Carotid artery infusion via implantable catheters for squamous cell carcinoma of the tonsils

Carotid artery infusion via implantable catheters for squamous cell carcinoma of the tonsils Background: Chemoradiotherapy has a dominant role in therapy for head and neck cancers. However, impressive results are often disturbed by adverse events such as dysphagia, xerostomia, and functional speech and hearing loss. To avoid exceeding toxicity limits in patients with primary and recurrent cancers of the tonsils, chemotherapy was administered intra-arterially via implantable Jet-Port-Allround catheters. Methods: We report on patients with primary and recurrent cancers of the tonsils. Eleven patients who refused chemoradiation were included in this trial. Of the seven patients without prior therapy, one was stage I, one was stage III, three were stage IVA, one was stage IVB, and one was stage IVC. The four patients who were in progression after prior chemoradiation were stage IVA. The median follow-up time was 47 months (20 to 125 months). After the implantation of a Jet-Port-Allround catheter into the carotid artery, the patients received intra-arterial infusion chemotherapy with venous chemofiltration for systemic detoxification. The stage I patient received lower-dose chemotherapy without chemofiltration. The stage IVC patient with lung metastases and a primary tumor that extended across the midline to the contralateral tonsil received additional isolated thoracic perfusion chemotherapy. Results: All seven chemoradiation-naïve patients exhibited clinically complete responses and are still alive after 20 to 125 months. Among the four patients who had relapsed after prior chemoradiation, the intra-arterial therapy elicited only poor responses, and the median survival time was 7.5 months. After carotid artery infusion chemotherapy, none of the patients required tube feeding. No cases of dysphagia, xerostomia, or functional speech and hearing loss have been reported among the patients without prior chemoradiotherapy. Conclusion: Despite the administration of low total dosages, intra-arterial infusion generates high concentrations of chemotherapeutics. In combination with chemofiltration, the systemic toxicity is kept within acceptable limits. Among the non-pretreated patients, better tumor responses and long-term tumor control were noted compared with those who had prior chemoradiation. Implantable Jet-Port-Allround carotid artery catheters facilitate the application of regional chemotherapy. Keywords: Regional perfusion, Intra-arterial infusion, Squamous cell carcinoma of the tonsils, Toxicity, Port catheters, Locally advanced cancers, Head and neck cancer * Correspondence: info@prof-aigner.de Department of Surgical Oncology, Medias Klinikum GmbH & Co KG, Krankenhausstr. 3a, 84489 Burghausen, Germany © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Aigner et al. World Journal of Surgical Oncology (2018) 16:104 Page 2 of 6 Background Local tumor control and survival rates for all stages of head and neck cancers have been improved by the appli- cation of high-dose chemoradiation as a standard therapy. However, the quality of life for patients who undergo che- moradiation is substantially jeopardized due to increased toxicity, which can cause conditions such as dysphagia, mucositis, xerostomia, weight loss, functional speech and hearing loss and the need for a tracheostomy and feeding tube. To avoid exceeding acceptable toxicity levels in patients with primary and recurrent cancers of the tonsils, chemotherapy was administered intra-arterially via im- plantable Jet-Port-Allround catheters. Fig. 1 Contrast image of a Jet-Port-Allround catheter in the right Methods carotid artery Eleven patients with cancers of the tonsils were included in this retrospective case series. All patients were reluc- tant to undergo radiotherapy or chemoradiation and and above the rim located behind the tip (Fig. 2). The signed informed consent forms for intra-arterial chemo- catheter is then exited above the clavicula lateral to the therapy via an implantable system. Of the seven patients sternocleidomastoid muscle. The port is connected to without prior therapy, one was stage I, one was stage III, the catheter and placed into an infraclavicular subcuta- three were stage IVA, one was stage IVB, and one was neous pouch on the pectoral muscle. The exact position stage IVC. All four patients who were in progression of the catheter is controlled via the injection of indigo- after prior chemoradiation were stage IVA (Table 1). A carmine blue dye into the port, which creates a blue contrast image of the application technique is provided staining of the ipsilateral half of the face, tongue, and in Fig. 1. palate (Fig. 3). Implantation technique Regional chemotherapy cycles Through a transverse incision above the median part of After the implantation of the Jet-Port-Allround catheters the clavicula performed under general anesthesia, the into the carotid artery (Fig. 2), the blood distribution common carotid artery is exposed and secured with was controlled via the intra-arterial injection of indigo- tape. After placing a 5.0 prolene purse string suture, the carmine blue. Then, the chemotherapy agent was in- tip of the Jet-Port-Allround catheter (PfM Cologne) is fused intra-arterially (IAC) over 7 to 10 min through inserted through a stab incision and fixed tight below mono- or bilateral Jet-Port-Allround catheters into the Table 1 Patient characteristics Patient Age Sex TNM staging UICC Chemoradiation Time Diagnosis to Alive Progression Survival (months Cycles Response number RCT Treatment free time from therapy of RCT (months) start) 1 78 m cT1N0M0 I No 1 Yes 125+ 125+ 6 Complete response (CR) 2 58 m cT3N1M0 III No 3 Yes 47+ 47+ 5 CR 3 77 f cT2N2b IVA No 1 Yes 21+ 21+ 4 CR 4 72 m cT2N2Mx IVA No 2 Yes 20+ 20+ 6 CR 5 55 m pT2N2bM0G2R1 IVA No 1 Yes 57+ 57+ 1 CR 6 51 m cT3N3 IVB No 7 Yes 30+ 30+ 7 CR/relapse after 12 months 7 65 m cT3N2bG2 IVC No 2 Yes 89+ 89+ 4 CR 8 68 m cT2-3N2bpG2 IVA Yes 45 No 0 5 4 No response 9 67 f pT2N0MxG1R0 IVA Yes 27 No 1 9 2 Partial response 10 58 f pT4aN1Mx IVA Yes 12 No 4 7 6 Partial response 11 63 m pT3N2bM0R0L1V1 IVA Yes 20 No 1.5. 8 4 Partial response Aigner et al. World Journal of Surgical Oncology (2018) 16:104 Page 3 of 6 20 mg mitomycin per cycle). The first cycle involved iso- lated thoracic perfusion [1] and was followed by 3 cycles of intra-arterial infusions and chemofiltration with the same drug combinations. Details of the therapy cycles are described in Table 2. For prophylaxis against arterial thrombosis and clotting at the tip of the Jet-Port-Allround catheter, the patients re- ceived aspirin (100 mg/day) for 3 months. Repeated flush- ing of the port catheters was not necessary. Results Seven chemoradiation naïve patients exhibited clinically complete responses after IAC, and six of these patients are still alive and disease-free after 20 to 125 months. One patient experienced a relapse after 12 months, ex- Fig. 2 End-to-side implantation and fixation of a Jet-Port-Allround in hibited only partial responses to further intra-arterial carotid the artery therapies, and was transferred to radiotherapy. He has been alive for 30 months without relapse. Complete re- isolated circuit. The dosages varied depending on the sponses in the chemoradiation naïve patients were clinical staging and tumor extension. The number of cy- reached upon the administration of the following regi- cles varied depending on the response. The intervals be- mens: (i) IAC without chemofiltration (6 cycles, one pa- tween the regional chemotherapy cycles were 3 weeks. tient, stage I, still alive at 125 months), (ii) IAC with Nine patients (clinical stages III to IVB) received regular chemofiltration (4–7 cycles, five patients, stages III to dosages (50 mg cisplatin, 30 mg Adriamycin, and 15 mg IVB, all still alive at 20–57 months), and (iii) isolated mitomycin per cycle). Venous chemofiltration regimens thoracic perfusion and IAC with chemofiltration (1 and with up to 4 l of filtrate over 30 to 45 min for systemic 3 cycles, respectively, one patient, stage IVC, still alive at detoxification were implemented. The procedure was 89 months). The time from the initial diagnosis to the repeated in 4 to 7 cycles. One patient in clinical stage I initiation of treatment with IAC was 1 to 7 months. The received 6 cycles with slightly lower dosages (30 mg cis- responders to IAC exhibited tumor shrinkage within 2 platin, 20 mg Adriamycin, 15 mg mitomycin, and to 3 weeks after the first therapy. A complete remission 500 mg 5-FU per cycle) without chemofiltration. An- of a lymph node metastasis 16 days after IAC and che- other patient (IVC) with three lung metastases and a pri- mofiltration is demonstrated in Fig. 4. mary tumor extending across the midline to the In the patients who relapsed after chemoradiation and contralateral tonsil and invading the entire soft palate received IAC thereafter, only poor responses were noted, along with large lymph node metastases received higher and median survival time was 7.5 months (5, 7, 8, and dosages (100 mg cisplatin, 60 mg Adriamycin, and 9 months). All patients with prior chemoradiation were in stage IVA and in a state of ongoing progression. The time from the initial diagnosis to the initiation of treat- ment with IAC was 12 to 45 months, and during this time, chemoradiation was applied. The minimum time from the last systemic chemotherapy to the first IAC was 4 weeks. Side-effects and toxicity With the given drug combinations, dosages, and infusion times, no cases of dysphagia, xerostomia, or neurological damage in terms of functional speech loss or ototoxicity were noted. No patient required a tracheostomy or tube feeding. The bone marrow depression was within the ac- ceptable range of grade 2 for the patients without pre- treatment. The patients who had undergone prior chemoradiation with extensive doses of systemic chemo- Fig. 3 Intra-arterial injection of indigocarmine blue stain showing therapy exhibited WHO grade 3 to 4 bone marrow de- the area of the blood distribution of the carotid artery pression after intra-arterial exposure at moderate doses. Aigner et al. World Journal of Surgical Oncology (2018) 16:104 Page 4 of 6 Table 2 Treatment details Stage (UICC) I III, IVA, IVB IVC Number of cases 1 9 1 Location Tonsils Tonsils Primary tumor extending across the midline to the contralateral tonsils invading the entire soft palate three lung metastases and large lymph node metastases Technique Intra-arterial infusion chemotherapy Intra-arterial infusion chemotherapy 1 cycle isolated thoracic perfusion 3 cycles intra-arterial infusion chemotherapy Number of cycles 6 4–74 Chemotherapeutics per cycle 30 mg cisplatin, 20 mg Adriamycin, 50 mg cisplatin, 30 mg Adriamycin, 100 mg cisplatin, 60 mg Adriamycin, 15 mg mitomycin, 500 mg 5-FU 15 mg mitomycin 20 mg mitomycin Infusion time 7–10 min 7–10 min 10 min Chemofiltration No Venous chemofiltration with up to Venous chemofiltration with up to 4 l 4 l filtrate over 30 to 45 min for filtrate over 30 to 45 min for systemic systemic detoxification detoxification Additional treatment Aspirin 100 mg/day for 3 months. Aspirin 100 mg/day for 3 months. Aspirin 100 mg/day for 3 months. Repeated flushing of the port Repeated flushing of the port catheters Repeated flushing of the port catheters is not necessary. is not necessary. catheters is not necessary. Response Complete response No response, partial response or Complete response complete response depending on pretreatment, more details on table patient characteristics Febrile neutropenia was never observed. At most, the number of evaluated patients (T score) was noted, and patients reported some type of strange and uncomfort- this increase translated into an increased incidence of able feeling in the throat, but they reported no pain or acute and late toxicity of 500% [2]. Due to the high inci- major discomfort. The catheters never caused vascular dence of permanent long-lasting treatment-associated adverse events such as thrombosis. toxicities, there is a call for the effective management of the post-therapeutic quality of life issues faced by heavily Discussion treated patients [3]. Continuously impaired quality of life The increasing intensity of standard treatments, such as can even contribute to an increased risk of head and increased exposure to radiation as well as to chemother- neck cancer treatment-related suicide and remains virtu- apy, during the past decades has been associated with ally throughout a cancer survivor’s life [4, 5]. Suicide is improved responses and survival rates, but unfortu- considered a major threat to head and neck cancer nately, these increases have also entailed intolerable tox- survivorship [6]. icity in many cases. In a meta-analysis of clinical trials Some attempts have been made to reduce the side conducted between 1990 and 1999, a continuous in- effects of HNC treatment. It has been demonstrated crease in the number of grade 3 to 4 toxicity events per that radiation-related toxicity can be reduced with Fig. 4 Lymph node metastasis before therapy and 16 days after the first intra-arterial infusion therapy with chemofiltration Aigner et al. World Journal of Surgical Oncology (2018) 16:104 Page 5 of 6 intensity-modulated radiotherapy (IMRT), which de- with isolated perfusion techniques [14]. The drug dos- posits high-dose radiation at the tumor site while re- ages for intra-arterial application in general can be lower ducing the toxic exposure of the surrounding normal than those required for intra-venous application. tissues, which in turn, results in significantly im- Through intra-arterial application, the drugs are distrib- proved swallowing and nutritional statuses [7, 8]. uted in a reduced blood volume and therefore achieve Acute and long-term toxicities from chemotherapy are higher concentrations during the first pass through the other issues and cause severe kidney-, neuro-, and oto- tumor site. Prior chemoradiotherapy seems to have a toxicity due to the extremely high doses of cisplatin. negative influence on the response to intra-arterial Previous studies of intra-arterial chemotherapy for chemotherapy. However, immediately after irradiation, HNC treatment have been performed by several groups. there is a synergetic effect that involves increased drug Robbins et al. applied high-dose cisplatin over short in- uptake due to vasodilatation from local hyperemia. Six tervals (4× supradose of 150 mg/m applied at 1-week to eight months after irradiation, the intra-arterial infu- intervals). Renal toxicity was reduced by the subsequent sion of indigocarmine blue dye reveals a demarcation administration of sodium thiosulfate, which is a covalent line around the field of radiation, which, due to soft tis- binder of cisplatin [9–11]. sue fibrosis, exhibits reduced vascular supply and no A randomized study comparing the intra-arterial ver- longer stains blue. Soft tissue fibrosis is thus the reason sus the systemic administration of cisplatin has been for the poor response behavior after radiotherapy. published by Rasch et al. [12]. In this study, the dosages The greatest advantage of regional chemotherapy is for intra-arterial application were higher than those used the high local efficacy with low toxicity. In our experi- for systemic application (150 vs. 100 mg/m ). The inter- ence, efficiency is strongly related to the mode of drug vals for intra-arterial application were shorter than those exposure with intra-arterial infusion times between 7 to for systemic application (1 vs. 3 weeks). Both arms of 10 min. this study additionally received high-dose radiation (total For all patients without prior chemoradiation, dose 70 Gy). For these dosages and interval modalities, complete remission was achieved, and neuro-, oto-, and oto- and neurotoxicity have been reported to not renal toxicity were never observed. There was no xeros- significantly differ between the two application modes. tomia, and no tube feeding was required. As an outcome of this study, intra-arterial chemotherapy In case of relapse, however, irradiation is considered administered via angiographic catheters was considered mandatory. more technically complex and invasive than A potential deficit of this study is the lack of know- intra-venous application. The chemotherapy infusion ledge about the human papillomavirus (HPV) statuses. times in these two studies were either not reported or However, regarding the results in terms of adverse ef- specified as rapidly infused. fects and survival, the method outperforms any other Our approach differs from those of previous studies in treatment option even if only compared with several aspects; for example, intra-arterial chemotherapy HPV-positive cases, which indeed are known to have is technically facilitated by implantation and infusion via better prognoses. implantable Jet-Port-Allround catheters, and it is admin- istered without additional radiation if a response is dem- Conclusion onstrated after at least 2 cycles. The dosages range from Despite the administration of low total dosages of drugs, 17 to 56 mg/m cisplatin (30 to 100 mg total dose per intra-arterial infusion generates high regional concentra- cycle) accompanied by moderate dosages of Adriamycin tions of chemotherapeutics. When combined with che- and mitomycin (the exact dosages per cycle are listed in mofiltration, the systemic toxicity can be kept low and Table 2). An infusion time of 7 to 10 min has been dem- within acceptable limits. In patients without prior che- onstrated to be effective and is considered mandatory to moradiation, very good long-term locoregional and dis- achieve an enduring exposure to the chemotherapeutics tant tumor control can be achieved with almost no side at the tumor region. Chemofiltration to remove the che- effects. Patients who relapse after regional chemotherapy motherapeutics from the venous return from the tumor are submitted to irradiation. In summary, regional site reduces the immediate and cumulative toxicities of chemotherapy through implantable Jet-Port-Allround the drugs. The number of cycles is one to seven depend- carotid artery catheters facilitates intra-arterial chemo- ing on the response behavior. therapy and represents a significant improvement over Greater drug exposures can be achieved by means of standard therapies due to the reduction of side effects. the intra-arterial infusion of slightly higher dosages with Abbreviations simultaneous chemofiltration of the venous return from 5-FU: 5-Fluorouracil; HPV: Human papillomavirus; IAC: Intra-arterial the tumor site [13]. Maximally increased drug exposure chemotherapy; IMRT: Intensity-modulated radiotherapy; WHO: World Health is achieved when the intra-arterial infusion is combined Organization Aigner et al. World Journal of Surgical Oncology (2018) 16:104 Page 6 of 6 Availability of data and materials 9. Robbins KT, Kumar P, Regine WF, et al. Efficacy of targeted supradose cisplatin The datasets used and/or analyzed in the current study are available from and concomitant radiation therapy for advanced head and neck cancer: the the corresponding author on reasonable request. Memphis experience. Int J Radiat Oncol Biol Phys. 1997;38:263–71. 10. Robbins KT, Kumar P, Harris J, et al. Supradose intra-arterial cisplatin and Authors’ contributions concurrent radiation therapy for the treatment of stage IV head and neck KRA made substantial contributions to the study conception and design, the squamous cell carcinoma is feasible and efficacious in a multi-institutional acquisition of the data, and the analysis and interpretation of the data. KRA setting: results of Radiation Therapy Oncology Group Trial 9615. J Clin was involved in drafting the manuscript and critically revising it for important Oncol. 2005;23:1447–54. intellectual content and has given final approval of the version to be published. 11. Robbins KT, Storniolo AM, Kerber C, et al. Phase I study of highly selective KRA agrees to be accountable for all aspects of the work and ensuring the supradose cisplatin infusions for advanced head and neck cancer. J Clin accuracy and integrity of any part of the work. SG made substantial Oncol. 1994;12:2113–20. contributions to the study conception and design, the acquisition of the 12. Rasch CR, Hauptmann M, Schornagel J, et al. Intra-arterial versus intravenous data, and the analysis and interpretation of the data. SG was involved in chemoradiation for advanced head and neck cancer: results of a drafting the manuscript and critically revising it for important intellectual randomized phase 3 trial. Cancer. 2010;116:2159–65. content and has given final approval of the version to be published. SG 13. Aigner K, Tonn JC, Hechtel R, et al. Die intraarterielle Zytostatikatherapie mit agrees to be accountable for all aspects of the work and ensuring the venöser Filtration im halboffenen System. Onkologie. 1983;6:74–6. accuracy and integrity of any part of the work. KA made substantial 14. Aigner KR, Selak E, Schlaf R. Isolated thoracic perfusion with carotid artery contributions to the study conception and design, the acquisition of the infusion for advanced and chemoresistant tumors of the parotid gland and data, and the analysis and interpretation of the data. KA was involved in tonsils. In: Aigner KR, Stephens FO, editors. Induction drafting the manuscript and critically revising it for important intellectual chemotherapy—systemic and locoregional. Second ed. Berlin-Heidelberg: content and has given final approval of the version to be published. KA Springer-Verlag; 2016. p. 123–30. agrees to be accountable for all aspects of the work and ensuring the accuracy and integrity of any part of this work. Ethics approval and consent to participate The investigations were performed in compliance with the principles of good clinical practice outlined in the Declaration of Helsinki and federal guidelines, and approval from the Medias Institutional Review Committee was acquired. Informed consent was obtained from each participant or the participant’s guardian. Consent for publication Consent for publication was obtained from every individual whose data are included in this manuscript. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Received: 23 March 2018 Accepted: 28 May 2018 References 1. Aigner KR, Selak E. Isolated thoracic perfusion with chemofiltration (ITP-F) for advanced and pretreated non-small-cell lung cancer. In: Aigner KR, Stephens FO, editors. Induction chemotherapy – systemic and Locoregional. Second ed. Berlin-Heidelberg: Springer-Verlag; 2016. p. 487–95. 2. Trotti A, Pajak TF, Gwede CK, et al. TAME: development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol. 2017;8:613–24. 3. Ringash J. Survivorship and quality of life in head and neck cancer. J Clin Oncol. 2015;33:3322–7. 4. Epstein JB, Thariat J, Bensadoun RJ, et al. Oral complications of cancer and cancer therapy: from cancer treatment to survivorship. CA Cancer J Clin. 2012;62:400–22. 5. Misono S, Weiss NS, Fann JR, et al. Incidence of suicide in persons with cancer. J Clin Oncol. 2008;26:4731–8. 6. Osazuwa-Peters N, Boakye EA, Walker RJ, et al. Suicide: a major threat to head and neck cancer survivorship. J Clin Oncol. 2016;34:1151. 7. Marur S, Li S, Cmelak AJ, et al. E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx—ECOG-ACRIN Cancer Research Group. J Clin Oncol. 2016;35:490–7. 8. Setton J, Caria N, Romanyshyn J, et al. Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: an update of the Memorial Sloan-Kettering Cancer Center experience. Int J Radiat Oncol Biol Phys. 2012;82(1):291–8. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png World Journal of Surgical Oncology Springer Journals

Carotid artery infusion via implantable catheters for squamous cell carcinoma of the tonsils

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Abstract

Background: Chemoradiotherapy has a dominant role in therapy for head and neck cancers. However, impressive results are often disturbed by adverse events such as dysphagia, xerostomia, and functional speech and hearing loss. To avoid exceeding toxicity limits in patients with primary and recurrent cancers of the tonsils, chemotherapy was administered intra-arterially via implantable Jet-Port-Allround catheters. Methods: We report on patients with primary and recurrent cancers of the tonsils. Eleven patients who refused chemoradiation were included in this trial. Of the seven patients without prior therapy, one was stage I, one was stage III, three were stage IVA, one was stage IVB, and one was stage IVC. The four patients who were in progression after prior chemoradiation were stage IVA. The median follow-up time was 47 months (20 to 125 months). After the implantation of a Jet-Port-Allround catheter into the carotid artery, the patients received intra-arterial infusion chemotherapy with venous chemofiltration for systemic detoxification. The stage I patient received lower-dose chemotherapy without chemofiltration. The stage IVC patient with lung metastases and a primary tumor that extended across the midline to the contralateral tonsil received additional isolated thoracic perfusion chemotherapy. Results: All seven chemoradiation-naïve patients exhibited clinically complete responses and are still alive after 20 to 125 months. Among the four patients who had relapsed after prior chemoradiation, the intra-arterial therapy elicited only poor responses, and the median survival time was 7.5 months. After carotid artery infusion chemotherapy, none of the patients required tube feeding. No cases of dysphagia, xerostomia, or functional speech and hearing loss have been reported among the patients without prior chemoradiotherapy. Conclusion: Despite the administration of low total dosages, intra-arterial infusion generates high concentrations of chemotherapeutics. In combination with chemofiltration, the systemic toxicity is kept within acceptable limits. Among the non-pretreated patients, better tumor responses and long-term tumor control were noted compared with those who had prior chemoradiation. Implantable Jet-Port-Allround carotid artery catheters facilitate the application of regional chemotherapy. Keywords: Regional perfusion, Intra-arterial infusion, Squamous cell carcinoma of the tonsils, Toxicity, Port catheters, Locally advanced cancers, Head and neck cancer * Correspondence: info@prof-aigner.de Department of Surgical Oncology, Medias Klinikum GmbH & Co KG, Krankenhausstr. 3a, 84489 Burghausen, Germany © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Aigner et al. World Journal of Surgical Oncology (2018) 16:104 Page 2 of 6 Background Local tumor control and survival rates for all stages of head and neck cancers have been improved by the appli- cation of high-dose chemoradiation as a standard therapy. However, the quality of life for patients who undergo che- moradiation is substantially jeopardized due to increased toxicity, which can cause conditions such as dysphagia, mucositis, xerostomia, weight loss, functional speech and hearing loss and the need for a tracheostomy and feeding tube. To avoid exceeding acceptable toxicity levels in patients with primary and recurrent cancers of the tonsils, chemotherapy was administered intra-arterially via im- plantable Jet-Port-Allround catheters. Fig. 1 Contrast image of a Jet-Port-Allround catheter in the right Methods carotid artery Eleven patients with cancers of the tonsils were included in this retrospective case series. All patients were reluc- tant to undergo radiotherapy or chemoradiation and and above the rim located behind the tip (Fig. 2). The signed informed consent forms for intra-arterial chemo- catheter is then exited above the clavicula lateral to the therapy via an implantable system. Of the seven patients sternocleidomastoid muscle. The port is connected to without prior therapy, one was stage I, one was stage III, the catheter and placed into an infraclavicular subcuta- three were stage IVA, one was stage IVB, and one was neous pouch on the pectoral muscle. The exact position stage IVC. All four patients who were in progression of the catheter is controlled via the injection of indigo- after prior chemoradiation were stage IVA (Table 1). A carmine blue dye into the port, which creates a blue contrast image of the application technique is provided staining of the ipsilateral half of the face, tongue, and in Fig. 1. palate (Fig. 3). Implantation technique Regional chemotherapy cycles Through a transverse incision above the median part of After the implantation of the Jet-Port-Allround catheters the clavicula performed under general anesthesia, the into the carotid artery (Fig. 2), the blood distribution common carotid artery is exposed and secured with was controlled via the intra-arterial injection of indigo- tape. After placing a 5.0 prolene purse string suture, the carmine blue. Then, the chemotherapy agent was in- tip of the Jet-Port-Allround catheter (PfM Cologne) is fused intra-arterially (IAC) over 7 to 10 min through inserted through a stab incision and fixed tight below mono- or bilateral Jet-Port-Allround catheters into the Table 1 Patient characteristics Patient Age Sex TNM staging UICC Chemoradiation Time Diagnosis to Alive Progression Survival (months Cycles Response number RCT Treatment free time from therapy of RCT (months) start) 1 78 m cT1N0M0 I No 1 Yes 125+ 125+ 6 Complete response (CR) 2 58 m cT3N1M0 III No 3 Yes 47+ 47+ 5 CR 3 77 f cT2N2b IVA No 1 Yes 21+ 21+ 4 CR 4 72 m cT2N2Mx IVA No 2 Yes 20+ 20+ 6 CR 5 55 m pT2N2bM0G2R1 IVA No 1 Yes 57+ 57+ 1 CR 6 51 m cT3N3 IVB No 7 Yes 30+ 30+ 7 CR/relapse after 12 months 7 65 m cT3N2bG2 IVC No 2 Yes 89+ 89+ 4 CR 8 68 m cT2-3N2bpG2 IVA Yes 45 No 0 5 4 No response 9 67 f pT2N0MxG1R0 IVA Yes 27 No 1 9 2 Partial response 10 58 f pT4aN1Mx IVA Yes 12 No 4 7 6 Partial response 11 63 m pT3N2bM0R0L1V1 IVA Yes 20 No 1.5. 8 4 Partial response Aigner et al. World Journal of Surgical Oncology (2018) 16:104 Page 3 of 6 20 mg mitomycin per cycle). The first cycle involved iso- lated thoracic perfusion [1] and was followed by 3 cycles of intra-arterial infusions and chemofiltration with the same drug combinations. Details of the therapy cycles are described in Table 2. For prophylaxis against arterial thrombosis and clotting at the tip of the Jet-Port-Allround catheter, the patients re- ceived aspirin (100 mg/day) for 3 months. Repeated flush- ing of the port catheters was not necessary. Results Seven chemoradiation naïve patients exhibited clinically complete responses after IAC, and six of these patients are still alive and disease-free after 20 to 125 months. One patient experienced a relapse after 12 months, ex- Fig. 2 End-to-side implantation and fixation of a Jet-Port-Allround in hibited only partial responses to further intra-arterial carotid the artery therapies, and was transferred to radiotherapy. He has been alive for 30 months without relapse. Complete re- isolated circuit. The dosages varied depending on the sponses in the chemoradiation naïve patients were clinical staging and tumor extension. The number of cy- reached upon the administration of the following regi- cles varied depending on the response. The intervals be- mens: (i) IAC without chemofiltration (6 cycles, one pa- tween the regional chemotherapy cycles were 3 weeks. tient, stage I, still alive at 125 months), (ii) IAC with Nine patients (clinical stages III to IVB) received regular chemofiltration (4–7 cycles, five patients, stages III to dosages (50 mg cisplatin, 30 mg Adriamycin, and 15 mg IVB, all still alive at 20–57 months), and (iii) isolated mitomycin per cycle). Venous chemofiltration regimens thoracic perfusion and IAC with chemofiltration (1 and with up to 4 l of filtrate over 30 to 45 min for systemic 3 cycles, respectively, one patient, stage IVC, still alive at detoxification were implemented. The procedure was 89 months). The time from the initial diagnosis to the repeated in 4 to 7 cycles. One patient in clinical stage I initiation of treatment with IAC was 1 to 7 months. The received 6 cycles with slightly lower dosages (30 mg cis- responders to IAC exhibited tumor shrinkage within 2 platin, 20 mg Adriamycin, 15 mg mitomycin, and to 3 weeks after the first therapy. A complete remission 500 mg 5-FU per cycle) without chemofiltration. An- of a lymph node metastasis 16 days after IAC and che- other patient (IVC) with three lung metastases and a pri- mofiltration is demonstrated in Fig. 4. mary tumor extending across the midline to the In the patients who relapsed after chemoradiation and contralateral tonsil and invading the entire soft palate received IAC thereafter, only poor responses were noted, along with large lymph node metastases received higher and median survival time was 7.5 months (5, 7, 8, and dosages (100 mg cisplatin, 60 mg Adriamycin, and 9 months). All patients with prior chemoradiation were in stage IVA and in a state of ongoing progression. The time from the initial diagnosis to the initiation of treat- ment with IAC was 12 to 45 months, and during this time, chemoradiation was applied. The minimum time from the last systemic chemotherapy to the first IAC was 4 weeks. Side-effects and toxicity With the given drug combinations, dosages, and infusion times, no cases of dysphagia, xerostomia, or neurological damage in terms of functional speech loss or ototoxicity were noted. No patient required a tracheostomy or tube feeding. The bone marrow depression was within the ac- ceptable range of grade 2 for the patients without pre- treatment. The patients who had undergone prior chemoradiation with extensive doses of systemic chemo- Fig. 3 Intra-arterial injection of indigocarmine blue stain showing therapy exhibited WHO grade 3 to 4 bone marrow de- the area of the blood distribution of the carotid artery pression after intra-arterial exposure at moderate doses. Aigner et al. World Journal of Surgical Oncology (2018) 16:104 Page 4 of 6 Table 2 Treatment details Stage (UICC) I III, IVA, IVB IVC Number of cases 1 9 1 Location Tonsils Tonsils Primary tumor extending across the midline to the contralateral tonsils invading the entire soft palate three lung metastases and large lymph node metastases Technique Intra-arterial infusion chemotherapy Intra-arterial infusion chemotherapy 1 cycle isolated thoracic perfusion 3 cycles intra-arterial infusion chemotherapy Number of cycles 6 4–74 Chemotherapeutics per cycle 30 mg cisplatin, 20 mg Adriamycin, 50 mg cisplatin, 30 mg Adriamycin, 100 mg cisplatin, 60 mg Adriamycin, 15 mg mitomycin, 500 mg 5-FU 15 mg mitomycin 20 mg mitomycin Infusion time 7–10 min 7–10 min 10 min Chemofiltration No Venous chemofiltration with up to Venous chemofiltration with up to 4 l 4 l filtrate over 30 to 45 min for filtrate over 30 to 45 min for systemic systemic detoxification detoxification Additional treatment Aspirin 100 mg/day for 3 months. Aspirin 100 mg/day for 3 months. Aspirin 100 mg/day for 3 months. Repeated flushing of the port Repeated flushing of the port catheters Repeated flushing of the port catheters is not necessary. is not necessary. catheters is not necessary. Response Complete response No response, partial response or Complete response complete response depending on pretreatment, more details on table patient characteristics Febrile neutropenia was never observed. At most, the number of evaluated patients (T score) was noted, and patients reported some type of strange and uncomfort- this increase translated into an increased incidence of able feeling in the throat, but they reported no pain or acute and late toxicity of 500% [2]. Due to the high inci- major discomfort. The catheters never caused vascular dence of permanent long-lasting treatment-associated adverse events such as thrombosis. toxicities, there is a call for the effective management of the post-therapeutic quality of life issues faced by heavily Discussion treated patients [3]. Continuously impaired quality of life The increasing intensity of standard treatments, such as can even contribute to an increased risk of head and increased exposure to radiation as well as to chemother- neck cancer treatment-related suicide and remains virtu- apy, during the past decades has been associated with ally throughout a cancer survivor’s life [4, 5]. Suicide is improved responses and survival rates, but unfortu- considered a major threat to head and neck cancer nately, these increases have also entailed intolerable tox- survivorship [6]. icity in many cases. In a meta-analysis of clinical trials Some attempts have been made to reduce the side conducted between 1990 and 1999, a continuous in- effects of HNC treatment. It has been demonstrated crease in the number of grade 3 to 4 toxicity events per that radiation-related toxicity can be reduced with Fig. 4 Lymph node metastasis before therapy and 16 days after the first intra-arterial infusion therapy with chemofiltration Aigner et al. World Journal of Surgical Oncology (2018) 16:104 Page 5 of 6 intensity-modulated radiotherapy (IMRT), which de- with isolated perfusion techniques [14]. The drug dos- posits high-dose radiation at the tumor site while re- ages for intra-arterial application in general can be lower ducing the toxic exposure of the surrounding normal than those required for intra-venous application. tissues, which in turn, results in significantly im- Through intra-arterial application, the drugs are distrib- proved swallowing and nutritional statuses [7, 8]. uted in a reduced blood volume and therefore achieve Acute and long-term toxicities from chemotherapy are higher concentrations during the first pass through the other issues and cause severe kidney-, neuro-, and oto- tumor site. Prior chemoradiotherapy seems to have a toxicity due to the extremely high doses of cisplatin. negative influence on the response to intra-arterial Previous studies of intra-arterial chemotherapy for chemotherapy. However, immediately after irradiation, HNC treatment have been performed by several groups. there is a synergetic effect that involves increased drug Robbins et al. applied high-dose cisplatin over short in- uptake due to vasodilatation from local hyperemia. Six tervals (4× supradose of 150 mg/m applied at 1-week to eight months after irradiation, the intra-arterial infu- intervals). Renal toxicity was reduced by the subsequent sion of indigocarmine blue dye reveals a demarcation administration of sodium thiosulfate, which is a covalent line around the field of radiation, which, due to soft tis- binder of cisplatin [9–11]. sue fibrosis, exhibits reduced vascular supply and no A randomized study comparing the intra-arterial ver- longer stains blue. Soft tissue fibrosis is thus the reason sus the systemic administration of cisplatin has been for the poor response behavior after radiotherapy. published by Rasch et al. [12]. In this study, the dosages The greatest advantage of regional chemotherapy is for intra-arterial application were higher than those used the high local efficacy with low toxicity. In our experi- for systemic application (150 vs. 100 mg/m ). The inter- ence, efficiency is strongly related to the mode of drug vals for intra-arterial application were shorter than those exposure with intra-arterial infusion times between 7 to for systemic application (1 vs. 3 weeks). Both arms of 10 min. this study additionally received high-dose radiation (total For all patients without prior chemoradiation, dose 70 Gy). For these dosages and interval modalities, complete remission was achieved, and neuro-, oto-, and oto- and neurotoxicity have been reported to not renal toxicity were never observed. There was no xeros- significantly differ between the two application modes. tomia, and no tube feeding was required. As an outcome of this study, intra-arterial chemotherapy In case of relapse, however, irradiation is considered administered via angiographic catheters was considered mandatory. more technically complex and invasive than A potential deficit of this study is the lack of know- intra-venous application. The chemotherapy infusion ledge about the human papillomavirus (HPV) statuses. times in these two studies were either not reported or However, regarding the results in terms of adverse ef- specified as rapidly infused. fects and survival, the method outperforms any other Our approach differs from those of previous studies in treatment option even if only compared with several aspects; for example, intra-arterial chemotherapy HPV-positive cases, which indeed are known to have is technically facilitated by implantation and infusion via better prognoses. implantable Jet-Port-Allround catheters, and it is admin- istered without additional radiation if a response is dem- Conclusion onstrated after at least 2 cycles. The dosages range from Despite the administration of low total dosages of drugs, 17 to 56 mg/m cisplatin (30 to 100 mg total dose per intra-arterial infusion generates high regional concentra- cycle) accompanied by moderate dosages of Adriamycin tions of chemotherapeutics. When combined with che- and mitomycin (the exact dosages per cycle are listed in mofiltration, the systemic toxicity can be kept low and Table 2). An infusion time of 7 to 10 min has been dem- within acceptable limits. In patients without prior che- onstrated to be effective and is considered mandatory to moradiation, very good long-term locoregional and dis- achieve an enduring exposure to the chemotherapeutics tant tumor control can be achieved with almost no side at the tumor region. Chemofiltration to remove the che- effects. Patients who relapse after regional chemotherapy motherapeutics from the venous return from the tumor are submitted to irradiation. In summary, regional site reduces the immediate and cumulative toxicities of chemotherapy through implantable Jet-Port-Allround the drugs. The number of cycles is one to seven depend- carotid artery catheters facilitates intra-arterial chemo- ing on the response behavior. therapy and represents a significant improvement over Greater drug exposures can be achieved by means of standard therapies due to the reduction of side effects. the intra-arterial infusion of slightly higher dosages with Abbreviations simultaneous chemofiltration of the venous return from 5-FU: 5-Fluorouracil; HPV: Human papillomavirus; IAC: Intra-arterial the tumor site [13]. Maximally increased drug exposure chemotherapy; IMRT: Intensity-modulated radiotherapy; WHO: World Health is achieved when the intra-arterial infusion is combined Organization Aigner et al. World Journal of Surgical Oncology (2018) 16:104 Page 6 of 6 Availability of data and materials 9. Robbins KT, Kumar P, Regine WF, et al. Efficacy of targeted supradose cisplatin The datasets used and/or analyzed in the current study are available from and concomitant radiation therapy for advanced head and neck cancer: the the corresponding author on reasonable request. Memphis experience. Int J Radiat Oncol Biol Phys. 1997;38:263–71. 10. Robbins KT, Kumar P, Harris J, et al. Supradose intra-arterial cisplatin and Authors’ contributions concurrent radiation therapy for the treatment of stage IV head and neck KRA made substantial contributions to the study conception and design, the squamous cell carcinoma is feasible and efficacious in a multi-institutional acquisition of the data, and the analysis and interpretation of the data. KRA setting: results of Radiation Therapy Oncology Group Trial 9615. J Clin was involved in drafting the manuscript and critically revising it for important Oncol. 2005;23:1447–54. intellectual content and has given final approval of the version to be published. 11. Robbins KT, Storniolo AM, Kerber C, et al. Phase I study of highly selective KRA agrees to be accountable for all aspects of the work and ensuring the supradose cisplatin infusions for advanced head and neck cancer. J Clin accuracy and integrity of any part of the work. SG made substantial Oncol. 1994;12:2113–20. contributions to the study conception and design, the acquisition of the 12. Rasch CR, Hauptmann M, Schornagel J, et al. Intra-arterial versus intravenous data, and the analysis and interpretation of the data. SG was involved in chemoradiation for advanced head and neck cancer: results of a drafting the manuscript and critically revising it for important intellectual randomized phase 3 trial. Cancer. 2010;116:2159–65. content and has given final approval of the version to be published. SG 13. Aigner K, Tonn JC, Hechtel R, et al. Die intraarterielle Zytostatikatherapie mit agrees to be accountable for all aspects of the work and ensuring the venöser Filtration im halboffenen System. Onkologie. 1983;6:74–6. accuracy and integrity of any part of the work. KA made substantial 14. Aigner KR, Selak E, Schlaf R. Isolated thoracic perfusion with carotid artery contributions to the study conception and design, the acquisition of the infusion for advanced and chemoresistant tumors of the parotid gland and data, and the analysis and interpretation of the data. KA was involved in tonsils. In: Aigner KR, Stephens FO, editors. Induction drafting the manuscript and critically revising it for important intellectual chemotherapy—systemic and locoregional. Second ed. Berlin-Heidelberg: content and has given final approval of the version to be published. KA Springer-Verlag; 2016. p. 123–30. agrees to be accountable for all aspects of the work and ensuring the accuracy and integrity of any part of this work. Ethics approval and consent to participate The investigations were performed in compliance with the principles of good clinical practice outlined in the Declaration of Helsinki and federal guidelines, and approval from the Medias Institutional Review Committee was acquired. Informed consent was obtained from each participant or the participant’s guardian. Consent for publication Consent for publication was obtained from every individual whose data are included in this manuscript. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Received: 23 March 2018 Accepted: 28 May 2018 References 1. Aigner KR, Selak E. Isolated thoracic perfusion with chemofiltration (ITP-F) for advanced and pretreated non-small-cell lung cancer. In: Aigner KR, Stephens FO, editors. Induction chemotherapy – systemic and Locoregional. Second ed. Berlin-Heidelberg: Springer-Verlag; 2016. p. 487–95. 2. Trotti A, Pajak TF, Gwede CK, et al. TAME: development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol. 2017;8:613–24. 3. Ringash J. Survivorship and quality of life in head and neck cancer. J Clin Oncol. 2015;33:3322–7. 4. Epstein JB, Thariat J, Bensadoun RJ, et al. Oral complications of cancer and cancer therapy: from cancer treatment to survivorship. CA Cancer J Clin. 2012;62:400–22. 5. Misono S, Weiss NS, Fann JR, et al. Incidence of suicide in persons with cancer. J Clin Oncol. 2008;26:4731–8. 6. Osazuwa-Peters N, Boakye EA, Walker RJ, et al. Suicide: a major threat to head and neck cancer survivorship. J Clin Oncol. 2016;34:1151. 7. Marur S, Li S, Cmelak AJ, et al. E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx—ECOG-ACRIN Cancer Research Group. J Clin Oncol. 2016;35:490–7. 8. Setton J, Caria N, Romanyshyn J, et al. Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: an update of the Memorial Sloan-Kettering Cancer Center experience. Int J Radiat Oncol Biol Phys. 2012;82(1):291–8.

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World Journal of Surgical OncologySpringer Journals

Published: Jun 5, 2018

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