- Email: [email protected]
Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer
· Advances in Medical Sciences · Vol. 57(1) · 2012 · pp 46-50 · DOI: 10.2478/v10039-012-0002-1 © Medical University of Bialystok, Poland
Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer Milczek T1*, Klasa-Mazurkiewicz D2, Sznurkowski J1, Emerich J3 1 Department of Gynaecology, Gynaecological Oncology and Gynaecological Endocrinology, Medical University of Gdansk, Gdansk, Poland 2 Department of Obstetrics and Perinatology, Medical University of Gdansk, Gdansk, Poland 3 Department of Gynaecology and Gynaecological Oncology, Medical University of Gdansk, Gdansk, Poland
* CORRESPONDING AUTHOR: Department of Gynaecology, Gynaecological Oncology and Gynaecological Endocrinology, Medical University of Gdansk, Gdansk, Poland Kliniczna 1a, 80-402 Gdansk, Poland, Tel +48 583493441, Fax +48 583493518 e-mail: [email protected] (Milczek Tomasz)
Received 11.07.2011 Accepted 29.12.2011 Advances in Medical Sciences Vol. 57(1) · 2012 · pp 46-50 DOI: 10.2478/v10039-012-0002-1 © Medical University of Bialystok, Poland
ABSTRACT Purpose: We compared response, survival and side effects of regiments with intravenous cyclophosphamide followed by intraperitoneal cisplatin versus intravenous cyclophosphamide followed by intraperitoneal carboplatin as second line treatment in one center retrospective study. Material and Methods: Inclusion criteria were: relapse or recurrence of the disease after surgery and first line treatment; stage III histologicaly documented serous epithelial ovarian cancer after one or more prior regiments of chemotherapy. Recurrence were confirmed throughout restaging laparotomy or second look laparotomy. Patients from one of the groups received 90mg/m2 cisplatin on the first day and 750mg/m2 cyclophosphamide intravenously, while the second group members AUC 6 carboplatin intraperitoneally and 750mg/m2 cyclophosphamide intravenously. Four courses were administrated for each patient. Results: Of the 49 patients in the cisplatin group the response rates were 21 (43%), 10 (20%) and 18 (37%) in the groups of pathologic complete response, pathologic partial response and progressive disease, respectively. The median survival from the initiation of intraperitoneal chemotherapy was 59 months. Of the 25 patients in the carboplatin group the response rates were 10 (40%), 4 (16%) and 11 (44%) respectively. The median survival -51 months. The differences between the groups were not statistically significant p>0.05 either in response or in toxicity. Conclusions: The results of our research including relatively long survival from intraperotoneal chemotherapy initiation confirm that carboplatin treatment is as good as cisplatin in second line intraperitoneal chemotherapy for ovarian cancer. Key words: ovarian cancer, intraperitoneal chemotherapy
INTRODUCTION Peritoneal cavity is the principal site of disease in ovarian cancer [1]. Ovarian cancer is the leading cause of death of gynecologic cancer and the fifth leading cause of cancer death in women in Poland and in the Western World [1,2]. For these reasons, researchers are looking for prognostic factors and new treatments for this disease [3,4] Recurrent or refractory ovarian cancer is a major problem, especially in stage III and IV
[1]. There are many drugs to choose in relapsed ovarian cancer, but all show a response ranging between 10-15% occasionally to 36%, either as a single agent or in combinations [5]. Currently it is difficult to recommend the best option, but it is important to calculate the function of bone marrow, kidneys and other organs in patients who have had many lines of chemotherapy [5]. The intensity of intravenous chemotherapy is limited by nephrotoxicituy, myelotoxicity and neurotoxicity [6]. Several active drugs can be administered directly into the peritoneal cavity. The rationale for intraperitoneal therapy in ovarian
47
Milczek T et al.
Table 1. Distribution of patient cohort by the cisplatin and carboplatin group age, stage, grade histology of the tumor and the residual disease. Cisplatin therapy group Number(%)
Carboplatintherapy group Number(%)
49
25
Medium
58
57
p<0.05
Range
22-71
22-70
p<0.05
49(100)
35(100)
p<0.05
12(24)
7(28)
p<0.05
Moderately differentiated
21(43)
11(44)
p<0.05
Poorly differentiated
12(24)
6(24)
p<0.05
Unknown
4(8)
1(4)
p>0.05
49(100)
25(100)
p<0.05
Total number
p value
Age
Histology Serous Differentiation grade Well differentiated
FIGO stage III Residual disease microscopic
3(6)
2(8)
p<0.05
R<0.5cm
39(80)
21(84)
p<0.05
0.5cm< R< 2cm
6(12)
2(8)
p<0.05
R-Residual disease in time of IP initiation IP- Intraperitoneal Chemotherapy
cancer is that the peritoneum, the predominant site of tumor occurrence, receives sustained exposure to high concentration of antitumor agents while normal tissues, such as the bone marrow, are relatively spared [6, 7]. To be clinically relevant, high intraperitoneal (IP) drug concentrations must result in high intracellular concentrations of the drug in order to successfully kill the tumour. Tissue penetration is therefore one of the key issues in IP therapy. Platinum distribution was studied in rat peritoneal tumours after IP installation of equimolar doses of carboplatin and cisplatin [8]. Low platinum concentrations were detected on the surface of the tumour after carboplatin treatment, whereas no platinum was detected at 0.5 mm tumour depth. In contrast, after cisplatin treatment, high platinum concentrations were measured in the periphery of the tumour and moderate concentrations were measured in its centre. In all, 7 times more platinum was detected after cisplatin treatment than after carboplatin treatment, and 10 times more carboplatin than cisplatin had to be injected to obtain comparable platinum concentrations in the tumour tissue. These data show a clear discrepancy between the potentials of different antineoplastic drugs to penetrate tumour cells, and clinical data supported these observations [9]. After publishing the results of these two studies the use of intraperitoneal carboplatin was almost ignored for years. Since intravenously-administered (IV) carboplatin has been shown to be as effective as cisplatin being at the same time less toxic and easier to administer it is reasonable, as National Cancer Institute (NCI) has suggested, followed by the expert’s opinions, to test the role of IP carboplatin [10, 11].
MATERIALS AND METHODS In observation analysis seventy four patients had stage III histologically documented serous epithelial ovarian cancer, as defined by International Federation of Gynecology and Obstetrics (FIGO) and have undergone one or more prior regimens of chemotherapy (with at least one platinum-containing regime). All patients were after primary cytoreductive surgery. Conditions of inclusion for intraperitoneal treatment were relapse or recurrence of disease, performance status 0-2 (with 0 being fully active and 4 completely disabled) according to Gynecologic Oncology Group (GOG), age over 18, life expectancy over 4 months, neutrophile count exceeding 1.5 x 109/l, platelet count exceeding 100 x 109/l, serum creatinine not exceeding 1.5 x the upper normal limit (UNL), bilirubin not exceeding UNL and AST and/or ALT 2.5 x UNL. The researched homogenous subgroup was elected from the group of 223 patients who were treated intraperitonealy with four or six IP cycles at the Department of Gynecology and Gynecologic Oncology, Medical University of Gdansk. Second look laparotomy (SLL) was performed for the detection of cancer after the initial cytoreductive surgery and first line treatment; the SLL was performed in all patients who agreed to such surgery. For the detection of recurrence of disease CA 125, CT, scan and restaging laparotomy were performed. Before each treatment, a physical examination was performed and a medical history taken, together with complete blood count, blood chemical measurement and measurement of CA 125. Seventy-four patients elected to the analysis received
Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer
48
Table 2. Analysis of IP treatment effects on response and the overall survival from the initiation of IP therapy, related to the type of platinum contained agent. pCR
pPR
PD
Median Duration of OS (months)
III serous ovarian cancer cisplatin group 49 patients
21 (43%)
10 (20%)
18 (37%)
59
III serous ovarian cancer carboplatin group 25 patients
10 (40%)
4(16%)
11(44%)
51
Total
31 (42%)
7 (9%)
29 (39%)
52
p value between all groups p > 0.05 pCR: pathological complete response PD: progressive disease pPR: pathological partial response IP: intraperitoneal chemotherapy OS: overall survival
treatment of four IP courses delivered once every 3 weeks. Forty- nine patients received 90mg/m2 cisplatin (IP) and sodium thiosulphate intravenously for 1 day, and 750mg/ m2 cyclophosphamide IV. Twenty five patients received AUC 6 carboplatin intraperitonealy and 750mg/ m2 cyclophosphamide IV (Tab.1). Standard premedication was given to prevent hypersensitivity reaction. Hydratation and antiemetic agents were given before cisplatin administration. For intraperitoneal therapy cisplatin and carboplatin were reconstituted in 2 litres of normal saline and infused as rapidly as possible through an implantable open-ended Tenckhoff catheter placed at the time of Second Look Laparotomy, Secondary Cytoreductive Surgery (SCS) or restaging laparotomy. No ascites occurred at the initiation of IP chemotherapy. Before they received subsequent cycles of therapy, patients were required to have absolute neutrophil count of no less than 1.5 x 109/l, platelet count of more than 100 x 109/l and serum creatinine of less than 1.5x UNL. After the therapy a restaging laparotomy associated with catheter removal was performed. During restaging laparotomy, similarly to SLL, biopsies were taken from multiple sites, including paracolic gutter, diaphragm, urinary bladder and pouch of Douglas. Routine washing of the peritoneal cavity was done. The followup consisted of a physical examination, complete blood count, blood chemical measurement and measurement of CA 125. The primary end point of the study was treatment responses in all group members defined as follows: pathological complete response (pCR) is the absence of disease at surgical evaluation, including multiple random biopsies and peritoneal washing. Pathological partial response (pPR) is a partial remission at surgical evaluation including pathological examination of resected or biopsy material. The following conditions were considered progressive disease (PD) or relapse: ≥25% increase of visible residual lesion, recurrence of disease at previously-affected sites or appearance of any new lesions. Single informed consent was obtained from all patients before their inclusion, and the study protocol received ethical approval from the research ethics committee. Secondary end point was overall survival from the start of IP therapy to March 2007 or till death.
Figure 1. Survival analysis (Kaplan-Meier) in relation to IP treatment response, the administration of four IP cisplatin or four IP carboplatin cycles, as of the time of IP treatment initiation.
A: Survival of all patients from the start of IP therapy. B: Survival time from the start of IP treatment in relation to the administration of four IP cisplatin or four IP carboplatin cycles (Log rank carboplatin versus cisplatin p>0.05). IP: intraperitoneal chemotherapy.
Statistical analysis Probability of survival was calculated by Kaplan-Meier method. The χ² test was used for the comparison of proportions and the Log rank test was used for the difference in median survival time. p values <0.05 were considered statistically significant.
49
Milczek T et al.
Table 3. Comparison of frequency and statistic difference catheter related, surgery related, and chemotherapy related adverse events in cisplatin and carboplatin groups. Adverse Event
Cisplatin therapy group Number(%)
Carboplatin therapy group Number(%)
p value
Total number
49(100)
25(100)
Leucopenia <1 x 109/l
20(39)
11(42)
0.05
Plate count < 250 x 109/l
5 (10)
4(16)
0.045
Other hematological events
39(81)
22(89)
0.04
Gastrointestinal events
24(49)
12(48)
0.05
Renal events
4(8)
1(4)
0.04
Pulmonary events
1(2)
1(4)
0.05
Cardiovascular events
1(2)
1(4)
0.05
Neurological events
11 (22)
4(15)
0.03
Cutaneous changes
39(81)
20 (80)
0.05
Fever
5 (10)
3(10)
0.05
Infections
8 (15)
4(15)
0.05
Pain
5 (10)
3(10)
0.05
Bowel perforation during catheter insertion
2(4)
1(4)
0.05
Bowel perforation during catheter removal
3(6)
2(7)
0.05
Inability to flush into the abdomen
4(8)
2(8)
0.05
Erosion into the bowels
2 (4)
0
0.05
Erosion into the vagina
0
1(4)
0.05
RESULTS
DISCUSSION
For the analysis the group of 74 homogenous patients who completed all four assigned IP cycles with cisplatin or carboplatin only and who had stage III serous ovarian cancer were chosen. Twenty-five patients were included in the carboplatin group, 49 in the cisplatin group. No statistical differences between these groups were found. Disease characteristics of the 74 patients are summarised in Tab. 1. Response to IP chemotherapy in reference to the type of platinum-containing agent is presented in Tab. 2. The median survival time from the start of IP therapy in all group members reached 52 months. It was shorter in the carboplatin group than in the cisplatin group but the difference was not statistically significant (Fig. 1a,b, Tab. 2). Adverse effects of the treatment are summarised in Tab. 3. The toxicity associated with the presence of an IP catheter, IP administration of the chemotherapy directly into the peritoneal cavity and the kind of anticancer agent was relatively low. For patients in the cisplatin group neurological and renal events occurred relatively more often. Hematological events occurred slightly more frequently in the carboplatin group. There were no differences between any other surgical adverse events, or any other typical events associated with IP therapy, like fatigue, pain, gastrointestinal or metabolic adverse events.
With the current knowledge the natural history of ovarian cancer is clinical remission followed by relapse and another remission. Although overall response rates of up to 80% are achieved after the first line treatment, only 47% of the patients with complete response (CR) will have pCR at SLL [12]. Over 50% of this group members experience the return of the disease within 24 months after SLL and over 60% of them in peritoneal cavity [13]. There are not enough randomised studies to suggest a strategy for the therapy in recurrent or persistent ovarian cancer [5]. Some patients with local recurrence may benefit from secondary cytoreductive surgery, the others from different kinds of therapy [5]. A recent survival analysis of IP cisplatin use in patients with recurrent ovarian cancer indicated a longer survival time in selected patients, especially with minimal residual disease. The choice of SLL was necessitated by lack of high-quality image examination that could locate changes of less than 2cm in diameter. Additionally, successive catheter removals were a result of using Tenckhoff catheters with two Dacron rings. Currently, IP treatment usually is accompanied by a sub-dermal inlet catheter which can be removed under regional anaesthesia without the need of laparotomy. As it was mentioned in introduction the utility of carboplatin to IP therapy is not clear [8-11]. Critical review of Markman retrospective study shows that the group researched was too small and the equivalency between carboplatin and cisplatin was too low [11]. According to the GOG 158 trial the equivalency of carboplatin AUC 7.5
Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer
50
is 471mg/m² [14, 15]. Markman used 200-300 mg/m² IP as the equivalency of 100 mg/m² of cisplatin [10]. That is probably the reason of the worse results in carboplatin treatment than in the cisplatin group [11]. Given the limitations that this was not a randomised trial, and that the group was elected retrospectively it is natural to conclude that carboplatin IP is as effective as cisplatin when considering the response rate (63% versus 56%) and the overall survival rate (59 months to 51 respectively) in second line treatment (p>0.05) (Tab. 2). Additionally, very similar results were demonstrated by Speyer, where only 200mg/m² of carboplatin was administered and the response rate in second line treatment reached 74 % [16]. The toxicity in both groups is comparable and leads to the conclusion that the substance which is to be used for IP therapy in second line treatment should be chosen according to the individual predispositions of the patient. Taking into consideration the generally good results of our research, which confirm the observations of other works [16-18] it is safe to conclude that carboplatin can be safely used as an alternative of cisplatin in IP therapy.
REFERENCES 1. Cannistra SA. Cancer of the ovary. N Engl J Med. 2004 Dec 9;351(24):2519-29. 2. Wojciechowska U, Dikowska J, Tarkowski W, Zatoński W. Nowotwory złośliwe w Polsce w 2002 roku [Cancer in Poland in 2002]. Warszawa: Centrum Onkologii– Instytut im. Marii Sklodowskiej-Curie; 2004. 112 p. ISSN: 0867-8251. 3. Tempfer C, Obermair A, Hefler L, Haeusler G, Gitsch G, Kainz C. Vascular endothelial growth factor serum concentrations in ovarian cancer. Obstet Gynecol. 1998 Sep;92(3):360-3. 4. Laudański P, Kowalczuk O, Klasa-Mazurkiewicz D, Milczek T, Rysak-Luberowicz D, Garbowicz M, Baranowski W, Charkiewicz R, Szamatowicz J, Chyczewski L. Selective gene expression profiling of mTOR-associated tumor suppressor and oncogenes in ovarian cancer. Folia Histochem Cytobiol 2011;49(2):317-24. 5. Benedet JL, Bender H, Jones H 3rd, Ngan HY, Pecorelli S. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 2000 Aug;70(2):209-62. 6. Hofstra LS, de Vries EG, Mulder NH and Willemse PH. Intraperitoneal chemotherapy in ovarian cancer. Cancer Treat Rev. 2000 Apr;26(2):133-43. 7. Laudański P, Szamatowicz J, Oniszczuk M. Profiling of peritoneal fluid of women with endometriosis by chemokine protein array. Adv Med Sci. 2006;51:148-52. 8. Los G, Verdegaal EM, Mutsaers PH, and McVie JG. Penetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy. Cancer Chemother Pharmacol. 1991;28(3):159-65.
9. Markman M, Reichman B, Hakes T, Rubin S, Lewis JL Jr, Jones W, Barakat R, Curtin J, Almadrones L, Hoskins W. Evidence supporting the superiority of intraperitoneal cisplatin compared to intraperitoneal carboplatin for salvage therapy of small-volume residual ovarian cancer. Gynecol Oncol. 1993 Jul;50(1):100-4. 10. Markman M and Walker JL. Intraperitoneal chemotherapy of ovarian cancer: a review, with a focus on practical aspects of treatment: J Clin Oncol. 2006,Feb 20;24(6)988-94. 11. Fujiwara K, Armstrong D, Morgan M and Markman M. Principles and practice of intraperitoneal chemotherapy for ovarian cancer: Int J Gynecol Cancer. 2007. JanFeb;17(1):1-20. 12. Howell SB, Zimm S, Markman M, Abramson IS, Cleary S, Lucas WE, Weiss JR. Long-term survival of advanced refractory ovarian carcinoma patients treated with small volume disease treated with intraperitoneal chemotherapy. J Clin Oncol. 1987 Oct;5(10):1607-12. 13. Barakat RR, Almadrones L, Venkatraman ES, Aghajanian C, Brown C, Shapiro F, Curtin JP, Spriggs D. A phase II trial of intraperitoneal cisplatin and etoposide as consolidation therapy in patients with Stage II-IV epithelial ovarian cancer following negative surgical assessment. Gynecol Oncol. 1998 Apr;69(1):17-22. 14. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM, Baergen R. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003 Sep 1;21(17):3194-200. 15. du Bois A, Lück HJ, Meier W, Adams HP, Möbus V, Costa S, Bauknecht T, Richter B, Warm M, Schröder W, Olbricht S, Nitz U, Jackisch C, Emons G, Wagner U, Kuhn W, Pfisterer J. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003 Sep 3;95(17):1320-9. 16. Speyer JL, Beller U, Colombo N, Sorich J, Wernz JC, Hochster H, Green M, Porges R, Muggia FM, Canetta R. Intraperitoneal carboplatin: favorable results in women with minimal residual ovarian cancer after cisplatin therapy. J Clin Oncol. 1990 Aug;8(8):1335-41. 17. McClay EF, Braly PD, Kirmani S, Plaxe SC, Kim S, McClay ME, Wilgus L, Howell SB. A phase II trial of intraperitoneal high-dose carboplatin and etoposide with granulocyte macrophage-colony stimulating factor support in patients with ovarian carcinoma. Am J Clin Oncol. 1995 Feb;18(1):23-6. 18. Fujiwara K, Suzuki S, Ishikawa H, Oda T, Aotani E and Kohno I. Preliminary toxicity analysis of intraperitoneal carboplatin in combination with intravenous paclitaxel chemotherapy for patients with carcinoma of the ovary, peritoneum, or fallopian tube. Int J Gynecol Cancer. 2005 May-Jun;15(3):426-31.
Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer Milczek T1*, Klasa-Mazurkiewicz D2, Sznurkowski J1, Emerich J3 1 Department of Gynaecology, Gynaecological Oncology and Gynaecological Endocrinology, Medical University of Gdansk, Gdansk, Poland 2 Department of Obstetrics and Perinatology, Medical University of Gdansk, Gdansk, Poland 3 Department of Gynaecology and Gynaecological Oncology, Medical University of Gdansk, Gdansk, Poland
* CORRESPONDING AUTHOR: Department of Gynaecology, Gynaecological Oncology and Gynaecological Endocrinology, Medical University of Gdansk, Gdansk, Poland Kliniczna 1a, 80-402 Gdansk, Poland, Tel +48 583493441, Fax +48 583493518 e-mail: [email protected] (Milczek Tomasz)
Received 11.07.2011 Accepted 29.12.2011 Advances in Medical Sciences Vol. 57(1) · 2012 · pp 46-50 DOI: 10.2478/v10039-012-0002-1 © Medical University of Bialystok, Poland
ABSTRACT Purpose: We compared response, survival and side effects of regiments with intravenous cyclophosphamide followed by intraperitoneal cisplatin versus intravenous cyclophosphamide followed by intraperitoneal carboplatin as second line treatment in one center retrospective study. Material and Methods: Inclusion criteria were: relapse or recurrence of the disease after surgery and first line treatment; stage III histologicaly documented serous epithelial ovarian cancer after one or more prior regiments of chemotherapy. Recurrence were confirmed throughout restaging laparotomy or second look laparotomy. Patients from one of the groups received 90mg/m2 cisplatin on the first day and 750mg/m2 cyclophosphamide intravenously, while the second group members AUC 6 carboplatin intraperitoneally and 750mg/m2 cyclophosphamide intravenously. Four courses were administrated for each patient. Results: Of the 49 patients in the cisplatin group the response rates were 21 (43%), 10 (20%) and 18 (37%) in the groups of pathologic complete response, pathologic partial response and progressive disease, respectively. The median survival from the initiation of intraperitoneal chemotherapy was 59 months. Of the 25 patients in the carboplatin group the response rates were 10 (40%), 4 (16%) and 11 (44%) respectively. The median survival -51 months. The differences between the groups were not statistically significant p>0.05 either in response or in toxicity. Conclusions: The results of our research including relatively long survival from intraperotoneal chemotherapy initiation confirm that carboplatin treatment is as good as cisplatin in second line intraperitoneal chemotherapy for ovarian cancer. Key words: ovarian cancer, intraperitoneal chemotherapy
INTRODUCTION Peritoneal cavity is the principal site of disease in ovarian cancer [1]. Ovarian cancer is the leading cause of death of gynecologic cancer and the fifth leading cause of cancer death in women in Poland and in the Western World [1,2]. For these reasons, researchers are looking for prognostic factors and new treatments for this disease [3,4] Recurrent or refractory ovarian cancer is a major problem, especially in stage III and IV
[1]. There are many drugs to choose in relapsed ovarian cancer, but all show a response ranging between 10-15% occasionally to 36%, either as a single agent or in combinations [5]. Currently it is difficult to recommend the best option, but it is important to calculate the function of bone marrow, kidneys and other organs in patients who have had many lines of chemotherapy [5]. The intensity of intravenous chemotherapy is limited by nephrotoxicituy, myelotoxicity and neurotoxicity [6]. Several active drugs can be administered directly into the peritoneal cavity. The rationale for intraperitoneal therapy in ovarian
47
Milczek T et al.
Table 1. Distribution of patient cohort by the cisplatin and carboplatin group age, stage, grade histology of the tumor and the residual disease. Cisplatin therapy group Number(%)
Carboplatintherapy group Number(%)
49
25
Medium
58
57
p<0.05
Range
22-71
22-70
p<0.05
49(100)
35(100)
p<0.05
12(24)
7(28)
p<0.05
Moderately differentiated
21(43)
11(44)
p<0.05
Poorly differentiated
12(24)
6(24)
p<0.05
Unknown
4(8)
1(4)
p>0.05
49(100)
25(100)
p<0.05
Total number
p value
Age
Histology Serous Differentiation grade Well differentiated
FIGO stage III Residual disease microscopic
3(6)
2(8)
p<0.05
R<0.5cm
39(80)
21(84)
p<0.05
0.5cm< R< 2cm
6(12)
2(8)
p<0.05
R-Residual disease in time of IP initiation IP- Intraperitoneal Chemotherapy
cancer is that the peritoneum, the predominant site of tumor occurrence, receives sustained exposure to high concentration of antitumor agents while normal tissues, such as the bone marrow, are relatively spared [6, 7]. To be clinically relevant, high intraperitoneal (IP) drug concentrations must result in high intracellular concentrations of the drug in order to successfully kill the tumour. Tissue penetration is therefore one of the key issues in IP therapy. Platinum distribution was studied in rat peritoneal tumours after IP installation of equimolar doses of carboplatin and cisplatin [8]. Low platinum concentrations were detected on the surface of the tumour after carboplatin treatment, whereas no platinum was detected at 0.5 mm tumour depth. In contrast, after cisplatin treatment, high platinum concentrations were measured in the periphery of the tumour and moderate concentrations were measured in its centre. In all, 7 times more platinum was detected after cisplatin treatment than after carboplatin treatment, and 10 times more carboplatin than cisplatin had to be injected to obtain comparable platinum concentrations in the tumour tissue. These data show a clear discrepancy between the potentials of different antineoplastic drugs to penetrate tumour cells, and clinical data supported these observations [9]. After publishing the results of these two studies the use of intraperitoneal carboplatin was almost ignored for years. Since intravenously-administered (IV) carboplatin has been shown to be as effective as cisplatin being at the same time less toxic and easier to administer it is reasonable, as National Cancer Institute (NCI) has suggested, followed by the expert’s opinions, to test the role of IP carboplatin [10, 11].
MATERIALS AND METHODS In observation analysis seventy four patients had stage III histologically documented serous epithelial ovarian cancer, as defined by International Federation of Gynecology and Obstetrics (FIGO) and have undergone one or more prior regimens of chemotherapy (with at least one platinum-containing regime). All patients were after primary cytoreductive surgery. Conditions of inclusion for intraperitoneal treatment were relapse or recurrence of disease, performance status 0-2 (with 0 being fully active and 4 completely disabled) according to Gynecologic Oncology Group (GOG), age over 18, life expectancy over 4 months, neutrophile count exceeding 1.5 x 109/l, platelet count exceeding 100 x 109/l, serum creatinine not exceeding 1.5 x the upper normal limit (UNL), bilirubin not exceeding UNL and AST and/or ALT 2.5 x UNL. The researched homogenous subgroup was elected from the group of 223 patients who were treated intraperitonealy with four or six IP cycles at the Department of Gynecology and Gynecologic Oncology, Medical University of Gdansk. Second look laparotomy (SLL) was performed for the detection of cancer after the initial cytoreductive surgery and first line treatment; the SLL was performed in all patients who agreed to such surgery. For the detection of recurrence of disease CA 125, CT, scan and restaging laparotomy were performed. Before each treatment, a physical examination was performed and a medical history taken, together with complete blood count, blood chemical measurement and measurement of CA 125. Seventy-four patients elected to the analysis received
Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer
48
Table 2. Analysis of IP treatment effects on response and the overall survival from the initiation of IP therapy, related to the type of platinum contained agent. pCR
pPR
PD
Median Duration of OS (months)
III serous ovarian cancer cisplatin group 49 patients
21 (43%)
10 (20%)
18 (37%)
59
III serous ovarian cancer carboplatin group 25 patients
10 (40%)
4(16%)
11(44%)
51
Total
31 (42%)
7 (9%)
29 (39%)
52
p value between all groups p > 0.05 pCR: pathological complete response PD: progressive disease pPR: pathological partial response IP: intraperitoneal chemotherapy OS: overall survival
treatment of four IP courses delivered once every 3 weeks. Forty- nine patients received 90mg/m2 cisplatin (IP) and sodium thiosulphate intravenously for 1 day, and 750mg/ m2 cyclophosphamide IV. Twenty five patients received AUC 6 carboplatin intraperitonealy and 750mg/ m2 cyclophosphamide IV (Tab.1). Standard premedication was given to prevent hypersensitivity reaction. Hydratation and antiemetic agents were given before cisplatin administration. For intraperitoneal therapy cisplatin and carboplatin were reconstituted in 2 litres of normal saline and infused as rapidly as possible through an implantable open-ended Tenckhoff catheter placed at the time of Second Look Laparotomy, Secondary Cytoreductive Surgery (SCS) or restaging laparotomy. No ascites occurred at the initiation of IP chemotherapy. Before they received subsequent cycles of therapy, patients were required to have absolute neutrophil count of no less than 1.5 x 109/l, platelet count of more than 100 x 109/l and serum creatinine of less than 1.5x UNL. After the therapy a restaging laparotomy associated with catheter removal was performed. During restaging laparotomy, similarly to SLL, biopsies were taken from multiple sites, including paracolic gutter, diaphragm, urinary bladder and pouch of Douglas. Routine washing of the peritoneal cavity was done. The followup consisted of a physical examination, complete blood count, blood chemical measurement and measurement of CA 125. The primary end point of the study was treatment responses in all group members defined as follows: pathological complete response (pCR) is the absence of disease at surgical evaluation, including multiple random biopsies and peritoneal washing. Pathological partial response (pPR) is a partial remission at surgical evaluation including pathological examination of resected or biopsy material. The following conditions were considered progressive disease (PD) or relapse: ≥25% increase of visible residual lesion, recurrence of disease at previously-affected sites or appearance of any new lesions. Single informed consent was obtained from all patients before their inclusion, and the study protocol received ethical approval from the research ethics committee. Secondary end point was overall survival from the start of IP therapy to March 2007 or till death.
Figure 1. Survival analysis (Kaplan-Meier) in relation to IP treatment response, the administration of four IP cisplatin or four IP carboplatin cycles, as of the time of IP treatment initiation.
A: Survival of all patients from the start of IP therapy. B: Survival time from the start of IP treatment in relation to the administration of four IP cisplatin or four IP carboplatin cycles (Log rank carboplatin versus cisplatin p>0.05). IP: intraperitoneal chemotherapy.
Statistical analysis Probability of survival was calculated by Kaplan-Meier method. The χ² test was used for the comparison of proportions and the Log rank test was used for the difference in median survival time. p values <0.05 were considered statistically significant.
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Milczek T et al.
Table 3. Comparison of frequency and statistic difference catheter related, surgery related, and chemotherapy related adverse events in cisplatin and carboplatin groups. Adverse Event
Cisplatin therapy group Number(%)
Carboplatin therapy group Number(%)
p value
Total number
49(100)
25(100)
Leucopenia <1 x 109/l
20(39)
11(42)
0.05
Plate count < 250 x 109/l
5 (10)
4(16)
0.045
Other hematological events
39(81)
22(89)
0.04
Gastrointestinal events
24(49)
12(48)
0.05
Renal events
4(8)
1(4)
0.04
Pulmonary events
1(2)
1(4)
0.05
Cardiovascular events
1(2)
1(4)
0.05
Neurological events
11 (22)
4(15)
0.03
Cutaneous changes
39(81)
20 (80)
0.05
Fever
5 (10)
3(10)
0.05
Infections
8 (15)
4(15)
0.05
Pain
5 (10)
3(10)
0.05
Bowel perforation during catheter insertion
2(4)
1(4)
0.05
Bowel perforation during catheter removal
3(6)
2(7)
0.05
Inability to flush into the abdomen
4(8)
2(8)
0.05
Erosion into the bowels
2 (4)
0
0.05
Erosion into the vagina
0
1(4)
0.05
RESULTS
DISCUSSION
For the analysis the group of 74 homogenous patients who completed all four assigned IP cycles with cisplatin or carboplatin only and who had stage III serous ovarian cancer were chosen. Twenty-five patients were included in the carboplatin group, 49 in the cisplatin group. No statistical differences between these groups were found. Disease characteristics of the 74 patients are summarised in Tab. 1. Response to IP chemotherapy in reference to the type of platinum-containing agent is presented in Tab. 2. The median survival time from the start of IP therapy in all group members reached 52 months. It was shorter in the carboplatin group than in the cisplatin group but the difference was not statistically significant (Fig. 1a,b, Tab. 2). Adverse effects of the treatment are summarised in Tab. 3. The toxicity associated with the presence of an IP catheter, IP administration of the chemotherapy directly into the peritoneal cavity and the kind of anticancer agent was relatively low. For patients in the cisplatin group neurological and renal events occurred relatively more often. Hematological events occurred slightly more frequently in the carboplatin group. There were no differences between any other surgical adverse events, or any other typical events associated with IP therapy, like fatigue, pain, gastrointestinal or metabolic adverse events.
With the current knowledge the natural history of ovarian cancer is clinical remission followed by relapse and another remission. Although overall response rates of up to 80% are achieved after the first line treatment, only 47% of the patients with complete response (CR) will have pCR at SLL [12]. Over 50% of this group members experience the return of the disease within 24 months after SLL and over 60% of them in peritoneal cavity [13]. There are not enough randomised studies to suggest a strategy for the therapy in recurrent or persistent ovarian cancer [5]. Some patients with local recurrence may benefit from secondary cytoreductive surgery, the others from different kinds of therapy [5]. A recent survival analysis of IP cisplatin use in patients with recurrent ovarian cancer indicated a longer survival time in selected patients, especially with minimal residual disease. The choice of SLL was necessitated by lack of high-quality image examination that could locate changes of less than 2cm in diameter. Additionally, successive catheter removals were a result of using Tenckhoff catheters with two Dacron rings. Currently, IP treatment usually is accompanied by a sub-dermal inlet catheter which can be removed under regional anaesthesia without the need of laparotomy. As it was mentioned in introduction the utility of carboplatin to IP therapy is not clear [8-11]. Critical review of Markman retrospective study shows that the group researched was too small and the equivalency between carboplatin and cisplatin was too low [11]. According to the GOG 158 trial the equivalency of carboplatin AUC 7.5
Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer
50
is 471mg/m² [14, 15]. Markman used 200-300 mg/m² IP as the equivalency of 100 mg/m² of cisplatin [10]. That is probably the reason of the worse results in carboplatin treatment than in the cisplatin group [11]. Given the limitations that this was not a randomised trial, and that the group was elected retrospectively it is natural to conclude that carboplatin IP is as effective as cisplatin when considering the response rate (63% versus 56%) and the overall survival rate (59 months to 51 respectively) in second line treatment (p>0.05) (Tab. 2). Additionally, very similar results were demonstrated by Speyer, where only 200mg/m² of carboplatin was administered and the response rate in second line treatment reached 74 % [16]. The toxicity in both groups is comparable and leads to the conclusion that the substance which is to be used for IP therapy in second line treatment should be chosen according to the individual predispositions of the patient. Taking into consideration the generally good results of our research, which confirm the observations of other works [16-18] it is safe to conclude that carboplatin can be safely used as an alternative of cisplatin in IP therapy.
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