Gastrointestinal Cancer Research Division
Key outcomes of the translational research activities of the Division:
- The Division has developed the procedure for combination treatment of patients with colorectal cancer and liver metastases. The objective response rate to pre-surgery chemotherapy among patients with colorectal cancer and liver metastases is at least 50%. Pre-surgery chemotherapy does not increase the probability of post-surgery complications and allows to perform surgeries with an R0 resection margin for most of such patients.
- The obtained data have shown that pre-surgery chemoradiation can result in significant tumor regression in patients with locally advanced rectal cancer, which allows to make a minimally invasive surgery a viable treatment option for many patients and improves the long-term treatment outcomes. It is necessary to find effective criteria for defining radiosensitivity and the degree of tumor regression due to chemoradiation.
- The obtained results are indicative of the safety of modified extralevator abdominoperineal resection and can predict enhanced long-term treatment outcomes of patients with rectal lower ampulla cancer due to the decreased local recurrence rates of the disease.
The Division’s main research activities are:
It has been established that 15% of patients with colorectal cancer already have liver metastases as they are first diagnosed with the disease. Some researchers suggest that a maximal possible cytoreduction followed by chemotherapy should be the first stage of treatment. This approach has some disadvantages, namely, in most cases, it is impossible to achieve a complete cytoreduction, and residual micro- and macro-metastases will still be present, and cancer cells may disseminate due to chemotherapy being delayed by the post-surgical period. Other researchers suggest a different approach, which involves the removal of the primary tumor, followed by palliative chemotherapy, and, pending the response to chemotherapy, a decision will be made if it is possible to remove the metastases. This approach seems to have more advantages, since the effect of chemotherapy or its absence can largely impact the outcomes of a patient and the feasibility of delayed metastases removal. However, even with this approach the time spent to prepare for the surgery and the post-surgery period are regarded as the time wasted, which instead could be occupied by chemotherapy and prevention of further dissemination of the disease. There is a third treatment option, i.e. giving patients pre-surgery chemotherapy followed by a combined one-stage surgery and, if necessary, more chemotherapy, which seems to be the most effective treatment option, since pre-surgery chemotherapy allows to prevent further dissemination of the disease, reduce the size of metastases and the primary tumor, and make an optimal cytoreduction as possible as can be. In this case, the decision on the extent of a surgery must also be made depending on the prognostic factors of each specific patient. Response to chemotherapy is a major prognostic factor in colorectal cancer. Nevertheless, less than a quarter of all patients with stage IV colorectal cancer can be candidates for an optimal cytoreduction. Selection of cases for such an aggressive treatment must be very careful and based on a number of prognostic factors. It has been shown that unfavorable prognostic factors include a carcinoembryonic antigen level of more than 100 ng/mL, more than 3-5 metastases, the size of the metastases and a patient’s response to pre-surgery chemotherapy. Taking into consideration the above, it would make sense to develop a new modern approach to the treatment of this disease.
Therefore, the Division has been developing a new technique for combination treatment of disseminated colorectal cancer that would improve the resectability of primary tumors and distant metastases due to pre-surgery chemotherapy. We have already pointed out that, in order to achieve this, it is necessary to assess the resectability after pre-surgery chemotherapy, the pre-surgery chemotherapy objective response rate and the expression of molecular genetic markers in the tumor (TP, TS, DPD, cox-2, ercc1, MSI) before and after chemotherapy, as well as to compare the chemotherapy objective response rates depending on the expression of molecular genetic markers. It is also important to assess the recurrence free survival (in case of a complete cytoreduction) and overall survival rates of patients.
The Division has developed the procedure for multimodality treatment of such patients. The process of case selection following the adopted strategy has already been stared. The monitoring was performed in a group consisting of 54 patients with disseminated colorectal cancer. The study group included 15 patients, the control group included 39 patients (i.e. 37.5% was selected against the target number). The patients in the study group first underwent 3-12 cycles of chemotherapy, using the regimen standard for this tumor site. Nine patients gave objective tumor response to the treatment, i.e. partial regression or stable disease. Six patients had disease progression. The patients who demonstrated positive effect of chemotherapy underwent an optimal surgical cytoreduction or suboptimal surgical cytoreduction as the second stage of treatment. Eleven patients from the control group first underwent an optimal cytoreduction and twenty-eight patients underwent primary tumor removal only. All the patients from the control group were recommended to undergo palliative chemotherapy at a later stage. The rates of post-surgery complications in both groups were similar. The molecular prognostic factors (K-ras gene mutation) were studied in 23 patients.
The study included 145 patients with locally advanced rectal cancer who had undergone a complete course of chemoradiation followed by a surgery. All the patients had a morphologically verified diagnosis. In 78 patients, the tumor was located in the rectal lower ampulla. In 57 patients, the tumor was located in the rectal middle ampulla, and in 10 patients, the tumor was located in the rectal upper ampulla. The stage of the disease was established by a digital rectal examination, endorectal ultrasound, and CT or MRI scan of the lesser pelvis.
The depth of bowel wall invasion (T) was: T2 – 5 cases (3.5%), T3 – 100 (68.9%), and T4 – 40 (27.6%).
MRI revealed that 103 patients (71.0%) were lymph node-positive. Forty-two patients (29.0%) were lymph node-negative. The size criterion was used to determine whether lymph nodes contained cancer.
MRI was performed using the GE Signa Excite HD 1.5T MRI System. During the test (surface coil), the fast spin echo technique and the fat suppression gradient echo technique were used. The thickness of slices was 3 mm. To assess the local spread of the tumor, MRI was performed in two planes: one was perpendicular to the axis of the tumor, the other was parallel to the anal sphincters of the rectum. The exam was performed without additional contrast enhancement.
All the patients underwent neoadjuvant chemotherapy as the first stage of treatment.
Before radiation therapy, the patients had a simulation using the Toshiba x-ray system.
The areas to be treated were the primary tumor or tumor bed, the regional lymph nodes and the area adjacent to the sacrum. Depending on the topographic and anatomical features of the site of the target tumor, either the SL75-5-MT or the LUEV-15 medical linear electron accelerator with the cumulative dose of 50.4 Gy was used to deliver external radiation therapy.
The chemotherapy regimen included administration of Xeloda (825 mg/m2 twice daily alongside radiation therapy).
MRI was performed in 8-10 weeks after chemoradiation, directly prior to surgical intervention. The aim of the second MRI scan was to assess the level of regression of the primary tumor and metastatic lymph nodes.
This assessment used the response evaluation criteria in solid tumors:
- Complete response (CR): Disappearance of all target lesions;
- Partial response (PR): At least a 30% decrease in the sum of the longest diameter of target lesions;
- Stable disease (SD): Less than a 30% decrease or less than a 20% increase in the sum of the longest diameter of target lesions;
- Progressive disease (PD): At least a 20% increase in the sum of the longest diameter of target lesions.
The results of the pathomorphological study of the removed preparation were compared with the results of the MRI scan performed prior to the surgery. All MRI tests were performed by the same MRI technologist, and included an assessment of the depth of bowel wall invasion and the presence of lymphadenopathy.
Results.
The assessment of the results of chemoradiation performed 8 weeks after its completion showed the complete response in 25 patients (17.2%). The partial response was observed in 75 patients (51.7%) and stable disease in 45 patients (31.1%). Forty patients (27.6%) were lymph-node positive. The pathomorphological study of the removed preparation revealed that 37 patients (25.5%) had the complete pathologic response (pT0-N0), 72 patients (49.6%) had the partial response was and in 36 patients (24.9%) tumor tissue dominated fibrous tissue. Metastases of regional lymph nodes were found in 31 patients (21.4%). No metastases of lymph nodes were found in 114 patients (78.6%). We have observed on several occasions that although a digital rectal examination, an endoscopy or MRI revealed the partial response after the completion of chemoradiation, the pathomorphological study of the preparation found no viable tumor cells. These changes in the bowel wall were considered to be due to radiation therapy.
Each patient underwent a surgery: 75 patients underwent abdominoperineal resection, 65 patients underwent lower anterior resection and 5 patients underwent abdomino-anal resection of the rectum. Twenty-one patients who underwent lower anterior resection also had preventive transverse colostomy. Two patients had undergone protective colostomy before the commencement of treatment due to a high grade stenosis of the bowel lumen and a risk of obturation intestinal obstruction. In addition, 10 patients underwent a combined one-stage surgery or simultaneous removal of other organs. During lower anterior resections, enteroenteroanastomosis was formed, using a circumferential stapler with the diameter of 29 or 30 mm.
In recent years, MRI has become the gold standard in assessing the local-regional spread of cancers of the rectum, since it allows to identify patients who have the highest risk of local recurrences of the disease. The patients in which a digital rectal examination, endoscopy or MRI revealed the complete response (17.2%) were of principal interest. The pathomorphological study of the removed preparation showed the complete pathologic response in 25.5% of all cases. Precisely this fact shapes the best results of the combination treatment of rectal cancer. According to our data, the sensitivity of MRI in the forecast of the complete pathologic response is 28.9% and its specificity is 96%. The sensitivity of MRI in assessing the condition of lymph nodes is 70.4% and its specificity is 77.3%. It is important to note that the positive predictive value for primary tumors is 66.7%, and for lymph nodes that have cancer it is 70.4%. Discrepancies in the clinical and pathology assessments of the degree of tumor regression are due to the fact that it is difficult to identify postradiation changes within the bowel wall. The rate of errors in assessing the condition of lymph nodes was slightly lower, since MRI is more accurate in assessing the condition of lymph nodes.
Conclusion.
Chemoradiation allowed to achieve considerable regression in 74% of all rectal cancer cases.
An MRI scan of the lesser pelvis without additional contrast enhancement is quite an effective technique for the original assessment of the degree of local-regional spread of rectal cancer, including in respect to the mesorectal fascia. Challenges in predicting the pathological complete regression of the tumor using the MRI techniques are due to the fact that it is difficult to make a differential diagnosis between postradiation changes and neoplastic changes of the bowel wall and surrounding tissue. The obtained results suggest the use of MRI in conjunction with other techniques to verify or modify the initially selected treatment plan. When analyzing the remote outcomes of treatment, local-regional recurrences of the disease were identified in 7 patients (4.8%). It is essential to add that none of the patients (0%) with the pathological complete regression of the tumor had local recurrences of the disease. Thus, we can see a clear dependence of the rate of recurrences on the degree of regression of the tumor due to chemoradiation.
The obtained data show that the use of chemoradiation during the pre-surgery period in most cases results in the evident regression of the tumor, which definitely improves the remote outcomes of treatment.
The main aim of this study is to enhance the immediate and remote outcomes of surgical treatment of rectal cancer. It has been established that bowel wall perforation and a positive lateral resection margin are important prognostic factors of the development of local-regional recurrences. In the past decade, extralevator abdominoperineal excisions of the rectum have been dominating in the area of distal rectal cancer treatment. A disadvantage of this technique is that a major defect of the pelvis floor is created by the surgery, which has a high risk of inflammatory complications in the post-surgery period. To close the perineal wound, a number of techniques has been suggested, some involving the use of patients’ own tissue, others using allogeneic transplants.
The study included the data on 67 patients who have undergone extralevator abdominoperineal excisions of the rectum. The average age of the patients was 62.4±13.1 years. 46 patients underwent pre-surgery chemotherapy. The average duration of the surgery was 170.14 (±18.4) minutes. The blood loss during extralevator abdominoperineal excisions was less than 250 ml. The average volume of intraoperative blood loss was 148.17 (±71.06) ml. One patient sustained injuries to the urethra with subsequent formation of a urethroperineal fistula.
The patients were divided into three groups, depending on the used technique for closure of the defect. The first group included 23 patients who underwent a simple reconstruction surgery of the pelvic floor. The second group consisted of 17 patients who underwent alloplasty, and the third group had 27 patients who underwent myoplasty. As there are no specific recommendations on which technique to use in the literature, at the initial stage of the study the decision on which technique to use was made by the operating surgeon.
Perineal wound complications occurred in 28 patients (42%). Clinically significant postoperative hemorrhage from the perineal wound was observed in two patients after a simple reconstruction surgery and in two patients after gluteoplasty. Infectious complications of the perineum were mostly common in the patients who underwent a simple reconstruction surgery (12 patients/52%). 5 patients (29%) who underwent alloplasty and 6 patients (22%) who underwent myoplasty also had infectious complications of the perineum.
Postoperative perineal hernias were observed in 5 patients (22%) who underwent a simple reconstruction surgery. The patients who underwent alloplasty or myoplasty did not have postoperative perineal hernias. In addition, the study assessed the frequency of postoperative infectious complications of the perineum both in the patients who underwent pre-surgery radiation therapy (chemoradiation) and in the patients who did not. The assessment of the data revealed that the frequency of postoperative infectious complications of the perineum after simple reconstruction was the same both in the patients who underwent radiation therapy and in the patients who did not (about 50%). As regards complex plastic reconstruction techniques, the frequency of postoperative infectious complications of the perineum was greater in the patients who underwent radiation therapy – 45% for alloplasty and 26% for myoplasty.
Opinion
All the above techniques for the closure of pelvic bottom defects have advantages and disadvantages. The obtained data have shown that the frequency of perineal wound complications is the greatest after a simple reconstruction surgery (52%). During a simple reconstruction surgery, the pelvic floor is not reconstructed, and a cavity collecting fluid is formed between the bowel loops and closed skin, which can lead to inflammation and perineal hernias. However, this technique can be used in older patients who have severe comorbidities, or in cases of local infectious complications.
The technique using mesh endoprostheses is relatively easy to perform and has satisfactory immediate outcomes (our data shows that there are not more than 29% percent of complications). It is advisable to use mesh endoprostheses with an anti-adhesive coating; however, uncoated surgical mesh can also be used. In this case, certain measures must be taken to prevent the direct contact of the small intestine with the endoprosthesis. For this purpose, the surgeon may use one of these solutions: to repair the pelvis peritoneum, to use the greater omentum or the uterus (in women) for isolation of the mesh from intestinal loops. The use of mesh endoprostheses seems to be the best option in cases when a patient has not received pre-surgery radiation therapy. Mesh endoprostheses do not ensure volume filling of perineal defects, therefore they must be used when post-surgery residual cavities are not large in size. High cost of coated endoprostheses makes it impossible to use the technique in routine clinical practice.
Patients who underwent pre-surgery radiation therapy and have large residual cavities seems to achieve better outcomes when gluteoplasty is performed (complications are observed only in 22% of cases). The gluteus maximus is located close to the perineal defect, and, as a rule, it is well-developed and well-vascularized. So, it is possible to make a graft of a required size. If a perineal defect is large, double-sided gluteoplasty is also possible. Another advantage of gluteoplasty is its relatively low cost. The advantage of using a vertical rectus abdominis musculocutaneous (VRAM) flap is that it provides a large skin paddle to repair a perineal skin defect or posterior vaginal wall damage. The VRAM-flap technique is a complicated surgery and has a risk of necrosis of the flap and complications of the donor site. Therefore, we believe that the use of the VRAM-flap technique must be limited to the cases that require the use of musculocutaneous flaps.
The following conclusions have been made based on the obtained data:
- The frequency of postoperative perineal wound complications is the highest (61%) in cases of “simple” reconstructive surgeries.
- When alloplasty is performed, the frequency postoperative perineal wound complications is 29%. Surgeries using synthetic mesh are the best option for patients who have not undergone pre-surgery radiation therapy (chemoradiation) and who have small post-surgery residual cavities.
- Myoplasty allows to decrease the rate of postoperative perineal wound complications up to 29%. Surgeries using a pedicled muscle flap is the best option after radiation therapy and in cases of large post-surgery residual cavities.
- The VRAM-flap technique must be used in cases of large perineal defects that require the use of musculocutaneous flaps.
The Department is headed by Dr Aleksey M. Karachun , D.Sc. and a professor at the Oncology Department of the I.I. Mechnikov North-Western State Medical University.