Hyperthermic Intraperitoneal Chemotherapy and Systemic Chemotherapy in Metastatic Colorectal Cancer - Thesis Example

Assessing whether Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is more effective than conventional/systemic Chemotherapy in Metastatic Colorectal Cancer treatment Institution affiliation Name Introduction Colorectal cancer (CRC) is a major disease that is associated with mortality globally with over one million people diagnosed annually with the disease. A dissemination characteristic of this disease is the principal cause of increased mortality and most of the patients are often having advanced disease locally or systemic dissemination to other tissues. It is approximated that by the time of its diagnosis, 30-40% of the disease has advanced locally and an estimate of 20% have metastases to distant tissues. Haematogenous spread to the liver is the most rampant route, which is closely followed by metastasis to the lungs. It has been observed that individuals with stage IV disease, who have been given supportive therapy alone, have been surviving for approximately five years and they rarely exceed 5%. Over the past decades there has been a widespread of new chemotherapies agents like oxaliplatin, irinotecan and a novel of other targeted therapies, have led to a major improvement in the overall survival of patients with colorectal cancer. However, several specialists have shown a considerable increase in surgical resection or ablation to manage the cancer in stage four as well as intent liver and lung metastasectomy routinely performed (Pel et al., 2006). Peritoneal carcinomatosis has been identified at basic surgeries in approximately five to ten patients who are undergoing colorectal cancer resection. In addition, nearly 20-50% of those patients who are undergoing curative-intent CRC resection can have disease recurrence that is limited to the peritoneal cavity. It can be stated theoretically that colorectal peritoneal disease begins when the primary tumour ruptures and invasion through the serosa, and then later followed by seeding of the intraperitoneal cancer cells that are free. The distinct mechanism that governs how the tumour gets distributed within the peritoneal cavity is governed by several factors, which have been described as “redistribution phenomena.” Some of these factors include pooling of the cancer cells into the pelvis through gravitational force and a directional flow of the peritoneal fluid in the abdomen that results to subphrenic implantation as well as increased phagocytosis in the omentum (Glockzin, Schlitt, & Piso, 2009). The availability of the peritoneal disease in relation to colorectal cancer has a poor prognosis; therefore, traditional treatment such as systemic chemotherapy is usually associated with less survival rate. Currently, several pioneering individuals globally have sought to utilise more rapid and radical strategies for the management of CRC. Cytoreductive surgery (CRS) is one of the most popularised methods of managing the disease in some selected patients. Peritoneal carcinomatosis has been established as one of the major causes of treatment failure among patients with colorectal cancer. Even though it is considered fatal, scientist have postulated that a localised peritoneal carcinomatosis without any other metastases can be considered as a regional disease metastasis and should be amenable to local-regional therapy (Msika et al., 2010). Despite the fact that curative liver resection for colorectal cancer is well established with a survival rate of 5 years, peritoneal cancer has been considered as an end stage disease. The notion that some individuals who have peritoneal carcinomatosis possess a regional disease rather than a metastatic malignancy has led to the development of multiple complex surgeries that can result in a macroscopic excision of the cancer completely (cytoreduction), which is combined with hyperthermic intraperitoneal chemotherapy to manage some of the microscopic diseases (Yang et al., 2011). Several scholars have advocated for the combination of surgical approaches since it eradicates the residual cancer cells fully. The peritoneal route of administering the drug is usually based on the concept of peritoneal plasma partition idea, whereby chemotherapy of a high concentration is directly administered into the cancer cells. Several strategies have been proposed and investigated on their benefits such as hyperthermic intraperitoneal chemotherapy (HIPEC) as well as the Early post-op intraperitoneal chemotherapy (Sugarbaker & Ryan, 2012). Several surgeons who have reported significant benefits from CRS and HIPEC as compared to using systemic chemotherapy only have supported such notions. Despite these nice reports from different specialists, there is a lack of level one evidence that has studied the pre and postoperative mortality, quality of life and morbidity. This has led to a significant increase in polarised opinions in relation to these aggressive multiple approaches; thus, the management of colorectal metastasis has remained controversial. This article shall involve systematic literature reviews that have been published so as to come up with a comparison if Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is more effective than conventional/Systemic Chemotherapy in Metastatic Colorectal Cancer (Weber, Roitman, & Link, 2012). The available treatment options and their outcomes As mentioned earlier, colorectal cancer is one of the leading causes of mortality among cancer patient due to its ease of dissemination. Peritoneal carcinomatosis (PC) occurs when there is a dissemination of the colon cancer cells disseminate through the abdominal lining into the peritoneal cavity. Peritoneal cancer has been considered as a distant metastasis as well as a terminal form of colon cancer disease; therefore, palliative chemotherapy has been utilised in managing the disease. Retrospectives studies that have been done have shown poor responses to some of the chemotherapies utilised such as 5-fluorouracil and leucovorin (Wolpin & Mayer, 2008). Moreover, the treatment with those drugs have shown poor prognosis at the sites that colorectal cancer has disseminated to. Currently, more sophisticated and powerful cytotoxic drugs have been developed to manage the disease. These chemotherapies include cetuximab, oxaliplatin, bevacizumab and irinotecan among others. These drugs have shown significant improvement and prognosis among patients who have metastatic colon cancer. One common regimen in the management of colorectal cancer is the 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) is then combined with a bevacizumab. A study done by Salts et al on a two by two random assignment trial that was comparing capecitabine and oxaliplatin in relation to FOLFOX with bevacizumab revealed that 50% of the respondents treated with FOLFOX in combination with bevacizumab, survived 20 months longer (Vaira et al., 2010). Moreover, the fatal adverse toxicities related to bevacizumab and the chemotherapies were at 2.9%. It was noted that an addition of bevacizumab increased the fatal adverse risk, which were neutropenia, haemorrhage and GIT perforation. Some studies have shown that systematic chemotherapy, as well as biological therapies regimens, are commonly accepted standards of treating patients with gastrointestinal cancers. Toxicities can be seen in the utilisation of some drugs such as oxaliplatin and severely noted in bevacizumab. In essence, patients usually receive a protracted course of treatment in order to feel the clinical benefits; however, there is no systematic regiment that has been proved to be curative in metastatic colon disease (Meriggi, Bertocchi, & Zaniboni, 2013). Intraperitoneal chemotherapy Intraperitoneal administration of cytotoxic agents for the management of cancer into the abdominal cavity has been done since antiquity. During the 18th century, a surgeon named Christopher administered a mixture of carlet and water into the peritoneal cavity of a patient who was having an intractable ascites. The results were astonishing since the accumulation of in the abdominal cavity reduced drastically, and that provided an avenue to study more of intraperitoneal drug administration. It has been approximated that one out of five individuals with colonic cancer holds a minimal residual disease in the peritoneum even after surgical removal. This fact led to a hypothesis that intraperitoneal treatment following complete removal of T3 and T4 stage of colorectal cancer may reduce the recurrence of peritoneal cancer (Helm et al., 2008). A study done in animal models showed that intraperitoneal administration of drugs successfully minimised tumour development after a colon cancer cell was implanted in the abdominal cavity. However, clinical studies have not distinctly shown precise benefits from adjuvant intraperitoneal treatments for colon cancers. Vaillant and colleagues performed a randomised study among 267 patients who were having stage 2 and stage 3-colon cancer to either surgery only or a combination of surgery and intraperitoneal chemotherapy. The study focused on the administration of 5-FU intravenously during operation and 5-FU intraperitoneal post surgery. The result showed that adjuvant administration of 5-FU failed to improve the disease survival rate. Similarly, a randomised study done by Moran, Meade, & Murphy (2006), failed to elicit any benefits from the administration of chemotherapy intraperitoneal postoperatively. Bothe of these two studies taken together did not show any improvement in the peritoneal recurrence from an adjuvant administration of intraperitoneal chemotherapy among patients who were having colorectal carcinoma (Zhao, Dai, & Chen, 2012). Early postoperative intraperitoneal chemo Early postoperative intraperitoneal treatment/chemotherapy (EPIC) is a process that involves the administration of chemotherapy directly into the abdominal cavity through several ports. The procedure allows the circulation, as well as drainage of the chemotherapy for a couple of days, post Cytoreductive surgery, to destroy all the microscopic cancerous cells, as well as the free-floating cells. EPIC may be performed for a couple of months to kill all the cancerous cells after surgery. Mahteme et al conducted a study to compare 18 colon cancer patients who were underwent the treatment of EPIC, CRS and the systemic 5-FU basing on the chemotherapy with other 18 matched control group who undertook systemic chemotherapy only. The study results showed that, those patients in the CRS group had an average survival of 32 months, while those patients who were in the control group had a survival of 14 months. There is a variation on CRS chemotherapy among different institution thus limiting scholars to have a conclusion that can be drawn from some study groups (Franko et al., 2010). Hyperthermic intraperitoneal chemotherapy (HIPEC) Several research studies have hypothesised that hyperthermia significantly potentiate the effects of radiation therapy on tumours. However, some scholars argue that radiation therapy and hyperthermia works independently during the management of tumours. The primary goal of hyperthermia in colorectal cancer management is produce temperatures that ranges above 41-42 degrees centigrade. Temperatures above these levels have been seen to have a direct cytotoxic effect on tumour cells, as well as healthy cells. Hyperthermic intraperitoneal chemotherapy can be described as a highly concentrated and heated chemotherapy management, which is directly administered to into the abdomen during surgical procedures. Unlike the conventional chemotherapy administration that circulates in the entire body, hyperthermic intraperitoneal chemotherapy delivers the drug directly to the cancerous tissues in the abdomen. This technique is very significant in increasing the bioavailability of the drug in the body since it allows the higher dosage of drugs to be administered. Heating the solution has been proved to increase the absorption rate of the chemotherapy by the tumour cell thus destroying the cells up to the microscopic levels. The procedure is usually done after surgery to kill other microscopic cancer cells that were not removed during Cytoreductive surgery (Deraco et al., 2011). Method performed Before an individual receives hyperthermic intraperitoneal chemotherapy, the surgeon performs a Cytoreductive surgery to remove all the visible cancerous tissue within the abdomen. It is imperative to note that Cytoreductive surgery is achieved by using several techniques. Once several visible tissues have been removed, a heated and sterilised chemotherapy solution is directly delivered into the abdomen to penetrate the and kill all the micro cancerous cells that might have remained. The solution is usually heated and maintained at a temperature ranging between 41-42 degrees Celsius, which is approximately the temperature of water from a warm bath. The solution is circulated in the abdomen for about one and a half hours, and then drained off the abdomen and incision is closed. This technique is in the current practice of managing colorectal cancers, and it has been advocated for due to the following merits. HIPEC allows administration of large doses of chemotherapy into the patients abdomen. This is very significant because other systemic routes of drugs administration do not allow high dose administration due to the risk of liver damage. The technique enhances and concentrates the drug within the abdomen; this makes the drug focus on the tumour cells that have disseminated into the abdomen thus destroying them all. HPEC has a major advantage of minimising other body parts from being exposed to the chemotherapy because it is just localised into the abdomen. Most of the cytotoxic drugs occasionally harm even healthy tissues that are not targeted; therefore, when the chemotherapy is confined it helps in maintaining other tissues healthy. The technique improves the absorption of the chemotherapy by the susceptible cancerous tissues, thus leading to an enhanced destruction of the cells. In addition, HIPEC minimises the risk of chemotherapy side effects because very little of the drug is systemically absorbed to the rest of the body (Iversen et al., 2012). Several studies have been performed to explore whether there is any advantage in regards to the combination of Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-IIPEC). Zhu et al (2012) conducted a study to compare the survival rate of patients with colorectal cancer and were treated with a systemic drug, which was oxaliplatin, and those who were treated with CRS-HIPEC. The study showed that those patients who received systemic chemotherapy had an average survival of 24 months, while those who received CRS-HIPEC had a survival of 63 months. Randomised studies and other cohort studies have provided encouraging information on the overall survival in patients who have undergone CRS-HIPEC treatment with or without early postoperative intraperitoneal chemotherapy (EPIC), as compared to those who obtained systemic chemotherapy (Witkamp et al., 2001). Since the burden related to colon cancer is very critical to predicting the ultimate outcomes of CRS-HIPEC, there is a need to develop scoring tools and methods that shall help in quantifying the extent of peritoneal disease as well as complete resection. Sugarbaker is one of the scholars who have postulated a tool that scores peritoneal cancer and the scores range from zero to thirty-nine that can be determined prior to surgery. These models shall help in understanding different modes of treatment and necessary planning shall be made to enhance good outcomes. It is imperative noting that the effectiveness of CRS-HIEC can be significantly improved with the increase of knowledge as well as continues to invent new drugs that are more effective. Summary of the pieces of literature and methods of treatment Colonic cancer has been regarded as a disease that is very difficult to manage, and despite significant advances  made in the medical field still pose a challenge for an oncologist to treat precisely the disease. In several decades patients who were suffering from colorectal cancer that has disseminated into the peritoneum, were considered to be beyond any contemporary treatment. However, recent studies and advancement in technology have shown a significant improvement in disease management. The introduction of cytoreduction technique in combination with hyperthermic intraperitoneal chemotherapy has shown great benefit. In addition, randomised trials have shown significant survival gain as compared to offering palliative care in-patient with colorectal cancer. The conventional/systemic procedures have been shown to have some levels of significance in the treatment of colorectal cancer disease. It is imperative to note that CRS-HIPEC procedure is not available to most institutions, but it is only offered in specialised hospitals. Moreover, several surgeons don not always advocate for exposing their clients to CRS-HIPEC with an aim of prolonging life for ten months, given that the expectation of treating or curing the cancer is minimal. Furthermore, CRS-HIPEC has not shown to alleviate some of the systemic cancer symptoms such as loss of weight and malnutrition that are the disturbing features hindering life. Discussion Colorectal cancer is a disease that has existed for several decades yet no particular treatment has shown great benefit to the patients. The conventional treatment of cancer involves the use of systemic drugs that target the cancerous tissues. These drugs have evolved for several ages due to the continued research of hoping to get a better chemotherapy. The new drugs that are in the market have the potential to minimise the morbidity and mortality from metastatic colon cancer. The role of adjuvant systemic treatment of patients with colorectal cancer remains uncertain. Chemotherapy and radiotherapy have been the conventional way of managing several patients with cancer; however, different studies still provide conflicting opinions as per the merits of such treatment. From the literatures that have been reviewed, it is quite evident that the management of cancer using fluorouracil-based chemotherapy has shown little improvement among the patients. Indeed, it is stated that the overall prognosis is low as well as the survival rate. The combination of different chemotherapies with a different mode of action such as FULFOX was seen to have better results in patient’s outcomes. However, various scholars still have divergent opinions basing their arguments on the side effects that those chemotherapy drugs pose to the patient. In essence, it is worth noting that little studies have been done to monitor the effects of the adjuvant therapy on patient prognosis. Nevertheless, studies have been focused on measuring the size of the tumour after the therapies. Systemic management of colorectal cancer puts the patient at high risk of immunosuppression and damage to other normal tissues. Studies showed that, patients who are using cytotoxic drugs to manage cancers at an early stage have dramatically lost weight due to increased catabolism by the chemo. Furthermore, the patients do raise several complaints due to the side effects the drugs pose such as anorexia, loss of appetite and weight loss among others. These major occasionally complains make some patient not to comply fully with the treatment since the physical damage appears to be worsened by chemotherapy. It can be ruled out that systemic treatment of cancer using single or combinations of chemotherapy has failed. Nevertheless, there is an urgent need for new drugs to be developed with minimal side effects. The introduction of hyperthermic intraperitoneal chemotherapy (HIPEC) is one of the methods that several scholars have been advocating for as a better method of colorectal cancer management. This technique is applied after surgery, it means that it is not a standalone procedure but is combined with surgery. The pieces of literature assert that, those patients who are diagnosed earlier and started and are treated using HIPEC gets 100% cured. Even though this is debatable, crucial aspects of combining some treatments are very vital. Since HIPEC does not work, alone it can be argued that the treatment should not be viewed as a package because perhaps Cytoreductive surgery is the one that is having more merits than HIPEC. It means that HIPEC may be working as a synergist to Cytoreductive surgery thus facilitating healing among these patients. Research showed that heating the drugs have an excellent pharmacological advantage on the cancerous cells, heat make the drugs get absorbed quickly into the tissues. Directly injecting the drug into the peritoneal cavity has a direct impact on the cancerous tissues making them be destroyed up to their microcellular levels. Despite HIPEC being advocated for as the one of the best techniques, it should be noted that there is no study that has been done to assess its consequences. The unintended consequences always have silent mortality and morbidity and several surgeons shall be causing them unknowingly. An example of a situation where unintended consequences caused a lot of damages was in breast cancer management using high dose chemotherapy. The oncologist was administering a high dose of chemotherapy with an intention of killing the cancerous cells. Little did they know that were predisposing women to leukaemia as well as myelodysplastic syndromes that accounted for 3-5% of all the individuals who went through the procedure. Conclusion Basing my arguments from the review of different types of conventional techniques and HIPEC, as well as the several literature reviews of various studies that have been done. It can be concluded that hyperthermic intraperitoneal chemotherapy is more effective in managing colorectal metastatic cancer than the conventional/systemic chemotherapy. The systemic chemotherapy has been shown to have high failure rates and low survival rates among the studies that have been done. Averagely, it can be stated that those patients who undergone Cytoreductive surgery and were put on HIPEC had ten months survival than those placed on systemic chemotherapy. It was noted that the side effects that accompany systemic medication was adverse and fatal making some of the patients not to finish their intended medication. Moreover, treatment of metastatic colorectal cancer requires vigorous management by the use of high-dose chemotherapy to achieve an optimum result. This can only be done in HIPEC since the drug administered is localised and little is absorbed thus posing a less threat to other healthy tissues. Several studies have also shown that reoccurrence of colon cancer after CRS-HIPEC is minimal; pointing that HIPEC has a major impact on destroying the cancerous microcells. Patients who are put on systemic chemotherapy use the drug for a prolonged time sometimes several months to years while those who have been done to HIPEC repeat the procedure for few weeks or months and stop. Despite that, there is no research that has been done to evaluate the unintended effects that HIPEC brings along; those patients who have undergone the procedure have raised little complaints. Reference Deraco, M., Kusamura, S., Virzì, S., Puccio, F., MacRì, A., Famulari, C., … Baratti, D. (2011). Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: Multi-institutional phase-II trial. Gynecologic Oncology, 122(2), 215–220. Franko, J., Ibrahim, Z., Gusani, N. J., Holtzman, M. P., Bartlett, D. L., & Zeh, H. J. (2010). Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis. Cancer, 116(16), 3756–3762. Glockzin, G., Schlitt, H. J., & Piso, P. (2009). Peritoneal carcinomatosis: patients selection, perioperative complications and quality of life related to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. World Journal of Surgical Oncology, 7, 5. Helm, C. W., Bristow, R. E., Kusamura, S., Baratti, D., & Deraco, M. (2008). Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. In Journal of Surgical Oncology (Vol. 98, pp. 283–290). Iversen, L.H., Rasmussen, P.C., Hagemann, R., & Laurberg, S. (2012). Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis: the Danish experience. Colorectal disease. Meriggi, F., Bertocchi, P., & Zaniboni, A. (2013). Management of potentially resectable colorectal cancer liver metastases. World Journal of Gastrointestinal Surgery, 5(5), 138–45. Msika, S., Gruden, E., Sarnacki, S., Orbach, D., Philippe-Chomette, P., Castel, B., … Kianmanesh, R. (2010). Cytoreductive surgery associated to hyperthermic intraperitoneal chemoperfusion for desmoplastic round small cell tumor with peritoneal carcinomatosis in young patients. Journal of Pediatric Surgery, 45(8), 1617–1621. Moran, I., Meade, B., Murphy, E. (2006). Hyperthermic intraperitoneal chemotherapy and cytoreductive surgery for peritoneal carcinomatosis of colorectal origin: a novel treatment strategy with promising results in selected patients. Collorectal disease. Pelz, J. O. W., Doerfer, J., Dimmler, A., Hohenberger, W., & Meyer, T. (2006). Histological response of peritoneal carcinomatosis after hyperthermic intraperitoneal chemoperfusion (HIPEC) in experimental investigations. BMC Cancer, 6, 162. Sugarbaker, P. H., & Ryan, D. P. (2012). Cytoreductive surgery plus hyperthermic perioperative chemotherapy to treat peritoneal metastases from colorectal cancer: Standard of care or an experimental approach? The Lancet Oncology. Vaira, M., Cioppa, T., D’Amico, S., De Marco, G., D’Alessandro, M., Fiorentini, G., & De Simone, M. (2010). Treatment of Peritoneal carcinomatosis from colonic cancer by cytoreduction, peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC). Experience of ten years. In Vivo, 24(1), 79–84. Weber, T., Roitman, M., & Link, K. H. (2012). Current status of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis from colorectal cancer. Clinical Colorectal Cancer. Witkamp, A. J., De Bree, E., Van Goethem, R., & Zoetmulder, F. A. N. (2001). Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy. Cancer Treatment Reviews. Wolpin, B. M., & Mayer, R. J. (2008). Systemic Treatment of Colorectal Cancer. Gastroenterology. Yang, X.-J., Huang, C.-Q., Suo, T., Mei, L.-J., Yang, G.-L., Cheng, F.-L., … Li, Y. (2011). Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Annals of surgical oncology (Vol. 18). Zhao, C., Dai, C., & Chen, X. (2012). Whole-body hyperthermia combined with hyperthermic intraperitoneal chemotherapy for the treatment of stage IV advanced gastric cancer. International Journal of Hyperthermia : The Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, 28(8), 735–41. Zhu, Y., Hanna, N., Boutros, C., & Alexander, R. H. (2012). Assessment of clinical benefit and quality of life in patients undergoing cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for management of peritoneal metastases. Gastrointest oncol, 4(1), 62–71. Read More