Bowel perforation associated with robust response to BRAF/MEK inhibitor therapy for BRAF-mutant melanoma: a case report

SUMMARY 

Combination BRAF/MEK inhibition has shown improved response rates and longer progression-free and overall survival for patients with BRAF-mutant metastatic melanoma. A 63-year-old female with widely metastatic BRAF V600E-mutant melanoma was treated with dabrafenib/trametinib. Ten weeks into therapy, she was treated conservatively for a partial bowel obstruction involving a lesion in the distal ileum. She presented two weeks later with CT evidence of a high-grade bowel obstruction with perforation. Emergent surgery was performed. Intraoperative inspection and pathologic analysis of the resected specimen revealed no evidence of melanoma. Seven months postoperatively she is disease free and fully functional. Rapid BRAF/MEK inhibitor-induced regression of small bowel lesions can result in bowel perforation, which is critical to distinguish from the consequences of disease progression.

Practice points.

• BRAF/MEK inhibitors can produce rapid tumor responses in patients with BRAF-mutant melanoma.

• Patients with extensive bowel metastases may develop perforation in association with rapid response to BRAF/MEK inhibitor treatment.

• Bowel perforation from rapid response of melanoma to BRAF/MEK inhibitor therapy may masquerade as disease progression with perforation and/or obstruction.

• Surgery can be done safely in patients recently on BRAF/MEK inhibitor therapy.

• An aggressive surgical approach is therefore indicated in patients with BRAF-mutant melanoma, especially involving the GI tract, presenting with symptoms and findings suggestive of bowel perforation in the setting of BRAF/MEK inhibitor therapy.

Most cases of malignant melanoma are diagnosed at an early stage through routine dermatologic exam and cured with surgical excision. However, the management of patients with metastatic disease continues to be challenging. Current options for patients with metastatic melanoma include immunotherapy with either high-dose IL-2 or the CTLA-4 inhibitor ipilimumab, as well as targeted therapies that inhibit various steps in the MAPK pathway.

BRAF mutations are present in approximately 50% of cases of metastatic melanoma. The mutation typically involves the substitution of glutamic acid for valine at position 600 in the amino acid chain (V600E mutation). Treatment with BRAF inhibitors, such as vemurafenib and dabrafenib, results in frequent and dramatic tumor regression, and significant clinical improvement for patients with BRAF-mutant metastatic melanoma. In a Phase II clinical trial, treatment with vemurafenib produced a RECIST-defined tumor response in over half of patients with BRAF-mutant metastatic melanoma [1]. These results were confirmed in a Phase III study in which patients receiving vemurafenib exhibited improved tumor response rate and overall survival as well as increased median time to progression relative to dacarbazine chemotherapy [2]. Similar results have been reported with single agent dabrafenib [3–6].

Treatment with BRAF inhibitors, however, is usually followed by the development of treatment resistance and disease progression within a median of 6–9 months. Development of resistance to BRAF inhibitors has been shown to be often related to reactivation of the MAPK pathway. This phenomenon may occur through a variety of mechanisms; among them, development of de novo or induction of NRAS or MEK mutations, upregulation of alternative pathways by receptor tyrosine kinases, or alternate splicing of the mutant BRAF mRNA [7–9]. These data suggested that downstream inhibition of the MAPK pathway through the addition of a MEK inhibitor could delay the development of resistance.

Indeed, combination BRAF and MEK inhibition has been shown to significantly enhance tumor response rates and increase median progression-free survival [10] relative to BRAF inhibitor therapy alone. In a recent Phase Ib study, Ribas et al. [11] found that combination therapy with vemurafenib and the MEK inhibitor cobimetinib resulted in confirmed objective responses in 87% of the patients who were BRAF inhibitor treatment naive, as well as in 15% of patients whose disease had progressed on vemurafenib. Further, both randomized Phase II and Phase III trials have shown improved response rate and significantly longer median progression-free survival for patients receiving the combination of dabrafenib and the MEK inhibitor, trametinib, compared with those receiving dabrafenib alone [10,12–13]. These data have led to the US FDA approval of the dabrafenib/trametinib combination and its widespread use in patients with metastatic BRAF V600-mutant melanoma.

Case presentation

A 63-year-old female patient presented with a history of a changing mole on her right arm in the summer of 2004. Punch biopsy revealed melanoma with a Breslow depth of 1.25 mm. She underwent a wide local excision and a right axillary sentinel lymph node biopsy, both of which showed no additional malignancy. She remained disease free until September of 2013, at which time she noticed a soft tissue nodule on her right upper abdominal wall and a lump in her right breast. A comprehensive workup, including mammogram and ultrasound-guided biopsy, revealed metastatic melanoma. Analysis of the biopsy material revealed a BRAF V600E mutation in exon 15. She had a staging PET-CT scan in January 2014, which revealed widespread metastatic disease to bilateral adrenal glands, brain, left lower lobe of the lung, multiple sites on the abdominal wall, peritoneum and the small bowel. The small bowel lesion was in the distal ileum, and measured 7.0 × 4.9 cm (Figure 1A).

Figure 1. . CT scan images of the distal ileum.

(A) 2/11/2014: pre-treatment scans showing disease at initial presentation. There is a lesion in the distal ileum measuring 7.0 × 4.9 cm with a cavitary component and marked irregularity of the luminal margin. (B) 5/5/2014: following ipilimumab therapy; start of BRAF/MEK inhibitor treatment. Index cavitary mass in the distal ileum is now 10.4 × 8.0 cm. (C) 7/5/2014: 2 months into therapy. The previously seen distal ileal cavitary mass has now become more ill-defined and infiltrating measuring approximately 3.5 × 1.9 cm. Distal to the ileal infiltrating mass are decompressed ileal loops in the pelvis. (D) 7/19/2014: presentation with acute abdomen. Ongoing distention of the proximal and mid small bowel up to the previously noted transition point in the mid/upper pelvis, in close proximity to the known distal ileal infiltrating mass small bowel wall proximal to the transition point is markedly thickened, measuring up to 0.7 cm. There is extraluminal air in this region.

She received stereotactic radiosurgery to two brain metastases and then began ipilimumab-based immunotherapy. During treatment she required multiple transfusions of packed red blood cells due to gastrointestinal bleeding from her bowel metastases. She had no treatment-related diarrhea or evidence of colitis. Follow-up imaging after completion of four cycles of ipilimumab revealed disease progression, with increased size of the distal ileal tumor to 10.4 × 8.0 cm (Figure 1B). She was started on combination therapy with dabrafenib/trametinib in May 2014. A CT scan 6 weeks into treatment revealed significant tumor regression. At this time, the distal ileal lesion measured 2.3 × 2.1 cm.

She presented to the emergency department at Georgetown University Hospital in early July 2014 with nausea, vomiting and abdominal pain. A CT scan revealed a partial small bowel obstruction, involving the site of the known lesion in the distal ileum, which now measured 3.5 × 1.9 cm (Figure 1C). She was hemodynamically stable without evidence of leukocytosis and acidosis, and her LDH was slightly increased to 279 (pre-treatment baseline was 204). She was treated non-operatively with bowel rest, including placement of a nasogastric tube, and intravenous hydration. She regained bowel function and was tolerating a normal diet upon discharge. She resumed dabrafenib/trametinib therapy without immediate further complication.

She again presented to the emergency department at Georgetown University Hospital 10 days later with nausea, vomiting and abdominal pain. A CT scan performed at this time revealed a high-grade small bowel obstruction with perforation, and a focal transition point near the known infiltrating distal ileal mass (Figure 1D). Clinically, the patient was febrile and hypotensive. Her labs revealed a significant leukocytosis with a left shift. After multidisciplinary discussion, she was taken to the operating room for an emergent laparotomy, resection of small bowel and primary anastomosis on 20 July 2014. During surgery she was noted to have no evidence of gross disease in her abdomen. Pathology of the specimen showed transmural perforation of the small bowel wall, with acute inflammation and an organizing hematoma of underlying subserosal adipose tissue, but no evidence of malignancy (Figure 2A & B). The specimen was immunostained with H&E and melanoma markers, but no subtle disease was found. The patient recovered quickly from surgery and was able to be discharged within 1 week, at which time she resumed dabrafenib/trametinib therapy.

Figure 2. . Pathological evaluation of resected bowel specimen.

(A) Transmural perforation of the small bowel wall, associated with marked acute inflammatory response, capillary congestion and fibrosis (H&E stain, ×20) and detail of the acute (neutrophilic) infiltrate (inset, H&E, ×100). (B) Organizing necrotic and hemorrhagic material, probably representing necrotic tumor, associated with foamy histiocytes and fibrosis (H&E stain, ×40) and detail of foamy histiocytes (H&E stain, ×100).

At 7 months postoperatively, she was well with no symptoms, normal LDH values and no evidence of disease on CT scan.

Discussion

The development of combination therapy with BRAF/MEK inhibition has revolutionized the way that patients with BRAF V600-mutant melanoma are treated. Therefore, for patients with metastatic disease that has progressed despite immunotherapy or is symptomatic and/or rapidly progressive, such as the patient described above, treatment with dabrafenib/trametinib is considered the standard of care.

The case presented above describes an extremely rapid tumor response of a large tumor burden with this regimen. The sequence of events suggests that this patient's bowel perforation resulted from the rapid disease response rather than the pre-treatment disease progression. Specifically, we suspect that the rapid treatment-induced regression of her lesion left a defect or weakness in her bowel wall that resulted in the clinically manifest perforation. To our knowledge, this treatment complication has not been previously reported in patients with metastatic melanoma who are treated with combination BRAF/MEK inhibitors.

Although she had previously received treatment with ipilimumab, an immune checkpoint inhibitor that can cause colitis and occasional colitis-related bowel perforation, this is unlikely to be the precipitating cause in this patient for several reasons. She had no evidence of colitis on ipilimumab therapy, she was nearly 3 months following her last dose of ipilimumab when the perforation occurred, and her bowel perforated at a site of significant prior tumor mass and regression on the CT imaging. Finally, there was no evidence of colitis or ileitis in the surgical pathology specimen.

Treatment-related bowel perforation has been demonstrated numerous times in patients with other cancers, particularly lymphomas. The exquisite chemosensitivity of some lymphomas may predispose patients with full thickness involvement of the bowel wall to treatment-related bowel perforation. Fallon et al. [14] reported a case of bowel perforation in a pediatric patient with Burkitt's lymphoma treated with cyclophosphamide, vincristine, prednisone, methotrexate and hydrocortisone. A concomitant literature review revealed that of the known patients with lymphoma-associated bowel perforation, 87% were related to chemotherapy [14]. Importantly, they also noted that the mortality of the group of children with chemotherapy-induced perforations was significantly higher (60%, as compared with 15–20% mortality for patients with bowel involvement of lymphoma but no perforation related to responsiveness to chemotherapy).

This case illustrates the potential for severe complications with the use of combination BRAF/MEK inhibition in patients with melanoma that is metastatic to the small bowel. Patients who fit this description may require increased surveillance, and providers should have a high suspicion for treatment-related complication rather than tumor progression, and a low threshold for recommending early surgical intervention for patients who present with either obstructive symptoms or evidence of bowel perforation early in therapy. Ideally, the patient described above should have had surgery at the time her initial admission in early July 2014 for a partial bowel obstruction, as this was likely the first sign of perforation. The apparent interval growth of the bowel lesion likely resulted from inflammation around the perforation rather than actual expansion of the tumor. Surgical intervention at that time might have prevented the potentially fatal complication of high-grade obstruction with perforation that followed.

Management of bowel perforation in the setting of patients with metastatic cancer on chemotherapy can be very challenging. Surgery is often indicated; however, patients with perforation related to disease progression frequently do poorly. In particular, there is a high incidence of infection, impaired healing and prolonged surgical recovery that may delay the institution of additional and/or alternative systemic therapy, and significantly impact a patient's quality of life. Thus, consideration is often given to withholding surgery and providing supportive care, as was contemplated in this patient. However, as this case suggests, it is important to distinguish those patients whose perforation might result from an overly brisk response to systemic therapy, and to intervene quickly.

Conclusion

This case report suggests that patients with metastatic BRAF V600-mutant melanoma who have bowel metastases and are receiving combination BRAF/MEK inhibitor therapy are at risk for tumor response-related bowel perforation. The early suspicion and detection of bowel perforation in the setting of a rapid response to BRAF/MEK inhibitor treatment in patients with metastatic melanoma is essential in guiding clinical decision making. Timely surgical resection may enable a more rapid reinstitution of BRAF/MEK inhibitor therapy with anticipated considerable future clinical benefit.

Future perspective

The current availability of more effective systemic therapies for patients with metastatic BRAF V600-mutant melanoma is changing the role of surgery in these patients. Previously, patients with symptomatic small bowel metastases were treated with surgical resection, if feasible, prior to consideration of systemic therapies. The decision to operate was often based on the extent of other metastatic disease, as systemic therapies were largely ineffective. Recent data suggest that the institution of BRAF/MEK inhibitor therapy can produce rapid clinical benefit, obviating the need for upfront surgery. Similar and perhaps even more durable tumor responses can be seen with the use of checkpoint inhibitor immunotherapies, for example, ipilimumab and anti-PD1 blocking antibodies, either alone and in combination with one another [15]. As a consequence, surgery in this patient population may be increasingly relegated to resection of residual or unresponsive disease and the management of complications of therapy. As illustrated by this case, in the setting of highly effective systemic therapy, multidisciplinary input and expertise will likely be increasingly important in guiding surgical management decisions in patients with advanced melanoma in order to optimize individual patient outcomes.