Toward trial, liver resection in clrm trial

Medical research journal

1. Journal scan 9/1/24 Dr Srujana

2. Sno Name of article Journal Type of study Impact factor 1. Total neoadjuvant therapy followed by a watch-and-wait strategy for patients with rectal cancer ( TOWARd ): protocol for single-arm phase II/III confirmatory trial (JCOG2010) BJS DEC 2023 Phase Ii / Iii Single Arm Trial 5.572 2. Transgastric drainage of the perforated esophagus : our experiences over 10 years Diseases of esophagus Jan 2024 Observational study 2.6 3. Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer NEJM June 2022 RCT 176.079 4. Trends and overall survival after combined liver resection and thermal ablation of colorectal liver metastases: a nationwide population-based propensity score-matched study HPB Jan 2024 Retrospective observational study 2.9 5. Impact of circumferential resection margin on survival in ampullary cancer: retrospective analysis BJS Sep 2023 Retrospective observational study 5.572

3. Introduction Rectal cancer (RC) is the eighth leading cause of cancer-related mortality worldwide. The standard treatment for cT2–3 N0 M0 RC in Japan is surgical resection followed by postoperative chemotherapy The European Society for Medical Oncology (ESMO) guidelines recommend upfront total mesorectal excision for T3a/b whereas the American Society of Clinical Oncology (ASCO) guidelines recommend preoperative chemotherapy with radiation for patients with elevated risk profiles of local regional recurrence in the pelvis. Furthermore, the concept of total neoadjuvant therapy (TNT) followed by a watch-and-wait strategy (W&W) has been put forward in recent years, in which surgery is not required in patients who have a cCR after TNT TNT, which includes neoadjuvant chemoradiation and preoperative chemotherapy, is presently being advanced in the USA and Europe with the objective of improving the local anti-tumour effect by integrating neoadjuvant chemoradiotherapy ( nCRT ) and the distant anti-tumour effect by systemic chemotherapy multiple courses of a modified FOLFOX (fluorouracil/leucovorin plus oxaliplatin) regimen for consolidation chemotherapy and found that the pCR rate in resected specimens increased with the duration of treatment

4. Methodology Therefore, JCOG2010 will use oral capecitabine alone as the chemotherapy regimen in combination with radiotherapy( pelvic cavity should be irradiated at a dose of 45 Gy /25 fractions with primary tumour boost irradiation at 5.4 Gy /3 fractions as the treatment approach With regard to the consolidation chemotherapy regimen FOLFOX is administered as six cycles at 2-week intervals over 12 weeks and CAPOX as four cycles at 3-week intervals over 12 weeks.

5. Aim The aim of this multi-institutional, single-arm phase II/III trial is to examine the safety and efficacy of TNT followed by W&W in patients with early-stage RC and high potential for non-operative management.

6. Objectives Primary: to confirm that TNT followed by W&W, which is less invasive and may avoid the need for colostomy, is non-inferior to the standard treatment of surgical resection for RC(cT2–3 N0 M0)by comparing the 5-year overall survival (OS) rate in the TNT and W&W group with that in a historical control group response will be evaluated according to the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Patients are classified into three response categories: cCR , near complete response (near CR), or incomplete response.

7. Study Multi institutional single arm. Phase II/III trial Study place Japan Sample size 105 patients journal BJS Published on DEC 2023

8. Eligibility criteria Inclusion: Histologically diagnosed well to moderately differentiated adenocarcinoma CECT/MRI – T2/T3N0M0, Maximum tumor diameter < 5cm Age – 18-75 years ECOG – 0/1 P atient does not wish to undergo surgical resection (that is the standard of care) as initial treatment, but wishes to undergo salvage treatment, including surgical resection, in the event of residual or recurrent disease N o history of rectal resection (except for endoscopic resection), radiation therapy to the pelvic region, or any previous treatment

9. Exclusion: synchronous or metachronous (within 5 years) malignancy infectious disease requiring systemic treatment; body temperature greater than or equal to 38.0°C women who are pregnant, within 28 days postpartum, or lactating, and severe psychiatric disease affecting everyday life; receiving continuous systemic corticosteroids or immunosuppressive agents; poorly controlled diabetes mellitus; uncontrolled hypertension; history of unstable angina pectoris within 3 weeks or myocardial infarction within 6 months before registration;

10. After completion of nCRT , the first response evaluation is performed on days 8–21 , with the final day of irradiation being day 0 Consolidation chemotherapy involves administration of four cycles of CAPOX, which comprises capecitabine at a dose of 2000 mg/m2 /day for 14 days in combination with oxaliplatin at a dose of 130 mg/m2 on day 1, starting on day 21 after the last irradiation. the second response evaluation (is performed on days 28–43 , with day 0 being the last day of the fourth course of CAPOX. Subsequent response evaluations are scheduled to be conducted no more than twice every 8 weeks for patients achieving near CR. After the final response evaluation, follow-up should be conducted at 12-week intervals for 2 years and at 24-week intervals for 3 years thereafter.

11. Outcomes The primary endpoint is the cCR rate in phase II and 5-year overall survival in phase III. Phase II component The primary endpoint of the phase II component is the proportion of patients with cCR at the final response evaluation The secondary endpoints in phase II are the proportion of patients with a clinical/near CR at the final response evaluation Phase III component The primary endpoint of the phase III component is OS in all enrolled patients The secondary endpoints include progression-free survival, rectal resection-free survival, colostomy-free survival, the proportion of patients with cCR at the final response evaluation (by central review), the proportion of patients with cCR /near CR at the final response evaluation (by central review), the proportion of patients who do not undergo rectal resection, adverse events, incidence of surgical morbidities,

12. Results around 60 per cent of patients classified as having near CR would be expected to select W&W and 40 per cent would opt for local resection. The cCR rate achieved by nCRT for cT3N0 rectal carcinoma,was noted to be 54.2 per cent 5 year OS rate was 95 per cent

13. Conclusion This trial will determine whether total neoadjuvant therapy and a watch-and-wait strategy is an effective alternative to radical surgery for early-stage rectal cancer in patients with cT2–3 N0 M0 and tumour size less than or equal to 5 cm.

14. Introduction Esophageal perforation is associated with a high morbidity and mortality. Etiology includes spontaneous ( Boerhaave’s syndrome), traumatic, iatrogenic, neoplasm, and foreign bodies. Perforation leads to mediastinal contamination, resulting in sepsis and multiorgan failure. Diagnosis is often delayed because of signs and symptoms overlapping with other pathologies and its rarity resulting in reduced suspicion from clinicians. Diagnosis and treatment within 24 hours result in a mortality of 10–25%. Delayed diagnosis demonstrates mortality of 40–60% The objectives of treatment include prevention of further contamination from the perforation, elimination of infection, restoration of integrity of the gastrointestinal tract, and establishment of nutritional support.

15. Multiple operative and nonoperative management strategies have been described. primary repair of the esophageal perforation, with or without reinforcement and drainage, has been advocated for perforations detected within 24 hours. Where primary closure is not feasible, other surgical options such as T-tube drainage, exclusion and diversion, and esophagectomy have been utilized but carry a high morbidity and mortality In the modern era, minimally invasive and nonoperative methods have been developed. These include stenting, endoluminal vacuum therapy, and clipping transgastric drainage of the esophagus in 2008, as a method of managing esophageal perforations not amenable to primary closure. 13 The technique establishes vacuum drainage of the lumen of the esophagus , while maintaining patency and effectively exteriorizing the perforation to allow healing. This is achieved by positioning a drain in the esophagus , across the perforation, and exteriorizing it through the stomach and abdominal wall. 10-year experience of using transgastric drainage for the treatment of esophageal perforation.

16. Study Retrospective observational study Study period Jan 2012 to July 2022 Study place Peninsula Oesophago Gastric Centre, Derriford Hospital, Plymouth, UK Sample size 58 Patients journal Diseases of esophagus Published on Jan 2024

17. Outcomes Primary : inpatient mortality Secondary : 30 day mortality Time to leak resolution Surgical reintervention rate

18. Inclusion criteria: Esophageal perforation due to any cause Exclusion criteria: Cervical perforations Anastomotic leaks Perforation managed outside this center

19. Indications of transgastric drainage are: For spontaneous, traumatic, ischemic, and iatrogenic perforations. Where primary closure of the esophagus is not appropriate because of the size of the defect, delay of presentation, fitness of patient, or tissue ischemia. Failure of leak resolution following other surgical intervention. Where primary repair has been performed and the injury is close to the gastroesophageal junction.

20. Procedure Under general anesthesia , endoscopy is performed to assess the esophageal defect and to identify and intubate the distal esophagus . Laparotomy or laparoscopy is performed. A suitable area in the anterior wall of the stomach is identified and a gastrotomy performed. The fenestrated end of a 36F silastic chest drain, with a Prolene suture loosely tied in a loop through it, is passed into the stomach, grasped by endoscopic forceps and withdrawn proximally into the esophagus so that the perforated end lies 5 cm above the level of the perforation. The holes in the chest drain should ideally cover the defect and the lowest hole sit in the stomach to encourage both drainage of the defect and drainage of gastric contents. The distal end of the drain is bought out through the abdominal wall. The gastric serosa is fixed as a gastropexy to the abdominal wall and the drain secured very securely to the skin with sutures. The drain is connected to an underwater suction drain A variation by Boland et al. 14, which uses a PEG guidewire to advance a chest drain antegrade down the esophagus through the gastric and abdominal wall.

21. Postop management Transgastric drain is connected to a closed underwater seal drain system at − 10 to 15 cmH20. The patient is encouraged to drink water to maintain drain patency and to increase patient comfort. Nutrition can be provided by jejunostomy or total parenteral nutrition. It is important to continually check for free drainage of water taken by mouth through the transgastric drain, which may need flushing Weekly contrast swallows are obtained to assess healing of esophageal perforation. Contrast swallow should be performed with transgastric drain clamped to prevent contrast draining preferentially via the transgastric drain. The drain can be removed when contrast swallow shows resolution of leak. Small, contained sinuses are acceptable for removal.

22. Results Spontaneous perforation accounted for 31 cases, iatrogenic injuries for 21 cases, 3 were neoplastic, 2 secondary to ischemia, and 1 case was traumatic. Transgastric drainage was utilized in 35 of the 58 cases of esophageal perforation. Of the 23 cases managed without transgastric drainage, 10 were spontaneous perforations, 10 iatrogenic, and 3 because of neoplasm. Of the patients diagnosed with Boerhaave’s syndrome, 4- contained perforations - nonoperative management. There were two mortalities shortly after initial surgical management of washout and drainage.2 patients -end of life care. Endoluminal stenting and primary closure – 1 patient Of the 10 patients with iatrogenic perforations, 8 - nonoperatively and 2 - endoluminal covered stenting. All three patients presenting with perforated neoplasms - endoluminal covered stent.

23. Spontaneous perforation accounted for 60% of the cases (21 of 35). Median height of perforation was 32.5 cm (20–40). Median length of perforation treated, as measured by endoscopy, was 3.5 cm (1– 15 cm). Over half of patients underwent thoracotomy (20 of 35), with nine patients receiving no treatment for the thorax at presentation. Transgastric drain was sited during laparotomy in 80% of patients (28 of 35), six patients underwent laparoscopic insertion of transgastric drain and one had a percutaneous gastrostomy upsized to a transgastric drain. Resolution of leak with transgastric drainage was demonstrated in 83% of patients, with five mortalities and one patient needing closure of leaking gastrotomy accounting for treatment failure

24. Surgical reintervention for sepsis control was required for eight patients following transgastric drain insertion. Of these reinterventions, four patients required thoracotomy and intercostal chest drain insertion: Esophagectomy was performed in one patient, one patient needed repositioning of transgastric drain, and one patient required up sizing of drain. Laparotomy and closure of gastrotomy, with omental patch repair for leaking transgastric drain was necessary in one patient. Displaced drains during treatment occurred in three patients. These did not require further intervention. There were five deaths in hospital. Inpatient and 30-day mortality rate were both 14%. The median follow-up, in patients who were discharged from hospital, was 3 months (0–54). During follow-up, two patients required dilatations for esophageal stricture and one patient underwent incisional hernia repair.

25. Introduction Although the benefit of adjuvant chemotherapy has been established in stage III colon cancer, its usefulness in stage II disease continues to be debated. Surgery alone can cure more than 80% of stage II colon cancer, and no clear overall survival benefit has been observed in trials of adjuvant therapy. Therefore, guidelines currently recommend that adjuvant chemotherapy in patients withhigh -risk clinicopathological features survival benefit - <5% Circulating tumor DNA ( ctDNA ) analysis is a promising alternative strategy in which peripheral blood (a “liquid biopsy”) is directly evaluated for evidence of minimal residual disease that could ultimately be the source of a later clinical recurrence. high risk of recurrence (>80%) when ctDNA is detected The Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Stage II Colon Cancer ( DYNAMIC) trial was a randomized trial designed to investigate whether a ctDNA -guided approach as compared with a standard approach in stage II colon cancer could reduce the use of adjuvant treatment without compromising the risk of recurrence

26. Inclusion criteria: stage II (T3 or T4, N0, M0) colon or rectal adenocarcinoma with negative resection margins. able to receive adjuvant oxaliplatin based or single-agent fluoropyrimidine chemotherapy. Exclusion criteria: macroscopic metastatic disease history of an other primary cancer within the previous 3 years, the presence of synchronous primary colorectal cancer, treatment with neoadjuvant chemoradiotherapy.

27. Methodology Patients were enrolled within 3 weeks after surgery, and an adequate specimen from the resected tumor needed to be provided for mutation analysis by 4 weeks after surgery. Plasma specimens were obtained for ctDNA analysis from all patients at week 4 and week 7 after surgery. results were made available to the treating clinician 8 to 10 weeks after surgery. Patients with a positive ctDNA result at either week 4 or week 7 received adjuvant single agent fluoropyrimidine or oxaliplatin-based chemotherapy All patients were to be followed for 5 years, with carcinoembryonic antigen measured every 3 months for 24 months and then every 6 months for 36 months. Contrast-enhanced CT of the chest, abdomen, and pelvis was performed every 6 months for 24 months and then at 36 months.

28. Outcomes The primary efficacy end point was recurrence free survival at 2 years. A key secondary end point was treatment with adjuvant chemotherapy. Other secondary end points included recurrence-free survival among ctDNApositive and ctDNA -negative patients, time to recurrence, and overall survival Exploratory end points included the ctDNA clearance rate in ctDNA -positive patients treated with adjuvant chemotherapy, levels of fear of recurrence among the patients, and cost-effectiveness. Clinical high-risk disease, defined as one or more clinicopathological risk features (T4, poor tumor differentiation, lymph node yield <12, lymphovascular invasion, tumor perforation, or bowel obstruction) in association with a proficient mismatch-repair tumor

29. Study Randomised controlled trial Study period 2015 to 2019 Study place 23 Australian centers Sample size 459 journal NEJM Published on June 2022

30. The estimated 3-year recurrence-free survival was 92.5% among ctDNA -negative patients and 86.4% among ctDNA -positive patients

31. Introduction Approximately 50% of patients with CRC develops colorectal liver metastases (CRLM). To date, partial liver resection is considered the only potential curative therapy, with 5 year overall survival (OS) rates of approximately 50%. Only 20% of the patients with CRLM are eligible for liver resection. CRLM can be considered unresectable due to the location of CRLM, insuf fi cient future liver remnant, or comorbidities prohibiting liver resection. A combination of liver resection with thermal ablation can extend curative options and may permit a more parenchymal sparing approach for patients who would otherwise require a major liver resection. Studies comparing liver resection alone with combined liver resection and ablation described improved postoperative outcomes, such as reduced morbidity and mortality.

32. Aim The aim of this study was to compare overall survival between patients who underwent liver resection only versus a combined approach

33. Inclusion : All adult patients who underwent liver resection or combined liver resection and ablation for > 2 CRLM Exclusion : with a single (1) CRLM history of liver resection (i.e., treatment of recurrence) who underwent thermal ablation alone, who had missing data on date of birth, date of surgery, and tumour type. In addition, two hospitals that did not perform combined liver resection and ablation were excluded from the analysis of hospital variation

34. Study Retrospective observational study Study period Jan 2014 to dec 31, 2022 Study place Dutch hepatobiliary audit Sample size 3593 Patients(2257 vs 1336) journal HPB Published on Jan 2024

35. Outcomes The main outcome of this study was overall survival (OS) of resection and ablation. Short-term outcomes compared between both treatment groups included overall and major morbidity ( Clavien-Dindo 3A) 30-day or in hospital mortality. several speci fi c complications, including, intra-abdominal infection, liver failure and bile leakage, surgical site infection, pneumonia and cardiac complications

36. RESULTS Patients with 2 – 3 lesions < 3 cm were selected and assigned into two treatment groups (major liver resection vs. minor liver resection combined with thermal ablation) Combined resection and ablation could permit a more parenchymal-sparing approach in patients with centrally located tumours. After propensity score matching 1005 in each group speci fi c postoperative complications like liver failure (1.9% vs. 0.6%, P = 0.004) and 30-day mortality (2.1% vs. 0.8% P = 0.025)were less often in the combined resection and ablation group Postoperative overall morbidity, major morbidity were not different Over all survival same(77.8 vs 76.5 months) 5 year OS – 39.3 VS 33.9%

37. CONCLUSION These data suggest that combined resection and ablation, while not superior to liver resection alone, potentially expands effective treatment options for patients who do not qualify for major liver resections. the present study showed similar postoperative outcomes and overall survival rates in patients treated with combined liver resection/ablation to resection alone. Combined resection and ablation should be available and considered as an alternative to resection alone in any patient with multiple metastases.

38. Introduction AC is thought to have a better prognosis than pancreatic ductal adenocarcinoma (PDAC) or distal bile duct carcinoma, partly due to its localization , which leads to characteristic symptoms such as jaundice and pain. Five-year overall (OS) and disease-free survival rates (DFS) of resected patients are reported around 50 per cent . Differences with regards to prognosis and treatment strategies have also been attributed to the different histopathological subtypes. While some studies reported patients with a pancreatobiliary (PB) subtype to have a significantly poorer 5-year OS and DFS than those with intestinal (INT) differentiation some others have shown that the histological subtype is not an independent factor when accounting for stage The most important predictors of survival identified are positive lymph node status ( pN +) and lymph node ratio (LNR Data on the role and impact of the resection margin status (R status) is limited with some reports showing association with worse survival

39. AIM The aim of this study was to analyse the long-term outcome of resected AC focusing on differences between histological subtypes and risk factors for survival.

40. Study Retrospective observational study Study period Jan 2002 to Dec 2017 Study place University of Heidelberg Sample size 234 journal BJS Published on Sep 2023

41. R status was evaluated according to the revised classification for PDAC based on the Leeds protocol for histopathological workup Radicality was stratified as R0 CRM– (tumour clearance > 1 mm), R0 CRM+ (tumour clearance < 1 mm) and R1 (direct tumour infiltration of the resection margin).

42. Results The majority of patients ( n = 215; 91.9 per cent) underwent partial pancreatoduodenectomy (PD). Fourteen patients (6.0 per cent) underwent total pancreatectomy (TP) and 5 (2.1 per cent) ampullary resection (AR). Some 16 patients (6.8 per cent) underwent vascular resection. Some 126 (53.9 per cent) had nodal positive disease and 103 (44.0 per cent) were nodal negative with a median number of 23 examined lymph nodes In 198 patients microscopically, clear resection margin (R0) was reached, while 33 (14.1 per cent) were R1. There were 175 of 234 patients with R0 CRM– (74.8 per cent) and 23 (9.8 per cent) with R0 CRM+ . Information on adjuvant treatment was available for 159 patients, of whom 72 (45.3 per cent) received adjuvant therapy In 80, 109 and 27 patients an INT, PB and mixed subtype was identified respectively There was no significant difference in median age ( P = 0.836), gender ( P = 0.146), duration of hospital stay ( P = 0.626), operation ( P = 0.937) and ICU stay ( P = 0.670) between the three subgroups Median preoperative CA 19-9 was lower in the INT than in the PB subtype (16 U/ml, i.q.r . 11–38 versus 31 U/ml, i.q.r . 12–99) ( P = 0.430)

43. Neoadjuvant treatment was performed in 2 (2.5 per cent) patients in the INT group, 4 (3.7 per cent) in the PB and 1 (3.7 per cent) in the mixed group ( P = 0.895). There was no significant difference in adjuvant treatment. Patients in the PB group had more advanced tumours with more pT4 stages (n = 49 (45 per cent) versus 22 (27.5 per cent); P = 0.042), G3 differentiation ( n = 45 (42.1 per cent) versus 15 (19.5 per cent); P = 0.002) and pN + patients (72 (66.1 per cent) versus 34 (42.5 per cent); P = 0.004) with similar rates of ELN (22, i.q.r . 18–28 versus 24, i.q.r . 18–31) compared to the INT group. there was a significant difference in median tumour size: 2.6 cm ( i.q.r . 1.8–3.5) in the INT compared with 2 cm ( i.q.r . 1.5 − 2.5) in the PB and 2.2 cm ( i.q.r . 2–2.5) in the mixed group ( P = 0.007) R0 CRM– resection was reached in 67 (83.8 per cent) of INT compared with 75 (68.8 per cent) PB and 17 (63.0 per cent) mixed type patients. R0 CRM+ was reached in 4 (5 per cent) INT, 15 (13.8 per cent) PB and 3 (11.1 per cent) mixed type patients. R1 resection was observed in 7 (8.8 per cent) INT, 19 (17.4 per cent) PB and 6 (22.2 per cent) mixed subtype patients ( P = 0.064).

44. In terms of postoperative complication rate, no statistically significant differences were observed. Analysis of the histological subtypes showed a significant difference in 5-year OS in the three subgroups. Analysis of all patients showed a significant difference in OS between true R0 resection and CRM+/R1 resection

45. True R0 resection was directly associated with survival (HR 2.13; c.i. 1.31–3.46, P = 0.002). R0 CRM+ was significantly associated with worse survival (HR 3.24; c.i. 1.65–6.38, P < 0.001). In multivariable analysis both PLN ratio and pN + were confirmed as independent variables significantly associated with worse postresection survival ( P = 0.006 and P = 0.04 respectively). This analysis underlines that the PB subtype is associated with more aggressive features such as higher tumour stage, poorer differentiation, higher rate of pN + and worse prognosis compared with the INT subtype

46. Conclusion Postresection survival of ampullary carcinoma patients is determined by histological subtype and surgical radicality.

47. Sno Name of article Journal Type of study Impact factor 1. Total neoadjuvant therapy followed by a watch-and-wait strategy for patients with rectal cancer ( TOWARd ): protocol for single-arm phase II/III confirmatory trial (JCOG2010) BJS DEC 2023 Phase Ii / Iii Single Arm Trial 5.572 2. Transgastric drainage of the perforated esophagus : our experiences over 10 years Diseases of esophagus Jan 2024 Observational study 2.6 3. Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer NEJM June 2022 RCT 176.079 4. Trends and overall survival after combined liver resection and thermal ablation of colorectal liver metastases: a nationwide population-based propensity score-matched study HPB Jan 2024 Retrospective observational study 2.9 5. Impact of circumferential resection margin on survival in ampullary cancer: retrospective analysis BJS Sep 2023 Retrospective observational study 5.572