The conundrum of total neoadjuvant therapy in rectal cancer.

Total neoadjuvant therapy (TNT) has fast become the paradigm in the management of rectal cancer. The widespread adoption of this approach across the world, not only for locally advanced cancers but even for cancers that otherwise would not merit chemotherapy, leads both to an increase in treatment-related toxicity for patients and burdens the healthcare services of the country. It is important to tailor treatment to each patient based not only on the tumour but, even more importantly, on the patient's expectations and goals. The intent of treatment while prescribing TNT needs to be clear, understanding that not all patients are suitable for an organ preservation (watch and wait) approach and that the survival benefits of TNT are not as obvious as most proponents believe.

Colon cancer: feeling the imbalance?

While neoadjuvant chemotherapy has become the standard of care for rectal cancers in most centres, there is much interest in neoadjuvant chemotherapy in colon cancer after the recent publication of the FOxTROT trial. The management of colon cancers seems to be heading down the same path as rectal cancer, where the radicality of surgery is replaced by chemotherapy intensification. The role of demanding procedures such as complete mesocolic excision with central venous ligation in this new paradigm of upfront chemotherapy remains uncertain and uninvestigated.

Complete mesocolic excision for right colon cancer: Is D3 lymphadenectomy necessary?

AIM: Although complete mesocolic excision (CME) for colon cancer is oncologically sound, to date, there has been no consensus on the extent of lymphadenectomy in radical right colectomy. This study essentially compared the perioperative and survival outcomes of CME with two templates of lymphadenectomy for right colon cancer. METHOD: This was a propensity matched, retrospective analysis of a single centre, prospectively maintained database of all patients undergoing elective right colectomy for nonmetastatic, biopsy-proven adenocarcinoma from November 2013 to October 2018. CME + D3 was adopted selectively, documented prospectively, and compared with patients undergoing CME + central vascular ligation (CVL). The only technical difference between the groups was the excision of the surgical trunk of Gillot in the CME + D3 group. Postoperative, long-term outcomes and patterns of recurrence were compared between the groups. RESULTS: Of the 244 eligible patients, 88 (36.1%) and 156 (63.9%) underwent CME + D3 and CME + CVL, respectively. Matched groups (72 [CME + D3] vs. 108 [CME + CVL]) showed no difference in histology, tumour grade, postoperative complications, mortality, and hospital stay. CME + D3 was preferentially performed laparoscopically (35.2% vs. 9%), was associated with lower blood loss (215 mL vs. 297 mL, p = 0.001), higher nodal yield (31 vs. 25 nodes, p = 0.003) and a higher incidence of chyle leak (4 vs. 0, p = 0.013). At a median follow-up of more than 57 months, there was no significant difference in local recurrence, disease-free or overall survival. CONCLUSION: In this retrospective study, lymphadenectomy along the superior mesenteric vein, as a component of CME for right colon cancer, offered a higher nodal yield with no improvement in oncological outcome. Dissection of the SMV, over and above a D2 dissection, could therefore be restricted to specialized colorectal units until further studies establish the incremental oncological benefit of this extended lymphadenectomy or define a patient group in whom it is beneficial.

Splenic flexure cancer: is right extended hemicolectomy better than left hemicolectomy?

INTRODUCTION: There is no consensus on the optimal surgery for splenic flexure cancers. METHODS: Review of a prospectively maintained database of patients with splenic flexure cancer undergoing either a right extended hemicolectomy or left hemicolectomy at a tertiary care cancer hospital from 14.5.2010 to 16.9.2021. The primary outcome measures were postoperative morbidity and hospital stay with secondary outcomes being overall survival, disease-free survival, and long-term patient reported functional and quality of life outcomes. RESULTS: The demographic variables were evenly distributed between groups, and median follow-up was 44 months. The groups were comparable in terms of postoperative morbidity (Clavien-Dindo complication ≥ 3a 10.6% vs 10%, p = 0.322) and hospital stay (8 days vs 7 days, p = 0.316). Oncological outcomes were similar in both groups (3-year disease-free survival 71.8% vs 67.8%, p = 0.877, and 3-year overall survival 83.9% vs 75.8%, p = 0.787), and long-term patient-reported functional outcomes were excellent in both groups. CONCLUSION: Oncological outcomes, post operative morbidity, and long-term patient reported functional outcomes are comparable in patients undergoing either a right extended or left hemicolectomy for splenic flexure cancer.

The RAPIDO trial-Reduction in disease-related treatment failure does not translate into improved overall survival: a mystery solved!

The initial publication of the RAPIDO trial resulted in widespread adoption of short-course radiotherapy and consolidation chemotherapy in locally advanced rectal cancer. The impressive reduction in disease-related treatment failure did not, however, translate into any overall survival benefit. The recent update of the RAPIDO trial with its 5-year results provides much insight into the actual effect that this approach has on patient outcomes and the detriment in local control leads to the question as to whether this approach can still be considered as standard of care in high-risk rectal cancer.

Incidence and Treatment Outcomes of Rectovaginal Fistula After Rectal Cancer Resection.

OBJECTIVES: Rectovaginal fistulas (RVFs) are an uncommon and disturbing complication with limited success in treatment. This study was aimed at determining the incidence of RVFs after rectal resections in the era of neoadjuvant radiation therapy and the outcomes of their treatment. METHODS: This was a retrospective study of female patients who underwent sphincter-preserving total mesorectal excision for rectal cancer and developed RVF. RESULTS: Four hundred eighty-eight patients underwent rectal resections between January 2013 and December 2019, and 9 developed RVF (1.8%). Average time to presentation was 280 days (range, 6-540 days). The median time to onset for those presenting prior to stoma reversal was 90 days, whereas the duration between stoma reversal and RVF detection in those presenting after stoma closures was 115 days. Success rates of fecal diversion and local procedures for treatment of RVF were 20% (2/10 procedures) and 40% (2/5 procedures), respectively. Redo coloanal anastomosis was performed for 2 patients with successful outcome. An average of 2.1 procedures were performed per patient (19/9) with a per-procedure success rate of 31.6% (6/19 procedures) and a per-patient success rate of 66.7% (6/9). At median follow-up of 64 months, 50% (3/6) of patients with a healed fistula were free of stoma, and all of them were continent. Four patients were sexually active. CONCLUSIONS: The incidence of RVF after rectal resection is low, but treatment outcomes are disappointing. Diversions and local repairs had high failure rates in our patients where the majority received preoperative radiation therapy. After successful healing, sexual function and continence are acceptable.

The Prevalence of BRAF, PIK3CA, and RAS Mutations in Indian Patients with Colorectal Cancer.

Omshree ShettyVikas OstwalIntroduction The present study evaluates the mutation pattern and frequency of BRAF , PIK3CA and RAS in colorectal carcinoma observed in the tertiary cancer center in India. Materials and Methods Consecutive cases of colorectal adenocarcinoma ( n = 330) registered from January 2015 to December 2019 (5-year duration) were selected for the study. Molecular analysis for BRAF . PIK3CA (exon 9 and 20) and RAS ( KRAS & NRAS ) was performed on representative formalin-fixed paraffin-embedded tissues by Sanger sequencing. Results were correlated with clinicopathological features. Patient overall survival (OS) was obtained using Kaplan-Meier method. Results The study cohort was in the age range of 22 to 81 years (median age: 52 years) that included 202 males and 96 females (male: female ratio 2.1:1). BRAF V600E mutation was observed in three cases (1%), while 17 cases (5.7%) had mutations in the PIK3CA gene (exon 9 or exon 20). Mutation analysis for RAS gene ( KRAS & NRAS ) was observed among 42 (15.4%) cases with KRAS mutation and 11 (4%) cases were positive for NRAS mutations. Among RAS, KRAS G12D was the predominant mutation. Median OS with wild-type RAS was 46.6 months (95% confidence interval [CI]: 22.4-70.8), while for RAS mutated patients, it was 25.6 months (95% CI: 16.7-34.5), hazard ratio: 1.7 (95% CI: 1.1-2.7, p = 0.025). Conclusion This study evaluated the prevalence of BRAF, PIK3CA and RAS mutations in the Indian cohort and its impact on clinical behavior. There was lower incidence of BRAF mutations in this cohort and PIK3CA mutation (single) did not impact survival of the patients.

Downstaging in Advanced Rectal Cancers: A Propensity-Matched Comparison Between Short-Course Radiotherapy Followed by Chemotherapy and Long-Course Chemoradiotherapy.

BACKGROUND: Short-course radiotherapy followed by chemotherapy has not been widely evaluated as an alternative to traditional long-course chemoradiotherapy in locally advanced rectal cancer. OBJECTIVE: This study compared the oncological and short-term outcomes between short-course radiotherapy + chemotherapy and long-course chemoradiotherapy in locally advanced rectal cancer. DESIGN: This is a retrospective propensity-matched study. SETTINGS: The study was conducted in a colorectal department at a tertiary care oncology center in India. PATIENTS: There were 173 patients. Group A had 47 patients and group B had 126 patients. A 1:2.7 matching was done for age, sex, distance of tumor from the anal verge, sphincter preservation surgeries, MRI-based pretreatment T stage, and circumferential resection margin. INTERVENTIONS: The interventions performed were short-course radiotherapy + chemotherapy (group A) and long-course chemoradiotherapy (group B) in locally advanced rectal cancer. MAIN OUTCOME MEASURES: The primary measures were pathological circumferential resection margin positivity, downstaging, tumor regression grade, and postoperative complications. RESULTS: Of the patients, 52% had a positive circumferential resection margin on MRI, 57% had low rectal tumors, and 20% had T4 tumors. Distribution of rectal surgeries was similar between the 2 groups. pT downstaging and tumor regression scores were significantly better in group B ( p = 0.028 and 0.026). Pathological circumferential resection margin, distal resection margin, and nodal yield were similar. On multivariate analysis, pretreatment N status was the only independent predictive factor for pathological circumferential resection margin status. Grade 3 to 4 Clavien-Dindo complications, anastomotic leak rates, and hospital stay were similar between the 2 groups. LIMITATIONS: This was a retrospective study. Although propensity matching was performed, selection bias cannot be eliminated completely, as seen in the difference in the surgical approaches between the 2 groups. CONCLUSIONS: In a cohort containing a significant portion of MRI circumferential resection margin-positive low rectal cancers, short-course radiotherapy + chemotherapy followed by delayed surgery resulted in lower T downstaging and lower tumor regression scores compared with long-course chemoradiotherapy, but pathological circumferential margin status, distal resection margin, nodal yield, and perioperative morbidity were similar between the 2 groups. This suggests that short-course radiotherapy + chemotherapy could be a viable alternative to long-course chemoradiotherapy in locally advanced rectal cancers. See Video Abstract at http://links.lww.com/DCR/B855 . REDUCCIN DEL ESTADIO EN LOS CNCERES RECTALES AVANZADOS UNA COMPARACIN DE PROPENSIN EQUIPARADA ENTRE LA RADIACIN DE CICLO CORTO SEGUIDA DE QUIMIOTERAPIA Y LA QUIMIO RADIACIN DE CICLO LARGO: ANTECEDENTES:La radioterapia de ciclo corto seguida de quimioterapia no ha sido evaluada ampliamente como una alternativa a la tradicional quimio radioterapia de ciclo largo en el cáncer de recto localmente avanzado.OBJETIVO:Estudio que compara los resultados oncológicos y a corto plazo entre la radioterapia de ciclo corto + quimioterapia y la quimio radioterapia de ciclo largo en el cáncer de recto localmente avanzado.DISEÑO:Estudio comparado de propensión de manera retrospectiva.AJUSTE:Departamento colorrectal en un centro de atención oncológica de tipo terciario en la India.PACIENTES:Hubo 173 pacientes. El grupo A tenía 47 y el grupo B tenía 126 pacientes. Se realizó una comparación de 1: 2,7 para edad, sexo, distancia del tumor desde el margen anal, cirugías de preservación del esfínter, estadio T previo al tratamiento basada en resonancia magnética y margen de resección circunferencial (CRM).INTERVENCIONES:Radioterapia de ciclo corto + quimioterapia (grupo A) y quimio radioterapia de ciclo largo (grupo B) en cáncer de recto localmente avanzado (LARC).PRINCIPALES MEDIDAS DE RESULTADO:Positividad histopatológica de CRM, reducción del estadio tumoral, grado de regresión tumoral, complicaciones posoperatorias.RESULTADOS:El 52% de los pacientes han tenido un margen de resección circunferencial positivo en la resonancia magnética, 57% de tumores rectales bajos, 20% de tumores T4. La distribución de cirugías rectales fue similar entre los 2 grupos. Las puntuaciones de regresión tumoral y de reducción del estadio de pT fueron significativamente mejores en el grupo B ( p = 0.028 y 0.026 respectivamente). El margen de resección circunferencial patológico, el margen de resección distal y los ganglios arrojados fueron similares. En el análisis multivariado, el estadio N previo al tratamiento fue el único factor predictivo independiente para el estadio de pCRM. Las complicaciones Clavien-Dindo de grado 3-4, las tasas de fuga anastomótica y la estancia hospitalaria fueron similares entre los dos grupos.LIMITACIONES:Retrospectiva; aunque la propensión coincide, existe potencial sesgo de selección.CONCLUSIONES:En una cohorte que contenía una porción significativa de cánceres rectales bajos con margen de resección circunferencial positivo por resonancia magnética, la radioterapia de ciclo corto + quimioterapia seguida de cirugía tardía dio como resultado una mayor reducción del estadio T y de regresión tumoral en comparación con la quimio radioterapia de ciclo largo. Pero el estatus histopatológico del margen circunferencial, el margen de resección distal, el rendimiento ganglionar y la morbilidad perioperatoria fueron similares entre los dos grupos. Esto sugiere que la radioterapia de ciclo corto + quimioterapia podría ser una alternativa viable a la quimio radioterapia de ciclo largo en cánceres rectales localmente avanzados. Consulte Video Resumen en http://links.lww.com/DCR/B855 . (Traducción-Dr. Osvaldo Gauto ).

Prognostic Significance of EMVI in Rectal Cancer in a Tertiary Cancer Hospital in India.

Background Presence of extramural venous invasion (EMVI) is a poor prognostic factor for rectal cancer as per literature. However, India-specific data are lacking. Aim The aim of the study is to determine the prognostic significance of EMVI in locally advanced rectal cancer on baseline MRI. Materials and Methods We retrospectively reviewed 117 MRIs of operable non-metastatic locally advanced rectal cancers in a tertiary cancer institute. Three dedicated oncoradiologists determined presence or absence of EMVI, and its length and thickness, in consensus. These patients were treated as per standard institutional protocols and followed up for a median period of 37 months (range: 2-71 months). Kaplan-Meier curves (95% CI) were used to determine disease-free survival (DFS), distant-metastases free survival (DMFS), and overall survival (OS). Univariate analysis was performed by comparing groups with log-rank test. Results EMVI positive cases were 34/114 (29%). More EMVI-positive cases developed distant metastasis compared with EMVI-negative cases (14/34-41% vs. 22/83-26%). The difference, however, was not statistically significant ( p = 0.146). After excluding signet-ring cell cancers ( n = 14), EMVI showed significant correlation with DMFS ( p = 0.046), but not with DFS or OS. The median thickness and length of EMVI was 6 and 14 mm, respectively in patients who developed distant metastasis, as compared with 5 and 11 mm in those who did not, although this difference was not statistically significant. Conclusion EMVI is a predictor of distant metastasis in locally advanced non-metastatic, non-signet ring cell rectal cancers. EMVI can be considered another high-risk feature to predict distant metastasis.

Demographics, Pattern of Care, and Outcome Analysis of Malignant Melanomas - Experience From a Tertiary Cancer Centre in India.

BACKGROUND: Treatment of malignant melanoma has undergone a paradigm shift with the advent of immune checkpoint inhibitors (ICI) and targeted therapies. However, access to ICI is limited in low-middle income countries (LMICs). PATIENTS AND METHODS: Histologically confirmed malignant melanoma cases registered from 2013 to 2019 were analysed for pattern of care, safety, and efficacy of systemic therapies (ST). RESULTS: There were 659 patients with a median age of 53 (range 44-63) years; 58.9% were males; 55.2% were mucosal melanomas. Most common primary sites were extremities (36.6%) and anorectum (31.4%). Nearly 10.8% of the metastatic cohort were BRAF mutated. Among 368 non-metastatic patients (172 prior treated, 185 de novo, and 11 unresectable), with a median follow-up of 26 months (0-83 months), median EFS and OS were 29.5 (95% CI: 22-40) and 33.3 (95% CI: 29.5-41.2) months, respectively. In the metastatic cohort, with a median follow up of 24 (0-85) months, the median EFS for BSC was 3.1 (95% CI 1.9-4.8) months versus 3.98 (95% CI 3.2-4.7) months with any ST (HR: 0.69, 95% CI: 0.52-0.92; P = 0.011). The median OS was 3.9 (95% CI 3.3-6.4) months for BSC alone versus 12.0 (95% CI 10.5-15.1) months in any ST (HR: 0.38, 95% CI: 0.28-0.50; P < 0.001). The disease control rate was 51.55%. Commonest grade 3-4 toxicity was anemia with chemotherapy (9.5%) and ICI (8.8%). In multivariate analysis, any ST received had a better prognostic impact in the metastatic cohort. CONCLUSIONS: Large real-world data reflects the treatment patterns adopted in LMIC for melanomas and poor access to expensive, standard of care therapies. Other systemic therapies provide meaningful clinical benefit and are worth exploring especially when the standard therapies are challenging to administer.

Local recurrence with intersphincteric resection in adverse histology rectal cancers. A retrospective study with competing risk analysis.

BACKGROUND: The safety of inter-sphincteric resection (ISR) for low rectal cancer with adverse histologic subtypes has been incompletely studied. The present study aims at determining the risk of local recurrence with this procedure in poorly differentiated and signet ring cell (PDSR) adenocarcinoma. METHODS: Retrospective analysis from a single tertiary cancer centre of non-metastatic primary rectal cancer <6 cm from the anal verge that underwent ISR. Competing risk analysis and sub-distribution hazard ratios for local recurrence free survivals were calculated to determine factors that influenced local recurrence with the competing risk of death from any cause to overcome the exceeding risk of distant metastasis associated with adverse histologic types. RESULTS: One hundred forty-two patients underwent ISR and 22.6% has PDSR histology. At a median follow up of 61 months, 15.6% of the PDSR cohort developed local recurrence (five patients) compared to 11.7% in the non-PDSR group. PDSR histology influenced overall and disease free survival but not local recurrence on cox regression. On competing risk analysis, only ypT stage ≥3 predicted worse local recurrence free survival and not histology. CONCLUSIONS: The presence of PDSR histology did not increase the risk of local recurrence after ISR in this retrospective competing risk analysis.

V-Y Gluteal Advancement Fasciocutaneous Flap for Reconstruction of Perineal Defects After Surgery for Anorectal Cancers- A Single-Center Experience.

An ideal method of perineal closure after resection for low rectal cancer surgery is a topic of debate. Morbidity associated with primary perineal closure due to wound break down delays recovery from surgery and adjuvant treatment with poor oncological outcome at the end. Herewith, we present our experience with V-Y gluteal advancement fasciocutaneous flap done for 131 patients for reconstruction of perineal and pelvic defect. With our experience, this is a safe and simple method with an acceptable complication rate that can be practiced by colorectal surgeons, even in the absence of a dedicated plastic surgery team.

Hyperammonemia after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Report of Three Cases with Unusual Presentation.

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment modality for peritoneal surface malignancies. A variety of metabolic derangements have been reported in the perioperative period in these patients, most of which are a result of the complex interaction of peritoneal denudation, chemotherapy bath, and fluid imbalance. We report three cases of hyperammonemia-related neurological dysfunction seen in HIPEC patients. To the best of our knowledge, this is the first report of this presentation. Timely recognition of this condition needs a high degree of suspicion, and unless aggressively treated, is likely to be associated with poor outcome. How to cite this article: Sharma V, Solanki SL, Saklani AP. Hyperammonemia after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Report of Three Cases with Unusual Presentation. Indian J Crit Care Med 2021;25(5):590-593.