Rapid tumor necrosis and massive hemorrhage induced by bevacizumab and paclitaxel combination therapy in a case of advanced breast cancer
A 27-year-old premenopausal woman with no family history of breast cancer noticed a 1-cm lump in her left breast in January 2010. Thereafter, she became pregnant, and the lump gradually increased in size to occupy her entire left breast by July. She first visited a breast clinic that referred her to the Shinshu University Hospital with suspected breast cancer. Physical examination at her initial visit revealed a hard, swollen, and erythematous left breast, with many palpable and enlarged lymph nodes in the bilateral axillae and left supraclavicular to lateral cervical region. Histopathological examination of a core needle biopsy specimen revealed invasive ductal carcinoma (scirrhous carcinoma) that was histological grade 3, estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor type 2 (HER2)-positive. A relatively high Ki-67 index (30%–40%) was also observed. Computed tomography revealed multiple metastases to the liver, mediastinal lymph nodes, and supine and pelvic bones. A final diagnosis of stage IV breast cancer was made when she had entered gestational week 24.\nThe patient was treated with three triweekly cycles of cyclophosphamide (500 mg/m2), Adriamycin® (Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan) (60 mg/m2), and fluorouracil (500 mg/m2) therapy (). A slight decrease in size of the primary tumor in the left breast was induced by this therapy; however, the multiple liver metastases enlarged. Therefore, induced delivery was planned to enable the administration of trastuzumab-based therapy. A healthy fetus was delivered through the vagina without blood transfusion at gestational week 35 in February 2011, and weekly paclitaxel (80 mg/m2) with trastuzumab (2 mg/kg) treatment was initiated thereafter. A partial response was observed for the liver metastases; however, the primary lesion gradually increased in size and the inflammation became exacerbated despite the new treatment. In July 2011, her treatment was changed to lapatinib and capecitabine as a third-line therapy. The size of the primary tumor decreased slightly and its progression was temporarily inhibited. Although the multiple liver metastases were successfully controlled by these therapies, the primary tumor began to enlarge again in December 2011. Thereafter, treatment was changed to weekly trastuzumab (2 mg/kg on days 1, 8, and 15) and vinorelbine (25 mg/m2 on days 1 and 8) as a fourth-line therapy; however, almost no clinical response was observed. Therefore, in January 2012, a fifth-line combination therapy was initiated with docetaxel (75 mg/m2 on day 1) and carboplatin (6 area under the curve [AUC] on day 1) plus trastuzumab (2 mg/kg on days 1, 8, and 15). This treatment also had to be discontinued after one cycle because of marked anorexia. In the meantime, the primary tumor grew rapidly and extended beyond the skin in April 2012. To inhibit this growth, eribulin (1.4 mg/m2) was initiated as a sixth-line therapy; however, she was readmitted with dyspnea due to massive left pleural effusion after one cycle. By that time, the size of the primary tumor had increased to 15 × 12 × 9 cm, and its surface had become nodular and partially erosive.\nAs it was considered that the primary tumor became resistant to anti-HER2-based therapy, combination therapy with paclitaxel (90 mg/m2 on days 1, 8, and 15) and bevacizumab (10 mg/m2 on days 1 and 15) was initiated as a seventh-line therapy after removal of the pleural effusion by thoracocentesis (). Three days after the first infusion of paclitaxel and bevacizumab, the volume of the primary tumor occupying her entire left breast began to decrease and its color turned to dusky red, followed by spread of skin erosion. The entire mass flattened drastically because of rapid tumor necrosis. Next, the erosion developed deep ulceration and necrosis, with loss of all skin layers over an extensive area. This led to exposure of the underlying pectoralis major muscles by the end of the first cycle of treatment. Gradually, most of the tumor became necrotic and a large area of the pectoralis major muscle was exposed, with the remaining tumor at the rim of the ulcerated lesion 4 weeks after bevacizumab initiation.\nSix days after initiation of the second treatment cycle, she was readmitted to our hospital because of massive hemorrhage from the surface of the necrotic residual tumor in her left breast. Hemostasis was achieved by applying pressure with gauze and oxidized cellulose. To prevent further hemorrhage, the surface of the residual tumor was covered and compressed firmly with thick gauze; however, massive hemorrhage occurred again on the following day, necessitating several hours of manual compression. The total blood loss during these 2 days was approximately 1,800 mL; therefore, she required 560 mL of leukocyte-reduced red cell concentrate transfusion on the first day and an additional 280 mL on the following day. The bleeding from the ulcerated tumor finally ceased. The combination therapy of paclitaxel and bevacizumab was discontinued and local treatment of the ulcerated lesion was continued. Because the ulcerated lesion caused severe pain, both opioid and nonopioid analgesics were administered. The patient desired to be with her family; therefore, she was discharged after 2 weeks of hospitalization. Thereafter, she visited our hospital daily for local treatment. Because of the lack of healing in the large ulcerated lesion as well as the patient’s request for temporary cessation of anticancer therapy, only local treatment was administered. Twelve days after discharge, however, her respiratory status suddenly deteriorated and she experienced cardiopulmonary arrest in the ambulance en route to the hospital. Cardiopulmonary resuscitation was unsuccessful and the patient eventually succumbed. Although an autopsy was not performed, we considered that she died from respiratory failure caused by carcinomatous lymphangitis as determined by a chest X-ray.