A retrospective study of the safety and efficacy of paclitaxel plus ramucirumab in patients with advanced or recurrent gastric cancer with ascites

This retrospective study was designed to evaluate the safety and efficacy of chemotherapy with paclitaxel plus ramucirumab in patients with AGC with ascites in comparison with patients without ascites. We reviewed the medical records of consecutive patients with AGC who had been treated with paclitaxel plus ramucirumab in a single institution from June 2015 to May 2016.

The eligibility criteria were the presence of histologically proven, inoperable AGC; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2; adequate bone marrow, hepatic, and renal function; history of previous treatment with one or more regimens; and at least one treatment with paclitaxel plus ramucirumab. We excluded the patients with another disease which cause ascites: congestive heart failure, liver cirrhosis, nephrotic syndrome. Written informed consent for chemotherapy was obtained from each patient prior to the initiation of treatment. The study was performed under an institutional review board waiver in accordance with the Japanese ethical guidelines for epidemiologic research.

The patients received 8 mg/kg of ramucirumab intravenously on days 1 and 15, plus 80 mg/m² of paclitaxel intravenously on days 1, 8, and 15 of a 28-day cycle. The patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. The dose reduction of paclitaxel at starting the treatment was decided by each investigator depending on ECOG PS or toxicities from previous treatments (especially remaining sensory neuropathy due to oxaliplatin). Dose modification and interruption of treatment were performed by each investigator based on the criteria of reported clinical trials [11]. The patients could continue with ramucirumab or paclitaxel alone if they experienced severe toxicity with either agent.

The amount of ascites was defined as small (limited to the pelvic cavity or around the liver), moderate (neither small nor massive), or massive (continuous ascites from the surface of the liver to the pelvic cavity) by computed tomographic (CT) scans. These definitions are the same as those used in previous studies [13, 14]. The volume of ascites was estimated by the five-point method, as previously reported [14‐16]. Briefly, the thickness of the ascites in centimeters was measured in three planes, the bilateral subphrenic space (A and B), the bilateral paracolic space (C and D), and the prebladder space (E). The average thickness, (A + B + C + D + E)/5, was then multiplied by the area of the standard abdominal cavity in the anterior projection, which was assumed to be 1000 cm², to yield the volume of ascites as (A + B + C + D + E) × 200 (mL). We divided the patients into those without ascites, those with small or moderate ascites, and those with massive ascites.

Toxicities were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0. In patients with measurable lesions, tumor response was assessed according to the guidelines of the Response Evaluation Criteria in Solid Tumors (version 1.1), and the best overall response was recorded as the antitumor effect for that patient. The objective response rate in these patients was defined as the percentage of patients with a complete response (CR) or a partial response (PR). Changes in ascites were defined as follows: disappeared (disappearance of ascites), decreased (from moderate to small or from massive to moderate or small), and increased (from small to moderate or massive or from moderate to massive). The time to treatment failure (TTF) was determined from the date of initiation of chemotherapy to the date of the last administration of paclitaxel or ramucirumab. The actual dose intensity was defined as the total dose of drug delivered per unit of body surface area per unit of time (mg/m²/week). The relative dose intensity of paclitaxel was calculated as the ratio between the actual dose intensity and the scheduled dose intensity in patients who received at least one cycle of paclitaxel plus ramucirumab. PFS was measured from the date of initiation of chemotherapy to the date of disease progression or death from any cause. OS was estimated from the date of initiation of chemotherapy to the date of death or last follow-up visit. Median PFS and median OS were estimated by the Kaplan–Meier method. P values for testing differences in baseline characteristics and response rates of each ascites group were calculated for homogeneity by chi-square tests and for trends by Fisher’s exact test. PFS and OS were compared among ascites groups by the log-rank test. Hazard ratios (HRs) were calculated by the Cox proportional hazards model and presented as HRs and 95% confidence intervals (95% CIs). Statistical analyses were performed with IBM ® SPSS ® Statistics software (version 21). All tests were two-sided, and P < 0.05 was considered to indicate statistical significance.

A total of 121 patients with AGC received ramucirumab-containing chemotherapy between June 2015 and May 2016. Of these patients, 83 received the chemotherapy with ramucirumab plus paclitaxel. They met the inclusion criteria and were analyzed in this study. The others were excluded due to different treatment regimens including irinotecan plus ramucirumab or ramucirumab monotherapy. Patient characteristics are shown in Table 1. Ascites was detected in 40 patients (49%); 14 patients (17%) had small ascites, 12 (14%) had moderate ascites, and 14 (17%) had massive ascites. The estimated median volumes of ascites according to this classification were 240 mL in small ascites (range, < 100–380 mL), 740 mL in moderate ascites (range, 320–1340 mL), and 2240 mL in massive ascites (range, 740–3340 mL). We could not estimate volumes of ascites in 10 patients with small ascites by this method because its distributions were out of described 5 points [14‐16]. Four patients with massive ascites needed drainage of ascites before ramucirumab treatment after above-mentioned CT examination. The proportion of patients with ECOG PS 2 was higher among those with massive ascites than in other groups (P = 0.008) (Table 1). Fifty-nine patients (71%) had received one previous treatment with platinum-based and fluoropyrimidine-based chemotherapy regimens, and 24 patients (29%) had received previous treatment with two or more regimens. Peritoneal metastasis was diagnosed by laparotomy or laparoscopy in 16 patients. The other 33 patients were diagnosed by CT scans.

The median TTF among all patients was 3.7 months during the median follow-up period of 7.1 months. The proportion of patients who started with a reduced dose of paclitaxel was higher for patients with massive ascites (50%; 7 of 14 patients) than for patients with small to moderate ascites (19%; 5 of 26 patients; P = 0.043) or without ascites (19%; 8 of 43 patients; P = 0.021). The dose of paclitaxel was reduced during treatment in 49 patients (59%), with no significant differences between the ascites groups in the number of patients receiving reduced doses. In four patients, they discontinued ramucirumab due to bleeding or hemorrhagic events; three patients discontinued ramucirumab because of uncontrolled anemia due to oozing from primary lesions, and one patient discontinued ramucirumab because of a large amount of gastrointestinal hemorrhage due to an enlarged peritoneal metastasis that infiltrated into the small intestine. The median relative dose intensities of ramucirumab and paclitaxel were 87.9% (range, 14.3–100%) and 68.2% (range, 11.2–100%), respectively. Seventy-two patients discontinued treatment because of disease progression (n = 65; 90.3%), toxicity (n = 4; 5.6%), or other reasons (n = 3; 4.1%). The frequency of discontinuation due to toxicity was not significantly different among the ascites groups: 2 of 14 patients with massive ascites, 0 of 24 patients with small to moderate ascites, and 2 of 34 patients without ascites discontinued treatment.

The frequencies of any grade 3 or 4 hematological toxicity were 51% (22 of 43 patients) in patients without ascites, 77% (20 of 26 patients) in patients with small to moderate ascites, and 71% (10 of 14 patients) in patients with massive ascites (Table 2). The frequency of grade 3 or 4 febrile neutropenia was 4% (3 of 83 patients). The frequencies of any grade 3 or 4 nonhematological toxicity were 9% (4 of 43 patients) in patients without ascites, 15% (4 of 26 patients) in patients with small to moderate ascites, and 14% (2 of 14 patients) in patients in massive ascites. The adverse events of special interest that were potentially associated with ramucirumab are shown in Table 3. One patient without ascites had a grade 3 gastrointestinal hemorrhage resulting from an enlarged peritoneal metastasis that infiltrated into the small intestine 4 days after the last dose of ramucirumab. Another patient with small to moderate ascites had a gastrointestinal perforation due to disease progression and obstruction of the small intestine 10 days after the last ramucirumab treatment. Both patients received best supportive care and died 1 week and 2 weeks after these events.

Of the 45 patients with measurable lesions, 14 achieved a PR with an overall response rate of 31.8%. Of the patients with ascites (n = 40), disappearance of ascites was observed in 3 patients (8%), and a decrease of ascites was observed in 11 patients (28%). Among 4 patients requiring drainage of ascites, 2 patients became free from drainage. The response rates in terms of measurable lesions or ascites were similar among the ascites groups (Tables 4 and 5). Seventy patients had experienced disease progression at the time of analysis, with a median PFS of 4.0 months (95% CI, 2.5–5.4 months). Forty-two patients (50.1%) were dead, with a median OS of 9.6 months (95% CI, 9.2–10.1 months). The median PFS was shorter in patients with massive ascites (1.9 months; 95% CI, 1.7–2.1 months) than in patients with small or moderate ascites (3.2 months; 95% CI, 2.0–4.3 months; HR 0.57; 95% CI, 0.29–1.14; P = 0.11) or patients without ascites (5.1 months; 95% CI, 4.7–5.4 months; HR 0.65; 95% CI, 0.47–0.90; P = 0.01) (Fig. 1). The median OS was also shorter in patients with massive ascites (3.9 months; 95% CI, 3.2–4.5 months) than in patients with small or moderate ascites (9.6 months; 95% CI, 7.9–11.4 months; HR 0.41; 95% CI, 0.19–0.90; P = 0.026) or patients without ascites (11.3 months; 95% CI, 9.3–13.3 months; HR 0.54; 95% CI, 0.36–0.81; P = 0.003) (Fig. 1). Forty patients (56%) received post-discontinuation therapy, most commonly with irinotecan-based chemotherapy (n = 26). Fewer patients with massive ascites received post-discontinuation chemotherapy (29%; 4 of 14 patients) than patients with small or moderate ascites (67%; 16 of 24 patients) or without ascites (59%; 20 of 34 patients), although the difference was not statistically significant (P = 0.065).