腹膜转移癌腹腔化疗的创新与挑战

doi:10.19401/j.cnki.1007-3639.2024.09.003

摘要/Abstract

摘要：

腹膜转移癌是指从原发部位扩散至腹膜的恶性肿瘤，常见于胃癌、结直肠癌、卵巢癌及腹膜假黏液瘤（pseudomyxoma peritonei，PMP）等多种癌症类型的晚期阶段。腹膜转移癌的复发率和死亡率高，严重危害人类健康，通常在根治术后或晚期腹膜转移阶段采用以化疗为主的姑息性治疗方案。腹膜转移癌治疗的难点在于缺少靶向治疗药物以及药物较难透过血-腹膜屏障，以致全身治疗效果欠佳。腹腔化疗（intraperitoneal chemotherapy，IPC）作为一种重要的临床治疗手段，在腹膜转移癌的治疗中具有广阔的应用前景。近年来，腹腔热灌注化疗（hyperthermic intraperitoneal chemotherapy，HIPEC）、腹腔加压气溶胶（pressurized intraperitoneal aerosol chemotherapy，PIPAC）等IPC技术的革新和新型药物的出现显著延长了患者的生存期。然而，腹膜转移癌的多样性和复杂性使临床IPC在给药方式、药物类型和剂量等治疗策略上仍然存在差异性和疗效不确定性。尽管已经制定了基于循证医学证据的指南和推荐治疗策略，但是仍需要通过更多的临床试验和更高级别的循证医学证据来进一步支持这些方案。本文对IPC的发展历程和最新进展进行归纳总结，对比分析手术治疗联合传统IPC、HIPEC及PIPAC等治疗手段的疗效，并对近期开展的IPC技术的研究进展进行汇总。此外，在IPC技术的临床应用方面，本文详细阐述其在胃癌、结直肠癌、妇科肿瘤、PMP、胆管癌及胰腺癌等疾病中的应用。针对IPC技术的局限性，提出纳米药物的创新开发有望为腹膜转移癌的治疗提供更安全有效的选择。综上所述，本文通过梳理IPC研究的最新进展、不足和未来发展方向，以期为腹膜转移癌更有效的临床治疗提供可行性方向。

关键词: 腹膜转移癌, 腹腔化疗, 腹腔热灌注化疗, 腹腔加压气溶胶, 纳米药物, 靶向治疗

Abstract:

Peritoneal metastatic carcinoma refers to the spread of malignant tumors from the primary site to the peritoneum. It is commonly observed in the advanced stages of various cancer types, including gastric cancer, colorectal cancer, ovarian cancer and pseudomyxoma peritonei (PMP). Peritoneal metastatic carcinoma seriously impair human health due to their high recurrence and mortality rates, and palliative treatment based on chemotherapy is usually provided after radical surgery or in the advanced stage of peritoneal metastases. The difficulties in the treatment of peritoneal metastatic carcinoma are the lack of targeted drugs and the difficulty of drugs to cross the blood-peritoneal barrier, resulting in poor systemic effects. Intraperitoneal chemotherapy, as an important therapeutic means, has a broad application prospect in the treatment of peritoneal metastatic carcinoma. In recent years, innovations in intraperitoneal chemotherapy techniques such as hyperthermic intraperitoneal chemotherapy (HIPEC), pressurized intraperitoneal aerosol chemotherapy (PIPAC) and the development of novel drugs have significantly improved patients' quality of life. The development of novel drugs has significantly improved patient survival. However, the diversity and complexity of these diseases have led to clinical variability and uncertainty in the efficacy of intraperitoneal chemotherapy in terms of treatment strategies such as mode of administration, drug type and dose. Although evidence-based guidelines and recommended treatment strategies have been developed, there is a need to further support these regimens through additional clinical trials and higher levels of evidence-based medicine. This review summarized the development history and recent advances in intraperitoneal chemotherapy, compared and analyzed the treatments such as surgery combined with traditional IPC, HIPEC and PIPAC, and summarized the research progress of recently conducted intraperitoneal chemotherapy techniques; moreover, in terms of the clinical application of intraperitoneal chemotherapy techniques, this paper elaborated on its use in diseases such as gastric cancer, colorectal cancer, gynecological oncology, PMP, cholangiocarcinoma and pancreatic cancer. For the limitations of intraperitoneal chemotherapy technology, it is proposed that the innovative development of nanomedicine is expected to provide a safer and more effective option for the treatment of peritoneal metastatic carcinoma. In conclusion, this review summarized the latest progress, shortcomings and future development of intraperitoneal chemotherapy, with the aim of providing a feasible direction for more effective clinical treatment of peritoneal metastatic carcinoma.

Key words: Peritoneal metastatic carcinoma, Intraperitoneal chemotherapy, Hyperthermic intraperitoneal chemotherapy, Pressurized intraperitoneal aerosol chemotherapy, Nano-drug, Targeted therapy

中图分类号:

R730.53

冯欣滢, 王冰, 刘培峰. 腹膜转移癌腹腔化疗的创新与挑战[J]. 中国癌症杂志, 2024, 34(9): 827-837.

FENG Xinying, WANG Bing, LIU Peifeng. Innovations and challenges in intraperitoneal chemotherapy for peritoneal metastatic carcinoma[J]. China Oncology, 2024, 34(9): 827-837.

图/表 4

图1

图2

表1

临床常用的IPC方案"

Preoperative diagnosis	Surgical program	Research type	Number of sample		Chemotherapy protocol		Result	Reference
Preoperative diagnosis	Surgical program	Research type	Trial	Control	Trial	Control	Result	Reference
Gastric cancer +Peritoneal cancer	CRS	Gastripec-Ⅰ	52	53	CRS+HIPEC (mitomycin 15 mg/m²+cisplatin 75 mg/m², 42 ℃, 60 min)	Simple CRS; 11 cases of postoperative chemotherapy (such as fluorouracil)	Better PFS and MFS	[27]
Gastric cancer (c>T3)	Radical gastrectomy for gastric cancer+D2 lymphnode dissection	Phase Ⅲ clinical trial	40	40	CRS+HIPEC [cisplatin 50 mg/m², 60 min, (42.0±1.0) ℃]; 22 cases within 1 month after surgery XELOX regimen with 6 standard doses	XELOX regimen with 6 standard doses within 1 month after surgery	Low DFS and peritoneal recurrence	[42]
Colon cancer (T4N0-2M0)	CRS	Phase Ⅲ clinical trial	89	95	CRS+HIPEC (mitomycin 30 mg/m² ); Receive routine adjuvant systemic chemotherapy combined with oxaliplatin and capecitabine within 12 weeks after surgery	CRS+systemic chemotherapy combined with oxaliplatin and capecitabine within 12 weeks	Improve 3 years LC rate	[43]
Colon cancer (T4N0-2M0)	CRS	Phase Ⅲ clinical trial	100	102	HIPEC after surgery 5-8 weeks (oxaliplatin 460 mg/m², 30 min)+ chemotherapy with intravenous fluorouracil/calcium folinate	Hydrostatic injection of fluorouracil/calcium folinate adjuvant chemotherapy	No significant difference	[44]
Appendix/colorectal cancer+peritoneal cancer		Phase Ⅰ clinical trial	12		PIPAC (oxaliplatin 90 mg/m² )+whole body chemotherapy (fluorouracil+calcium folinate)		Safe and feasible	[36]
Phase Ⅲ/Ⅳ ovarian cancer	CRS	Phase Ⅲ clinical trial	92	92	CRS+HIPEC (cisplatin 75 mg/m², 90 min, 41.5 ℃); 6 cycles of adjuvant chemotherapy (paclitaxel 175 mg/m²+ carboplatin 5 mg/mL)	6 cycles of adjuvant chemotherapy (paclitaxel 175 mg/m² +carboplatin 5 mg/mL)	Cannot improve PFS and OS	[45]
Ovarian cancer	CRS	Clinical research	100		PIPAC (cisplatin 7.5 mg/m²+ doxorubicin 1.5 mg/m²)		The result is meaningless	[46]
Breast cancer/endometrial cancer+peritoneal cancer	Hysterectom/mastectomy	Cohort study	44		PIPAC (cisplatin 7.5 mg/m² +doxorubicin 1.5 mg/m²); Later changed to PIPAC (cisplatin 10.5 mg/m²+doxorubicin 2.1 mg/m²)		Improve survival rate and histological regression	[47]
Mucinous carcinoma of the appendix +PMP	CRS+Peritoneal resection surgery	Case report	1		CRS+HIPEC (mitomycin 35 mg/m², 42 ℃, 90 min)		Improve survival rate	[48]
Appendiceal tumor +PMP	CRS+Peritoneal resection surgery	Case report	1		CRS+IPC (cisplatin 30 mg/m²+ docetaxel 30 mg/m²)+ HIPEC (oxaliplatin 4 300 mg+fluorouracil 500 mg, 42.5-43.5 ℃, 40 min)		Good postoperative recovery	[49]
Intrahepatic cholangiocarcinoma + peritoneal cancer	CRS	Cohort study	51	61	CRS+HIPEC (fluorouracil 1 000 mg/BSA+cisplatin 40 mg/m², 400-600 mL/min)+ IPC (fluorouracil or oxaliplatin)	Simple CRS +IPC (fluorouracil or oxaliplatin)	Improve OS and survival rate	[50]
Pancreatic cancer +peritoneal cancer	Pancreatic surgery or systemic chemotherapy	Prospective study	35		PIPAC (30 mL/min, cisplatin 7.5 mg/m²+ doxorubicin 1.5 mg/m², 92 min)		Improve survival rate and histological regression	[51]

表1

表2

纳米药物在IPC中的研究"

Carrier	Material	Load	Cell/animal model	Administration method	Indication	Advantage/result	Reference
Polymeric micelles	Polyethylene glycol, lactic acid hydroxy acetic acid copolymer	Oxaliplatin	Tumor bearing mouse model	IP, IV	Colorectal cancer with peritoneal metastasis	IP reduces the systemic distribution of drugs and the toxicity to major organs, improves the precision of treatment	[67]
Nano hydrogel	Carboxymethyl chitosan, polylactic acid hyperbranched polyglycerol	Paclitaxel, anti-PD-1 antibody	C57BL/6 mouse model	IP	Ovarian cancer with peritoneal metastasis	① Low system toxicity and good therapeutic effect; ② Good biocompatibility	[68]
¹⁴C-eNP	eNPs, ¹⁴C	Paclitaxel	Mesothelioma of peritoneum tumor bearing mouse model	IP, IV	Mesothelioma of peritoneum	IP efficiency is higher	[34]
Liposomes	Liposomes encoding firefly luciferase mRNA	mRNA	C57BL/6 mouse model	IP, IV	Pancreatic related cancer	IP enhances the ability of mRNA delivery to the pancreas	[69]
Liposomes	Cationic assisted lipids, liposomes encoding firefly luciferase mRNA	mRNA	C57BL/6 mouse model	IP, IV	Pancreatic related cancer	IP reduces off target delivery to the liver and spleen	[69]
Liposomes	Phosphatidylserine, β-sitosterol	mRNA	CT26-luc mouse model	IP		High transfection efficiency and selectivity	[70]
CAR-Ms		PD-1 antibody	CT26 mouse model	IP	Late stage diffuse peritoneal tumor	Activate adaptive immune response provide new strategies for solid tumor treatment	[70]
Liposomes	C12-200 cation, Cy5.5 dye	siRNA	Mouse model	IP		Enhancing the potential of using LPM to transport oligonucleotides encapsulated in nanoparticles for cancer treatment	[71]
Liposomes	4A3-SCC-10/PH	mRNA	tdTomato mouse model	IP	Liver cancer	Improving mRNA delivery efficiency in vivo has the potential to treat liver cancer	[71]
Nanoparticles	Silicon dioxide, polystyrene nanoparticles, polylactic acid hydroxyacetic acid copolymer		Mouse model	IP, IV	Ovarian cancer with abdominal metastasis	① IP has high targeting efficiency; ② Lay the foundation for the treatment of metastatic ovarian cancer	[72]
Nanoparticles	PEG^5k-BA4, PEG^5k-Cys4-L8-CA8	Paclitaxel, Betulinic acid	A2780/Adr cells, ovarian cancer mouse model	IP	Ovarian cancer	① Achieve precise drug release; ② Overcome multidrug resistance in ovarian cancer	[73]

表2

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