A 73-year-old woman with a past medical history of well-controlled hypertension undergoes a colonoscopy for symptomatic iron deficiency anemia. The colonoscopy reveals a mass in the cecum; the biopsy reveals adenocarcinoma. She then undergoes staging CT of the chest, abdomen, and pelvis that reveals multiple peritoneal implants. There is no other evidence of metastatic disease. Molecular profiling of the tumor reveals microsatellite instability-high status, absence of KRAS and NRAS mutation, presence of BRAF V600E mutation, and very high tumor mutation burden. HER2 was not amplified. She is in otherwise good health. Her anemia improved with iron supplementation. She maintains an Eastern Cooperative Oncology Group (ECOG) performance status of zero and normal liver and kidney function.
- mFOLFOX-6 (leucovorin, 5-fluorouracil, and oxaliplatin) plus cetuximab
- Encorafenib and cetuximab
- FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan) plus bevacizumab
Question 2: Genitourinary Cancers
A 21-year-old man presents with back pain and an enlarged right testicle. Tumor markers confirm germ cell tumor. Alpha-fetoprotein (AFP) is 500 ng/mL, human chorionic gonadotropin (HCG) is 273 mIU/mL, and lactate dehydrogenase is 214 U/L. CT reveals a 3.5-cm right para-aortic lymph node. Orchiectomy pathology shows 60% seminoma, 20% choriocarcinoma, and 20% embryonal carcinoma. One week after orchiectomy HCG has dropped to 100 mlU/mL, but AFP has risen to 622 ng/mL.
Which of the following would be the most appropriate treatment?
- Primary retroperitoneal lymph node dissection (RPLND)
- Radiation therapy to the retroperitoneal lymph nodes using a "dog leg" field
- BEP (bleomycin, etoposide, and cisplatin) chemotherapy for three cycles
Question 1 Rationale and References
Correct Answer: B. Pembrolizumab
Rationale: Microsatellite instability-high (MSI-H) colorectal cancer accounts for approximately 15% of all colorectal cancer cases (5% of metastatic cases) and is related to a deficiency of the mismatch repair system. 20% to 30% of all cases are hereditary and related to Lynch syndrome; the remaining are somatic events with epigenetic methylation/silencing of the MLH1 promoter being the most common etiology (80%). Keynote 177 is a randomized, phase III study comparing pembrolizumab to investigator choice chemotherapy (mFOLFOX-6 or FOLFIRI with an appropriate biologic agent); crossover was allowed upon progression. The two primary endpoints were progression-free survival (PFS) and overall survival (OS). Patients in the pembrolizumab arm had superior PFS compared to chemotherapy (median, 16.5 vs. 8.2 months; HR 0.60; 95% CI, 0.45 to 0.80; p = 0.0002). Further, the overall response rate (ORR) was 44% in the pembrolizumab group vs. 33% in the chemotherapy group. Based on this study, this preferred initial treatment for this patient is pembrolizumab rather than mFOLFOX-6 plus cetuximab or FOLFIRI plus bevacizumab. In the randomized phase III BEACON trial, encorafenib plus cetuximab was compared to irinotecan- and cetuximab-based chemotherapy in patients with metastatic colorectal cancer who had experienced disease progression after one or two previous systemic therapies. OS with encorafenib plus cetuximab was superior to chemotherapy (HR for death vs. control, 0.60; 95% CI, 0.45 to 0.79; p < 0.001) and was also associated with higher ORR, but it is not the most appropriate initial treatment option for this patient as it was tested in the second- and third-line setting and not in the first line.
Question 2 Rationale and References
Correct Answer: C. BEP (bleomycin, etoposide, and cisplatin) chemotherapy for three cycles
Rationale: Three cycles of BEP are associated with a high cure rate in good-risk nonseminomatous germ cell tumors (NSGCT) stage II, with 95% of patients experiencing a complete response. Post-chemotherapy, RPLND should be considered if there is a residual mass. While primary RPLND can be considered in IIA NSGCT if the markers are within normal limits following an orchiectomy, given stage IIB disease with markedly abnormal markers, surgery is not preferred. In analysis, patients with persistent markers and IIB disease had lower 4-year PFS with upfront RPLND compared to primary chemotherapy with possible post-chemo RPLND as needed for residual nodes over 1 cm. Radiation therapy is only used for seminoma with RPLN involvement. Observation is not appropriate because this patient has active disease.