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A 65-year-old man presented with episodes of fainting. Assessment showed his symptoms were related to compression of the superior vena cava from extensive swelling of the supraclavicular, mediastinal, and paratracheal lymph nodes, with some as large as 10 cm.

Clinicians biopsied the left supraclavicular lymph node, and histologic analysis identified Merkel cell carcinoma (MCC) with no signs of a primary cutaneous tumor. The patient was treated with six cycles of carboplatin plus etoposide and concurrent radiation therapy (36 Gy) to the mediastinal and supraclavicular lymph nodes.

Treatment was effective initially, with regression observed in all tumors.

Three months after the sixth and last cycle of chemotherapy, however, there was evidence of disease progression in several new lymph nodes in his chest.

Clinicians then initiated treatment with pazopanib (Votrient) 800 mg daily. The dose was later reduced to 400 mg daily when the patient developed liver toxicity, and that lowered dose alleviated the adverse effect on the liver. The dose was gradually titrated up to 600 mg daily, with no further hepatic toxicity.

Three months after starting treatment with pazopanib, the patient underwent a restaging fluorodeoxyglucose-positron emission tomography computed tomography (FDG-PETCT) scan. This showed that previously FDG-avid lymph nodes in the chest (right hilar, right paratracheal, mediastinal, prevascular, and subcarinal lymph nodes) had completely resolved.

The patient continued treatment with pazopanib for 14 months, but the disease progressed significantly in the abdominal and retroperitoneal lymph nodes. Clinicians initiated treatment with single-fraction high-dose radiation and depot octreotide acetate injections, which continued for another 10 months, but the patient ultimately developed obstructive jaundice from pancreatic metastases, and died.

Discussion

This of a man with metastatic MCC is one of a series of five patients that the authors described involving at least initially successful second-line treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) with pazopanib (four patients) and cabozantinib (Cabometyx, Cometriq; one patient).

In the absence of access to immunotherapy trials, these treatments -- which followed cytotoxic chemotherapy -- were associated with several months of disease control with good tolerability, the authors said. The report "highlights the possibility of clinical benefit with VEGFR TKIs in this aggressive cancer," the team wrote.

MCC is a rare neuroendocrine skin carcinoma that affects about 2,500 people per year in the U.S., but the incidence is increasing, the case authors noted. The Merkel cell polyomavirus is evident in about 80% of these tumors.

Survival is based on staging, with a 5-year overall survival rate of 51% for local disease, 35% for nodal disease, and 14% for distant disease, which is associated with a median survival of approximately 10 months after initial metastasis.

Among all patients with local or regional disease, two independent studies each found that 48% of patients ultimately developed , and among patients who recurred, the median time between diagnosis and recurrence was 9 months.

First-line therapy for metastatic MCC generally involves cytotoxic chemotherapy, typically with platinum-based agents plus etoposide, the case authors noted, and while the disease generally responds to cytotoxic chemotherapy -- objective response rates (ORRs) of over 50% -- responses are not usually long-lasting. Median progression-free survival (PFS) is just 94 days, and response rates to subsequent treatment with cytotoxic chemotherapy is much lower (23%), with a median PFS of only 61 days.

The authors noted that in the larger context of advanced MCC treatment, there have been promising outcomes in prospective clinical trials with PD-1 and PD-L1 inhibitors. Although many patients with metastatic MCC do not respond to PD-1/PD-L1 blockade, those who did had "strikingly durable" responses to first-line treatment.

And in small studies of fewer than 40 patients overall, ORRs were 56% with pembrolizumab, 62% with avelumab, and 73% with nivolumab; avelumab had an ORR of 31.8% in 28 of 88 chemotherapy-refractory patients.

There remains an unaddressed need for a range of alternatives to immunotherapy for MCC patients with autoimmune or immunosuppressive conditions, the case authors said. "There has been little success in identifying tumor-signaling pathways amenable to molecular targeting in MCC."

There is, however, increasing support for the role of angiogenesis in development of MCC, with "evidence of prominent vascular proliferation in up to 20% of MCC tumors, which appears to be a shared feature across many neuroendocrine tumors," the team added.

There are several histopathological variations of MCC, including an apparent between tumor size and VEGFR-2 expression, which was more prevalent (91% vs 70%) in tumors larger than 2.0 cm.

The case authors said that based on their experience with standard (as opposed to investigational) use of TKIs in the five patients in their series, stable disease should be considered a meaningful clinical endpoint in addition to objective responses, since several patients in the series had prolonged stabilization of disease without an objective response as defined by Response Evaluation Criteria in Solid Tumors.

Future research, the team said, should explore use of predictive biomarkers to refine patient selection, and several prospective clinical trials are currently investigating the use of pazopanib and cabozantinib in patients with metastatic MCC.

This patient series showed longer lasting benefits with pazopanib than with prior chemotherapy regimens in patients who had received chemotherapy, the authors observed. As well, one patient's arthritic symptoms improved sufficiently with pazopanib to allow immune suppression to be discontinued.

Given the role of angiogenic mechanisms in inflammatory arthritis, the anti-angiogenic effects of VEGFR-TKIs may allow arthritic patients with MCC to discontinue immune suppression, which the authors noted is associated with "dismal outcomes." The period of stabilized disease with VEGFR-TKIs can provide "a bridge towards standard or investigational immunotherapy," the team explained.

In contrast to cytotoxic chemotherapy, anti-angiogenic therapy is not thought to be immune-suppressive and may improve the efficacy of immunotherapy by modulating the tumor microenvironment through reduction of immune suppressive cytokines and regulatory T cells, the case authors wrote.

Because this particular patient's MCC expressed , the effect of VEGFR-TKIs was prolonged by the addition of long-acting octreotide agents, the case authors noted. Furthermore, "the favorable toxicity profile of VEGFR-TKIs and somatostatin analogues supports the safety of combining the two modalities."

The authors cautioned, however, that while single-fraction high-dose radiation can be used to shrink large or symptomatic tumors before starting TKI treatment, concurrent use has been linked with complications.

Conclusion

The authors concluded that their retrospective series highlights the potential utility of VEGFR-TKIs in MCC patients. Given the modest benefit with cytotoxic chemotherapy in advanced MCC, VEGFR-TKIs may thus provide clinical benefit in patients who progressed after or were not eligible for PD-1 blockade. Further data from prospective clinical trials are needed, however, to determine the efficacy of TKIs as monotherapy and in combination with immunotherapy.

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