Intraoperative Hyperthermic Intraperitoneal Chemotherapy in Patients With Advanced Ovarian Cancer

Ovarian cancer, because it is largely confined to the peritoneal cavity, has a unique tumor biology and metastatic spread pattern. Its metastatic potential comes from detached tumor cells in the peritoneal cavity that re-attach to the mesothelial lining of the peritoneal surface. It is proposed that these micrometastases without neovasculature, as well as floating malignant cells, are drivers of early recurrence, since they can be neither resected nor adequately treated by systemic chemotherapy. This represents the major rationale for local treatment by means of postoperative intraperitoneal (IP) chemotherapy, which is the standard of care in the United States in patients with advanced-stage ovarian cancer who have minimal residual disease following cytoreductive surgery. An alternative loco-regional treatment strategy is the “HIPEC” procedure-hyperthermic IP chemoperfusion that is performed during the operation immediately following completion of gross tumor resection, and which provides improved tissue penetration and distribution of the chemotherapeutics. However, prospective data are limited and an outcomes benefit has yet to be shown. Here we discuss the advantages and pitfalls of HIPEC, as well as current data and ongoing prospective trials.

Introduction

Ovarian cancer causes more deaths than any other gynecologic malignancy, accounting for 14,180 deaths in the United States annually, and with a prevalence of 21,290 new cases estimated for 2015.[1] Cure rates vary between 20% and 30%, with most patients experiencing recurrence of their disease within the first 3 years. The reason for the poor prognosis is that the majority of patients (60% to 70%) present at an advanced stage (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV).[2,3] Beyond stage, histology, and grade, a high prognostic value is attributed to the amount of postoperative residual tumor.[4-7] Optimal cytoreduction, defined as residual tumor < 1 cm after surgical debulking, is associated with considerable improvement in overall survival (OS) and progression-free survival (PFS). More recent publications have demonstrated that a complete resection of tumor with only microscopic tumor residuals will improve the prognosis to a median OS of 64 months.[8] The goal of current cytoreductive surgery should therefore be to attempt a complete resection of all visible tumor, and it is preferable that such surgery be performed at centers with high levels of specialization and expertise.[4,9] Even so, and despite improvements in surgical technique, most patients will die from ovarian cancer regardless of their increased disease-free interval, making the improvement of chemotherapy regimens imperative.

Cisplatin’s remarkable activity in ovarian cancer was discovered in the early 1980s, followed by the introduction of the less toxic but equally active second-generation platinum agent carboplatin in the early 1990s. Both agents were predominantly used in combination regimens along with cyclophosphamide or an anthracycline-until the introduction of the taxanes in the late 1990s led to today’s gold standard of chemotherapy that combines carboplatin and paclitaxel in a 3-week cycle.[10]

Biologically, ovarian cancer behaves in a unique way. After undergoing an epithelial-mesenchymal transition, cancer cells simply detach from the main tumor bulk and are carried by the physiologic peritoneal circulation throughout the peritoneal cavity, either as single cells or as multicellular spheroids-something one could call “passive” metastasis.[11] The cells do not undergo several steps of intravasation and extravasation to form metastases as in hematologically spreading tumor types. In fact, ovarian cancer cells seem to selectively invade the mesothelium of the peritoneal surface, forming micrometastases that are adequately supplied solely by means of diffusion until they reach a size of 1 mm².[12,13] Consequently, because of the lack of vascularization, it is likely that neither micrometastases nor free-floating cancer cells can be addressed adequately by either surgery or systemic chemotherapy. Intraperitoneal (IP) treatment modalities attempt to close this therapeutic gap.

IP Chemotherapy: Rationale

In 1978, Dedrick et al hypothesized that because the peritoneal surface forms a barrier between the peritoneal compartment and the blood compartment, it would be possible for significantly higher concentrations of chemotherapeutic agents to be delivered to the peritoneal cavity, with only limited systemic toxicity[14]; this hypothesis set the stage for the introduction of modern IP treatments. Any drug that shows a high response rate as systemic therapy for ovarian cancer comes under consideration for IP administration. However, there are important pharmacokinetic differences between the different drugs used for IP therapy; these play a role in drug selection and therefore must be mentioned. There is a correlation between molecular size and the ratio of the drug level in the peritoneal cavity to the drug level in plasma. For example, peak paclitaxel concentrations in the peritoneal cavity exceed plasma concentrations by 1,000-fold and persist in the peritoneal cavity for over 24 hours due to the large size of the paclitaxel molecule compared with cisplatin; the latter shows only a 12-fold higher concentration in the peritoneal compartment compared with the concentration in serum.[15] The significantly higher IP drug concentration might reduce the effect of chemotherapy resistance by simply achieving higher intracellular concentrations and, in the case of cisplatin, by overpowering the mechanisms of decreased drug influx that result from loss of copper transporter 1, increased absorption of cisplatin in the cytoplasm by glutathione and metallothionein, increased drug efflux by ATP7A/ATP7B and glutathione S-conjugate export GS-X pumps, improved DNA repair, and insufficient DNA binding.[16]

Most studies of IP chemotherapy in ovarian cancer have involved cisplatin, because of positive results with this agent in murine models and more experience with it as a systemic therapy. However, recent prospective studies were able to demonstrate the feasibility of IP carboplatin application,[17,18] which is an appealing alternative to cisplatin because of its lesser side effects, especially less polyneuropathy and nephrotoxicity.

IP paclitaxel infusion showed dose-limiting toxicity (abdominal pain) at 175 mg/m² in a phase I trial.[19] Subsequent studies of a weekly IP regimen at 60 mg/m² showed acceptable toxicity,[20,21] with the result that a phase II trial combining IP cisplatin and IP paclitaxel was performed,[22] demonstrating both feasibility and a high median OS. Because of the positive results, the combination of IP cisplatin and IP paclitaxel was tested as the study arm in the phase III Gynecologic Oncology Group (GOG) 172 trial described further on in detail. It is unclear whether the increased adverse effects of paclitaxel are Cremophor EL–related, since the hydrophobic paclitaxel requires it as a vehicle. It has been shown that Cremophor EL can have biologic effects such as severe anaphylactic hypersensitivity reactions, abnormal lipoprotein patterns, and peripheral neuropathy.[23] The use of water-soluble taxanes, such as docetaxel or the albumin-bound nab-paclitaxel, might prevent these adverse effects in the future.

IP Chemotherapy: Clinical Significance

GOG 104, the first phase III trial to evaluate the role of IP treatment, showed a significant improvement in OS: 49 months in the IP cisplatin treatment group vs 41 months in patients who received intravenous (IV) treatment only.[24] Because the participants in this study were recruited in the pre-paclitaxel era, survival rates were rather low compared with the rates in current adjuvant chemotherapy studies. In the subsequent GOG 114 trial, patients were randomly assigned to receive either 6 cycles of cisplatin and paclitaxel IV therapy or 6 cycles of the combination of paclitaxel IV plus cisplatin IP after 2 previous cycles of carboplatin (area under the curve [AUC], 9),[25] with significant improvement in median PFS (28 months vs 22 months) and close to significant improvement in median OS (63 months vs 52 months) favoring the IP regimen. The most recently published phase III trial, GOG 172, randomly assigned patients-after primary debulking of stage III ovarian, fallopian tube, or peritoneal cancer with postoperative residual tumor < 1 cm-to receive either IV paclitaxel, 135 mg/m² over 24 hours, on day 1 and IV cisplatin, 75 mg/m², on day 2, or IV paclitaxel, 135 mg/m² over 24 hours, on day 1 and IP cisplatin, 100 mg/m² over 24 hours, on day 2, followed by IP paclitaxel, 60 mg/m², on day 8 of a 3-week cycle. The investigators showed a significantly increased PFS and OS of 23.8 months vs 18.3 months and 65.5 months vs 49.7 months, respectively, favoring the IP regimen. Based on these results, the National Cancer Institute issued an alert encouraging the incorporation of IP therapy into the care of women with advanced ovarian cancer in the United States.[26]

However, the strong effect of the IP regimens in GOG 114 and GOG 172 may have been due to the higher dosing in the IP treatment arms: 2 additional IV carboplatin cycles as well as a higher IP cisplatin dose in GOG 114; and an additional dose of paclitaxel on day 8 of every cycle in GOG 172, resembling a dose-dense IV regimen. Additionally, 44% of patients in the IP treatment arm of GOG 172 received IV carboplatin and paclitaxel after discontinuing the IP protocol. This IV regimen may have been less toxic and more effective than the IV regimen used in the control arm (paclitaxel on day 1 and cisplatin day 2), which itself does not resemble today’s standard-of-care treatment. Because of these issues and toxicity concerns, as well as an only marginally significant OS benefit in the GOG 172 trial, an opposing statement was published in the Journal of Clinical Oncology in October 2006 advising against IP therapy outside of clinical trials.[27]

Recently, Tewari et al[28] presented an updated long-term survival analysis of GOG 114 and GOG 172, with a median follow-up of 10.7 years. Median OS with IP therapy was 61.8 months, compared with 51.4 months in the IV group, with a reduction in the risk of death of 23%. Additionally, the number of IP cycles revealed itself as an independent prognostic factor: completing all 6 cycles had a statistically significant association with improved OS, whereas completion of fewer than 6 cycles of IP therapy did not. IP therapy also improved the survival of patients with gross residual disease (≤ 1 cm); for this reason, patients with suboptimal debulking have been included in the ongoing GOG 252 trial. GOG 252 compares the following three treatment groups: conventional dose-dense IV chemotherapy, dose-dense IV chemotherapy with IP (instead of IV) carboplatin delivery, and a modified GOG 172 IP protocol. In all treatment arms, patients have received 22 cycles of every-3-weeks bevacizumab, 15 mg/kg. The first results of GOG 252 are anticipated either this year or next.

Challenges Regarding Establishment of IP Chemotherapy as Standard of Care

The major disadvantages of IP chemotherapy are the increased toxicity and the highly complex management of patients and their side effects. In GOG 172, 58% of patients discontinued therapy due to increased hematologic and gastrointestinal toxicity; inadequate hydration or inadequate antiemetic therapy; or port complications, including obstruction, leakage, and infection.[29,30] Additionally, Havrilesky et al, using a Markov state transition model, showed that IP treatment was not cost-effective compared with IV therapy, mainly because of the need for inpatient treatment for the 24-hour delivery of paclitaxel.[31] Both the 24-hour paclitaxel infusion in the GOG 172 protocol and the increased adverse effects of IP chemotherapy have been addressed by a modified GOG 172 outpatient regimen that was developed at Memorial Sloan Kettering Cancer Center (MSKCC) in recent years: IV paclitaxel, 135 mg/m², infused on day 1 within 3 hours, followed by reduced IP cisplatin (75 mg/m²) and IP paclitaxel (60 mg/m²) on day 8, along with implementation of new potent antiemetic drugs (eg, aprepitant). This approach has been validated in a single-arm phase II study that showed low discontinuation rates[32]: 30 patients (73%) received all 6 cycles of IP chemotherapy and 35 patients (85%) received at least 4 cycles. The greatly reduced toxicity of this regimen is reassuring, given that it is one of the treatment arms of the ongoing GOG 252 trial.

Independent of whether the outpatient protocol will have a comparable efficacy to that of the GOG 172 regimen, IP treatment will still be challenging for healthcare providers due to higher complication rates, the need for additional homecare to ensure adequate IV hydration, longer treatment times, and intensified nurse involvement. These factors remain the major limitations impeding the establishment of IP chemotherapy as the standard of care.

HIPEC: Rationale

In recent years, a new form of IP therapy has emerged for patients with ovarian carcinoma: intraoperative hyperthermic IP chemotherapy (HIPEC). Many investigators are now evaluating and conducting critical discussions of the role and the rationale for this delivery technique, which requires intraoperative perfusion machines, elaborate logistics, and a high degree of organizational effort. It is still unknown whether HIPEC is associated with an improved survival that would justify the effort involved, but there are several potential advantages that make it a promising therapeutic option as part of a multimodality treatment:

• A high volume of chemotherapy can be delivered, and a homogenous distribution can be achieved. This is often not practical in conventional IP therapy, because of abdominal distension and pain, but it is feasible in HIPEC, since the patient is under anesthesia.

• There is no interval between cytoreduction and chemotherapy. The cytotoxic therapy is applied at the time of minimal disease manifestation, and there are no adhesions that might alter the distribution of the drug.

• Hyperthermia has a pharmacokinetic benefit. Several studies have convincingly shown that hyperthermia can increase both the tumor penetration of cisplatin[33] as well as the DNA crosslinking.[34]

• High concentrations of chemotherapy can be achieved in the intraperitoneal compartment with low systemic exposure-in a single intraoperative treatment.

HIPEC: Clinical Significance

HIPEC is already an established treatment alternative in three tumor types, based on some prospective evidence and a large number of retrospective studies: peritoneal carcinomatosis of colorectal cancer, appendiceal cancer (pseudomyxoma peritonei), and malignant peritoneal mesothelioma. Two randomized trials from France and the Netherlands[35,36] have shown a significant improvement in OS with HIPEC in peritoneal dissemination of colorectal cancer-albeit with a major limitation: the control arms in these studies did not resemble the current gold standard of oxaliplatin-based[37,38] or irinotecan-based therapy[39] (FOLFOX [folinic acid, fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, fluorouracil, and irinotecan], respectively). Nevertheless, compared with fluorouracil (5-FU) and folinic acid (leucovorin), HIPEC improved median OS from 10 months to 29 months, especially favoring patients with complete cytoreduction (in whom OS improved from 28 months to 60 months).[40] In pseudomyxoma peritonei, there is evidence of a substantial benefit from HIPEC[41,42]; however, there have been no randomized trials of HIPEC in this entity, and it is unclear whether the improved outcome is attributable to the successful cytoreduction at the highly specialized centers at which studies have been performed or whether it is actually due to the addition of the IP chemotherapy. In malignant peritoneal mesothelioma, HIPEC has been accepted as the first-line treatment, despite the lack of randomized trials. Large retrospective studies have shown improved OS compared with historical controls.[43,44] In all the above studies in various malignancies, a compelling benefit was shown for patients with a complete cytoreduction. Attention must now be focused on the issue of patient selection for this very involved procedure, through the use of objectified tumor volume scores, such as the peritoneal cancer index (PCI).[45]

In recent years, HIPEC has been studied in ovarian cancer; however, due to the lack of randomized trials there are no substantive efficacy data. The largest retrospective study in persistent and recurrent ovarian cancer, by Bakrin et al, described survival and morbidity in 246 patients over a period of 17 years,[46] and showed both acceptable morbidity (12%) and a median OS of 48.9 months. Still, this study has substantial limitations that cannot be ignored: the use of different postoperative treatment regimens over the 17-year time period (1991 to 2008), high complete resection rates of 92% (which are usually not achieved even by leading institutions), and the inclusion of platinum-resistant and platinum-sensitive disease.[47] Despite its weaknesses, the study proves the feasibility of the procedure and encourages prospective randomized trials. At the same time, however, this study demonstrates an unfortunate development in the treatment of ovarian cancer patients: more than 500 patients in this and other smaller retrospective evaluations have been treated with HIPEC outside a prospective study protocol, without control arms and consequently without proof of efficacy, indicating a wide application of a yet immature and not validated treatment modality.

TO PUT THAT INTO CONTEXT

David L. Bartlett, MD
University of Pittsburgh Medical Center, Pittsburgh, PennsylvaniaThe concept of intraperitoneal (IP) chemotherapy for peritoneal metastases makes intuitive sense: it maximizes the concentration of chemotherapy delivered to the tumor cells while minimizing systemic toxicity. Randomized trials have demonstrated a significant and meaningful benefit to IP dwell therapy, but this approach also has significant limitations: technical complexity, pain for the patient, increased toxicity, and limited distribution of the drug due to adhesions after surgery.WHY HIPEC?
In an attempt to address these limitations, gastrointestinal (GI) surgical oncologists began to use hyperthermic IP chemotherapy (HIPEC) in the early 1990s. This approach has theoretical advantages over IP dwell therapy: it is delivered under general anesthesia at the time of cytoreduction; it utilizes hyperthermia, which has direct cytotoxic effects and which potentiates chemotherapy; and it virtually assures complete distribution of drug throughout the abdominal cavity. What makes sense for GI tumors makes even more sense for ovarian cancer, since the latter is more chemosensitive. This means that a brief exposure to cisplatin and hyperthermia can have dramatic effects.WHY IS HIPEC STILL CONTROVERSIAL?
After almost 25 years of data, however, the utility of HIPEC is not uniformly accepted, techniques vary, drugs and dosages differ, and we have no idea which aspect of the treatment (cytoreduction, hyperthermia, or chemotherapy) makes it effective.WHAT DOES THE FUTURE HOLD?
It is exciting to see the results of one randomized trial demonstrating a greater than doubling of median survival in patients with recurrent ovarian cancer. It is even more encouraging to see that seven randomized trials examining HIPEC are ongoing in ovarian cancer. The results of these ongoing trials will help answer important questions regarding the efficacy of HIPEC and the most appropriate indications for its use. The implications for clinical practice will likely be significant.

For this reason, many groups are advising against the use of HIPEC in ovarian cancer patients outside of clinical trials.[48] Two main criticisms are dominating the discussion: OS data are missing, and complication rates are higher than with conventional surgical treatment. Although there is no question that the lack of OS data is a problem, there are convincing studies that refute safety and feasibility concerns regarding this treatment modality. A number of phase I trials were conducted in both primary[49,50] and recurrent disease.[50,51] Severe complications ranged between 15% and 25% and morbidity between 0% and 4.2%. In one of these trials, even heavily pretreated patients with recurrent disease who had already undergone extensive surgery and adjuvant chemotherapy tolerated secondary cytoreductive surgery and HIPEC with low complication rates, no deaths, no delay in the initiation of standard postoperative carboplatin and gemcitabine chemotherapy, and no increased chemotherapy-associated adverse effects.[51] This dose-finding study showed that high IP cisplatin concentrations (100 mg/m²) are feasible in pretreated patients.

Much as with postoperative IP chemotherapy, paclitaxel has only recently been investigated in the setting of HIPEC. With the peritoneal uptake of paclitaxel significantly slower than that of cisplatin,[52] an increased antitumor effect has been shown in vitro.[53] In a single-arm phase I study, the delivery of paclitaxel, 175 mg/m², in the setting of HIPEC showed acceptable morbidity (38%; minor and major complications), with no postoperative deaths.[54] Ansaloni et al conducted a multi-regimen phase II trial, including 11 patients who received cisplatin and paclitaxel in the setting of HIPEC; however, the authors did not provide complication rates for this specific regimen.[55] A pharmacokinetic evaluation of concurrent cisplatin and paclitaxel in HIPEC indicated that the serum concentration of paclitaxel would be below that associated with the regimen’s dose-limiting toxicity yet would constitute an effective IP concentration.[56]

HIPEC: Randomized Trials

A single-institution randomized phase III trial by Spiliotis et al was recently published that compared conventional cytoreduction in a first recurrence with cytoreduction and HIPEC (with cisplatin, 100 mg/m², and paclitaxel, 175 mg/m², in platinum-sensitive disease; and doxorubicin, 35 mg/m², and paclitaxel, 175 mg/m², or mitomycin, 15 mg/m², in platinum-resistant disease).[57] The authors demonstrated a significant improvement in the mean OS: 29.7 months in the HIPEC arm vs 13.4 months in the surgery-only arm (P = .006). Interestingly, patients with platinum-resistant disease showed a stronger improvement in median OS, while still having a significantly impaired OS compared with the OS seen in patients with platinum-sensitive disease. As anticipated, the highest OS was observed in patients with complete cytoreduction who received HIPEC; in addition, the preoperative tumor burden as reflected in the PCI score was described as an independent prognostic factor, with PCI score > 15 associated with a significantly impaired survival. Unfortunately, there are several weaknesses in the presentation of the data that decrease the validity of this first randomized HIPEC trial: There is no information on PFS, the authors do not provide median follow-up data, and the Kaplan-Meier survival curve shows a high number of censored cases. There is no information regarding the postoperative first-line treatment, nor are the complication rates addressed. Also, different regimens were used in patients with platinum-sensitive and platinum-resistant disease.

Currently, there are six open randomized trials (Table) recruiting patients with both primary and recurrent disease, as well as women who have already received 3 cycles of neoadjuvant chemotherapy. The CARCINOHIPEC study has completed recruitment, and the first results are anticipated soon. These studies will certainly provide more useful information about this treatment modality.

HIPEC: Future Outlook

As unclear as the patient outcome benefit may be, HIPEC is highly important as a platform for studying the effect of IP chemotherapy and hyperthermia on cancer cells in vivo. It offers the unique possibility of evaluating macroscopic lesions within the peritoneal cavity during chemoperfusion and then harvesting them after the procedure. The application of gene expression and proteomics to biopsy specimens could shed new light on the escape mechanisms of cancer cells and mechanisms of drug resistance. Pre- and post-perfusion biopsies could facilitate human in vivo studies of either new agents for IP therapy or methods for the improvement of chemotherapy uptake, thereby accelerating the process by which new therapeutics become available for clinical use. Two of the most promising emerging approaches are nanoparticle delivery systems and immunotherapy.

Nanoparticle delivery of paclitaxel and cisplatin has been the subject of recent clinical studies. The chief rationale for nanoparticle-facilitated IP chemotherapy is reduced clearance of the nanoparticle-bound drug from the peritoneal cavity compared with the clearance of a conventional drug in solution, and because of that, a higher peritoneum-to-plasma ratio as well as reduced systemic effects and longer tumor exposure. Especially for the small-molecule and water-soluble drugs cisplatin and carboplatin, reduced peritoneal clearance would result in a higher diffusion gradient and thus enhanced tumor penetration. In a murine model, paclitaxel has been successfully incorporated into nanoparticles,[58] in order to achieve higher tumor selectivity after IP injection and longer retention times. It was combined with yttrium-90 as part of a multimodal treatment.[58] Instead of incorporating paclitaxel into a nanoparticle, a new synthesis technique called precipitation with compressed antisolvent (PCA) allows the production of 800 nm–sized paclitaxel crystals that do not require use of the toxic solvent Cremophor EL; this technique has shown promising results after IP injection in a murine model.[59] A phase I trial was completed and the results are anticipated. Clinical trials of nanoparticle delivery systems for cytotoxic drugs have until now involved predominantly IV injection, with two agents that use this mode of delivery approved by the US Food and Drug Administration: nanoparticle albumin-bound paclitaxel and pegylated liposomal doxorubicin.[60,61] Other nanoparticles incorporating paclitaxel[62] or platinum polymers[63] for IV injection are under clinical investigation. A phase III noninferiority trial of a novel water-soluble formulation of paclitaxel and XR-17 (paclical) has been completed and was presented at the 2015 American Society of Clinical Oncology Annual Meeting.[64] The trial showed comparable rates of adverse effects and PFS; however, contrary to expectations, Cremophor EL–related adverse effects, such as neuropathy and allergic reactions, were not significantly reduced. Paclical has been approved for use in the Russian Federation, but approvals in the United States and the European Union are still pending.

In addition to their use for the delivery of cytotoxic agents, nanoparticles can be utilized to encapsulate other substances that are unstable in serum or ascites, releasing agents such as small interfering RNAs (siRNAs) into the cell cytoplasm of cancer cells.[65] siRNAs can silence overexpressed genes and reduce tumor growth and invasion, with low toxicity. The use of nanoparticles to deliver siRNAs has recently been shown to be applicable to humans.[66] Major targets for siRNAs in ovarian cancer are the genes encoding folate receptor, follicle-stimulating hormone receptor, luteinizing hormone–releasing hormone receptor, mucin 1, and epidermal growth factor receptor.[67]

Another new approach is IP immunotherapy, which involves the delivery of programmed T cells. Since Zhang et al showed that tumor infiltration with CD8-positive lymphocytes is associated with improved 5-year survival in epithelial ovarian cancer,[68] several attempts have been made to modify the T-cell response.[69] This can be achieved either by harvesting cells, reprogramming them in vitro, and then reintroducing the cells via autologous injection,[70,71] or by stimulating T-cell activation in vivo.[72] There are several ongoing phase I trials, but the efficacy as well as the relevance of IP applications are unclear.

Conclusion

The rationale for HIPEC as part of a multimodal treatment in patients with advanced ovarian cancer is strong. Given that hyperthermia enhances tumor penetration and the cytotoxic effects of chemotherapy, recent improvements in drug distribution and in patient monitoring in the operating room, as well as encouraging results in nonrandomized trials, justify further investigation of HIPEC in randomized clinical trials. The possibility of easily acquiring pre- and post-treatment biopsies in the course of the procedure also makes HIPEC an excellent setting for human in vivo studies of antitumor effects and pharmacodynamics.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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