On August 2, 2023, the FDA approved trifluridine-tipiracil (Lonsurf) with bevacizumab for patients with metastatic colorectal cancer previously treated with with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
New anti-VEGFR TKI was approved by FDA for metastatic colorectal cancer progressed over 5-FU/ oxaliplatin/irenotecan /bevacizumab/EGFR inhibitor. In November 2023, the FDA has approved fruquintinib (Fruzaqla, Takeda) for the treatment of patients with metastatic colorectal cancer who experience disease progression during or after prior treatment regardless of bio marker status. More specifically, the approval extends to adult patients with metastatic colorectal cancer who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, in some cases, an anti-EGFR therapy. Approval of the oral anti-VEGFR tyrosine kinase inhibitor was based on a significant overall survival benefit demonstrated in the randomized, placebo-controlled, phase 3 FRESCO and FRESCO-2 trials in heavily pretreated adults with metastatic colorectal cancer. Patients in both trials were randomly assigned in a 2:1 ratio to receive the recommended dose of 5 mg of oral fruquintinib once daily or placebo for the first 21 days of each 28-day cycle. Treatment plus best supportive care continued until disease progression or unacceptable toxicity. Among the 416 patients evaluated in the FRESCO trial, those who received fruquintinib demonstrated a significant improvement in median overall survival - 9.3 vs 6.6 months in the placebo cohort (hazard ratio [HR], 0.65). Among the 691 patients in FRESCO-2, treatment with fruquintinib also resulted in a median overall survival benefit - 7.4 vs 4.8 months (HR, 0.66). The most common adverse reactions were hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia, which each occurred in at least 20% of patients.
On June 22, 2022, dabrafenib in combination with trametinib was granted accelerated approval for treatment of adult and pediatric patients (aged 6 and older) with unresectable or metastatic solid tumors with BRAF V600E mutation whose disease progressed following prior treatment and who have no satisfactory alternative treatment options. Unfortunately, Dabrafenib/trametinib is not indicated in colorectal cancer, due to known intrinsic resistance to BRAF inhibition.
www.nejm.org/doi/full/10.1056/NEJMoa2200075 Adjuvant chemotherapy is given only for high risk Stage II colon cancer, ie, with obstruction and tumor perforation. However, new study showed liquid biopsy to chck the circulating tumor (ct) DNA is a useful guide in determining the need of adjuvant chemotherapy for stage II colon cancer. The test is done 4-7 weeks after surgery. If (+), adjuvant chemo improved 3- yr- PFS.
Total neoadjuvant therapy with chemotherapy followed by concurrent long course radiation therapy and chemotherapy is better than short course radiation therapy in preserving rectum to avoid colostomy. Please read the article below: Long-course radiation therapy for rectal cancer is more likely to spare organs than short-course therapy, including when chemotherapy is provided first as part of a total neoadjuvant therapy (TNT) strategy, shows new research presented at the ASCO Gastrointestinal Cancers Symposium 2023. “When we looked at the 2-year organ preservation rates, they were numerically higher in the long-course group versus the short-course group,” said study author J. Joshua Smith, MD, PhD,FACS, a colorectal surgeon with Memorial Sloan Kettering Cancer Center, New York. “Our study will be the first, to our knowledge, that examines a significant proportion of patients treated with the induction total neoadjuvant therapy approach - chemo first.” An ideal outcome in rectal cancer is no need for surgery, Dr. Smith said. “If you can avoid surgery altogether and preserve the organ [the rectum], that’s a big win for the patient as they are usually able to avoid having a permanent or temporary ostomy.” The researchers retrospectively identified 563 consecutive patients treated with TNT from 2018 to 2021. They focused on 332 who didn’t have metastatic disease, synchronous/metachronous malignancies, or nonadenocarcinoma histology (long course = 256, short course = 76). The groups had similar high-risk features, and about 82% were clinical stage III). Patients most commonly received induction chemotherapy followed by consolidative radiation (78% long course, 70% short course). The 2-year survival rates were similar, but organ preservation was higher in the long-course group versus the short-course group (40%; 95% confidence interval, 35%-47% vs. 29%; 95% CI, 20%-42%). And the 2-year local regrowth rate was also better in the long-course group versus the short-course group (20%; 95% CI, 12%-27% vs. 36%; 95% CI, 16%-52%).
NCCN Guideline update 11/1/2022 Management of Malignant Polyps All malignant polyps should undergo mismatch repair (MMR) or microsatellite instability (MSI) testing at diagnosis. Rectal surgery (transanal local excision, if appropriate, or transabdominal resection) is recommended for patients with malignant polyps with unfavorable histologic features or when the specimen is fragmented or margins cannot be assessed. In patients with unfavorable pathologic features, transabdominal resection should be considered to include lymphadenectomy. Staging of Rectal Cancer Patients who present with rectal cancer appropriate for resection require a complete staging evaluation, which includes total colonoscopy to evaluate for synchronous lesions or other pathologic conditions of the colon and rectum. Proctoscopy is a consideration, as it can be useful in determining the distance of the cancer from the anal verge and length. Preoperative imaging for rectal cancer includes chest/abdominal computed tomography (CT) and pelvic magnetic resonance imaging (MRI) or chest CT and abdominal/pelvic MRI. Positron emission tomography (PET) scanning is not indicated, except to evaluate an equivocal finding on a contrast-enhanced CT scan or in patients with a strong contraindication to intravenous contrast. Treatment Patients with very-early-stage tumors that are node-negative by endorectal ultrasound or endorectal or pelvic MRI and who meet carefully defined criteria can be managed with transanal local excision. Transabdominal resection is appropriate for other rectal lesions. Total neoadjuvant therapy, consisting of chemoradiation therapy and chemotherapy, is preferred for most patients with suspected or proven T3-4 disease and/or regional node involvement. In patients who have a complete clinical response to neoadjuvant therapy, with no evidence of residual disease on digital rectal examination, rectal MRI, and direct endoscopic evaluation, a watch-and-wait nonoperative management approach may be considered, in centers with experienced multidisciplinary teams. If resection is contraindicated following primary treatment, patients should be treated with a systemic regimen for advanced disease.
J.Clin Oncol 2022; 40 (16): Phase 2 trial using pembrilozumab + capcitabine + bevacizumab for dMMR/MSI-h metastatic colorectal cancer failed to show efficacy with ORR 5%.
It seems that except for the treatment of rectal cancer no major or significant progress ( other than early detection, screening protocols and genomic profiling of cancers) has been made in the treatment of colon cancer.
Are the percentages on the graph showing survival rates with or without adjuvant therapy. Specifically the stage 3A. What is the percentage difference in doing adjuvant therapy or not with 3A?
Sorry for the late reply: I just noted. The prognosis of Stage lllA is one after adjuvant chemotherapy as is for Stage ll. Ironically the prognosis of Stage lllA is better than that of Stage ll. The reason is not known yet. Perhaps T4 N0 may be associated with more (+) surgical margins or occult peritoneal carcinomatosis. Yes, there is significant difference in 5-yr survival between adjuvant chemotherapy- treated and not treated Stage lllA as described in the presentation. But please note, some data are confused because the classification of the stages are different between 6th and 7th editions of AJCC TMN staging systems.
PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer N Engl J Med 2022; 386:2363-2376 DOI: 10.1056/NEJMoa2201445 Abstract Background: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer. Methods: We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy. Results: A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported. Conclusions: Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response.
Hello,my mother is diagnosed with T3N0M0 rectosigmoid adenocarcinoma moderately differentiated.Got the mass with the part removed without a stoma and the final biopsy had 21 lymphnodes removed and all negative without cancer.Should she receive some kind of chemotherapy?Thank you in advance
Both T and N status are markers of the extent of disease and the risk of recurrence. Stage 2 is a node negative disease and nodal involvement makes it stage 3. At the same time T4 disease is a locally advanced disease with a higher risk of local as well as distant recurrence than T3 or T2, hence T2N1 disease though stage 3 may have better survival than T4 N0 ( stage 2).
Thank you very much , your lectures are very helpful
On August 2, 2023, the FDA approved trifluridine-tipiracil (Lonsurf) with bevacizumab for patients with metastatic colorectal cancer previously treated with with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
New anti-VEGFR TKI was approved by FDA for metastatic colorectal cancer progressed over 5-FU/ oxaliplatin/irenotecan /bevacizumab/EGFR inhibitor.
In November 2023, the FDA has approved fruquintinib (Fruzaqla, Takeda) for the treatment of patients with metastatic colorectal cancer who experience disease progression during or after prior treatment regardless of bio marker status.
More specifically, the approval extends to adult patients with metastatic colorectal cancer who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, in some cases, an anti-EGFR therapy.
Approval of the oral anti-VEGFR tyrosine kinase inhibitor was based on a significant overall survival benefit demonstrated in the randomized, placebo-controlled, phase 3 FRESCO and FRESCO-2 trials in heavily pretreated adults with metastatic colorectal cancer.
Patients in both trials were randomly assigned in a 2:1 ratio to receive the recommended dose of 5 mg of oral fruquintinib once daily or placebo for the first 21 days of each 28-day cycle. Treatment plus best supportive care continued until disease progression or unacceptable toxicity.
Among the 416 patients evaluated in the FRESCO trial, those who received fruquintinib demonstrated a significant improvement in median overall survival - 9.3 vs 6.6 months in the placebo cohort (hazard ratio [HR], 0.65). Among the 691 patients in FRESCO-2, treatment with fruquintinib also resulted in a median overall survival benefit - 7.4 vs 4.8 months (HR, 0.66).
The most common adverse reactions were hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia, which each occurred in at least 20% of patients.
On June 22, 2022, dabrafenib in combination with trametinib was granted accelerated approval for treatment of adult and pediatric patients (aged 6 and older) with unresectable or metastatic solid tumors with BRAF V600E mutation whose disease progressed following prior treatment and who have no satisfactory alternative treatment options.
Unfortunately, Dabrafenib/trametinib is not indicated in colorectal cancer, due to known intrinsic resistance to BRAF inhibition.
www.nejm.org/doi/full/10.1056/NEJMoa2200075
Adjuvant chemotherapy is given only for high risk Stage II colon cancer, ie, with obstruction and tumor perforation.
However, new study showed liquid biopsy to chck the circulating tumor (ct) DNA is a useful guide in determining the need of adjuvant chemotherapy for stage II colon cancer.
The test is done 4-7 weeks after surgery. If (+), adjuvant chemo improved 3- yr- PFS.
Total neoadjuvant therapy with chemotherapy followed by concurrent long course radiation therapy and chemotherapy is better than short course radiation therapy in preserving rectum to avoid colostomy. Please read the article below:
Long-course radiation therapy for rectal cancer is more likely to spare organs than short-course therapy, including when chemotherapy is provided first as part of a total neoadjuvant therapy (TNT) strategy, shows new research presented at the ASCO Gastrointestinal Cancers Symposium 2023.
“When we looked at the 2-year organ preservation rates, they were numerically higher in the long-course group versus the short-course group,” said study author J. Joshua Smith, MD, PhD,FACS, a colorectal surgeon with Memorial Sloan Kettering Cancer Center, New York. “Our study will be the first, to our knowledge, that examines a significant proportion of patients treated with the induction total neoadjuvant therapy approach - chemo first.”
An ideal outcome in rectal cancer is no need for surgery, Dr. Smith said. “If you can avoid surgery altogether and preserve the organ [the rectum], that’s a big win for the patient as they are usually able to avoid having a permanent or temporary ostomy.”
The researchers retrospectively identified 563 consecutive patients treated with TNT from 2018 to 2021. They focused on 332 who didn’t have metastatic disease, synchronous/metachronous malignancies, or nonadenocarcinoma histology (long course = 256, short course = 76). The groups had similar high-risk features, and about 82% were clinical stage III).
Patients most commonly received induction chemotherapy followed by consolidative radiation (78% long course, 70% short course).
The 2-year survival rates were similar, but organ preservation was higher in the long-course group versus the short-course group (40%; 95% confidence interval, 35%-47% vs. 29%; 95% CI, 20%-42%). And the 2-year local regrowth rate was also better in the long-course group versus the short-course group (20%; 95% CI, 12%-27% vs. 36%; 95% CI, 16%-52%).
NCCN Guideline update 11/1/2022
Management of Malignant Polyps
All malignant polyps should undergo mismatch repair (MMR) or microsatellite instability (MSI) testing at diagnosis.
Rectal surgery (transanal local excision, if appropriate, or transabdominal resection) is recommended for patients with malignant polyps with unfavorable histologic features or when the specimen is fragmented or margins cannot be assessed. In patients with unfavorable pathologic features, transabdominal resection should be considered to include lymphadenectomy.
Staging of Rectal Cancer
Patients who present with rectal cancer appropriate for resection require a complete staging evaluation, which includes total colonoscopy to evaluate for synchronous lesions or other pathologic conditions of the colon and rectum. Proctoscopy is a consideration, as it can be useful in determining the distance of the cancer from the anal verge and length.
Preoperative imaging for rectal cancer includes chest/abdominal computed tomography (CT) and pelvic magnetic resonance imaging (MRI) or chest CT and abdominal/pelvic MRI. Positron emission tomography (PET) scanning is not indicated, except to evaluate an equivocal finding on a contrast-enhanced CT scan or in patients with a strong contraindication to intravenous contrast.
Treatment
Patients with very-early-stage tumors that are node-negative by endorectal ultrasound or endorectal or pelvic MRI and who meet carefully defined criteria can be managed with transanal local excision. Transabdominal resection is appropriate for other rectal lesions.
Total neoadjuvant therapy, consisting of chemoradiation therapy and chemotherapy, is preferred for most patients with suspected or proven T3-4 disease and/or regional node involvement.
In patients who have a complete clinical response to neoadjuvant therapy, with no evidence of residual disease on digital rectal examination, rectal MRI, and direct endoscopic evaluation, a watch-and-wait nonoperative management approach may be considered, in centers with experienced multidisciplinary teams.
If resection is contraindicated following primary treatment, patients should be treated with a systemic regimen for advanced disease.
J.Clin Oncol 2022; 40 (16):
Phase 2 trial using pembrilozumab + capcitabine + bevacizumab for dMMR/MSI-h metastatic colorectal cancer
failed to show efficacy with ORR 5%.
It seems that except for the treatment of rectal cancer no major or significant progress ( other than early detection, screening protocols and genomic profiling of cancers) has been made in the treatment of colon cancer.
Are the percentages on the graph showing survival rates with or without adjuvant therapy. Specifically the stage 3A. What is the percentage difference in doing adjuvant therapy or not with 3A?
Sorry for the late reply: I just noted.
The prognosis of Stage lllA is one after adjuvant chemotherapy as is for Stage ll.
Ironically the prognosis of Stage lllA is better than that of Stage ll.
The reason is not known yet. Perhaps T4 N0 may be associated with more (+) surgical margins or occult peritoneal carcinomatosis.
Yes, there is significant difference in 5-yr survival between adjuvant chemotherapy- treated and not treated Stage lllA as described in the presentation. But please note, some data are confused because the classification of the stages are different between 6th and 7th editions of AJCC TMN staging systems.
PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer
N Engl J Med 2022; 386:2363-2376 DOI: 10.1056/NEJMoa2201445
Abstract
Background: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer.
Methods: We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.
Results: A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.
Conclusions: Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response.
Dostarlimab was approved by FDA for dMMR/MSI-h solid tumor as a second line therapy for metastatic solid cancer
Hello,my mother is diagnosed with T3N0M0 rectosigmoid adenocarcinoma moderately differentiated.Got the mass with the part removed without a stoma and the final biopsy had 21 lymphnodes removed and all negative without cancer.Should she receive some kind of chemotherapy?Thank you in advance
jamanetwork.com/journals/jamanetworkopen/fullarticle/2808569
Vitamin D supplement reduced P53+ GI cancer mortality. But not with p53- cancers.
What is the reason why stage 3a has a higher survival rate than stage 2b?
Both T and N status are markers of the extent of disease and the risk of recurrence. Stage 2 is a node negative disease and nodal involvement makes it stage 3. At the same time T4 disease is a locally advanced disease with a higher risk of local as well as distant recurrence than T3 or T2, hence T2N1 disease though stage 3 may have better survival than T4 N0 ( stage 2).