In this case, we present the details of a 53-year-old male patient diagnosed with multi-metastasis rectal cancer. Following previous rounds of chemotherapy, the patient underwent laprascopic anterior resection and received five cycles of XELOX chemotherapy(Oxaliplatin and Capecitabine) after being diagnosed with rectal cancer on March 15, 2018. Pathological assessment revealed an uncertain T stage and positive lymph node involvement in all three nodes. Next-generation sequencing indicated a wild-type NRAS and MSS status. Unfortunately, in May 2019, metastasis was detected in the lymph node located at the groin, followed by a recurrence in the pelvis in May 2020. In September 2020, the patient experienced edema in the bilateral lower limbs and developed a hard nodule in the right groin. Further evaluation in February 2021 confirmed bone metastasis. Throughout this period, the patient received various lines of chemotherapy and targeted therapy, yet tumor progression persisted. The treatment regimens included oxaliplatin plus raltitrexed for one cycle, cis-platinum plus raltitrexed for four cycles, irinotecan for one cycle, irinotecan plus raltitrexed for three cycles, and docetaxel plus bevacizumab for one cycle. A timeline depiction of the case is provided in Figure 1.

Upon discovering edema in the patient's legs and metastasis in the right groin, a PET-CT scan revealed metastasis in both groins and multiple metastases in the bones (Figure 2 A-B). Subsequently, on November 16, 2020, the patient underwent three cycles of fruquintinib plus camrelizumab treatment. On January 13, 2021, a CT examination was conducted (Figure 2 C-D). A comparison with the previous assessment in May 2020 showed that the nodule in the right groin had grown to 3.5 cm*3.5 cm and had developed a fistula on the skin. However, there was partial alleviation of the edema and pain observed in the lower limbs. Given the increased size of the metastasis in the groin, the patient opted to undergo radiation therapy.

Due to the COVID-19 pandemic in China, the patient's access to radiotherapy was hindered. In the meanwhile, he continued with the original treatment strategy of fruquintinib plus camrelizumab until February 10, 2021. As the treatment progressed, a radiological image on February 24, 2021, revealed a significant reduction in the nodule in the right groin (Figure 2 E-F). The alleviation of the nodule obstruction resulted in partial relief of symptoms such as edema and pain after immunotherapy. However, during this period, the range of erythema on the skin gradually expanded. Based on the positive response to the fruquintinib plus camrelizumab treatment strategy, it was believed that the erythema appearing on the skin was closely associated with the adverse effects of PD-1 agents and TKI agents.

To mitigate the adverse effects of PD-1 and TKI drugs, the patient discontinued camrelizumab on February 10, 2021, and began the latest fruquintinib on January 25, 2021. Glucocorticoids were administered to manage the adverse events associated with immunotherapy. After discontinuing immunotherapy, the nodule in the groin showed sustained improvement, as depicted in the image on February 24, 2021 (Figure 2 E-F). However, the number and extent of erythema on the skin continued to worsen.

In order to achieve better tumor regression, the patient decided to undergo palliative radiotherapy for groin tumor control from February 24, 2021, to March 12, 2021, receiving a total dose of 50 Gy delivered in 25 fractions. After two weeks of treatment, there was partial regression of the lymph node, but the skin nodules accompanied by edema worsened without relief from itching and pain. As a result, the radiotherapy was discontinued on March 12, 2021, and the focus shifted to the management of the skin disorders.

The radiological diagnosis indicated that the lymph node was reduced significantly; however, the symptoms of skin and edema were exacerbated. With the treatment of immunotherapy and management of AE effects, the lymph node at the groin exhibited opposite clinical manifestations as the nodules of the skin. In consideration of the side effects of fruquintinib, we stopped fruquintinib starting on March 10, 2021. We requested a dermatological consultation on March 18, 2021. Nodules were exhibited in the right leg and waist (Figure 3 A-D), and the skin biopsy confirmed the metastasis, with limited amount of lymph cells (Figure 3 E-F). The immunohistochemical for skin biopsy can be seen in supplementary material (Supplementary Figure 1). After one week of steroid treatment for skin nodules and other symptomatic management, including improvement of vascular osmotic pressure and reduction of water retention, the pain became severe, and skin nodules appeared in the twist and abdomen. However, the situation of the patient was aggravated, and the T-2 image from March 24, 2021, is shown in Figure 2 G-H. Because of the poor response to steroid treatment, we suspected the nature of these skin nodules. Then, the patient received a skin biopsy for pathological confirmation. The pathological diagnosis indicated cutaneous metastases from colon-rectal cancer. After decreased steroids and continuous supportive treatment, the patient cooperated with our treatment with sincereness and trust. Finally, he left for a local hospital and died on April 2, 2021.

Following radiological assessment, significant reduction was observed in the lymph node, yet the symptoms of skin and edema worsened. Despite immunotherapy and effective adverse event management, the lymph node in the groin displayed conflicting clinical manifestations compared to the skin nodules. Considering the potential side effects of fruquintinib, its administration was ceased on March 10, 2021. A dermatological consultation was sought on March 18, 2021, which revealed the presence of nodules on the right leg and waist (Figure 3 A-D). Subsequent skin biopsy confirmed metastasis with limited lymph cell infiltration (Figure 3 E-F). Supplementary material (Supplementary Figure 1) displayed immunohistochemical analysis of the skin biopsy. Symptomatic management, including vascular osmotic pressure improvement and water retention reduction, along with one week of steroid treatment, was initiated for the skin nodules. Unfortunately, this approach resulted in severe pain and the emergence of nodules in the twist and abdomen. Consequently, the patient's condition deteriorated, as evidenced by the T-2 image on March 24, 2021 (Figure 2 G-H). Due to the inadequate response to steroid treatment, further investigation of the nature of these skin nodules was warranted. A subsequent skin biopsy was performed, confirming cutaneous metastases originating from colon-rectal cancer. Adjustments to the steroid dosage were made, and continuous supportive care was provided, with the patient demonstrating sincere cooperation and trust. Regrettably, the patient's condition worsened, necessitating transfer to a local hospital, where they passed away on April 2, 2021.