Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy with lobaplatin and docetaxel improves survival for patients with peritoneal carcinomatosis from abdominal and pelvic malignancies

Background This work was to evaluate the perioperative safety and efficacy of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) with lobaplatin and docetaxel in patients with peritoneal carcinomatosis (PC) from gastrointestinal and gynecological cancers. Methods Patients were treated by CRS + HIPEC with lobaplatin 50 mg/m2 and docetaxel 60 mg/m2 in 6000 mL of normal saline at 43 ± 0.5 °C for 60 min. Vital signs were recorded for 6 days after CRS + HIPEC procedures. Perioperative serious adverse events (SAE), hematological, hepatic, renal, and electrolytes parameters, the changes in serum tumor markers (TM) before and after operation, patient recovery, and overall survival (OS) were analyzed. Results One hundred consecutive PC patients underwent 105 CRS + HIPEC procedures and postoperative chemotherapy. The median CRS + HIPEC duration was 463 (range, 245–820) min, and the highest temperature and heart rate during six postoperative days were 38.6 °C (median 37.5 °C) and 124 bpm (median 100 bpm), respectively. The 30-day perioperative SAE occurred in 16 (15.2 %) and mortality occurred in 2 (1.9 %) patients. Most routine blood laboratory tests at 1 week after surgery turned normal. Among 82 cases with increased preoperative TM CEA, CA125, and CA199, 71 cases had TM levels reduced or turned normal. Median time to nasogastric tube removal was 5 (range, 3–23) days, to liquid food intake 6 (range, 4–24) days, and to abdominal suture removal 15 (range, 10–30) days. At the median follow-up of 19.7 (range, 7.5–89.2) months, the median OS was 24.2 (95 % CI, 15.0–33.4) months, and the 1-, 3-, and 5-year OS rates were 77.5, 32.5, and 19.8 %, respectively. Univariate analysis identified five independent prognostic factors on OS: the origin of PC, peritoneal cancer index, completeness of CRS, cycles of adjuvant chemotherapy, and SAE. Conclusions CRS + HIPEC with lobaplatin and docetaxel to treat PC is a feasible procedure with acceptable safety and can prolong the survival in selected patients with PC. Trial registration ClinicalTrials.gov, NCT00454519


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Conclusions: CRS + HIPEC with lobaplatin and docetaxel to treat PC is a feasible procedure with acceptable safety and can prolong the survival in selected patients with PC. Trial registration: ClinicalTrials.gov, NCT00454519 Keywords: Lobaplatin, Docetaxel, Peritoneal carcinomatosis, Cytoreductive surgery, Hyperthermic intraperitoneal chemotherapy

Background
The locoregional progression of gastrointestinal and gynecological malignancies such as gastric cancer (GC), colorectal cancer (CRC), ovarian cancer (OC), primary peritoneum carcinomatosis (PPC), pseudomyxoma peritonei (PMP), malignant peritoneal malignancies (MPM), frequently results in peritoneal carcinomatosis (PC), characterized by the presence of tumor nodules of various size, number, and distribution on the peritoneal surface, with significant negative impact on both survival and quality of life, due to refractory ascites, progressive intestinal obstruction, and unrelieved abdominal pain. The traditional therapies for PC include systemic chemotherapy, palliative surgery, and best support care, without any hope of cure. PC patients have a very poor prognosis with median survival less than 6 months [1,2].
With better understanding of the tumor biological behaviors and advances in treatment technologies, the landscape of PC has changed remarkably, in that PC is regarded as locoregional disease rather than widespread terminal condition. Over the past decades, novel therapeutic approaches to PC have emerged, combining cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), which integrate the advantages of surgically removing the bulky visible tumor burden and regional hyperthermic chemotherapy eradicating micrometastases and invisible free cancer cells [3].
Hyperthermia and chemotherapy have synergistic effects, which is significantly enhanced at 42°C [4][5][6]. The chemotherapeutic regimens for HIPEC include cisplatin, carboplatin, oxaliplatin, fluorouracil, mitomycin, paclitaxel and docetaxel, among others [7][8][9]. A study of antitumor drugs has been conducted because of the success of cisplatin. Forty years after the discovery of the biological activity of cisplatin for the first time, oxalipaltin and carboplatin as routine chemotherapeutics are widely used in clinical application today, while nedaplatin, heptaplatin, and lobaplatin have only been authorized, respectively, in Japan, South Korea, and China [10]. Though the response rate for first-line carboplatin and paclitaxel is 70 to 80 %, this approach still yields poor results and overall 5-year survival rate is less than 30 % [8]. Lobaplatin is a third-generation platinum compound, which has demonstrated various advantages, including potent antineoplastic activity, no significant nephrotoxicity or neurotoxicity [11], no cross-resistance with cisplatin [12], and relative molecular mass larger than other platinum drugs with the advantage of pharmacokinetics in intraperitoneal chemotherapy. Docetaxel is a semisynthetic compound in the taxane class of anticancer drugs. Although thought to operate through the same mechanism of action as paclitaxel by limiting microtubule depolymerization, the antimicrotubule depolymerization capacity of docetaxel is twice as much as paclitaxel. Moreover, docetaxel has been found to have different spectra of activity and incomplete cross-resistance.
Phase I/II clinical trials of lobaplatin in combination with docetaxel have demonstrated acceptable safety and efficacy for a variety of malignant solid tumors [13,14]. Several basic researches have suggested that lobaplatin and docetaxel prove synergistic antineoplastic effects when used in combination [15]. Therefore, we summarize the clinical results of CRS + HIPEC with lobaplatin and docetaxel to treat PC at our center.

Patient selection
This study included 100 consecutive patients of PC treated by 105 CRS + HIPEC procedures from January 2008 to June 2015, including 41 patients from CRC, 30 from GC, 16 from OC and PPC, and 13 from PMP. Major clinicopathological characteristics of the patients are listed in Table 1. The evaluations and major inclusion and exclusion criteria were reported previously [16].

CRS + HIPEC procedure
A designated team of surgical oncologists, anesthesiologists, and operating room staff focusing on PC therapy performed CRS + HIPEC procedure, with detailed description reported previously [7,16]. Before being anesthetized, the Expression Sequential Compression System Vascular Refill Detection device was wrapped to both legs of the patient in order to prevent deep venous thrombosis because of longer operation time. The abdominal exploration was conducted under general anesthesia and stable hemodynamic monitoring, through a midline xyphoidpubic incision. Once the abdominal wall was open, detailed assessment of PC was carried out, recording the size and distribution of tumor nodules, and the quantity and quality of ascites, to calculate the peritoneal cancer index (PCI) according to the principle by Sugarbaker [17]. Then maximal CRS was conducted to remove the primary and metastatic tumor with acceptable margins, any involved adjacent structures, regional lymph nodes, and peritonectomy where peritoneal surfaces were involved by tumor [17]. The completeness of cytoreduction (CC score) was determined according to Sugarbaker's criteria [18] before HIPEC. CC-0 indicates no residual peritoneal disease after CRS; CC-1 represents less than 2.5 mm of residual disease;  protector covered the open abdomen in order to keep the temperature stable and avoid chemotherapy drugs diffusing into the air before HIPEC, because the open coliseum technique was thought to provide optimal thermal homogeneity and spatial diffusion [17], with 50 mg/ m 2 of lobaplatin and 60 mg/m 2 of docetaxel each dissolved in 3 L of saline. When the perfusion saline was kept at 43.0 ± 0.5°C and monitored with temperature sensors on real time by an automatic hyperthermia chemotherapy perfusion device (ES-6001, Wuhan E-sea Digital Engineering, Wuhan, China), the perfusion solution was infused at a rate of 400 mL/min. The total HIPEC time was 60 min. After HIPEC, the perfusion solution in the peritoneal cavity was withdrawn by the suction. Then the operation field was checked again for any suspected mishaps. The anastomoses were made to restore the continuity of the digestive tract. Routine colostomy was not performed, but in patients with extensive pelvic resections of the sigmoid colon, rectum, uterus, and bladder, colostomy was made. Then drainage tubes were placed at appropriate sites of anastomosis and depending on the type of primary operation. The incision was closed with a tension-reduced suture, and patient was transferred to the intensive care unit (ICU) for recovery.

Postoperative monitoring
All patients were carefully monitored for the following parameters: (1) The changes in body temperature and heart rate were recorded for 6 days after surgery; (2) The complete peripheral blood routine, blood biochemical parameters were examined on the first and seventh postoperative days, and cardio-pulmonary function was monitored, the change in serum tumor markers (TM) before and after operation; (3) Anastomotic leakage, intra-abdominal infection, hemorrhage, intestinal obstruction, and other life-threatening serious adverse events (SAE); (4) Wound healing, including fat liquefaction, incision split, surgical site infection, incisional hernia, time to suture, and drainage tube removal; (5) Postoperative recovery of gastrointestinal and other organs functions, including bowel sound, flatus passage, defecation, time of removing nasogastric tube and urinary catheter, and liquid food intake time; and (6) Survival outcomes.

Postoperative chemotherapy and follow-up
Postoperative adjuvant chemotherapy included intraperitoneal chemotherapy (IP) through the IP port mostly using lobaplatin (50 mg/m 2 , on day 1, every 21 days) and docetaxel (60 mg/m 2 , on day 1, every 21 days), and systemic chemotherapy (SC) mainly with irinotecan, leucovorin, and 5-fluorouracil (FOLFIRI) and oxaliplatin, leucovorin, and 5-fluorouracil (FOL-FOX) regimens, all dosed according to body surface area calculation [17,19]. Platinum combined with docetaxel was used in IP as had been proved to improve OS for PC patients with acceptable safety [20]. IP were given after the patients fully recovered from the operation, and SC was delivered with IP synchronously or alternately. Chemotherapy information was listed in Table 1.
All patients underwent routinely postoperative followup with physical examination, chest and abdominopelvic computed tomography, full gastrointestinal contrast media, and serum tumor markers (TM) every 3 months during the first 2 years and then every 6 months thereafter by outpatient consultation or by telephone. The last follow-up was on June 8, 2015, and the overall follow-up rate was 100 %.

Statistical analysis and term definition
All data were obtained from a prospectively established database of clinical records, surgical and pathology reports, image examination and laboratory reports, and follow-up records. And data were analyzed by SPSS software for windows, version 19.0 (SPSS Inc., Chicago, IL, USA), with P < 0.05 considered as statistically significant. The numerical data were directly recorded, and the category data were recorded into different categories.
The following study parameters were defined: (1) Perioperative period: from the day of CRS + HIPEC to day 30 postoperation; (2) Metachronous PC: after the primary tumor had been treated, the patients developed PC during follow-up; (3) Synchronous PC: PC was diagnosed synchronously at first treatment; (4) PCI ≤20 was defined as low PCI (LPCI), and PCI >20 was defined as high PCI (HPCI) [18]; (5) The current research defined CC0-1 as complete cytoreduction and CC2-3 as incomplete cytoreduction [18]; (6) Adverse events: the CRS + HIPEC related complications during the perioperative period, including SAE and other side effects; the former mainly involved life-threatening complications such as intestinal or anastomotic leakage, intestinal obstruction, hemorrhage, and sepsis, and the latter included of anemia, hepatic and renal toxicity, electrolyte disturbance, hypoalbuminemia, myelosuppression, and delayed wound healing, all on the basis of NCI Common Terminology Criteria (CTC) for Adverse Events version 4.0 [21]; (7) Overall survival (OS): the time period from CRS + HIPEC to death as a result of disease for metachronous PC; and the time period from first treatment of PC to death due to synchronous PC.

Vital signs during perioperative period
The body temperature and heart rate decreased gradually to normal in a week after CRS + HIPEC, the number of patients with body temperature exceeding 37°C were 95, 57, 11, and 1 during the first 4 days after operation ( Table 2).

Serious adverse events (SAE)
SAE (grades 3-5) occurred in 16 (15.2 %) of 105 CRS + HIPEC procedures (Table 5). Five patients developed gastrointestinal obstruction, four gradually recovered by active conservation remedy, and one with severe gastroplegia returned to normal gastrointestinal function 13 days after surgery. Four patients developed intestinal leakage. The first patient with generalized peritonitis syndrome on postoperative day 4 received a reoperation to repair the anastomosis on postoperative day 10 but failed to repair the leakage and then turned to conservative treatment, the patient survived 2.2 months after the surgery. The second patient developed serious gastricjejunum anastomosis fistula and sigmoid-rectum anastomosis fistula on postoperative day 8, generalized peritonitis, peritoneal abscess formation and septicemia because of Staphylococcus aureus and Candida tropicalis infection, with flushing abdominal cavity, intraperitoneal drainage, antibiotics, and total parenteral nutrition support, the patient survived 2.3 months after the operation. The third patient with generalized peritonitis syndrome on postoperative day 11 then developed septicemia due to gram-negative bacilli; given the above active conservative treatment, the patient survived 24 days after the surgery. The fourth patient developed late-onset mild anastomosis fistula on postoperative day 30 and received conservative treatment; the patient survived 3 months after the surgery. Two patients developed severe diarrhea (grade 3) on postoperative days 6 and 8, respectively, received antidiarrheal therapy, restoration of intestinal flora and electrolytes supplementation therapy, and recovered after 15 and 20 days, respectively. Four patients developed septicemia, two of whom were secondary to above anastomosis leakage, and the other two patients were infected with Candida parapsilosis, Enterococcus faecium on postoperative days 10 and 9, respectively, received intensified antiseptic treatments, and these two patients completely recovered in about 8 days. The last SAE case developed acute myocardium infraction on postoperative day 2 and the patient died.

Discussion
CRS + HIPEC as a comprehensive treatment strategy makes the best of surgical resection, locoregional  [22]. We have launched experimental [23] and clinical [7,16] studies to prove the safety and effectiveness of CRS + HIPEC for PC. The Netherlands Cancer Institute has proved in colorectal PC patients the 70 % gain in overall survival (22.4 months in the CRS + HIPEC group vs. 12.6 months with standard palliative therapy) and recommends that CRS + HIPEC be the standard treatment model for CRC PC patients [22]. Spiliotis has conducted a phase III prospective randomized study in recurrent epithelial ovarian cancer and demonstrated that CRS + HIPEC could prolong OS nearly twice as much as single CRS (26.7 vs. 13.4 months) [24]. The peritoneal-plasma barrier limits the absorption of large molecule-weight drugs by the peritoneum, ensuring high concentration of drugs in the abdominal perfusion solution. As a result, HIPEC increases the direct cytotoxic effects of chemotherapeutic drugs on peritoneal surface tumors and reduces the systemic side effects. The mechanism of lobaplatin is similar to that of other platinum drugs. Specifically, lobaplatin induces the formation of inter-strand Pt-GG and Pt-AG crosslinks, hindering DNA replication and transcription ultimately inhibiting gene expression in tumor cells [25]. Lobaplatin has shown encouraging broad-spectrum anticancer activity against OC, CRC, GC, lung cancer, breast cancer, and nasopharynx cancer [13-15, 26, 27]. Docetaxel is a semisynthetic complex of the taxane class anti-tumor drugs. It binds to free tubulin, accelerates the assembly of tubulin into stable microtubules, and suppresses microtubule depolymerisation, blocks cell cycle in G-M phase, and inhibits cell proliferation. Docetaxel is also a broadspectrum cytotoxic drug with potent effects on several malignant solid tumors [28,29]. A phase I clinical trial demonstrated that lobaplatin combined with docetaxel to treat human solid tumors could exhibit short-term efficacy with a low incidence of SAE [13].
In addition to routine hematological examination, the detection of serum TM was necessary. In this study, 82 patients had elevated serum CEA, CA125, or CA199 levels before operation, and 71 cases (86.6 %) had postoperative TM levels reduced or returned to normal. As serum CEA, CA125, and CA199 levels could reflect tumor invasiveness [31], peritoneal free tumor cells in In the original surgery calculation OS overall survival, mo months the ascites [32], and proliferative activity of tumor cells in ascites or primary tumor [33], respectively, the reduction of these TM could provide direct evidence that CRS + HIPEC is effective to control PC. The median OS for the 100 patients was 24.2 (95 % CI, 15.0-33.4) months, with the 1-, 3-, and 5-year survival rates being 77.5, 32.5, and 19.8 %, respectively. From this study, several lines of evidence could be obtained to support the comprehensive strategy for PC. First, the median disease specific OS could reach 31.2 and 27.5 months for patients with non-neoadjuvant chemotherapy and synchronous PC, but 20.7 and 13.2 months for those with neoadjuvant chemotherapy and metachronous PC. Although such differences did not reach statistical significance, possibly due to followup time and sample size, the data do suggest that nonneoadjuvant chemotherapy and synchronous PC could obtain relatively better survival from the therapy.
Second, in terms of origin of PC, the PMP and OC PC achieved better OS than the others. In our study, the median OS of OC PC, GC PC, and CRC PC was 34.6, 15.7, and 14.9 months, respectively, similar to the literature reports of 26.7, 12.0, and 13.7 months [7,16,24], respectively, suggesting that CRS + HIPEC with lobaplatin and docetaxel to treat PC can achieve acceptable clinical outcome. Third, in terms of PCI, 56 % of the total patients in this study had HPCI, and the median OS was 16.3 (95 % CI, 8.6-24.0) months. The results suggest that HPCI patients could still benefit from CRS + HIPEC rather than the traditional treatment with a poor median survival of less than 6 months. However, it was significantly shorter than the median OS of 46.1 (95 % CI, 10.7-81.5) months for LPCI. Fourth, in terms of CC score, 63 % of PC patients with CC0-1 CRS achieved a median OS of 42.9 (95 % CI, 28.3-57.5) months, much longer than the median OS of 13.6 (95 %   [13,14,34]. One was the observational study on patients with plural effusion or ascites [34]. The other two was phase I/II clinical trials on the safety and efficacy of the two agents on a variety of solid tumors. A phase I clinical trial demonstrated that lobaplatin (35 mg/m 2 ) combined with docetaxel (60 mg/m 2 ) to treat human solid tumors (non-small cell lung cancer 11, small cell lung cancer 2, breast cancer 2, gastric cancer 1, endometrial carcinoma 1) could exhibit shortterm efficacy (the response rate 7.1 %, the disease control rate 78.6 %) and a low incidence of SAE, such as leukopenia 30 % (grade 3), neutropenia 50 % (grades 3-4) without non-hematological toxicities, with median chemotherapy cycles of four (range, 1-6 cycles) [13]. This phase I study established that the maximal tolerated dose for this chemotherapy regimen is lobaplatin 35 mg/m 2 combined with docetaxel 60 mg/m 2 , and this regimen demonstrated broad-spectrum anti-tumor properties against lung cancer, breast cancer, endometrial cancer, and gastric cancer. A phase II study evaluated the clinical efficacy and safety of lobaplatin (30 mg/m 2 ) combined with docetaxel (75 mg/m 2 ) on 39 patients with recurrent or metastatic nasopharygenal carcinoma [14]. This study demonstrated 61.5 % overall response rate, 84.6 % disease control rate, and the median time of progression 10 (95 % CI, 7.3-12.8) months. The most common grade 3/4 toxicities included leucopaenia and neutropenia 17.9 %, anemia 5.1 %, and increased aminotransferase level 2.6 %. This study again demonstrated that this lobaplatin-docetaxel combination is effective against squamous cell carcinoma. A clinical observational study demonstrated that lobaplatin (20-30 mg/ m 2 ) used in intrapleural or intraperitoneal infusion is a safe and effective treatment for patients with malignant pleural effusion or ascites from colorectal cancer or uterine cancer [34]. Compared with these studies, our study is the first to demonstrate that the lobaplatin-docetaxle regimen used in HIPEC is safe and effective against peritoneal carcinomatosis from colorectal cancer, gastric cancer, ovarian cancer, primary peritoneal carcinoma, and pseudomyxoma peritonei. Our dose (50 mg/m 2 of lobaplatin and 60 mg/m 2 of docetaxel) used is comparable to those reported above. And the adverse events were also comparable to the reported results.

Conclusions
CRS + HIPEC with lobaplatin and docetaxel to treat PC is a feasible procedure with acceptable safety and can prolong the OS of patients with PC from gastrointestinal and gynecological malignancies.