggressive pathology and poor outcome. METHODS: We retrospectively reviewed histopathological features, surgery and outcome in 67 patients with RIS treated between 1990 and 2005 at a single tertiary referral center. RESULTS: Previous breast cancer was the most common indication for radiotherapy. The median interval from irradiation to development of RIS of was 11 years (3-36 years). Median tumour size was 7 cm with 56% classified as high grade, 31% intermediate grade and 13% low grade. The commonest histology was leiomyosarcoma. The only relationship for histology with site was for angiosarcoma (n=9), all of which developed on the chest wall/breast after irradiation for breast cancer. Of 67 patients, 34 underwent potentially curative surgery, and microscopically clear margins were achieved in 75% of cases. Pedicled or free tissue transfer was required in 12 patients and abdominal or chest wall mesh reconstructions were required in 8 patients. No patient received adjuvant radiotherapy but 7 received adjuvant/neoadjuvant chemotherapy. Median follow up is 53 months. Median sarcoma specific survival was 54 months (2- & 5-year survival: 75% & 45%). The local relapse rate was 65%. Negative histopathological margins were a significant predictor of sarcoma specific survival (HR 3.0 95% CI 1.1-8.6 p=0.04). Grade and size of tumour approached, but did not attain significance. CONCLUSION: RIS is a biologically aggressive tumour with high rates of local relapse despite aggressive attempts at curative surgery.

Surgical management of soft tissue sarcoma in patients over 80 years.

AIMS: To report outcome on patients over 80years of age with soft tissue sarcoma (STS), with respect to surgical treatment, co-morbidity, complications and survival. METHODS: From a prospective database of 3400 patients with STS presenting over a 13-year period, all patients over 80years of age were identified and reviewed, with respect to tumour characteristics morbidity, mortality and outcome. RESULTS: 128 patients over 80years were treated for STS with 63 referred for treatment of primary disease, of whom 50 underwent resectional surgery. The remaining 65 patients were treated for recurrent or incompletely excised disease. Of the 50 patients treated primarily with surgery, 56% of tumours where high grade and 56% were greater than 10cm in diameter. The overall complication rate was 34%, with a 30-day mortality of 4%. Two- and 5-year survival rates were 56% and 46%, with a local recurrence rate of 22% at a mean follow-up of 22months. CONCLUSION: This patient group presented with poor prognosis tumours that were associated with poor outcomes in the medium to long term. Age need not be considered a contra-indication to radical surgery with curative intent.

Surgical management of primary and recurrent retroperitoneal liposarcoma.

BACKGROUND: Surgery plays a dominant role in the initial and subsequent treatment of retroperitoneal liposarcoma (RPLS). This study was a review of outcomes of patients treated at the Royal Marsden Hospital. METHODS: Records of all patients who had surgery for RPLS since 1990 were reviewed, with particular attention to local recurrence and disease-specific survival. Patients with primary RPLS and those with recurrent RPLS, who had palliative surgery after a variable number of operations performed elsewhere, were considered separately. RESULTS: Seventy-two patients had surgery for primary RPLS, over half of whom underwent resection of a contiguous organ to achieve clearance. Follow-up of at least 12 months was available for 58 patients. Thirty-four patients had no evidence of recurrence after median follow-up of 26 (range 12-151) months. Low-grade tumour and macroscopic clearance of tumour were significantly associated with a reduced risk of local recurrence and improved survival. Forty-seven patients had palliative surgery for recurrent RPLS. Median survival from time of last operation to death was 27 (range 0-79) months. Follow-up was to a median of 68 (range 14-261) months. CONCLUSION: Patients with low-grade RPLS that has been completely resected at the initial operation have the most favourable prognosis. Palliative resection is worthwhile to treat troublesome symptoms of recurrence.

Pneumoperitoneum and peritoneal surface changes: a review.

BACKGROUND: Recent evidence suggests that the use of carbon dioxide to create a pneumoperitoneum during laparoscopy can lead to adverse structural, metabolic, and immune derangements within the peritoneal cavity, and that these can be dependent on the specific insufflation gas used. These changes include structural alterations in the mesothelial lining, pH disturbances, and alterations in peritoneal macrophage responsiveness. This contrasts with an apparent systemic benefit associated with laparoscopic, as compared with open, surgery. METHODS: Recently published clinical and experimental studies related to the effect of pneumoperitoneum on the peritoneal surface are reviewed, and their relevance is discussed. RESULTS: Structural changes in the peritoneal mesothelial surface layer such as widening of the intercellular junctions can be demonstrated with electron microscopy. Acidification of the peritoneum in response to carbon dioxide insufflation occurs not only at the peritoneal surface, but also in the underlying connective tissue, resulting in disturbances in the electrical surface charge and the release of various immune mediators such as endotoxin. Pneumoperitoneum also affects the local peritoneal immune environment resulting in alterations in cytokine production and phagocytic function, as well as diminished antitumor cell cytotoxicity. CONCLUSIONS: Ultrastructural, metabolic, and immune alterations are observed at the peritoneal surface in response to a pneumoperitoneum. Experimental evidence suggests that these changes are carbon dioxide-specific effects. The consequences of these alterations to the local peritoneal environment are not well understood, but they may facilitate tumor implantation within the peritoneal cavity and adversely affect the ability to clear intraperitoneal infections. Further investigation into this area is warranted.

Excision of laparoscopic port sites increases the likelihood of wound metastases in an experimental model.

BACKGROUND: Case reports of patients developing tumor metastases at port sites following laparoscopic surgery have prompted the development of preventive strategies to address this potential problem, including local excision of the port sites. While it has been suggested that this strategy could be used clinically, its efficacy has not been established. METHODS: Twenty four immune-competent Dark Agouti rats underwent laparoscopy and standardized intraperitoneal laceration of an implanted abdominal flank tumor, using an established laparoscopic cancer model. Rats were randomized to either control (n = 12) or wound excision (n = 12) groups. Both groups underwent laparoscopy using carbon dioxide (CO2) insufflation and two mini-laparoscopy ports. In the wound excision group, one of the port site wounds was excised following desufflation of the abdominal cavity. One week later, the port site wounds were excised for histological examination. RESULTS: Wound involvement with tumor was significantly more common following wound excision than with untreated control wounds (nine of 12 vs two of 12, p = 0.002). In the wound excision group, tumor metastases arose preferentially in the excised port site wound. CONCLUSION: This study suggests that excision of laparoscopy port site wounds following laparoscopic surgery for cancer does not prevent the subsequent development of port site tumors. Furthermore, the excision of port sites may actually increase the risk of tumor metastases arising in port sites, suggesting that the clinical application of this strategy should be avoided pending further evaluation.

Oncologic implications of laparoscopic and open surgery.

Although instrumental manipulation and mechanical tumor cell spillage seem to play the major role in port-site metastases from laparoscopic cancer surgery, minimally invasive procedures are used more and more in the resection of malignancies. However, port-site metastases also have been reported after resection of colon cancer in International Union Against Cancer (UICC) stage I [2, 14]. Therefore, changes in the peritoneal environment during laparoscopy also might influence intra- and extraperitoneal tumor growth during laparoscopy and pneumoperitoneum. Different results of experimental studies presented at the Third International Conference for Laparoscopic Surgery are analyzed and discussed.

Helium and other alternative insufflation gases for laparoscopy.

BACKGROUND: Carbon dioxide (CO(2)) is currently the insufflation gas of choice for laparoscopy. It fulfills most of the requirements for an ideal insufflation gas, being colorless, noninflammable, and rapidly excreted from the circulation. However, its use is associated with adverse cardiorespiratory effects, especially in patients with preexisting cardiorespiratory compromise. METHODS: The descriptive review of relevant literature, moreover, has been proposed that it increases the incidence of port site (wound) metastases from abdominal cancers when used during oncological surgery. In addition, it may cause postoperative pain due to peritoneal irritation, and its use is associated with physiological and immunological impairment. Hence, there is scope for the investigation of alternative insufflation gases. Other possibilities include gasless laparoscopy, helium, nitrous oxide, (N(2)O), and argon. Helium insufflation has been used extensively in animal models but only to a limited extent in humans. In experimental studies, it has been shown to produce fewer changes in cardiorespiratory and intraperitoneal immunological status than CO(2) insufflation, and its use is associated with less spread of tumors to port sites in a variety of small animal tumor models. However, helium also has the potential for some adverse effects. Helium pneumothorax probably resolves more slowly than CO(2) pneumothorax, and helium gas embolism is tolerated poorly in animal models. The clinical significance of these potential problems has yet to be determined. CONCLUSIONS: Although the use of alternative gases appears to be promising, further evaluation is needed within both clinical and laboratory settings before their routine clinical use can be supported.

Metabolic and immunologic consequences of laparoscopy with helium or carbon dioxide insufflation: a randomized clinical study.

BACKGROUND: Previous studies using animal models have demonstrated that carbon dioxide (CO2) pneumoperitoneum during laparoscopy is associated with adverse physiological, metabolic, immunological and oncological effects, and many of these problems can be avoided by the use of helium insufflation. The present study was performed in patients to compare the effect of helium and CO2 insufflation on intraperitoneal markers of immunological and metabolic function. METHODS: Eighteen patients undergoing elective upper gastrointestinal laparoscopic surgery were randomized to have insufflation achieved by using either helium (n = 8) or CO2 (n = 10) gas. Intraperitoneal pH was monitored continuously during surgery, and peritoneal macrophage function was determined by harvesting peritoneal macrophages at 5 min and 30 min after commencing laparoscopy, and then assessing their ability to produce tumour necrosis factor-alpha (TNF-alpha), and their phagocytic function. RESULTS: Carbon dioxide laparoscopy was associated with a lower intraperitoneal pH at the commencement of laparoscopy, although this difference disappeared as surgery progressed. The production of TNF-alpha was better preserved by CO2 laparoscopy, but the insufflation gas used did not affect macrophage phagocytosis. Patients undergoing helium laparoscopy required less postoperative analgesia. CONCLUSION: The choice of insufflation gas can affect intraperitoneal macrophage function in the clinical setting, and possibly acid-base balance. The present study suggested no immunological advantages for the clinical use of helium as an insufflation gas. The outcomes of the present study, however, are different to those obtained from previous laboratory studies and further research is needed to confirm this outcome.

Influence of gases on intraperitoneal immunity during laparoscopy in tumor-bearing rats.

Laparoscopy has been associated with metastases to abdominal wall wounds. In addition, many recent experimental studies suggest that laparoscopy is associated with increased tumor dissemination. It is possible that immune or metabolic disturbances due to the use of a pneumoperitoneum could contribute to this problem. To investigate this possibility, we studied the effect of two insufflation gases and gasless laparoscopy on in vivo peritoneal macrophage function and intraperitoneal pH in an experimental model. A carcinoma was implanted into the flank of 32 experimental rats that underwent laparoscopic surgery in one of four treatment groups: anesthesia alone, gasless laparoscopy, helium insufflation, and CO2 insufflation. Intraperitoneal pH was monitored during surgery, and peritoneal macrophage function was determined 3 days after surgery by harvesting peritoneal macrophages and then examining their ability to produce tumour necrosis factor-alpha (TNF-alpha). CO2 insufflation was associated with a consistent fall in intraperitoneal pH and a significant reduction in TNFalpha production. These findings did not occur in the other study groups. The results of this study demonstrate that CO2 insufflation results in depressed intraperitoneal macrophage activity. It is possible that it is mediated by pH changes. In addition, it could be a contributing factor to the development of port-site metastases. Further studies are needed to determine whether the factors identified act during clinical surgery.

The effect of immune enhancement and suppression on the development of laparoscopic port site metastases.

BACKGROUND: Recent clinical case reports and experimental studies have suggested that laparoscopic cancer surgery is associated with an increased risk of tumor spread to abdominal wall wounds. While the etiology of this problem was initially believed to be related to mechanical contamination of wounds, it is now recognized that there are other contributory factors, including disturbed immune function within the peritoneal cavity. To investigate this question further, we evaluated the effect of immune modulation within an established laparoscopic cancer model. METHODS: Eighteen immune-competent syngeneic rats underwent modulation of their immune system, followed 18 h later by laparoscopy with the introduction of a suspension of adenocarcinoma cells into the peritoneal cavity. Rats were randomly allocated to receive either systemic cyclosporin (immune suppressor), intraperitoneal endotoxin (immune enhancer), or no agent (controls). Seven days later, all rats were killed and their peritoneal cavity was inspected for tumor implantation and port site metastases. RESULTS: Cyclosporin did not influence the study outcome, but tumor growth (p = 0.008) and port site metastases (p < 0.0001) were less common following the administration of intraperitoneal endotoxin. CONCLUSION: The results of this study suggest that the immune system plays a role in the genesis of port site metastases. A preventive role for endotoxin in patients undergoing laparoscopic cancer surgery, however, remains speculative.

Influence of cytotoxic agents on intraperitoneal tumor implantation after laparoscopy.

PURPOSE: Recent experimental studies suggest that laparoscopic surgery for abdominal malignancy may be associated with increased tumor implantation. This study investigated the influence of cytotoxic agents (administered intraperitoneally or intramuscularly) on implantation of a tumor cell suspension after laparoscopic surgery in an experimental model. METHODS: Thirty-three Dark Agouti rats underwent laparoscopy with CO2 insufflation and instillation of a tumor cell suspension into the abdominal cavity. Rats were randomly allocated to one of the following study groups (9 rats in the control group, 6 rats in all other groups): 1) control (no intraperitoneal instillation); 2) intraperitoneal normal saline (0.9 percent); 3) intraperitoneal povidone-iodine (Betadine to normal saline 1:10 dilution); 4) intraperitoneal methotrexate (2 doses of 0.125 mg/kg body weight in normal saline administered 24 hours apart); 5) intramuscular injection of 2 doses of 0.125 mg/kg body weight administered 24 hours apart (no intraperitoneal agent). Rats were killed 7 days after the procedure, and the peritoneal cavity and port sites were examined for the presence of tumor. RESULTS: A significant reduction in tumor implantation and port-site metastases was observed in all treatment groups (povidone-iodine and intramuscular and intraperitoneal methotrexate). CONCLUSIONS: This study suggests that tumor implantation after laparoscopic surgery and port-site metastases might be prevented by the intraperitoneal or systemic administration of cytotoxic agents. Further studies are needed to determine whether these findings can be applied to clinical practice.

Experimental study of the effect of intraperitoneal heparin on tumour implantation following laparoscopy.

BACKGROUND: Conclusions drawn from clinical reports of port site metastases following laparoscopic resection of intra-abdominal malignancy are now supported by a burgeoning experimental literature which suggests that laparoscopy promotes tumour metastasis to wounds. This study investigated the effect of intraperitoneal blood and heparin on the incidence of tumour cell implantation and port site metastasis. METHODS: Twenty-four Dark Agouti rats underwent laparoscopy with carbon dioxide insufflation and the instillation of a tumour cell suspension and/or blood into the peritoneal cavity. Rats were allocated randomly to one of the following study groups (six rats per group): (1) controls; (2) intraperitoneal blood (2 ml blood introduced from a syngeneic donor rat); (3) intraperitoneal heparin; (4) intraperitoneal blood and heparin. Rats were killed 7 days after the procedure, and the peritoneal cavity and port sites were examined for the presence of tumour. RESULTS: Tumour implantation and port site metastases were reduced by the intraperitoneal administration of heparin, but increased by the presence of intraperitoneal blood. CONCLUSION: The results of this study suggest that tumour implantation following laparoscopy is promoted by the presence of intraperitoneal blood and that this effect may be reduced by the use of intraperitoneal heparin.

In vitro inhibition of tumour growth in a helium-rich environment: implications for laparoscopic surgery.

BACKGROUND: The recent results of several experimental studies have suggested that tumour implantation after laparoscopic surgery for intra-abdominal malignancy may be partly related to the chemical composition of the insufflation gas used during surgery. These studies have demonstrated that the use of helium as a laparoscopic insufflation agent for cancer surgery results in less tumour implantation and growth at port sites. To further investigate these findings, the present study was performed to compare the growth of cultured tumour cells after exposure to simulated laparoscopic environments, rich in helium, carbon dioxide (CO2), or air. METHODS: A rat mammary adenocarcinoma cell suspension was exposed to a simulated laparoscopic environment for 40 min in one of the following groups: (i) control (atmospheric air, equivalent to a 'gasless' laparoscopic environment); (ii) a CO2-rich environment; and (iii) a helium-rich environment. Cells were then cultured for 18 h and optical density readings were used to assess the number of viable tumour cells at the end of this period. The experiment was performed twice using an identical protocol to ensure consistency in the results. In a further study, pH was continuously measured using an antimony probe during a 40 min insufflation period and for 10 min after insufflation. RESULTS: Cell growth was significantly lower after incubation in the helium-rich environment compared to both the CO2 and control groups (P < 0.001). There was a significant decrease in pH in the CO2 group which was not observed during exposure to either air or helium. CONCLUSIONS: The inhibition of tumour growth in a helium-rich environment demonstrated by this study, and the reduced incidence of port-site metastases seen in other experimental studies, suggests that the clinical use of helium as an insufflation gas may have important advantages over CO2.

Tumor implantation following laparoscopy using different insufflation gases.

BACKGROUND: Laparoscopic manipulation of malignancies is associated with an increased incidence of metastasis to port sites in experimental models. This study investigated the effect of different insufflation gases on the implantation of a tumor cell suspension following laparoscopic surgery in an established small animal model. METHODS: Forty Dark Agouti rats underwent laparoscopy and the introduction into the peritoneal cavity of a tumor cell suspension. The insufflating gas used for each procedure was one of the following gases (10 rats in each group): carbon dioxide (CO2), nitrous oxide (N2O), helium, and air. The rats were killed 7 days after surgery, and the peritoneal cavity and port sites were examined for the presence of tumor. RESULTS: Although no significant differences were seen between air, CO2, and N2O insufflation groups, tumor involvement of peritoneal surfaces was less likely following helium insufflation. CONCLUSION: The results of this study suggest that tumor metastasis to port sites following laparoscopic surgery may be influenced by the choice of insufflation gas. In this study, helium was associated with reduced tumor growth.

Efficacy of cytotoxic agents for the prevention of laparoscopic port-site metastases.

BACKGROUND: Recent experimental studies support initial clinical impressions that laparoscopic surgery for malignant neoplasms may be associated with an increased incidence of metastases to port sites. This study investigated in an experimental model the influence of cytotoxic agents (administered intraperitoneally or intramuscularly) on the development of port-site metastases following laparoscopic surgery. METHODS: Seven days after the implantation of an adenocarcinoma in the left abdominal flank, 72 Dark Agouti rats underwent laparoscopy with carbon dioxide insufflation, instillation of an intraperitoneal agent, and intraperitoneal tumor laceration within the following study groups (12 rats in each group): (1) control (no intraperitoneal instillation); (2) intraperitoneal instillation of isotonic sodium chloride solution (0.9%); (3) intraperitoneal instillation of povodine-iodine (1:10 dilution of povidine-iodine and isotonic sodium chloride solution); (4) intraperitoneal instillation of methotrexate (0.125 mg of methotrexate in 3 mL of isotonic sodium chloride solution); and (5) intraperitoneal instillation of aqueous chlorhexidine acetate. Twelve additional rats underwent laparoscopic tumor laceration following intramuscular injection of 0.125 mg of methotrexate (no intraperitoneal agent). Rats were killed 7 days after the procedure, and the wounds were examined histologically by a blinded histopathologist for the presence of tumor metastases. RESULTS: No tumor was found in any port site following the intraperitoneal administration of povidine-iodine (P=.04). In contrast, port-site metastases developed in the control group (5 [41.7%] of 12), the isotonic sodium chloride solution group (4 [33.3%] of 12), the chlorhexdine group (4 [33.3%] of 12), the intraperitoneal methotrexate group (2 [16.7%] of 12), and the parenteral methotrexate group (5 [41.7%] of 12). CONCLUSIONS: The results of this study suggest that the development of metastases to port sites following laparoscopic surgery may be prevented by the intraperitoneal instillation of diluted povodine-iodine. Other agents failed to influence the incidence of port-site metastases. Further studies are needed to determine if these findings can be applied to humans.

Port-site metastases following laparoscopic surgery.

BACKGROUND: Application of laparoscopy to the resection of malignancy has been followed by a literature describing cases of metastatic involvement at laparoscopic port sites. These include patients who underwent surgery for early stage carcinoma and instances following laparoscopic procedures during which tumours were not dissected. METHODS: Recently published clinical and experimental studies, and case reports related to this problem are reviewed; their relevance is discussed. RESULTS: Experimental studies incorporating bench top and large animal models have confirmed that tumour cells may be redistributed to port sites during laparoscopic surgery either directly from contaminated instruments or indirectly via the insufflation gas. Small animal models suggest that the incidence of wound metastasis is increased following conventional laparoscopic surgery, and that it may be decreased by gasless laparoscopy or helium insufflation. This evidence suggests that the development of port-site metastases depends not only on the physical redistribution of tumour cells but also on the specific insufflation gas used, possibly because of influences on local metabolic or immune factors acting at the wound site. CONCLUSION: Further research in this area is urgent. Until the issue is better understood, patients undergoing laparoscopic surgery for malignancy should be entered into clinical trials.

Wound metastasis after laparoscopy with different insufflation gases.

BACKGROUND: There is growing evidence that laparoscopy for malignancy is associated with an increased incidence of metastasis to port sites. This study investigated the effect of different insufflation gases on port-site metastasis after laparoscopy in an established animal model. METHODS: Forty-eight Dark Agouti rats with an established adenocarcinoma in the left flank underwent laparoscopic intraperitoneal tumor laceration. The gas used for insufflation was one of the following (12 rats in each group): (1) CO2, (2) N2O, (3) helium, or (4) air. Rats were killed 7 days after the procedure, and the port sites were examined for the presence of tumor metastasis. RESULTS: Tumor involvement of port sites was significantly less likely after helium insufflation than in the other groups (p < 0.0001). There was no significant difference between the air, CO2, and N2O groups. CONCLUSIONS: This study suggests that the development of metastases in port sites after laparoscopy may be influenced in part by the choice of insufflation gas used to create the pneumoperitoneum. In particular, helium was associated with a reduced rate of metastases.