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Blog aimed at residents in surgery
 URL :  www.surgical-oncology.net             e mail surgoncnet@gmail.com
Intraperitoneal Chemotherapy in gastric cancer: updating.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.



March 2002.     Review Article.        To previous article about intraperitoneal chemotherapy

Hyperthermia is one of the modalities used to treat various forms of malignancies, including esophageal, stomach, or rectal cancers.
Hyperthermia exerts a cytotoxic effect in combination with various mechanisms. Hyperthermia is applied in combination with chemotherapy and/or radiotherapy in the clinical setting. Among the anticancer drugs that are synergistic with hyperthermia is cisplatin, which is prevalent for clinical application. The mechanism of enhanced cytotoxicity of cisplatin includes increased intracellular drug accumulation, increased platinum-DNA adducts, and inhibition of DNA repair.
Regarding the factors that influence thermosensitivity, in vitro experiments demonstrated the heat-shock proteins or tumor suppressor gene p53 to be related to thermosensitivity. In the clinical setting, these factors remain to be firmly established as predictive factors for thermosensitivity ( 1 ).

Chikara Kunisaki et al affirm that P-CHPP by their methods had no efficacy as prophylactic treatment for peritoneal recurrence induced by gastric cancer. New therapeutic strategies, such as chemosensitivity assessment, are necessary to obtain good therapeutic results with CHPP.
From 1992 to 1999, a total of 124 patients with advanced gastric cancer with tumors invading deeper than the serosa but with no peritoneal metastasis underwent potentially curative gastrectomy and were enrolled in this study, based on the comparison of 2 groups who were not fully comparable. Also, this study was not a prospective randomized controlled study. Prophylactic continuous hyperthermic peritoneal perfusion (P-CHPP) was performed in 45 patients younger than 65 years old and without comorbidity who gave informed consent. Seventy-nine patients who did not meet the inclusion criteria represented the control group. After reconstruction of the alimentary tract, P-CHPP was carried out for 40 minutes with 150 mg cisplatin, 15 mg mitomycin C, and 150 mg etoposide in 5 to 6 L physiologic saline maintained at 42C to 43C. The surgical results, recurrent pattern, and postoperative morbidity were assessed by univariate and multivariate analysis ( 2 ).
The authors underline that other groups have reported efficacy with hyperthermic intraperitoneal chemotherapy ( 3, 4, 5 ). It has also been reported that hyperthermic intraperitoneal chemotherapy combined with peritonectomy is effective against peritoneal dissemination of gastric cancer ( 6, 7, 8 ).
But according to Kunisaki's article peritonectomy combined with intraperitoneal hyperthermic chemoperfusion would raise the incidence of postoperative morbidity and lower the quality of life for patients because of the burden of excessive surgery. Therefore, procedures such as peritonectomy should still be carried out under strict research protocols. In Japan, CHPP is not commonly adopted by surgeons, because they consider that the therapeutic results obtained with it are likely to be poor and because postoperative morbidity is frequent, as our results suggest ( 2 ).

Nomura et al report a study carried out to evaluate the efficacy of intraperitoneal ( IP ) and intravenous ( IV ) chemotherapy, as well as left upper abdominal evisceration ( LUAE - left upper abdominal evisceration- ), for patients with advanced gastric cancer. They carried out a retrospective study of 348 patients who underwent gastrectomy for advanced gastric carcinoma between 1978 and 1998 at their institution and who had macroscopic type 3 or 4 cancer ( Japanese classification ) with depth of invasion to the serosal surface, but no liver metastasis or lymph node metastasis around the abdominal aorta.
Cumulative survival rates were compared in patients who underwent gastrectomy together with: 1) intraoperative IP chemotherapy alone, 2) postoperative IV chemotherapy alone, 3) both IP and IV, or 4) no chemotherapy. Then patients were stratified according to the presence of peritoneal dissemination ( P+ ) and its absence ( P- ).
For P- patients there was no survival advantage with adjuvant IP or IV therapy when compared with surgery alone. For P+ patients, however, there was an improvement in survival when patients received both IP and IV, compared with survival with surgery alone. In P+ patients aged less than 60 years, there was improvement in survival for those who underwent IP therapy together with surgery, but not for those who had IV chemotherapy after surgery.
When LUAE was examined, there was a survival advantage for this procedure when there was no peritoneal dissemination. Four long-term survivors ( surviving for more than 5 years ) were identified. Three of four patients were aged less than 60 years, and all 4 had macroscopic type 4 gastric cancers.
Although the prognosis for patients with invasive type gastric cancer remains poor, there have been a few long-term survivors, in whom this survival was associated with aggressive combination therapy, including surgery, IP, and IV therapy. P+ patients aged less than 60 years and patients with type 4 gastric cancer may stand to benefit most from such therapy. For P - patients, the role of adjuvant therapy continues to be ambiguous, although LUAE in this population may be superior to PS - total gastrectomy combined with resection of the pancreatic body, tail, and spleen - ( 9 ).

Jeung et al investigated the feasibility of using intraperitoneal chemotherapy to treat gastric cancer with intra-abdominal gross residual lesions after palliative gastrectomy with maximal cytoreduction. Early postoperative intraperitoneal chemotherapy started on the day of operation with 5-fluorouracil 500 mg/m2 and cisplatin 40 mg/m2 (days 1-3) over a 4-week interval. The progression-free survival (PFS) was 7 months and the overall survival was 12 months. In multivariate analysis, performance status was the only significant defining factor for PFS (P = 0009). The predominant toxicity was neutropenia and nausea/vomiting. The relative dose intensity of 5-fluorouracil and cisplatin was 89 and 63 per cent respectively ( 12 ).
Survival in this study was comparable to that reported by Terashima et al, who noted a median survival time of 343 days with overt peritoneal metastasis. They used intraperitoneal cisplatin and intravenous 5-FU infusion ( 13 ).
Several factors could account for this modest result.
1) Most randomized reports advocating the role of intraperitoneal chemotherapy have utilized a hyperthermic technique.
2) The resection might unavoidably have left gross residual tumour behind, and drug penetration might therefore have been inadequate.
3) A second factor relates to the long-term use of Tenckhoff catheters, which fail to provide uniform drug delivery because of a natural fibrotic reaction to the plastic catheter. In addition, many chemotherapeutic agents have a sclerotic effect on the peritoneum. These factors, together with the adhesive effects of surgery itself, may cause uneven and inefficient drug delivery.
4) Although the planned dosage in this study was small compared with the clinically recommended dose, half of the courses were postponed owing to toxicity. Neither of the chemotherapeutic agents used in this protocol could achieve adequate dose intensity. The dose intensity of cisplatin was only 63 per cent. Adequate dose adjustment is necessary. Systemic therapy following or combined with intraperitoneal chemotherapy might be an alternative approach.
5) Bone marrow suppression was the most predominant toxic effect. This toxicity profile was similar to that of Terashima et al. Such profiles indicate that chemotherapeutic agents enter the systemic circulation even in the presence of gross residual peritoneal disease.
6) Quantification of intra-abdominal seeding is important. Patients in whom complete cytoreduction cannot be achieved, such those with distant nodal metastasis and large peritoneal implants, should not receive chemotherapy ( 12 ).

Tsujitani et al. document the results of the first phase I study of hypotonic intraperitoneal cisplatin in patients with locally advanced gastric cancer.
Isotonic intraperitoneal cisplatin was administered immediately after gastrectomy in increasing doses to patients with locally advanced gastric cancer until dose-limiting toxicity (DLT) was observed in 2 or more of 3 patients who were treated at a specific dose level. The osmolarity reduction and dose escalation trial for hypotonic intraperitoneal cisplatin was then performed until DLT was observed in 2 or more of 6 patients.
Hypotonic intraperitoneal cisplatin treatment with distilled water at the time of a gastric resection is well tolerated. Hypotonic intraperitoneal cisplatin does not increase the plasma level of platinum at a dose of 70 mg/m2. Phase II/III studies are still required to clarify the efficacy of hypotonic intraperitoneal cisplatin for the treatment of the peritoneal dissemination in gastric cancer ( 14 ).

Treatment of carcinomatosis may involve in the Coliseum Technique the use of heated intraperitoneal chemotherapy; the cytotoxic solution is administered in the operating room with the abdomen open so that manual distribution results in uniform treatment. The potential risk of this procedure to the operating room personnel has not been previously investigated.
Analysis of samples of operating room air and urine from 10 procedures showed no detectable levels of mitomycin C. Six tests of three different types of gloves showed a 10-fold range of mitomycin C penetration. The least permeable gloves leaked a mean of 3.8 parts per million over 90 minutes ( 16 ).

References

1) Ikuo Takahashi et al. Clinical application of hyperthermia combined with anticancer drugs for the treatment of solid tumors. Surgery 2002; 131: S78-84.

2) Chikara Kunisaki, Hiroshi Shimada, Masato Nomura, Hirotoshi Akiyama, Masazumi Takahashi, Goro Matsuda. Lack of efficacy of prophylactic continuous hyperthermic peritoneal perfusion on subsequent peritoneal recurrence and survival in patients with advanced gastric cancer. Surgery 2002; 131: 521-8.

3) Yu W, Whang I, Suh I, Averbach A, Chang D, Sugarbaker PH. Prospective randomized trial of early postoperative intraperitoneal chemotherapy as an adjuvant to resectable gastric cancer. Ann Surg 1998;228:347-54.

4) Sugarbaker PH. Management of peritoneal surface malignancy: the surgeon's role. Langenbecks Arch Surg 1999;384:576-87.

5) Fujimoto S, Takahashi M, Mutou T, Kobayashi K, Toyosawa T. Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in patients with advanced gastric carcinoma. Cancer 1999; 85:529-34.

6) Yonemura Y, Fujimura T, Fushida S, Fujita H, Bando E, Nishimura G, et al. A new surgical approach (peritonectomy) for the treatment of peritoneal dissemination. Hepatogastroenterology 1999;46:601-9.

7) Sugarbaker PH, Yonemura Y. Clinical pathway for the management of resectable gastric cancer with peritoneal seeding: best palliation with a ray of hope for cure. Oncology 2000;58:96-107.

8) Hirose K, Katayama K, Iida A, Yamaguchi A, Nakagawara G, Umeda S, et al. Efficacy of continuous hyperthermic peritoneal perfusion for the prophylaxis and treatment of peritoneal metastasis of advanced gastric cancer: evaluation by multivariate regression analysis. Oncology 1999;57:106-14.

9) Eiji Nomura et al. Efficacy of intraperitoneal and intravenous chemotherapy and left upper abdominal evisceration for advanced gastric cancer. Gastric Cancer 2001, 4: 75-82.

10) Yonemura Y et al. Postoperative results of left upper abdominal evisceration for advanced gastric cancer. Hepatogastroenterology 2000; 47; 571-4.

11) Yonemura Y et al. Mechanism of the formation of the peritoneal dissemination in gastric cancer. Int J Oncol 1996; 8: 795-802.

12) H. C. Jeung, S. Y. Rha, W. I. Jang, S. H. Noh and H. C. Chung. Treatment of advanced gastric cancer by palliative gastrectomy, cytoreductive therapy and postoperative intraperitoneal chemotherapy. British Journal of Surgery Volume 89 Issue 4 Page 460 - April 2002.

13) TerashimaM, TakaganeA, OyamaK, AbeK, ArayaM, YonezawaH et al. Therapeutic efficacy of intra-peritoneal infusion of cisplatin and continuous intravenous infusion of 5-fluorouracil in gastric cancer patients with peritoneal metastasis. Gan To Kagaku Ryoho 1999; 26: 1806-8.

14) Shunichi Tsujitani, Kenji Fukuda, Hiroaki Saito, Akira Kondo, Masahide Ikeguchi, Michio Maeta, Nobuaki Kaibara. The administration of hypotonic intraperitoneal cisplatin during operation as a treatment for the peritoneal dissemination of gastric cancer. Surgery 2002;131:S98-104. 15) Makoto Tahara et al. Sequential methotrexate and 5-fluorouracil therapy for gastric cancer patients with peritoneal dissemination: a retrospective study. Gastric Cancer Volume 4 issue 4 ( 2001 ), pp 212-218.

16) O. Anthony Stuart, BS, Arvil D. Stephens, BS, Laura Welch, MD and Paul H. Sugarbaker, MD. Safety Monitoring of the Coliseum Technique for Heated Intraoperative Intraperitoneal Chemotherapy With Mitomycin C. Annals of Surgical Oncology 9:186-191 (2002)

17) Beaujard AC, Glehen O, Caillot JL, Francois Y, Bienvenu J, et al. Intraperitoneal chemohyperthermia with mitomycin C for digestive tract cancer patients with peritoneal carcinomatosis. Cancer 2000;88:2512-9.

18) Kunisaki C, Shimada H, Yamaoka H, Takahashi M, Ookubo K, Akiyama H, et al. Indications for paraaortic lymph node dissection in gastric cancer patients with paraaortic lymph node involvement. Hepatogastroenterology 2000;47:586-9.

19) Kunisaki C, Shimada H, Yamaoka H, Wakasugi J, Takahashi M, Akiyama H, et al. Significance of para-aortic lymph node dissection in advanced gastric cancer. Hepatogastroenterology 1999;46:2635-42.

20) Akiyama H, Yamaoka H, Tanaka K, Ishikawa T, Ichikawa Y, Wakasugi J, et al. Continuous hyperthermic peritoneal perfusion for peritoneal dissemination of gastric cancer. Hepatogastroenterology 1998;45:2079-86.

21) DogliettoGB, PacelliF, CaprinoP, AlfieriS, CarrieroC, MalerbaM et al. Palliative surgery for far-advanced gastric cancer: a retrospective study on 305 consecutive patients. Am Surg 1999; 65: 352-5.

22) HanazakiK, SodeyamaH, MochizukiY, MachidaT, YokoyamaS, SodeY et al. Efficacy of extended lymphadenectomy in the noncurative gastrectomy for advanced gastric cancer. Hepatogastroenterology 1999; 46: 2677-82.

23) HanazakiK, SodeyamaH, YokoyamaS, SodeY, WakabayashiM, KawamuraN et al. Postoperative chemotherapy may improve prognosis in unresectable gastric cancer. J Clin Gastroenterol 1998; 26: 269-73.



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