Noi abordări în chirurgia gastrointestinală oncologică

Introduction

Malignant neoplasias have a major impact on the po­pu­­lation’s health, as in 2016 over 8.9 million individuals died in the entire world due to this pathology. On the other hand, cancer incidence is increasing worldwide, with an estimated growth rate of approximately 70% for the next two decades. This incidence translates into a significant increase in disability-adjusted life years (DALY) and mortality, especially in developing countries. This article reviews some of the new approaches adopted in recent years for the management of patients with gastrointestinal neoplasia. To identify relevant articles, we have used the PubMed/Medline and Web of Science electronic databases.

Minimally invasive approach in abdominal oncologic pathologies

Neoplastic conditions are more and more common these days. This fact brought them to the attention of the entire world. Therefore, it triggered an interest in the development of new techniques or in the enhancement of the existing techniques for treating this pathology⁽¹⁾.

Esophageal and gastroesophageal junction cancer has been a challenge, both in terms of topography and surgical technique⁽²⁾. Technological development has brought along an evolution in the approaches of this type of neoplasia, with a focus on invasiveness reduction, while maintaining the oncologic target⁽³⁾. Flexible endoscopy has evolved up to a point where intraluminal lesions that used to require laparoscopic surgery can now be treated by endoscopic mucosal or submucosal resection. Hybrid endoscopic and laparoscopic techniques are widely employed in the treatment of benign diseases⁽⁴⁾. The laparoscopic approach is used in all types of surgical resections, many of which are deemed to be highly difficult procedures even by open surgery^(5,6). With the development of new therapeutic approaches, new types of specific complications have occurred. In minimally invasive Ivor-Lewis esophagectomy, recurrent laryngeal nerve lesions were caused by the thermal energy being dissipated at the level of advanced haemostasis medical equipment, requiring a space and time recognition of the thermal spread of vascular sealing devices⁽⁷⁾. As compared to the McKeown resection, minimally invasive Ivor-Lewis esophagectomy is associated with a low incidence of anastomotic leak, with lower rates of 90-day mortality and post-operative morbidity. Both are feasible in terms of oncology⁽⁶⁾. Robotic surgery is also indicated in esophageal pathology, given its advantages in terms of complex movements in narrow spaces; but it requires a longer learning curve and it involves very high costs⁽⁸⁾.

Stomach surgery has also benefited from cutting-edge technology. Total or subtotal gastrectomy with D2 lymphadenectomy with preservation of spleen and pancreas is a surgery that shows significant postoperative morbidity and mortality rates, but it is the first-line therapy in gastric cancer⁽⁹⁾. Minimally invasive approaches, especially laparoscopic techniques, have begun to be commonly used in this organ malignancies^(8,10). This is due to a low postoperative morbidity rate, a decrease in hospital admission and oncologic outcomes that are superior to the classical approach^(11,12). The disadvantages of the laparoscopic approach in total gastrectomy are: limited mobility, the surgeon’s uncomfortable posture, difficult resection of some lymphatic areas, such as the peripancreatic ones. Robot-assisted surgery aids the surgeon, offering the latter a higher mobility and filtering the surgeon’s tremor. According to a study published this year, as compared to the laparoscopic approach, robotic gastrectomy has resulted in a smaller rate of postoperative complications^(13,14). Single-Incision Laparoscopic Intragastric Surgery (SILIS) is indicated in the treatment of submucosal tumors for selected patients. Under these circumstances, it is associated with low postoperative complications and a fast patient recovery⁽¹⁵⁾. Minimally invasive techniques are also used in the treatment of complications. Anastomotic leaks are one of the most fearsome complications. Endoscopic techniques are used in the treatment of anastomotic leaks in esophagogastric surgery, by inserting an EVAC device (Endoscopic Vacuum-assisted Closure Therapy) at the anastomotic leak level, allowing a local control of sepsis⁽¹⁶⁾.

Hepato-biliary-pancreatic surgery is considered to be an extensive, delicate surgery, associated with a high rate of complications. A study published in July 2018 by Chen et al. showed that minimally invasive methods are associated with a low rate of complications and a shorter hospital admission as compared to classical approaches⁽¹⁷⁾.

Laparoscopic pancreaticoduodenectomy requires an advanced training in order to achieve optimum results. Nagakawa shows that surgeons require at least 30 cases to master the technique and visceral fat cases or concomitant pancreatitis ones should be avoided during the training period⁽¹⁸⁾. Robotic pancreaticoduodenectomy can be successfully performed in oncology and it features certain advantages compared to classical or laparoscopic approaches⁽¹⁹⁾. The laparoscopic and robotic approaches show superior results in distal pancreatic resections⁽²⁰⁾. On the other hand, as compared to the open surgery, minimally invasive surgery is associated with a shorter recovery time, but without differences in the overall rate of complications^(21,22). However, radical resection cannot be applied in all pancreatic tumours. In locally-regionally advanced or metastatic pancreatic tumours, palliative care to mitigate symptoms can be performed by combining interventional radiology techniques with laparoscopic ones⁽²³⁾. A new technique, gaining more and more interest in the treatment of locally-regionally advanced pancreatic tumours, consists in tumour destruction by ablative techniques, such as high frequency (2.45 GHz) microwaves⁽²⁴⁾.

Hepatocellular carcinoma is the fifth cause of malignancy worldwide. Only 30-40% of the diagnosed cases can be eligible for curative intent treatment. Endovascular therapy is based on the fact that this type of cancer is hypervascularized by the hepatic artery. Thus, varied therapies have been developed, such as transarterial embolization (TAE), conventional transarterial chemo­embolization (cTACE), DEB-TACE (TACE with drug-eluting beads, DEB) and SIRT (selective internal radiation therapy, radioembolization)⁽²⁵⁾.

Major hepatic resections, such as left or right hemihepatectomy, are being performed in a significant proportion by minimally invasive means in high throughput centers.

Augmented reality guided intraoperative navigation, based on computer tomography scans or magnetic resonance imaging, is a technique whose usefulness can be of an important significance in hepatic surgery.  Thus, liver parenchymal transection is made by observing oncologic principles, but with a maximum preservation of the hepatic parenchyma^(26,27). Robotic surgery can also show advantages in central tumour resections⁽²⁸⁾.

The minimally invasive approach is also commonly used in colorectal surgery. Laparoscopic and robotic approaches are more and more used and new studies show a lower rate of complications, a shorter recovery time, a shorter hospital admission, with oncologic results similar to those of classical techniques⁽²⁹⁾. After minimally invasive techniques are performed, the resection specimen can be removed through the transanal natural orifice so as to reduce anterior abdominal wall incisions, thus enhancing perioperative outcomes⁽³⁰⁾. A minimally invasive approach can be used to treat not only primary lesions, but also postoperative complications. Low colorectal anastomotic leakage is associated with a high mortality rate and the transanal endoscopic approach could represent a means of dealing with gaped anastomoses⁽³¹⁾.

A very interesting technique, in terms of low invasiveness, is the rectal resection with a transanal total mesorectal excision. This approach may supply superior outcomes in ensuring the distal oncologic limit in middle and low rectal cancers. Nonetheless, a mesorectal fascia dissection is difficult to perform on a low-to-high rectal direction and perineal urethra tears as well as a higher local recurrence rate have been reported following this approach.

Neoadjuvant therapy

Neoadjuvant therapy (preoperative chemoradiotherapy) has the advantages of a fast administration for all patients, unlike adjuvant therapy, which is delayed or even cancelled for patients with postoperative complications. Moreover, it can lead to a reduction in tumour size and tumour stage, so that a surgical resection would be less morbid.

Neoadjuvant therapy in advanced esophageal cancer can lead from tumour downstaging and tumour downsizing to a full clinical or pathological response of the primary tumor⁽³²⁾. Treatment efficiency can benefit from an imaging analysis by CT or PET-CT or from the analysis of the resection specimen. Mention must be made that there are significant differences between the imaging appearance and the histopathological appearance of a tumour, depending on the type of the neoplastic cell (adenocarcinoma or squamous cell carcinoma)⁽³³⁾. The administration of paclitaxel and carboplatin in conjunction with synchronous radiotherapy in stage III gastroesophageal junction adenocarcinoma can help in achieving a R0 resection without an increase in postope­rative mortality or morbidity⁽³⁴⁾. Sunde et al. showed, in a trial that included 181 patients, that neoadjuvant chemotherapy was more efficient in the treatment of dysphagy as compared to adjuvant chemoradiotherapy, but no significant differences were noted considering the patients who responded fully to the neoadjuvant therapy⁽³⁵⁾.

As for gastric cancer, a stage II trial conducted by Hosoda et al. assessed the efficiency of neoadjuvant chemotherapy (docetaxel, cisplatin and S-1) followed by radical gastrectomy with D2 lymphadenectomy in advanced gastric cancer. R0 resection was achieved in approximately 90% of the cases, with a pathological response rate of about 57.5%^(36,37). The association of neoadjuvant radiotherapy in advanced gastric cancer had favorable outcomes, with a partial or even full response^(38,39).

Tsai et al. showed, in a trial published in October 2018, that a normalization of CA19-9 after adjuvant chemotherapy was a favourable prognostic for long-term survival of patients with pancreatic cancer⁽⁴⁰⁾. Neoadjuvant chemotherapy in borderline resectable tumours has morbidity and mortality rates similar to those of patients who had resectable tumours upon the first medical examination⁽⁴¹⁾. In 31.1% of the patients with borderline resectable tumours, the disease advanced under neoadjuvant therapy, but in 63.6% of the cases, patients could be operated, which led to an improvement in the overall survival rate⁽⁴²⁾. Maurel et al. studied the association of gemcitabin and erlotinib administered in 3 cycles and for the patients who did not show a progression of the disease, this was followed by an association with neoadjuvant radiotherapy (45 Gy). Twenty-five patients were included in this trial, with favourable outcomes, with a resectability rate of 76% and 63.1%, respectively, for R0 resection⁽⁴³⁾.

The full pathological response to neoadjuvant therapy in rectal cancer is correlated with a better survival rate.  Radiotherapy-associated short-course or long-course chemotherapy led to the achievement of a full response in 10% of the patients as compared to 5.1% of the patients on neoadjuvant radiotherapy exclusively⁽⁴⁴⁾.

Indocyanine green staining

Indocyanine green staining has an ever wider use in oncologic pathology and its main indications are the assessment of digestive tract vascularization and lymphatic drainage basin. Used for the first time in breast tumours, this tracer has also been included in gastrointestinal surgical oncology, as it proved to have a good detection rate of sentinel lymph nodes and showed an increased sensitivity. As compared to extensive dissections of regional lymph node groups, a selective resection of the sentinel lymph node has a low mortality rate. On the other hand, this technique has its disadvantages in terms of availability, as well as the risk of anaphylaxis (1% of the cases).

ICG (indocyanine green) fluorescence-guided surgery has become a new imaging method to identify hepatic, peritoneal and lymph node metastases for patients with colorectal cancer. Studies have shown that this method is adjuvant in identifying superficial hepatic metastases and lymph node metastases produced by colorectal cancer. Although newly introduced in abdominal surgical oncology, indocyanine green staining has a role in intraoperative detection of (lymph node, peritoneal and hepatic) metastases and it can improve staging and treatment for patients with colorectal cancer⁽⁴⁵⁾.

In gastric cancer, this technique has proven useful in resection completeness in the infrapyloric area, which is technically difficult due to anatomical variations of vascularization⁽⁴⁶⁾. Thus, lymph node metastases on the right gastroepiploic vessels, which are frequent in the middle and distal third gastric tumors, can be improperly dissected, with a likelihood of leaving behind unresected lymph node tissue in pylorus-preserving gastrectomy. Another major benefit of indocyanine green staining in gastric cancer is given by sentinel lymph node surgery, which could limit perioperative morbidity associated with an extensive lymph node dissection. A meta-analysis performed in 2018 showed that the accuracy of this method is encouraging in terms of diagnosis and specificity⁽⁴⁷⁾. The sensitivity of this method can be improved by following a strict protocol for dye handling and injection.

ICG is one of the fluorescent dyes that can also be used in hepato-biliary surgery because, once injected intravenously, it concentrates in the liver and it is exclusively drained through the gallbladder. Thus, this staining is useful in liver flow assessment, partial liver graft evaluation, cholangiography, liver tumour visualization, as well as in liver mapping. Considering the liver tumour assessment and visualization, its tissue penetration capability limited to 5-10 mm makes it impossible to visualize deep formations⁽⁴⁸⁾.

Indocyanine green staining can also be useful in laparoscopic pancreaticoduodenectomy, during meso­pancreas dissection from the superior mesenteric artery (SMA)⁽⁴⁹⁾. Nonetheless, a clear identification of the division line for retroperitoneal margin is not easy as the uncinate process of the pancreas is anatomically very close to SMA and to the superior mesenteric nerve plexus. During this dissection, the fluorescence alternatively taken intraoperative images can be really useful for surgeons.

Gut microbiota

The gut microbiota is an important component of the human body and its immunomodulation and metabolic activity is critical in maintaining digestive tract physiology. Gut bacteria are very sensitive to diet changes, exposure to antibiotics and infections, all leading to dysbiosis.

Dysbiosis is associated with multiple gastrointestinal diseases and its physiopathological onset mechanism is unclear. Identifying the bacterial spectrum associated with neoplastic pathology, understanding the contribution of bacterial metabolism in maintaining good health or in triggering a disease are challenges that can lead to defining and detecting bacteria biomarkers that can predict gastrointestinal dysfunctions. Understanding the complex interactions among gut microbiota, the immune system and the host’s genetics will be critical in the development of tailor-made treatment therapies⁽⁵⁰⁾.

Changes that occur in the interactions among gut microbiota, gut epithelium and the host’s immune system are associated with several pathologies, including cancer. Dysbiosis is caused not only by pathogenic bacteria, but also by environmental factors, such as antibiotics, xenobiotics, smoking, hormones or diet. The latter are also risk factors for developing gut cancer. The genetic flaws of the epithelium, myeloid or lymphoid components of the gut immune system may favour and promote inflammatory conditions, leading to inflammatory bowel diseases (Crohn’s disease or ulcerative hemorrhagic rectal colitis), which increase the risk of neoplastic transformation of tissues. Therefore, factors that disrupt gut microbiota and favour dysbiosis are similar to those that favour carcinogenesis⁽⁵¹⁾.

Evidence shows that specific bacteria and bacterial dysbiosis in the gastrointestinal tract can also favour the development and progression of gastrointestinal tract neoplasms by DNA damage, activating oncogenic signaling pathways, producing tumor-promoting metabolites such as secondary bile acids and suppressing anti-tumour immunity. Other bacterial species produce short-chain fatty acids, such as butyrate, which can suppress inflammation and carcinogenesis in the gastrointestinal tract. Consistent with this evidence, clinical trials using metagenomic analyses have shown the association of bacterial dysbiosis-specific bacteria with gastrointestinal tract cancers, including esophageal, gastric and colorectal cancers. Current data show that gut bacteria can modulate chemotherapy efficacy (new targeted immunotherapies, such as anti-CTLA4 and anti-CD274 therapies), the absorption process and the occurrence of complications after gastrointestinal surgery. A better understanding of the mechanisms through which gut microbiota influences tumour development and progression inside the gut would provide for opportunities to develop new strategies of prevention and treatment for patients with gastrointestinal tract cancer⁽⁵²⁾.

Conclusions

In conclusion, we can state that we are witnessing a significant progress in understanding and treating gastrointestinal oncologic pathologies. On the other hand, all this progress is difficult to be translated into clinical practice, given their significantly high cost. Nonetheless, we have a duty to make use of our best endeavors to ensure their responsible implementation, considering patients’ safety and in full compliance with bioethics principles in order to reduce current morbidity rates and to improve disease-free survival.  

Conflict of interests: The author declares no conflict of interests.