Gastrointestinal Malignancies
Benjamin L. Schlechter, MD
Hani Babiker, MD
Douglas Rubinson, MD, PhD
Nilay Sethi, MD, PhD
Sigurdis Haraldsdottir, MD, PhD
Thomas Abrams, MD
Kimberly Perez, MD
Leah Biller, MD
A 57-year-old man with well-controlled HIV presented with anal discomfort and bleeding for 3 months. A palpable mass is noted high in the anal canal and extending into the rectum. Biopsy showed squamous cancer. A PET-CT showed an FDG-avid mass at the anorectal junction measuring 4.3 × 2.3 cm consistent with a T2 tumor. No other sites of disease were identified. MRI of the pelvis showed no abnormal adenopathy in the pelvis or groin.
What is the appropriate management?
View Answer
The treatment of choice for anal cancer that is node positive or T2+ is definitive chemoradiotherapy with sensitizing mitomycin C and 5FU.
The mitomycin C dose should be capped at 20 mg to mitigate the risk of hemolytic uremic syndrome.
Cisplatin can be used as an alternative to mitomycin C. It has a lower risk of cytopenias but is associated with increased toxicity and a slightly lower rate of sphincter preservation. It has a similar overall survival compared to mitomycin C.
Squamous cancers of the anus, anorectal junction, and rectum are treated similarly with definitive chemoradiotherapy.
Suggested Readings:
James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. Lancet Oncol. 2013;14:516-524.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
After completing definitive chemoradiotherapy for anal cancer stage IIIA (T2N1aM0) with sensitizing mitomycin C and 5FU, a patient is found to have substantially improved right inguinal adenopathy as well as reduction in the palpable anal tumor 11 weeks from initiation of treatment. However, the known sites of disease are still palpable.
What is the next step in management for residual disease at this point?
View Answer
Surveillance after treatment for anal squamous cancer includes clinical examination at 11 weeks from initiation of chemoradiotherapy and imaging at 26 weeks. If the treated sites of disease are improving at 11 weeks, there is no need for biopsy or imaging.
Prospective data show that residual, but improving, disease at 11 weeks will likely resolve by 26 weeks from initiation of chemoradiotherapy. Only stable disease or progressive disease should prompt concern at this point.
By 26 weeks from initiation of therapy, all disease should have responded completely by clinical examination and imaging. Residual disease or locally recurrent disease should be managed with resection. In the absence of metastatic disease, no additional chemotherapy is indicated.
Suggested Readings:
Glynne-Jones R, Sebag-Montefiore D, Meadows HM, et al. Best time to assess complete clinical response after chemoradiotherapy in squamous cell carcinoma of the anus (ACT II): a post-hoc analysis of randomised controlled phase 3 trial. Lancet Oncol. 2017;18:347-356.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 68-year-old woman with a history of anal squamous cancer status post definitive chemoradiotherapy with sensitizing mitomycin C and 5FU initiated 30 months ago presented with fatigue, weight loss, and hypercalcemia. On examination, she had edema of the right leg with hyperpigmentation of the skin of the groin and thigh. Laboratory analysis revealed a calcium of 12 mg/dL. Imaging showed no evidence of DVT but extensive adenopathy involving the right inguinal nodes extending into the pelvis and along the femoral vein, plus multiple pulmonary metastases. A skin biopsy showed infiltration by squamous cell carcinoma, and a lung biopsy showed metastatic squamous cancer. Her calcium improved with hydration and bisphosphonate therapy, and her performance status improved to 1.
What is your initial treatment of choice?
View Answer
Carboplatin and paclitaxel represents the standard first-line treatment for advanced anal squamous cancer.
Carboplatin with paclitaxel is superior to cisplatin with 5FU in terms of progression-free survival (8.1 vs 5.7 months), overall survival (20 vs 12.3 months), and reduced toxicity. The response rates between these regimens are similar.
Suggested Readings:
Rao S, Sclafani F, Eng C, et al. International rare cancers initiative multicenter randomized phase II trial of cisplatin and fluorouracil versus carboplatin and paclitaxel in advanced anal cancer: InterAAct. J Clin Oncol. 2020;38:2510-2518.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 53-year-old HIV-positive man with a history of localized anal squamous cancer status post definitive chemoradiotherapy with sensitizing mitomycin C and 5FU presented with oligometastatic recurrence in his infrarenal retroperitoneal lymph nodes. PET-CT showed no additional sites of disease.
What would you recommend for therapy?
View Answer
For patients with oligometastatic anal squamous cancer, radiation or surgery should be considered before systemic therapy. Anal squamous cancer is inherently radiation-sensitive cancer, so limited disease may be managed with radiation or chemoradiation.
Patients with HIV infection should be treated with identical therapy as those without HIV, including radiation.
For patients with a local recurrence in the prior radiated field or isolated liver or lung metastases, resection is preferred.
Checkpoint inhibitors may be considered for refractory anal squamous cancer.
Suggested Readings:
Benson AB, Venook AP, Al-Hawary MM, et al. Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16(7):852-871.
Morris VK, Salem ME, Nimeiri H, et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(4):446-453.
Ott PA, Piha-Paul SA, Munster P, et al. Safety and antitumor activity of the anti-PD-1antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol. 2017;28(5):1036-1041.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 44-year-old woman with no known past medical history presents with a painful anal mass. On examination, she has a 3-cm bleeding, exophytic lesion in the anal canal. Biopsy of the anal lesion shows squamous cell carcinoma.
What additional infectious workup, diagnostic testing, and staging should be pursued in this woman?
View Answer
The staging of anal squamous cell cancer should include a PET-CT to identify sites of metastatic disease as well as an MRI of the pelvis to look for abnormal pelvic and inguinal lymph nodes that may be too small to detect on PET imaging.
Additional diagnostic testing for anal squamous cell carcinoma in women who present with disease should include a pelvic examination to look for cervical pathology given its association with HPV.
Infectious workup in all patients with anal squamous cell carcinoma should include HIV testing. While anal cancer is not an AIDS-defining illness like cervical squamous cancer, HIV is an associated risk factor.
Suggested Readings:
Benson AB, Venook AP, Al-Hawary MM, et al. Anal carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16(7):852-871.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 62-year-old man was diagnosed with unresectable hilar biliary adenocarcinoma (biliary type) and progressed on gemcitabine + cisplatin. The patient still maintains in excellent performance status.
What second-line regimen would you consider based on results of the ABC-06 trial?
View Answer
mFOLFOX demonstrated survival benefits as a second-line regimen in biliary adenocarcinoma based on the ABC-06 trial.
The ABC-06 trial was a phase III trial in patients with biliary cancers post progression randomized to either active symptom control and mFOLFOX versus active symptom control alone. The trial met its primary end point of overall survival and hence established FOLFOX as a second-line regimen in biliary adenocarcinoma.
Suggested Readings:
Lamarca A, Palmer D, Wasan HS, et al. ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clin Oncol. 2019;37(15_suppl):4003.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 76-year-old woman with no comorbidities is admitted to the hospital with jaundice and abdominal pain. A CT scan of the abdomen and pelvis revealed a biliary mass obstructing the right and left hepatic duct. The patient undergoes an ERCP with stent placement, brushings, and biopsies indicating adenocarcinoma biliary type. Molecular testing revealed PDL-1 of 30%, BRCA variant of indeterminate significance, and an FGFR2 fusion.
What regimen will you recommend?
View Answer
Gemcitabine and cisplatin should be recommended to this patient with newly diagnosed metastatic biliary adenocarcinoma based on the phase 3, ABC-02 trial.
Pemigatinib is FDA approved in the refractory setting for patients with the FGFR2 fusions or rearrangements based on the FIGHT-202 trial with an ORR of 38%.
Suggested Readings:
Abou-Alfa G, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced, or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21(5):671-684. doi:10.1016/S1470-2045(20)30109-1
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 45-year-old woman developed RUQ abdominal pain and visited the ED. An RUQ ultrasound revealed increased thickness of the gallbladder wall and positive Murphy sign. The patient did undergo a cholecystectomy and pathology identified a 2-cm neoplastic mass invading the muscular wall in the intraoperative frozen section.
What is the next step in management?
View Answer
En bloc hepatic resection + lymphadenectomy with a potential for bile duct excision for malignant involvement. This patient needs re-excision given the extent of involvement.
Suggested Readings:
NCCN Guidelines accesses August 2020.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
What are the targetable mutations that should be analyzed in cholangiocarcinoma?
View Answer
NTRK gene fusion (entrectinib), MSI/dMMR (pembrolizumab), FGFR2 fusions or rearrangements (pemigatinib), and IDH1 mutations (ivosidenib). These are the targetable mutations and, in the future, might include BRAF V600.
Suggested Readings:
NCCN Guidelines accesses August 2020.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 68-year-old is found to have multiple bilobar hepatic biliary lesions and a periampullary mass on CT scan with contrast. Biopsy of the lesions demonstrated poorly differentiated carcinoma with negative CK7, CK20, TTF-1, and CDX2 and positivity for synaptophysin with a high Ki-67.
What is the chemotherapy of choice?
View Answer
Metastatic periampullary small cell carcinoma should be treated with cisplatin/carboplatin and etoposide.
Positivity of synaptophysin indicates that this is a neuroendocrine tumor, and high Ki-67 reveals that this is a high-grade poorly differentiated neuroendocrine tumor. Other stains that are positive in neuroendocrine tumors include chromogranin A, INSM1, EMA, CD56, TTF1 (negative in 15%-20% of cases like this case), and napsin.
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 68-year-old man presented with 9 months of escalating constipation and rectal bleeding. At colonoscopy, he was found to have a high rectal mass, and biopsy showed adenocarcinoma that was microsatellite stable. A CT torso showed no evidence of metastatic disease, and an MRI of the pelvis showed a high rectal cancer extending through the muscularis propria (T3) just below the peritoneal reflection, but no evidence of adenopathy (N0).
What would you recommend for treatment?
View Answer
The conventional approach for T3+ or node positive rectal cancer is neoadjuvant chemoradiation, total mesorectal excision, and adjuvant FOLFOX x 8 cycles.
Both infusional 5FU and oral capecitabine have been shown to be effective as sensitizing agents in neoadjuvant chemoradiotherapy for rectal cancer.
The addition of oxaliplatin to neoadjuvant chemoradiotherapy does not improve outcomes.
Adjuvant 5FU alone appears to be ineffective while adjuvant FOLFOX improves disease-free survival.
Suggested Readings:
Allegra CJ, Yothers G, O’Connell MJ, et al. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst. 2015;107(11):djv248.
Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15(2):184-190.
Hong YS, Nam BH, Kim KP, et al. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2014;15(11):1245-1253.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 51-year-old man was found to have a mid-rectal mass on his first screening colonoscopy. Biopsy revealed adenocarcinoma that was microsatellite stable. CT torso showed no evidence of distant metastatic disease, and an endoscopic ultrasound (EUS) showed a T2 cancer without adenopathy. Preoperative CEA was normal. He underwent an uncomplicated sphincter preserving low-anterior resection. Pathology revealed a T3N0 cancer with negative margins.
What, if any, adjuvant therapy would you recommend?
View Answer
Prospective data supports the use of adjuvant chemoradiotherapy for resected T3 or node + rectal cancers who were not treated with neoadjuvant therapy.
Postoperative chemoradiotherapy is as effective as preoperative therapy but has increased toxicity.
MRI is superior to EUS in staging rectal cancer and is less user dependent.
Suggested Readings:
Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst. 1988;80(1):21-29.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 71-year-old woman presented with chronic rectal bleeding and increasing bowel urgency as well as pain when sitting. On examination, she had a mass at the anal sphincters. Colonoscopy revealed a low rectal tumor, and biopsy revealed adenocarcinoma that was microsatellite stable. A CT torso showed no metastatic disease, and an MRI of the pelvis showed a T3N1 cancer with two enlarged lymph nodes. She said she was unwilling to have a permanent ostomy unless absolutely necessary.
How would you advise her?
View Answer
There are emerging data supporting the use of total neoadjuvant therapy whereby FOLFOX and chemoradiation are given preoperatively in rectal cancer. A subset of patients, around 22%, will achieve a clinical complete response by physical examination, imaging, and endoscopic assessment.
Some patients who achieve a clinical complete response may elect to undergo a watch and wait strategy rather than resection.
For patients who achieve a clinical complete response and elect to pursue a watch and wait strategy, long-term survival may be inferior if they recur as compared to surgery at the completion of neoadjuvant therapy.
Suggested Readings:
Smith JJ, Strombom P, Chow OS, et al. Assessment of a watch-and-wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy. JAMA Oncol. 2019;5(4):e185896.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
Match the therapy with its respective indication in non-first-line setting for advanced colorectal cancer:
1. KRAS-mutated colorectal cancer
2. MSI high disease/dMMR disease
3. NRAS wild-type disease
4. HER2-amplified disease
A. Regorafenib
B. Panitumumab
C. Trastuzumab/pertuzumab/lapatinib
D. Nivolumab ± ipilimumab
View Answer
1. KRAS-mutated colorectal cancer—(A) Regorafenib
2. MSI high disease/dMMR disease—(D) Nivolumab ± Ipilimumab
3. NRAS wild-type disease—(B) Panitumumab
4. HER2-amplified disease—(C) Trastuzumab/pertuzumab or lapatinib
A. Regorafenib
B. Panitumumab
C. Trastuzumab/pertuzumab/lapatinib
D. Nivolumab ± ipilimumab
All patients with metastatic CRC should have tumor testing for KRAS/NRAS/BRAF mutations. In patients with KRAS/NRAS wild-type metastatic CRC, assessment of HER2 amplification should be considered.
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 60-year-old man underwent his second screening colonoscopy. He was incidentally found to have a mid-rectal mass, and biopsy showed adenocarcinoma that was microsatellite stable. CT torso showed no distant metastatic disease and MRI of the pelvis showed a T3N2b cancer with five enlarged lymph nodes. You offer him a combination of chemotherapy, radiation therapy, and surgery.
Given emerging data supporting total neoadjuvant therapy in locally advanced rectal cancer, what are the respective therapy options for this patient?
View Answer
Short-course radiation (25 Gy in five fractions) followed by FOLFOX and then surgery is associated with an improved rate of pathologic complete response and disease control but similar overall survival when compared to long-course chemoradiotherapy, resection, and adjuvant FOLFOX.
Long-course chemoradiotherapy followed by FOLFOX/CAPEOX has a slightly higher rate of clinical complete response and an improved rate of disease control when compared to FOLFOX/CAPEOX followed by chemoradiotherapy.
Suggested Readings:
Garcia-Aguilar J, Patil S, Kim JK, et al. Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial. J Clin Oncol. 2020;38(15 suppl):4008-4008.
Hospers G, Bahadoer RR, Dijkstra EA, et al. Short-course radiotherapy followed by chemotherapy before TME in locally advanced rectal cancer: The randomized RAPIDO trial. J Clin Oncol. 2020;38(15 suppl):4006-4006.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 26-year-old graduate student presented to the student health clinic with rectal bleeding. On examination, she had a near obstructing rectal mass. CT torso showed no distant metastatic disease, and an MRI of the pelvis showed a T4b cancer invading the sphincter muscles with at least seven enlarged lymph nodes, N2b. She asked how is it possible that she has rectal cancer in her 20s.
What can you tell her about the incidence, genetic risks, management, and screening regarding rectal cancer in the young?
View Answer
Incidence of rectal cancer in the young: Over the past 4 decades, there has been a substantial increase in the number of colorectal cancers in those younger than 50 years, and the majority of the increase has been in sigmoid and rectal cancers.
Genetic predisposition: While some young patients may have known problems such as Lynch syndrome or familial adenomatous polyposis, most have no identifiable mutations.
Management: Rectal cancer in the young should be approached similarly to that in older patients but particular attention should be given to fertility preservation.
Screening: For now, the USPSTF recommends colon cancer screening starting at the age of 50 years but emerging data suggest starting at the age of 40 or 45 years.
Suggested Readings:
Siegel RL, Fedewa SA, Anderson WF, et al. Colorectal cancer incidence patterns in the United States, 1974-2013. J Natl Cancer Inst. 2017;109(8):djw322.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 57-year-old man with stage IV-B colon cancer from a transverse colon primary involving the liver and lungs. The tumor harbors a KRAS G12D mutation and shows loss of expression of MLH1 and PMS2 with normal staining for MSH2 and MSH6. Immunohistochemistry shows cells are positive for CK20 and CDX2 and stains negative for CK7 and PD-L1.
What is the most appropriate first-line therapy?
View Answer
Pembrolizumab is the most appropriate first-line therapy option in this patient with metastatic MLH1-inactivated (MSI-H) colorectal cancer.
The KEYNOTE-177 trial showed a doubling of median overall survival with first-line pembrolizumab compared to FOLFOX or FOLFIRI with or without bevacizumab or cetuximab.
In contrast to other malignancies, PD-L1 is not a useful biomarker in predicting response to immunotherapy in MSI-H colorectal cancers.
The use of cetuximab is contraindicated in KRAS-mutated tumors.
Suggested Readings:
Andre, et al. (ASCO Plenary Session 2020).
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 63-year-old woman with metastatic microsatellite-stable (MSS), NRAS-mutant (G13D) colon cancer to the lungs. She received first-line therapy with FOLFOX/bevacizumab with good tolerance and an initial response lasting 5-months prior to progression of hepatic metastatic disease. She maintains a very good performance status with mild residual peripheral neuropathy related to her oxaliplatin therapy.
What is the most appropriate next-line treatment option after progression of FOLFOX/bevacizumab?
View Answer
The most appropriate next-line option in this microsatellite-stable (MSS), NRAS-mutant CRC patient who progressed on FOLFOX/bevacizumab is to change therapy to FOLFIRI/bevacizumab.
The ML18147 trial was a phase 3 trial in which patients progressing on chemotherapy with bevacizumab were randomized to receive either chemotherapy alone or chemotherapy plus bevacizumab. Median overall survival was 11.2 months for patients continuing bevacizumab beyond progression compared to 9.8 months in patients receiving chemotherapy alone.
There is no role for EGFR-inhibitors (cetuximab or panitumumab) in a patient with an NRAS-mutation.
Immunotherapy has no current role for the treatment of MSS colon cancer outside of clinical trials.
Suggested Readings:
Bennouna, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14:29-37.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 57-year-old man presents following a right hemicolectomy for a microsatellite stable stage IIIB (pT3N1bM0), grade 2 of 3, adenocarcinoma of the ascending colon. There are 3 of 15 lymph nodes involved by adenocarcinoma. He would like to minimize any chemotherapy without jeopardizing his chance for cure.
What would be the most reasonable recommendation for adjuvant therapy, and which trial supports the role of shortened course of therapy in this setting?
View Answer
Three months of CAPOX (oxaliplatin-based therapy) is the preferred adjuvant therapy regimen in patients with stage III colon cancer (T1-T3 and N1 disease) in this patient who wants to minimize treatment duration.
Historically, stage III colon cancers were offered 6 months of chemotherapy with either FOLFOX or capecitabine/oxaliplatin (CAPOX).
The IDEA trial was a prospective, preplanned pooled analysis of six randomized phase 3 trials assessing noninferiority of 3 versus 6 months of FOLFOX or CAPOX. While noninferiority was not confirmed in the overall study population, noninferiority was observed for 3 months of CAPOX but not 3 months of FOLFOX. Noninferiority was present for patients with T1, T2, or T3 and N1 (1-3 lymph nodes) cancers. Six months of therapy was superior for patients with T4, N2, or both. For patients looking to minimize chemotherapy and associated neuropathy, 3 months of CAPOX would be the most reasonable recommendation.
Suggested Readings:
Grothey A, Sobrero AF, Shields AF, et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018;378:1177-1188.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A patient with widely metastatic BRAF V600E-mutant, microsatellite stable colon cancer received first-line therapy with FOLFOXIRI/bevacizumab. Oxaliplatin was stopped after eight cycles due to progressive neuropathy. The patient had disease progression after four additional cycles of FOLFIRI/bevacizumab and continues to complain of bothersome neuropathy.
What would be the most reasonable next choice of therapy in this individual with toxicity limiting therapy?
View Answer
Encorafenib + cetuximab is an appropriate regimen in this patient with metastatic BRAF-mutant colon cancer who is intolerant to oxaliplatin.
The BEACON study randomized patients to receive combined BRAF and EGFR inhibition with encorafenib + cetuximab with or without an MEK inhibitor, binimetinib OR a control arm of either irinotecan + cetuximab or FOLFIRI + cetuximab. The initial study showed an improvement in median overall survival (mOS) of 9.0 months for triplet therapy compared to 5.4 months for the control group. Later analysis showed identical survival curves with encorafenib + cetuximab compared to triple therapy with encorafenib + cetuximab + binimetinib.
Initial therapy in this patient with FOLFOXIRI/bevacizumab was appropriate. A phase 3 trial of FOLFIRI/bevacizumab compared to FOLFOXIRI/bevacizumab for initial treatment of colorectal cancer showed improved ORR, PFS, and mOS with triple therapy. Subgroup analysis suggests an advantage for triplet therapy in BRAF V600E-mutant disease.
Suggested Readings:
Kopetz, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;281:1632-1643.
Loupakis, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;271:1609-1618.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 61-year-old woman has a new diagnosis of unresectable colon cancer to the liver. At diagnosis, she has an ALP of 528 with a total bilirubin of 3.2. Imaging shows multifocal disease without focal biliary obstruction. Molecular testing and MSI status is unknown. Her ECOG performance status is 0-1 with mild jaundice and RUQ discomfort.
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