A new treatment modality for colorectal cancer may have far reaching implications in managing this cancer, which accounts for 60,000 deaths per year in the US.¹ A common cause of surgical treatment failure is cancer dissemination into the peritoneal cavity surrounding the primary cancer in the abdomen and pelvis. This type of cancer spread, which is called carcinomatosis, is fatal for colorectal cancer patients.^2–4 The new treatment modality to treat carcinomatosis in selected patients combines cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy.#

Phase II studies at five prestigious cancer treatment centers show that approximately 30% of colorectal cancer patients with peritoneal carcinomatosis can be cured of an otherwise deadly manifestation of this disease process using the combined carcinomatosis treatment.⁵ A prospective phase III study was conducted comparing the standard of care, which is conservative surgery and systemic chemotherapy in the control group, to cytoreductive surgery and heated intraperitoneal mitomycin C chemotherapy in the treatment group. This study showed that there was a statistically significant improvement in median survival in the treatment group (22months) compared to the control group (12months) with a median follow-up of 35months (P<0.032).⁶ Finally, Glehen and colleagues in a retrospective multi-institutional effort collected 503 patients who had colorectal cancer and who were treated with this new combined treatment. In patients who had a complete cytoreduction there was a 31% 5-year survival.⁷#

One of many obstacles to the expansion of these new treatment strategies to more patients in the United States and in Europe is the lack of approval by regulatory agencies. Neither the surgical procedures (peritonectomy), the chemotherapeutic agents for intraoperative intraperitoneal combination chemotherapy with hyperthermia, nor the devices for recirculating the warm chemotherapy solutions to provide a hyperthermic environment have been approved by the regulatory agencies as “standard of practice.” As a treatment plan moves from clinical research to standard of practice with commercial product development there must be an acceptance of some and subsequently all aspects of the modality for its full application.#

There are many chemotherapy agents that are currently utilized in hyperthermic intraoperative intraperitoneal chemotherapy. These include as single agents or as combinations 5-fluorouracil, mitomycin C, cisplatin, oxaliplatin, taxotere, doxorubicin, gemcitabine, and melphalan.⁸ Although these drugs are Food and Drug Administration- and European Community-approved, they are approved only for certain indications; none of them are approved specifically for intraperitoneal application for the treatment of colorectal cancer. Also, none of these chemotherapeutic agents are specifically approved for use with hyperthermia. Under the practice of medicine exemption to the Food and Drug Administration's statutory authority to regulate marketed drugs, biologics, and devices, physicians can legally use a drug approved for one indication for other purposes. This is commonly referred to as an “Off label” use of a medicine. A 1998 Food and Drug Administration update stated regarding off label use, “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics, and devices according to their best knowledge and judgement.”⁹ If there is a firm scientific rationale and sound medical evidence the practice should not be hindered in any way.#

Also, the heater circulators that are required in the operating room to maintain hyperthermic conditions within the peritoneal cavity are usually “homemade” apparatus. They are made from various cardiovascular equipment or research laboratory equipment and modified so that hyperthermic peritoneal irrigation can occur. These apparatus do not require Food and Drug Administration clearance or approval as a medical device as long as they are used solely by the physicians who created them at their institutions. However, the situation is much different if these drugs or devices are to be marketed and promoted for sale to other hospitals or to physicians at other institutions. Only after Food and Drug Administration or European Community TUV approval can hyperthermic intraoperative intraperitoneal chemotherapy or the apparatus for drug administration be advertised or its use facilitated by commercial representatives. Promotion through journal articles, continuing medical education, and professional meetings is not restricted.¹⁰#

In order to make intraoperative hyperthermic intraperitoneal chemotherapy broadly available to patients outside peritoneal surface oncology treatment centers, it is necessary to obtain Food and Drug Administration and European Community approval to market a system that consists of both the chemotherapy and the device used to deliver it. Approvals from other regulatory bodies such as the American Medical Association to charge for new surgical procedures may also be indicated.#

The Food and Drug Administration has approved a very limited number of drugs specifically for intraperitoneal instillation. They include the antibiotic Kanamycin, which can be used for abdominal and pelvic irrigation in patients who have intraperitoneal infection. It also is frequently used as an irrigation in the operating room in an attempt to prevent intraabdominal sepsis. Another substance approved for intraperitoneal administration is Clorpactin (WCS-90), which is a stabilized organic derivative of hypochlorus acid. When mixed in an aqueous solution, active chlorine is derived. The irrigations are for topical treatment of infections with resistant organisms. Neither Kanamycin nor Clorpactin are chemotherapeutic agents and thus, they cannot be used for hyperthermic intraperitoneal chemotherapy.#

Two chemotherapy agents, Cytoxan and Mustargen have been approved for intraperitoneal administration. Cytoxan (cyclophosphamide) is a pro-drug and would have no activity within the peritoneal cavity until it is activated in the liver. However, the purpose of hyperthermic intraperitoneal chemotherapy is to have a local-regional effect on carcinomatosis by direct application to the cancerous tissue. A pharmacologic advantage for the use of intraperitoneal cyclophosphamide as compared to intravenous cyclophosphamide has never been established. From a theoretical perspective, no clinical benefit of hyperthermic intraoperative intraperitoneal chemotherapy would be achieved if cyclophosphamide were used as the chemotherapeutic agent.#

Mustargen (mechlorethamine HCl) or nitrogen mustard is a highly toxic cancer chemotherapy. Inhalation of vapors and contact with the skin or mucous membranes, especially those of the eyes should be avoided. It is a powerful vesicant type of chemotherapy that may be damaging to soft tissues by direct exposure. Nitrogen mustard has been approved for intracavitary administration into pleural, peritoneal, or pericardial spaces for the control of effusions. For use the excess fluid is removed from the body cavity and then the chemotherapy solution is instilled. Turning the patient from side to side helps distribute the drug evenly. The resolution of malignant ascites or malignant pleural effusion is thought to occur as a result of chemical poudrage. Mustargen cannot be safely used as a chemotherapeutic agent for intraoperative hyperthermic intraperitoneal chemotherapy via the open abdomen because operating room personnel would be exposed to this nerve gas.#

The use of intraperitoneal cyclophosphamide or nitrogen mustard in a clinical trial for the treatment of carcinomatosis has not been reported. Neither of these drugs seem appropriate for current requirements for heated intraoperative intraperitoneal chemotherapy.#

To our knowledge neither the Food and Drug Administration nor the European Community TUV has approved any chemotherapeutic agent for hyperthermic application. As mentioned above, the equipment currently used to heat chemotherapeutic agents at the medical centers currently performing intraoperative hyperthermic intraperitoneal chemotherapy are “homemade.” The Food and Drug Administration has granted 510(k) clearance to Biocontrol Technology's (Pittsburgh) ThermoChem-HT System, for “raising the core temperature of the peritoneum to the desired targeted temperature by continuously lavaging the peritoneum with circulating warmed Lactated Ringer's Solution, U.S.P, or another sterile solution.” Although this device's name implies that it is intended for hyperthermic chemotherapy and it is designed for intraperitoneal use, it is not approved specifically for hyperthermic intraoperative intraperitoneal chemotherapy. To our knowledge extensive clinical data to demonstrate that this device heats selected chemotherapeutic agent(s) to hyperthermic temperatures and thereby enhances the drug's effectiveness without adversely affecting its safety is not available.#

The situation in Europe is somewhat different than in the United States. In several European countries, hyperthermic intraperitoneal chemotherapy is an approved treatment for colorectal and appendiceal cancer. The European Community TUV has been obtained by several commercial groups. The EFS Electronique is marketing the Cavitherm device from Lyon, France. It has been European Community-approved for oncologic applications of heated intraperitoneal fluids. Also, the Rand Corporation has an apparatus which is approved for recirculation of warm biomedically-approved solutions into organs or into the peritoneal cavity for oncologic indications. The Skala apparatus manufactured in Prague, Czech Republic, is in the approval process. In summary none of these apparatus are officially approved for heated intraoperative intraperitoneal chemotherapy in the USA; two devices have been approved for oncologic indications in Europe and two more are pending (Table 1).#

The current opinion regarding combined treatment of colorectal carcinomatosis in Europe as a “standard of practice” is different from that in the United States. Combined treatment of peritoneal carcinomatosis is approved as a standard of care in France and the Netherlands. Also, specific referral centers in Basingstoke and Manchester have been established for management of carcinomatosis from appendiceal mucinous malignancy in the United Kingdom. On a country by country basis European Community approval of hyperthermic intraperitoneal chemotherapy has occurred along with the approval of heater circulators. The treatment strategy has, through persistent clinical research, become a standard of practice.#

As noted above, Food and Drug Administration approval of both the hyperthermic intraperitoneal chemotherapeutic agents and the device used to heat and deliver the drugs is necessary to market this treatment in the USA. As also noted above, the regulatory process for both products is long and expensive as it will require extensive new clinical data to demonstrate their safety and effectiveness.

• •Obstacle 1: The manufacturer of the chemotherapeutic agent must conclude that the financial BENEFITS of obtaining approval of the agent for hyperthermic intraoperative intraperitoneal chemotherapy exceeds the COST of obtaining approval.

As noted above, approval of an efficacy supplement for a chemotherapeutic agent for intraoperative hyperthermic intraperitoneal use will be an expensive and time-consuming process. Thus, a drug manufacturer probably will not seek additional approval of their drugs for such use unless the company believes it is likely to be highly profitable. The patent for most of the chemotherapeutic agents currently being used in peritoneal surface oncology centers for intraoperative hyperthermic intraperitoneal chemotherapy have expired. For this reason, drug manufacturers will probably conclude that the costs of seeking this approval will exceed the benefits for this indication. Thus, the best hope for obtaining an efficacy supplement approval of a chemotherapeutic agent for this indication may be a new drug still under patent.#

It is also unlikely that any of the chemotherapy agents currently in use for combined treatment will be approved for both intravenous administration or intraperitoneal administration as with cyclophosphamide. Although the scientific basis of this approval for a dual route of administration may be strong, additional expense by the drug company for a supplemental approval of a drug for intraperitoneal administration after an approval for intravenous administration seems unlikely. The approval process would be expensive. As an alternative plan, the drug company could promote its product not through a commercial process but by promotion of the research that showed an advantage of the intraperitoneal route of administration. Promotion of the “off label” use of the drug could be more profitable for the drug company than the approved use. This situation is currently operational for the intraperitoneal use of Taxanes, paclitaxel and docetaxel. This is likely to occur even though the cost of obtaining Food and Drug Administration approval for a drug for its first indication is likely to be higher than for obtaining supplemental approval for an additional indication because the latter has an established safety profile.

• •Obstacle 2: The heating of the chemotherapy agent and the intraperitoneal route of administration must be shown to increase its effectiveness.

The efficacy supplement for the chemotherapeutic agent must show that the drug is more effective and at least as safe when heated to 41–43°C as when it is not heated. Similar data to show greater effectiveness by intraperitoneal as compared to intravenous chemotherapy administration with at least the same safety would be required. The Food and Drug Administration is likely to require longer follow-up data to substantiate the claims, which increases the cost of conducting the clinical trial. From the drug manufacturer's prospective, the financial benefits must be even greater to justify seeking approval of the drug for hyperthermic use and for intraperitoneal use.

• •Obstacle 3: The Food and Drug Administration probably will require approval of a drug-delivery device in order to approve the chemotherapeutic agent for the proposed indication.

As mentioned earlier, many of the research institutions currently performing intraoperative hyperthermic intraperitoneal chemotherapy use “homemade” devices to recirculate the heated chemotherapy solution. If the equipment used for those purposes may affect the chemotherapy treatment, the Food and Drug Administration is likely to require the drug be labeled for use with only approved devices. Given that the Food and Drug Administration has not approved any device for the heating, delivery or removal of intraperitoneal chemotherapeutic agents, separate approval would probably be required for the device. In that case, the approval application for the device must include clinical data showing that it can safely and effectively heat, deliver, and remove the drug.

• •Obstacle 4: The Food and Drug Administration is likely to be concerned that the chemotherapeutic agent presents an acceptable safety risk to operating room personnel.

The Food and Drug Administration will almost certainly require clinical data in any submission for intraoperative hyperthermic intraperitoneal chemotherapy demonstrating that the operating room personnel's exposure to the chemotherapeutic agent does not present a safety risk. The benefits of the procedure cannot be used to offset the risk to operating room personnel because the patient, not the operating room personnel, will receive the benefits.#

Currently, there are three different methods used for administering heated intraoperative intraperitoneal chemotherapy. All methods involve chemotherapy treatments after maximal surgical efforts to remove visible evidence of cancer implants. In the “open method” the tubes and drains are positioned to administer chemotherapy and then the skin of the abdomen is elevated on a retractor to make a reservoir of the abdominal and pelvic space. In this methodology there is a mechanical effect as well as a chemical effect to eradicate cancer cells in that the surgeons' double-gloved hand debrides peritoneal surfaces. Special attention to ends of bowel that are to be anastomosed occurs in an attempt to prevent suture line recurrence. Also, the fascial edges of the abdominal incision are debrided with the chemotherapy solution. After chemotherapy treatments, abdominal retractors are repositioned and intestinal suturing is performed and then abdominal closure. Suture line recurrence and cancer progression within the abdominal incision are maximally reduced.¹¹#

In a second methodology the tubes and drains are positioned to administer the chemotherapy; then the skin of the abdomen is closed. Strong and repeated pressure on the abdominal sidewall are used to generate fluid turbulence in the peritoneal cavity to optimize distribution of the chemotherapy solution. The intestinal ends to be sutured are treated by chemotherapy but do not receive special attention by manual debridement. The fascial edges of the abdominal incision are exposed to the heated chemotherapy solution to help control recurrence in the abdominal incision. After the chemotherapy treatments are complete, the skin of the abdomen is opened, abdominal retractors reinserted, and intestinal reconstruction performed. This is referred to as the “partially closed” methodology.#

In a third methodology the tubes and drains for chemotherapy administration are positioned; then intestinal anastomoses are performed and a final closure of abdominal fascia and skin occurs. The hyperthermic chemotherapy is distributed by strong and repeated pressure to the abdominal sidewall. The ends of the intestine used for anastomosis and the abdominal closure are closed off to the hyperthermic chemotherapy treatments. This is referred to as the “closed” methodology.#

One of the major advances of combined treatment in the management of gastrointestinal cancer with peritoneal dissemination is the eradication of suture line recurrence and cancer progression within the abdominal closure. However, this major improvement of surgical technique can only occur if the bowel ends to be joined in intestinal reconstruction are washed by the warm chemotherapy solution prior to anastomosis. This means that wide re-exposure of the abdomen and pelvis to perform intestinal suturing or stapling must occur after the heated intraoperative intraperitoneal chemotherapy is complete. The body fluids by Occupational Safety and Health Administration guidelines are considered chemotherapy contaminated for 48h after treatment. Whether an “open” or “partially-closed” methodology of heated chemotherapy administration is used, the possibility of droplet or aerosol contamination is present during the period of intestinal reconstruction and abdominal closure. Only the closed technique in which the intestinal anastomosis and abdominal closure remain at risk for progressive carcinomatosis poses little safety hazard for heated intraoperative intraperitoneal chemotherapy. To summarize, if the safest methodology, the closed technique, is used the full benefit of heated intraoperative intraperitoneal chemotherapy is lost. If the open technique is routinely used the risk is expanded.#

There is a strong theoretical advantage to the open methodology so that the surgeon can place his double-gloved hand into the abdomen and achieve uniform distribution of heat and chemotherapy solution. This assures the oncology team that there are no surfaces within the abdomen or pelvis that have not had direct contact with the regional chemotherapy. It also encourages a mechanical release of cancer cells from surfaces that would otherwise be occluded. Although the proof of absolute safety may be impossible, the safety of this open methodology has been suggested for the surgeon and operating room personnel. Although the possibility of a chemotherapy aerosol escaping into the environment is possible, this situation has been studied and no evidence for chemotherapy aerosols found.¹² However, establishing absolute safety and the complete lack of contamination of the operating room environment is probably an impossible task.#

The Occupational Safety and Health Administration regulations do not specifically prohibit hyperthermic intraoperative chemotherapy administration by the open method. However, one must remember that this new method for chemotherapy delivery occurs in the operating room, an untested environment for chemotherapy safety. Low level of contamination for operating room personnel who directly contact the body fluids and the waste is possible. Persistent chemotherapy metabolites in the laundry that is contaminated by body fluids that contain a component of the administered chemotherapy has never been established but may pose a risk. Approval of the safety of these agents for operating room personnel has never been received. The submission would, at a minimum, have to include data showing that the device minimizes the risk to operating personnel and then negotiate with the Agency whether that risk is acceptable.#

The first step would be to identify the most promising new drug(s) for intraperitoneal treatment of colorectal cancer. One would seek approval for the use of these same drugs in hyperthermic solutions. Concomitantly, obtain approval of a reliable apparatus to recirculate hyperthermic chemotherapy solutions. Approval of a simple and inexpensive device will retain the possible use of combined treatment by underdeveloped nations. An important part of these organized efforts would be long-term studies on the safety and effectiveness of the treatment, as well as the risk of exposure to chemotherapy of operating room personnel. One would need to demonstrate that current usage is reasonably safe and show that all necessary precautions are being taken to protect operating room personnel. In order to realize reimbursement for surgical services the cooperative efforts of peritoneal surface oncology centers to gain acceptance of new procedural terminology codes for peritonectomy would be necessary.#

Currently, a majority of carcinomatosis patients are going to die if they do not have access to combined treatment. However, peritoneal carcinomatosis treatment centers do exist around the United States, in Europe and around the world. Selected patients are being treated with great benefit. How should these centers proceed under current conditions? In order to combine the “off label” use of hyperthermic intraoperative intraperitoneal chemotherapy there are special precautions to protect patients, physicians, and institutions. In dealing with patients, families, and health insurance companies the following are recommended: Inform patients that you are an experienced oncologist and your institution considers this approach an accepted therapeutic option for selected patients with carcinomatosis. Publish results of treatment and morbidity and mortality data in the peer-reviewed literature. Inform patients that the chemotherapy agents are not specifically approved for the diseases to be treated, not specifically approved for the intraperitoneal route of administration, and not specifically approved for the combination of chemotherapy with heat. Also that the apparatus that maintains a hyperthermic intraperitoneal environment is not approved as a device. These “off label” uses of chemotherapy are fully accepted, perhaps required, to realize a high standard of cancer management.#

Finally, inform health insurance companies prior to scheduling the surgical procedure that charges for all procedures will be submitted for an operation that routinely takes 11h. Also that procedures without current procedural terminology codes will be submitted. Bring patients into the billing process.#