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Systemic chemotherapy using paclitaxel and carboplatin plus regional hyperthermia and hyperbaric oxygen treatment for non-small cell lung cancer with multiple pulmonary metastases: Preliminary results

Systemic chemotherapy using paclitaxel and carboplatin plus regional hyperthermia and hyperbaric... Purpose: The purpose of this retrospective case series was to evaluate the toxicity and efficacy of systemic chemotherapy using paclitaxel and carboplatin plus regional hyperthermia (HT) and hyperbaric oxygen treatment (HBO) for non-small-cell lung cancer (NSCLC). Materials and methods: Twenty-two patients with NSCLC with multiple pulmonary metastases intravenously received paclitaxel (50 mg/m ), carboplatin (area under the curve of 1.0–1.5) and 10% glucose weekly for 3 out of 4 weeks. Hyperthermia (HT) of the whole thoracic region was also administered weekly during intravenous infusion of carboplatin in all patients. In addition, 16 (72%) of 22 patients received hyperbaric oxygen (HBO) treatment immediately after weekly chemotherapy. A total of 107 cycles were performed in 16 patients with HBO, and 27 cycles in 6 patients without HBO. The toxicity and efficacy of these patients were retrospectively analyzed. Results: Both the hematologic and non-hematologic toxicities were mild and leucopenia/neutropenia of = grade 3 was seen in one patient, while pneumonitis of = grade 3 occurred in one patient. Fourteen (64%) of 22 patients had an objective response. The median time to progression of disease in all patients was 8 months and in 16 patients with HBO was 9 months. Four (44%) of 9 patients with prior chemotherapy including paclitaxel and carboplatin obtained objective responses. Conclusions: The novel combined therapy of paclitaxel and carboplatin with HT and HBO may therefore be a feasible and promising modality for treating NSCLC with multiple pulmonary metastases, and the results justify further evaluation to clarify the benefits of this treatment regimen. Keywords: Hyperthermia, chemotherapy, hyperbaric oxygen, non-small-cell lung cancer Introduction a promising activity in patients with advanced non-small-cell lung cancer (NSCLC). In the USA, Lung cancer is currently the most common cause of the combination of paclitaxel and carboplatin has cancer deaths in many countries, including Japan. been a widely used regimen for NSCLC because of Although meta-analyses have proved that cisplatin- its low toxicity profile and efficacy [2]. based chemotherapy improves survival compared The rationale for the use of hyperthermia (HT) as with the best supportive care, the benefits have a treatment for cancer rests on several mechanisms been modest [1]. During the past several years, some [3, 4]. HT is known to cause direct cytotoxicity, new chemotherapeutic drugs with novel mechanisms while it also acts as a radiation-sensitizer and chemo- of action, including paclitaxel, have demonstrated sensitizer. Although the combination of HT with Correspondence: Dr T. Ohguri, Department of Radiology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. Tel: þ81-93-691-7264. Fax: þ81-93-692-0249. E-mail: ogurieye@med.uoeh-u.ac.jp ISSN 0265–6736 print/ISSN 1464–5157 online  2009 Informa Healthcare Ltd. DOI: 10.1080/02656730802610357 Chemo-hyperthermia and hyperbaric oxygen 161 radiation has been the focus of more attention, there plus regional HT and HBO was administered is an equally strong rationale for combining HT with to improve the clinical outcomes in NSCLC. The chemotherapy. The mechanisms of action have been combined therapy for NSCLC with multiple pul- considered to be as follows: HT increases drug monary metastases was started in 2003. The main uptake into cells, increases oxygen radical produc- purpose of our study was to evaluate the toxicity tion, increases DNA damage and inhibits DNA and efficacy of this combined therapy in patients repair [3]. Many chemotherapeutic agents exhibit with NSCLC. synergism with HT [3–8]. As for carboplatin, several previous in vitro/vivo studies showed synergism with HT at 40 to 44 C [5, 6]. The optimal sequence Materials and methods between the application of heat and drug adminis- Data collection tration is to administer them simultaneously or to give the drug immediately before the onset of heating Data were collected from patient medical records for [5, 6]. For paclitaxel, several in vitro/vivo studies this retrospective case series. This study focused also showed synergism with HT [7, 8], while other on data obtained from 52 NSCLC patients who studies failed to show a significant thermal enhance- received systemic chemotherapy with regional HT at ment of paclitaxel cytotoxicity [9, 10]. Despite the two hospitals in Japan. The patients were included in results of studies demonstrating the efficacy of che- the study if they were eligible to receive systemic motherapy with HT, the utilization of this combina- chemotherapy using paclitaxel and carboplatin plus tion in clinical practice is still limited. Recently, regional HT with or without HBO for NSCLC with Zoul et al. showed the treatment results of weekly multiple lung metastases. Thirty patients with extra- paclitaxel combined with local HT in patients with thoracic metastases, except for brain metastases, recurrent breast cancer; an objective local response were excluded from this study; because the heating was observed in all treated patients (complete electrodes of regional HT did not cover those response in 4 patients and partial response in 3) metastases and there were considerable un-heated [11]. In the patients with a pleural dissemination of or inadequately heated lesions in those cases we NSCLC, the treatment results of post-operative considered that the patients were not suitable for this HT combined with the intra-thoracic administration case series. We included ten patients with brain of cisplatin have been reported; the overall survival of metastases, since all the metastatic lesions of the the treated group (n¼ 24) was significantly pro- brain were able to be treated with stereotactic longed in comparison to a historical control group radiosurgery, which provides higher local control treated by either surgery alone (n¼ 17) or explora- rates regardless of whether or not chemo-hyperther- tory thoracotomy (n¼ 11) [12]. However, there are mia is performed. In addition, any patients who had no clinical reports of systemic chemotherapy using radiotherapy of the thoracic region added to the paclitaxel and carboplatin combined with regional combined therapeutic regimen were also eliminated. HT for NSCLC. Several researchers have combined hyperbaric Patients oxygen treatment (HBO) with chemotherapy to Twenty-two patients (13 men and 9 women, age enhance drug cytotoxicity for cancer [13–17]. range, 47–77 years; median, 66 years) were chosen Many human solid tumors are composed of regions from the data base using the inclusion and exclusion that are well vascularized and normoxic, while other criteria mentioned above. Sixteen of the 22 patients regions are relatively hypoxic. Hypoxic cells in the also received HBO therapy at one hospital, since malignant tumor are relatively more resistant to the remaining 6 patients were treated at the other chemotherapy. The increase in oxygen partial pres- hospital where a hyperbaric chamber was not sure in hypoxic populations may explain the increase in the anti-tumor effect of these chemical agents. available. Between September 2003 and September In animal cancer models, several studies that 2007, all 22 patients were placed on the above previously combined HBO with various chemother- described regimen. The patients were selected for apeutic agents have shown increases in the mean this treatment by the following criteria: histologic survival times and/or decrease in tumor growth or cytologic proof of NSCLC; age between 18 and [13–15]. In limited clinical studies, the combination 80 years; Eastern Cooperative Oncology Group of HBO and chemotherapy showed a potential value (ECOG) performance status 0–2; absolute neutro- of increased survival for advanced cancer and the phil count =3,000/mm and platelet count side effects did not increase by combining HBO with =100,000/mm ; serum bilirubin, ALT, AST, ALP, chemotherapy [16, 17]. urea, and creatinine levels within normal limits. In this context, a novel combined therapy of sys- The patient characteristics are given in Table I. The temic chemotherapy using paclitaxel and carboplatin ECOG performance status and site of the disease 162 T. Ohguri et al. Table I. Patient characteristics. 3 mg granisetron hydrochloride intravenously, 50 mg diphenhydramine hydrochloride orally, and 50 mg Characteristics N¼ 22 ranitidine intravenously. Median age, years (range) 66 (47–77) There were no patients who required a dose Gender, male/female 13/9 reduction of chemotherapy. The treatment was Performance status, 0/1/2 0/10/12 Histology delayed in 7 (5%) cycles. All patients could be Adenocarcinoma 20 treated on an outpatient basis. A total of 107 cycles Large cell carcinoma 2 were performed in 16 patients with HBO, and Sites of disease 29 cycles in 6 patients without HBO. The median Lung 22 number of cycles in the patients with HBO was 7 Pleural effusion 1 Lymph nodes (range 1–13) while in the patients without HBO it Mediastinal 10 was 4 (range, 3–8). Supraclavicular 1 The chemotherapy with paclitaxel and carbo- Brain 10 platin was performed as an initial chemotherapy in Prior surgery for primary 4 8 patients (36%), as a second-line in 8 (36%), as a Prior RT for primary 10 Prior chemotherapy 14 third-line in 3 (14%) and as a fourth or sixth-line in Cisplatin 2 3 (14%). Any drugs administered as prior chemo- Carboplatin 11 therapy were listed in Table I. Gemcitabine 6 Paclitaxel 9 Vinorelbine 5 Hyperthermia Gefitinib 4 HT was performed during every intravenous infusion HBO 16 SRT for brain metastasis 10 of carboplatin for all cycles of chemotherapy. The heating duration ranged from 40–60 min. The heat RT, radiotherapy; HBO, hyperbaric oxygen treatment; SRT, stereotactic radiosurgery. was applied using 8-MHz radiofrequency-capacitive regional HT (Thermotron RF-8, Yamamoto Vinita Co., Osaka, Japan). The physical features of the RF-8 clinical HT machine and thermal distribution characteristics in a phantom as well as in the human were evaluated at the start of treatment. There were body when heating with this device have all been 10 cases with brain metastases. Fourteen patients reported previously [20, 21]. In all cases, both the (64%) had prior chemotherapy, of which 9 patients upper and the lower electrodes measured 30 cm in (41%) had undergone paclitaxel and carboplatin. diameter, and they were placed on opposite sides of Ten patients (45%) had received prior RT for the entire thoracic region. The treatment posture for primary lesions. Four patients had postoperative all cases was the prone position. The patients were recurrence. Ten (45%) of 22 patients underwent instructed carefully to mention any unpleasant stereotactic radiosurgery for brain metastasis. Written sensations suggestive of a hot spot. The RF-output informed consent for treatment was obtained from increased to the maximum level tolerated by the all patients. patients after any unpleasant sensations either vanished or decreased to a fully sustainable level by Chemotherapy superficial cooling and/or fine adjustments of the The treatment cycle was 4 weeks long. The body position. For superficial cooling to reduce the chemotherapy was administered weekly for 3 weeks preferential heating of the subcutaneous fat tissue, followed by 1 week of rest. Paclitaxel (Taxol, Bristol- overlay boluses were applied in addition to regular Myers Squibb, Princeton, NJ; 50 mg/m ) was given boluses which were attached in front of the metal intravenously over 1 hour, followed by carboplatin electrodes. Some previous studies showed a strong (Paraplatin, Bristol-Myers Squibb; area under the positive correlation to exist between the RF-output curve (AUC) of 1.0–1.5, depending on the age, and temperature of tumors in this device [22, 23]. clinical status and bone marrow tolerance) by Because the measurement of direct intra-tumor intravenous infusion over 1 hour. The carboplatin temperature was clinically difficult, invasive or dose was calculated by using a Calvert formula distressing, previous correlative data between with creatinine clearance substituted for the glomer- RF-output and intra-esophageal temperature at the ular filtration rate [18]. The patients received above setting of the whole thoracic HT in a large premedication consisting of 10% glucose which number of patients was used to estimate the heating was administered to further increase the value temperature: Y¼ 0.0056Xþ 36.6, X¼ median of thermochemotherapy by lowering the tumor RF-output (W); Y¼ maximum intra-esophageal pH [19], 4–8 mg dexamethasone intravenously, temperature ( C) [23]. Chemo-hyperthermia and hyperbaric oxygen 163 Table II. Toxicity* in all the patients. Grade 0 (%) Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) Leucopenia 6 (27) 11 (50) 4 (18) 1 (5) 0 Neutropenia 6 (27) 10 (45) 5 (23) 1 (5) 0 Anemia 17 (77) 4 (18) 1 (5) 0 0 Thrombocytopenia 21 (96) 1 (5) 0 0 0 Neuropathy 20 (90) 1 (5) 1 (5) 0 0 Pneumonitis 20 (90) 1 (5) 0 1 (5) 0 Diarrhea 22 (100) 0 0 0 0 Nausea 21 (95) 1 (5) 0 0 0 Vomiting 21 (95) 1 (5) 0 0 0 Hypersensitivity reaction 21 (95) 0 1 (5) 0 0 Renal toxic effect 22 (100) 0 0 0 0 Cardiac toxic effect 22 (100) 0 0 0 0 Fatigue 12 (55) 8 (36) 2 (9) 0 0 *The National Cancer Institute Common Toxicity Criteria version 3. The median RF-output in all patients ranged measurable or non-measurable lesion. Any patients from 800 to 1600 W (median 1,250 W). The who did not meet the definitions of response or median maximum intra-esophageal temperature progression were classified as having no change in all the patients was calculated to be 43.6 C (NC). The time to PoD was calculated from the (range, 41.1–45.6 C) from the correlative data first day of the combined therapy of this study to the between the median RF-output and intra-esophageal date of disease progression. The overall and disease temperature. progression-free survival rates were calculated from the start of the combined therapy by the Kaplan- Hyperbaric oxygen therapy Meier method. HBO was performed as a chemotherapy adjuvant to increase tumor sensitivity to anticancer agents Results immediately after weekly chemotherapy and regional HT for all cycles. The patients underwent a single The follow-up from the start of the combined treat- treatment for 60–90 minutes in a monoplace HBO ment ranged from 6 to 32 months (median, 16). chamber (Sechrist Industries Inc., model 2800 J, The degrees of toxicity are listed in Table II. Anaheim, California) pressured with 100% oxygen to Both hematologic and non-hematologic toxicities 2.0 atmospheres absolute. were mild. For the toxicities of = grade 3, leucopenia/neutropenia of grade 3 was seen in only Evaluation of the toxicity and efficacy one patient, and pneumonitis of grade 3 occurred in one patient. For these toxicities, there were no clear The National Cancer Institute Common Toxicity differences between those who did and did not Criteria version 3 was used to score toxicity. The receive HBO. Generally, HT was well tolerated by highest toxicity grade for each patient in all cycles of the patients, and only the initial contact with the cold this therapy was used for the toxicity analysis. boluses caused some discomfort, which thereafter The primary endpoints of this study regarding rapidly dissipated. No patients experienced any efficacy were the objective response rate and the time thermal burns. The weekly HBO treatment was to progression of disease (PoD). The patients were evaluated every 4 weeks (after the completion of also well tolerated. Although some patients experi- one cycle) by computed tomography (CT) scanning enced hearing difficulties either during or shortly for measurable lesions. The objective response after HBO, no serious or life-threatening complica- was evaluated according to the World Health tions with HBO were observed. Organization criteria [24]. A complete response Table III lists all patients associated with the (CR) was defined as the complete disappearance of treatment parameters and results. Fourteen (64%) all clinically detectable tumors for at least 4 weeks. of 22 patients had an objective response (4 CRs, A partial response (PR) required at least a 50% 10 PRs). Twelve (75%) of 16 patients with HBO and reduction in the sum of the products of the longest 2 (33%) of 6 patients without HBO had an objective perpendicular diameters of all measurable lesions. response. The time to PoD was 2 to 18 months Progressive disease (PD) required a 25% increase in (median, 8 months). Figure 1 shows the progression- measurable lesions or the appearance of any new free survival rates in all patients. The median time to 164 T. Ohguri et al. Table III. Treatment results in all the patients. Line Prior CT Prior platinum Median RF Median No. of Tumor Time to Case Stage* of CT including PC based CT output** heating time cycles HBO response POD (mos) 1 IV 1st – – 1300 50 8 Yes CR 12 2 IV 1st – – 1500 50 7 Yes CR 10 3 IV 1st – – 1600 50 6 Yes CR 5 4 IV 1st – – 1500 50 13 Yes PR 13 5 IV 1st – – 1500 50 3 Yes NC 4 6 IV 1st – – 1100 40 3 Yes NC 4 7 IV 2nd No No 1200 50 10 Yes PR 13 8 IV 2nd No Yes 1200 50 5 Yes PR 6 9 IV 2nd No No 1500 50 8 Yes PR 8 10 IV 2nd No Yes 1350 50 11 Yes PR 9 11 IV 2nd Yes Yes 1000 40 1 Yes PD 2 12 IV 3rd No No 1500 50 7 Yes PR 17 13 IV 3rd Yes Yes 1300 40 4 Yes PR 18 14 IV 4th Yes Yes 1500 50 3 Yes NC 4 15 IV 4th Yes Yes 1200 50 10 Yes PR 8 16 IV 6th Yes Yes 800 50 8 Yes CR 18 17 IV 1st – – 800 50 6 Yes PR 8 18 IV 1st – – 800 50 8 Yes NC 10 19 IV 2nd Yes Yes 1000 50 4 Yes PR 4 20 IV 2nd Yes Yes 800 40 4 Yes NC 4 21 IV 2nd Yes Yes 1000 50 3 Yes NC 3 22 IV 3rd Yes Yes 1500 50 4 Yes NC 4 *TMN classification of malignant tumors (UICC). 6th ed. ** Mean maximum radiofrequency output power CT, chemotherapy; PC, paclitaxel and carbopatin; RF, radiofrequency; HBO, hyperbaric oxygen; POD, progression of disease; mos, months; CR, complete response; PR, partial response; NC, no change. using paclitaxel and carboplatin with regional HT and HBO in patients with NSCLC. As for regional HT-related toxicity, subcutaneous fat burns were observed in 3–12% of patients, but generally, these healed spontaneously and did not result in a discontinuation of the treatment [25, 26]. The previous phase II trials of systemic chemotherapy with regional HT demonstrated that HT did not adversely influence the tolerability of the chemo- therapeutic drugs, even when given at maximum tolerated single modality doses [27, 28]. In the current study, weekly regional HT and HBO treat- Figure 1. The progression-free survival rate. ment were well tolerated and = grade 3 hematologic or non-hematologic toxicities were recognized in PoD in the patients with HBO was 9 months and only 1 (5%) patient; the novel combined therapy of without HBO was 4 months. Of the 14 patients who paclitaxel and carboplatin with HT and HBO may therefore be a feasible treatment modality. It seems had prior chemotherapy, 9 (64%) patients achieved that regional HT also did not reveal any significant an objective response (1 CR, 8 PRs). In addition, of increase in the toxicity from either chemotherapy or the 9 patients with prior chemotherapy including HBO in our combined therapy. paclitaxel and carboplatin, 1 patient obtained a CR An interesting result in this study was that the and 3 patients a PR. The median overall survival reintroduction of paclitaxel and carboplatin caused time of all patients was 17 months. an objective response in 4 (44%) of 9 patients who had already received chemotherapy using paclitaxel and carboplatin. Experimental reports have shown Discussion that use of HT with many chemotherapeutic The present study is the first study trying to assess drugs had the potential ability to reverse the drug a combination therapy of systemic chemotherapy resistance, although the mechanisms underlying Chemo-hyperthermia and hyperbaric oxygen 165 the reversal of drug resistance are not well improve the radiation response in solid tumors [14]. defined [3]. Westermann et al. conducted whole Hypoxic cells in the malignant tumor are relatively body HT with carboplatin for the patients with more resistant to ionizing radiation than normoxic platinum-resistant ovarian cancer and a tumor portions within the same tumor. Since hypoxic cells response was observed in 5 of 12 patients [29]. in the malignant tumor are also relatively more These observations suggest that further investiga- resistant to chemotherapy, HBO could increase tions of the therapeutic potential of HT with the anti-tumor effect of chemical agents. Several or without HBO in a group of patients who histo- researchers have combined HBO with chemotherapy rically fail to respond to chemotherapy alone is thus to enhance drug cytotoxicity [13–17, 39]. A human warranted. prostatic carcinoma cell line grown under normoxic In our study, regional HT and HBO were conditions was exposed to paclitaxel for 90 minutes administered concurrently with a weekly decreased under HBO or normal pressure air, and HBO application of paclitaxel (50 mg/m ) and carboplatin increased the sensitivity of cells to paclitaxel [39]. (AUC of 1.0–1.5). The regimen of carboplatin In a bulky hypoxic tumor such as epithelial ovar- every 3 weeks and weekly paclitaxel chemotherapy ian cancer, dramatic tumor neovascularization was has been suggested to be the most effective and found in tumors of mice exposed to HBO, and there least toxic treatment for advanced NSCLC [30]. was significant tumor growth retardation in the Regarding the management of several other tumors, mice receiving both cisplatin and HBO in compar- however, weekly regimens of paclitaxel and carbo- ison to those treated with cisplatin alone [13]. platin have shown increased efficacy and decreased On the other hand, previous results of HT at toxicity [31, 32]. Recently, a phase II study of mild temperatures of 39–42 C also demonstrated weekly paclitaxel (100 mg/m ) and carboplatin an improvement in tumor oxygenation in human (AUC of 2.0) for advanced NSCLC appeared to tumors [40]. Therefore, the combination of HBO be less toxic than the standard 3-week regimen of and HT in these clinical results might strongly either a similar or smaller dose intensity, and also increase the tumor oxygenation and contribute showed comparable clinical outcomes; namely, to the favorable outcomes. To our knowledge, response rate was 44%, and the time to PoD was no in-vitro/vivo study has ever been reported on the median 5 months [33]. The other phase II study for combination of HBO and HT to improve the anti- the decreased dose of weekly paclitaxel (50 mg/m ) tumor efficacy of chemotherapy. Further evaluations and carboplatin (AUC of 2.0) for elderly patients of the details of this combined treatment protocol, (65 years of age) with NSCLC, the toxicities were such as the timing, dose of chemotherapy, atmo- mild; however, the objective response rate was only sphere and heating temperature, using both experi- 14%, and the time to PoD was median 4 months mental analyses and prospective clinical trials in a [34]. Several large phase III studies for chemother- large number of patients, are thus needed to confirm apy alone using the combination of paclitaxel and the clear benefits of this regimen. carboplatin for NSCLC have reported a response Promising results have been reported regarding rate of 17–32% and median time to PoD of 3–7 RT plus regional HT using RF-8 for lung can- months [30, 35–37]. Although the comparison of cers [41, 42], however, the disadvantages of an our retrospective small series with the prospective RF-capacitive device for the preferential heating trials is not valid, a response rate of 75% and of the subcutaneous fat tissue are well known, median time to PoD of 9 months was obtained for while Asian patients are considered to be relatively stage IV cases in spite of the mild toxicities with our suitable due to their slender constitution. The exces- therapy using a low dose level of paclitaxel and sive power deposition in the fatty tissue limits the carboplatin with regional HT and HBO. In con- effectiveness of the capacitive technique. In the cur- trast, all aforementioned phase II and III studies rent study, although direct tumor thermometry was included not only stage IV but also IIIB. In not employed, that tumor temperature in most of previous clinical results to identify prognostic our patients might reach, at least, 39–42 C, which factor for the patients with advanced NSCLC demonstrated an improvement in tumor oxyge- treated with carboplatin and paclitaxel, only disease nation, because 41.1 C of the maximum intra- stage of IV (IIIB versus IV) was a significantly worse esophageal temperature was estimated in all the prognostic factor on progression-free survival [38]. patients. Therefore, both HT and HBO might be potentially There are several limitations in this study. First, valuable due to their actions as chemo-sensitizers. because this study was a retrospective case series HBO has been investigated as a radio-sensitizer. report; the patients’ characteristics, such as the Many investigators showed that HBO improved degree of pretreated chemotherapy and whether tumor oxygenation, and treatment with HBO or not they had brain metastases, were variable during or immediately after RT has been shown to and might have influenced the results. A formal 166 T. Ohguri et al. ´ ´ 11. Zoul Z, Filip S, Melichar B, Dvorak J, Odrazka K, Petera J. phase II trial is consequently needed to deter- Weekly paclitaxel combined with local hyperthermia in the mine the efficacy for this combined therapy in the therapy of breast cancer locally recurrent after mastectomy – A patients with advanced NSCLC. Second, this study pilot experience. Onkologie 2004;27:385–388. could not assess the additional value of HBO to 12. 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The effect of hyperbaric Berchuck A, Clarke-Pearson DL, Rodriguez GC, Carney ME. oxygen on growth and chemosensitivity of metastatic prostate Weekly low-dose carboplatin and paclitaxel in the treatment cancer. Anticancer Res 1998;18:363–367. of recurrent ovarian and peritoneal cancer. Gynecol Oncol 40. Song CW, Park H, Griffin RJ. Improvement of tumor oxy- 2003;88:51–57. genation by mild hyperthermia. Radiat Res 2001;155:515–528. 33. Kallab AM, Nalamolu Y, Dainer PM, Jillella AP. A phase II 41. Hiraoka M, Masunaga S, Nishimura Y, Nagata Y, Jo S, study of weekly paclitaxel and carboplatin in previously Akuta K, Li YP, Takahashi M, Abe M. Regional untreated patients with advanced non-small-cell lung cancer. hyperthermia combined with radiotherapy in the treatment Med Oncol 2005;22:145–151. of lung cancers. Int J Radiat Oncol Biol Phys 34. Jatoi A, Stella PJ, Hillman S, Mailliard JA, Vanone S, 1992;22:1009–1014. Perez EA, Cannon MW, Geyer S, Wiesenfeld M, Jett JR. 42. Karasawa K, Muta N, Nakagawa K, Hasezawa K, Terahara A, Weekly carboplatin and paclitaxel in elderly non-small-cell Onogi Y, Sakata K, Aoki Y, Sasaki Y, Akanuma A. lung cancer patients (65 years of age): A phase II North Thermoradiotherapy in the treatment of locally advanced Central Cancer Treatment Group study. Am J Clin Oncol nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 2003;26:441–447. 1994;30:1171–1177. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Hyperthermia Taylor & Francis

Systemic chemotherapy using paclitaxel and carboplatin plus regional hyperthermia and hyperbaric oxygen treatment for non-small cell lung cancer with multiple pulmonary metastases: Preliminary results

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Taylor & Francis
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© 2009 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted
ISSN
1464-5157
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0265-6736
DOI
10.1080/02656730802610357
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19337916
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Abstract

Purpose: The purpose of this retrospective case series was to evaluate the toxicity and efficacy of systemic chemotherapy using paclitaxel and carboplatin plus regional hyperthermia (HT) and hyperbaric oxygen treatment (HBO) for non-small-cell lung cancer (NSCLC). Materials and methods: Twenty-two patients with NSCLC with multiple pulmonary metastases intravenously received paclitaxel (50 mg/m ), carboplatin (area under the curve of 1.0–1.5) and 10% glucose weekly for 3 out of 4 weeks. Hyperthermia (HT) of the whole thoracic region was also administered weekly during intravenous infusion of carboplatin in all patients. In addition, 16 (72%) of 22 patients received hyperbaric oxygen (HBO) treatment immediately after weekly chemotherapy. A total of 107 cycles were performed in 16 patients with HBO, and 27 cycles in 6 patients without HBO. The toxicity and efficacy of these patients were retrospectively analyzed. Results: Both the hematologic and non-hematologic toxicities were mild and leucopenia/neutropenia of = grade 3 was seen in one patient, while pneumonitis of = grade 3 occurred in one patient. Fourteen (64%) of 22 patients had an objective response. The median time to progression of disease in all patients was 8 months and in 16 patients with HBO was 9 months. Four (44%) of 9 patients with prior chemotherapy including paclitaxel and carboplatin obtained objective responses. Conclusions: The novel combined therapy of paclitaxel and carboplatin with HT and HBO may therefore be a feasible and promising modality for treating NSCLC with multiple pulmonary metastases, and the results justify further evaluation to clarify the benefits of this treatment regimen. Keywords: Hyperthermia, chemotherapy, hyperbaric oxygen, non-small-cell lung cancer Introduction a promising activity in patients with advanced non-small-cell lung cancer (NSCLC). In the USA, Lung cancer is currently the most common cause of the combination of paclitaxel and carboplatin has cancer deaths in many countries, including Japan. been a widely used regimen for NSCLC because of Although meta-analyses have proved that cisplatin- its low toxicity profile and efficacy [2]. based chemotherapy improves survival compared The rationale for the use of hyperthermia (HT) as with the best supportive care, the benefits have a treatment for cancer rests on several mechanisms been modest [1]. During the past several years, some [3, 4]. HT is known to cause direct cytotoxicity, new chemotherapeutic drugs with novel mechanisms while it also acts as a radiation-sensitizer and chemo- of action, including paclitaxel, have demonstrated sensitizer. Although the combination of HT with Correspondence: Dr T. Ohguri, Department of Radiology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. Tel: þ81-93-691-7264. Fax: þ81-93-692-0249. E-mail: ogurieye@med.uoeh-u.ac.jp ISSN 0265–6736 print/ISSN 1464–5157 online  2009 Informa Healthcare Ltd. DOI: 10.1080/02656730802610357 Chemo-hyperthermia and hyperbaric oxygen 161 radiation has been the focus of more attention, there plus regional HT and HBO was administered is an equally strong rationale for combining HT with to improve the clinical outcomes in NSCLC. The chemotherapy. The mechanisms of action have been combined therapy for NSCLC with multiple pul- considered to be as follows: HT increases drug monary metastases was started in 2003. The main uptake into cells, increases oxygen radical produc- purpose of our study was to evaluate the toxicity tion, increases DNA damage and inhibits DNA and efficacy of this combined therapy in patients repair [3]. Many chemotherapeutic agents exhibit with NSCLC. synergism with HT [3–8]. As for carboplatin, several previous in vitro/vivo studies showed synergism with HT at 40 to 44 C [5, 6]. The optimal sequence Materials and methods between the application of heat and drug adminis- Data collection tration is to administer them simultaneously or to give the drug immediately before the onset of heating Data were collected from patient medical records for [5, 6]. For paclitaxel, several in vitro/vivo studies this retrospective case series. This study focused also showed synergism with HT [7, 8], while other on data obtained from 52 NSCLC patients who studies failed to show a significant thermal enhance- received systemic chemotherapy with regional HT at ment of paclitaxel cytotoxicity [9, 10]. Despite the two hospitals in Japan. The patients were included in results of studies demonstrating the efficacy of che- the study if they were eligible to receive systemic motherapy with HT, the utilization of this combina- chemotherapy using paclitaxel and carboplatin plus tion in clinical practice is still limited. Recently, regional HT with or without HBO for NSCLC with Zoul et al. showed the treatment results of weekly multiple lung metastases. Thirty patients with extra- paclitaxel combined with local HT in patients with thoracic metastases, except for brain metastases, recurrent breast cancer; an objective local response were excluded from this study; because the heating was observed in all treated patients (complete electrodes of regional HT did not cover those response in 4 patients and partial response in 3) metastases and there were considerable un-heated [11]. In the patients with a pleural dissemination of or inadequately heated lesions in those cases we NSCLC, the treatment results of post-operative considered that the patients were not suitable for this HT combined with the intra-thoracic administration case series. We included ten patients with brain of cisplatin have been reported; the overall survival of metastases, since all the metastatic lesions of the the treated group (n¼ 24) was significantly pro- brain were able to be treated with stereotactic longed in comparison to a historical control group radiosurgery, which provides higher local control treated by either surgery alone (n¼ 17) or explora- rates regardless of whether or not chemo-hyperther- tory thoracotomy (n¼ 11) [12]. However, there are mia is performed. In addition, any patients who had no clinical reports of systemic chemotherapy using radiotherapy of the thoracic region added to the paclitaxel and carboplatin combined with regional combined therapeutic regimen were also eliminated. HT for NSCLC. Several researchers have combined hyperbaric Patients oxygen treatment (HBO) with chemotherapy to Twenty-two patients (13 men and 9 women, age enhance drug cytotoxicity for cancer [13–17]. range, 47–77 years; median, 66 years) were chosen Many human solid tumors are composed of regions from the data base using the inclusion and exclusion that are well vascularized and normoxic, while other criteria mentioned above. Sixteen of the 22 patients regions are relatively hypoxic. Hypoxic cells in the also received HBO therapy at one hospital, since malignant tumor are relatively more resistant to the remaining 6 patients were treated at the other chemotherapy. The increase in oxygen partial pres- hospital where a hyperbaric chamber was not sure in hypoxic populations may explain the increase in the anti-tumor effect of these chemical agents. available. Between September 2003 and September In animal cancer models, several studies that 2007, all 22 patients were placed on the above previously combined HBO with various chemother- described regimen. The patients were selected for apeutic agents have shown increases in the mean this treatment by the following criteria: histologic survival times and/or decrease in tumor growth or cytologic proof of NSCLC; age between 18 and [13–15]. In limited clinical studies, the combination 80 years; Eastern Cooperative Oncology Group of HBO and chemotherapy showed a potential value (ECOG) performance status 0–2; absolute neutro- of increased survival for advanced cancer and the phil count =3,000/mm and platelet count side effects did not increase by combining HBO with =100,000/mm ; serum bilirubin, ALT, AST, ALP, chemotherapy [16, 17]. urea, and creatinine levels within normal limits. In this context, a novel combined therapy of sys- The patient characteristics are given in Table I. The temic chemotherapy using paclitaxel and carboplatin ECOG performance status and site of the disease 162 T. Ohguri et al. Table I. Patient characteristics. 3 mg granisetron hydrochloride intravenously, 50 mg diphenhydramine hydrochloride orally, and 50 mg Characteristics N¼ 22 ranitidine intravenously. Median age, years (range) 66 (47–77) There were no patients who required a dose Gender, male/female 13/9 reduction of chemotherapy. The treatment was Performance status, 0/1/2 0/10/12 Histology delayed in 7 (5%) cycles. All patients could be Adenocarcinoma 20 treated on an outpatient basis. A total of 107 cycles Large cell carcinoma 2 were performed in 16 patients with HBO, and Sites of disease 29 cycles in 6 patients without HBO. The median Lung 22 number of cycles in the patients with HBO was 7 Pleural effusion 1 Lymph nodes (range 1–13) while in the patients without HBO it Mediastinal 10 was 4 (range, 3–8). Supraclavicular 1 The chemotherapy with paclitaxel and carbo- Brain 10 platin was performed as an initial chemotherapy in Prior surgery for primary 4 8 patients (36%), as a second-line in 8 (36%), as a Prior RT for primary 10 Prior chemotherapy 14 third-line in 3 (14%) and as a fourth or sixth-line in Cisplatin 2 3 (14%). Any drugs administered as prior chemo- Carboplatin 11 therapy were listed in Table I. Gemcitabine 6 Paclitaxel 9 Vinorelbine 5 Hyperthermia Gefitinib 4 HT was performed during every intravenous infusion HBO 16 SRT for brain metastasis 10 of carboplatin for all cycles of chemotherapy. The heating duration ranged from 40–60 min. The heat RT, radiotherapy; HBO, hyperbaric oxygen treatment; SRT, stereotactic radiosurgery. was applied using 8-MHz radiofrequency-capacitive regional HT (Thermotron RF-8, Yamamoto Vinita Co., Osaka, Japan). The physical features of the RF-8 clinical HT machine and thermal distribution characteristics in a phantom as well as in the human were evaluated at the start of treatment. There were body when heating with this device have all been 10 cases with brain metastases. Fourteen patients reported previously [20, 21]. In all cases, both the (64%) had prior chemotherapy, of which 9 patients upper and the lower electrodes measured 30 cm in (41%) had undergone paclitaxel and carboplatin. diameter, and they were placed on opposite sides of Ten patients (45%) had received prior RT for the entire thoracic region. The treatment posture for primary lesions. Four patients had postoperative all cases was the prone position. The patients were recurrence. Ten (45%) of 22 patients underwent instructed carefully to mention any unpleasant stereotactic radiosurgery for brain metastasis. Written sensations suggestive of a hot spot. The RF-output informed consent for treatment was obtained from increased to the maximum level tolerated by the all patients. patients after any unpleasant sensations either vanished or decreased to a fully sustainable level by Chemotherapy superficial cooling and/or fine adjustments of the The treatment cycle was 4 weeks long. The body position. For superficial cooling to reduce the chemotherapy was administered weekly for 3 weeks preferential heating of the subcutaneous fat tissue, followed by 1 week of rest. Paclitaxel (Taxol, Bristol- overlay boluses were applied in addition to regular Myers Squibb, Princeton, NJ; 50 mg/m ) was given boluses which were attached in front of the metal intravenously over 1 hour, followed by carboplatin electrodes. Some previous studies showed a strong (Paraplatin, Bristol-Myers Squibb; area under the positive correlation to exist between the RF-output curve (AUC) of 1.0–1.5, depending on the age, and temperature of tumors in this device [22, 23]. clinical status and bone marrow tolerance) by Because the measurement of direct intra-tumor intravenous infusion over 1 hour. The carboplatin temperature was clinically difficult, invasive or dose was calculated by using a Calvert formula distressing, previous correlative data between with creatinine clearance substituted for the glomer- RF-output and intra-esophageal temperature at the ular filtration rate [18]. The patients received above setting of the whole thoracic HT in a large premedication consisting of 10% glucose which number of patients was used to estimate the heating was administered to further increase the value temperature: Y¼ 0.0056Xþ 36.6, X¼ median of thermochemotherapy by lowering the tumor RF-output (W); Y¼ maximum intra-esophageal pH [19], 4–8 mg dexamethasone intravenously, temperature ( C) [23]. Chemo-hyperthermia and hyperbaric oxygen 163 Table II. Toxicity* in all the patients. Grade 0 (%) Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) Leucopenia 6 (27) 11 (50) 4 (18) 1 (5) 0 Neutropenia 6 (27) 10 (45) 5 (23) 1 (5) 0 Anemia 17 (77) 4 (18) 1 (5) 0 0 Thrombocytopenia 21 (96) 1 (5) 0 0 0 Neuropathy 20 (90) 1 (5) 1 (5) 0 0 Pneumonitis 20 (90) 1 (5) 0 1 (5) 0 Diarrhea 22 (100) 0 0 0 0 Nausea 21 (95) 1 (5) 0 0 0 Vomiting 21 (95) 1 (5) 0 0 0 Hypersensitivity reaction 21 (95) 0 1 (5) 0 0 Renal toxic effect 22 (100) 0 0 0 0 Cardiac toxic effect 22 (100) 0 0 0 0 Fatigue 12 (55) 8 (36) 2 (9) 0 0 *The National Cancer Institute Common Toxicity Criteria version 3. The median RF-output in all patients ranged measurable or non-measurable lesion. Any patients from 800 to 1600 W (median 1,250 W). The who did not meet the definitions of response or median maximum intra-esophageal temperature progression were classified as having no change in all the patients was calculated to be 43.6 C (NC). The time to PoD was calculated from the (range, 41.1–45.6 C) from the correlative data first day of the combined therapy of this study to the between the median RF-output and intra-esophageal date of disease progression. The overall and disease temperature. progression-free survival rates were calculated from the start of the combined therapy by the Kaplan- Hyperbaric oxygen therapy Meier method. HBO was performed as a chemotherapy adjuvant to increase tumor sensitivity to anticancer agents Results immediately after weekly chemotherapy and regional HT for all cycles. The patients underwent a single The follow-up from the start of the combined treat- treatment for 60–90 minutes in a monoplace HBO ment ranged from 6 to 32 months (median, 16). chamber (Sechrist Industries Inc., model 2800 J, The degrees of toxicity are listed in Table II. Anaheim, California) pressured with 100% oxygen to Both hematologic and non-hematologic toxicities 2.0 atmospheres absolute. were mild. For the toxicities of = grade 3, leucopenia/neutropenia of grade 3 was seen in only Evaluation of the toxicity and efficacy one patient, and pneumonitis of grade 3 occurred in one patient. For these toxicities, there were no clear The National Cancer Institute Common Toxicity differences between those who did and did not Criteria version 3 was used to score toxicity. The receive HBO. Generally, HT was well tolerated by highest toxicity grade for each patient in all cycles of the patients, and only the initial contact with the cold this therapy was used for the toxicity analysis. boluses caused some discomfort, which thereafter The primary endpoints of this study regarding rapidly dissipated. No patients experienced any efficacy were the objective response rate and the time thermal burns. The weekly HBO treatment was to progression of disease (PoD). The patients were evaluated every 4 weeks (after the completion of also well tolerated. Although some patients experi- one cycle) by computed tomography (CT) scanning enced hearing difficulties either during or shortly for measurable lesions. The objective response after HBO, no serious or life-threatening complica- was evaluated according to the World Health tions with HBO were observed. Organization criteria [24]. A complete response Table III lists all patients associated with the (CR) was defined as the complete disappearance of treatment parameters and results. Fourteen (64%) all clinically detectable tumors for at least 4 weeks. of 22 patients had an objective response (4 CRs, A partial response (PR) required at least a 50% 10 PRs). Twelve (75%) of 16 patients with HBO and reduction in the sum of the products of the longest 2 (33%) of 6 patients without HBO had an objective perpendicular diameters of all measurable lesions. response. The time to PoD was 2 to 18 months Progressive disease (PD) required a 25% increase in (median, 8 months). Figure 1 shows the progression- measurable lesions or the appearance of any new free survival rates in all patients. The median time to 164 T. Ohguri et al. Table III. Treatment results in all the patients. Line Prior CT Prior platinum Median RF Median No. of Tumor Time to Case Stage* of CT including PC based CT output** heating time cycles HBO response POD (mos) 1 IV 1st – – 1300 50 8 Yes CR 12 2 IV 1st – – 1500 50 7 Yes CR 10 3 IV 1st – – 1600 50 6 Yes CR 5 4 IV 1st – – 1500 50 13 Yes PR 13 5 IV 1st – – 1500 50 3 Yes NC 4 6 IV 1st – – 1100 40 3 Yes NC 4 7 IV 2nd No No 1200 50 10 Yes PR 13 8 IV 2nd No Yes 1200 50 5 Yes PR 6 9 IV 2nd No No 1500 50 8 Yes PR 8 10 IV 2nd No Yes 1350 50 11 Yes PR 9 11 IV 2nd Yes Yes 1000 40 1 Yes PD 2 12 IV 3rd No No 1500 50 7 Yes PR 17 13 IV 3rd Yes Yes 1300 40 4 Yes PR 18 14 IV 4th Yes Yes 1500 50 3 Yes NC 4 15 IV 4th Yes Yes 1200 50 10 Yes PR 8 16 IV 6th Yes Yes 800 50 8 Yes CR 18 17 IV 1st – – 800 50 6 Yes PR 8 18 IV 1st – – 800 50 8 Yes NC 10 19 IV 2nd Yes Yes 1000 50 4 Yes PR 4 20 IV 2nd Yes Yes 800 40 4 Yes NC 4 21 IV 2nd Yes Yes 1000 50 3 Yes NC 3 22 IV 3rd Yes Yes 1500 50 4 Yes NC 4 *TMN classification of malignant tumors (UICC). 6th ed. ** Mean maximum radiofrequency output power CT, chemotherapy; PC, paclitaxel and carbopatin; RF, radiofrequency; HBO, hyperbaric oxygen; POD, progression of disease; mos, months; CR, complete response; PR, partial response; NC, no change. using paclitaxel and carboplatin with regional HT and HBO in patients with NSCLC. As for regional HT-related toxicity, subcutaneous fat burns were observed in 3–12% of patients, but generally, these healed spontaneously and did not result in a discontinuation of the treatment [25, 26]. The previous phase II trials of systemic chemotherapy with regional HT demonstrated that HT did not adversely influence the tolerability of the chemo- therapeutic drugs, even when given at maximum tolerated single modality doses [27, 28]. In the current study, weekly regional HT and HBO treat- Figure 1. The progression-free survival rate. ment were well tolerated and = grade 3 hematologic or non-hematologic toxicities were recognized in PoD in the patients with HBO was 9 months and only 1 (5%) patient; the novel combined therapy of without HBO was 4 months. Of the 14 patients who paclitaxel and carboplatin with HT and HBO may therefore be a feasible treatment modality. It seems had prior chemotherapy, 9 (64%) patients achieved that regional HT also did not reveal any significant an objective response (1 CR, 8 PRs). In addition, of increase in the toxicity from either chemotherapy or the 9 patients with prior chemotherapy including HBO in our combined therapy. paclitaxel and carboplatin, 1 patient obtained a CR An interesting result in this study was that the and 3 patients a PR. The median overall survival reintroduction of paclitaxel and carboplatin caused time of all patients was 17 months. an objective response in 4 (44%) of 9 patients who had already received chemotherapy using paclitaxel and carboplatin. Experimental reports have shown Discussion that use of HT with many chemotherapeutic The present study is the first study trying to assess drugs had the potential ability to reverse the drug a combination therapy of systemic chemotherapy resistance, although the mechanisms underlying Chemo-hyperthermia and hyperbaric oxygen 165 the reversal of drug resistance are not well improve the radiation response in solid tumors [14]. defined [3]. Westermann et al. conducted whole Hypoxic cells in the malignant tumor are relatively body HT with carboplatin for the patients with more resistant to ionizing radiation than normoxic platinum-resistant ovarian cancer and a tumor portions within the same tumor. Since hypoxic cells response was observed in 5 of 12 patients [29]. in the malignant tumor are also relatively more These observations suggest that further investiga- resistant to chemotherapy, HBO could increase tions of the therapeutic potential of HT with the anti-tumor effect of chemical agents. Several or without HBO in a group of patients who histo- researchers have combined HBO with chemotherapy rically fail to respond to chemotherapy alone is thus to enhance drug cytotoxicity [13–17, 39]. A human warranted. prostatic carcinoma cell line grown under normoxic In our study, regional HT and HBO were conditions was exposed to paclitaxel for 90 minutes administered concurrently with a weekly decreased under HBO or normal pressure air, and HBO application of paclitaxel (50 mg/m ) and carboplatin increased the sensitivity of cells to paclitaxel [39]. (AUC of 1.0–1.5). The regimen of carboplatin In a bulky hypoxic tumor such as epithelial ovar- every 3 weeks and weekly paclitaxel chemotherapy ian cancer, dramatic tumor neovascularization was has been suggested to be the most effective and found in tumors of mice exposed to HBO, and there least toxic treatment for advanced NSCLC [30]. was significant tumor growth retardation in the Regarding the management of several other tumors, mice receiving both cisplatin and HBO in compar- however, weekly regimens of paclitaxel and carbo- ison to those treated with cisplatin alone [13]. platin have shown increased efficacy and decreased On the other hand, previous results of HT at toxicity [31, 32]. Recently, a phase II study of mild temperatures of 39–42 C also demonstrated weekly paclitaxel (100 mg/m ) and carboplatin an improvement in tumor oxygenation in human (AUC of 2.0) for advanced NSCLC appeared to tumors [40]. Therefore, the combination of HBO be less toxic than the standard 3-week regimen of and HT in these clinical results might strongly either a similar or smaller dose intensity, and also increase the tumor oxygenation and contribute showed comparable clinical outcomes; namely, to the favorable outcomes. To our knowledge, response rate was 44%, and the time to PoD was no in-vitro/vivo study has ever been reported on the median 5 months [33]. The other phase II study for combination of HBO and HT to improve the anti- the decreased dose of weekly paclitaxel (50 mg/m ) tumor efficacy of chemotherapy. Further evaluations and carboplatin (AUC of 2.0) for elderly patients of the details of this combined treatment protocol, (65 years of age) with NSCLC, the toxicities were such as the timing, dose of chemotherapy, atmo- mild; however, the objective response rate was only sphere and heating temperature, using both experi- 14%, and the time to PoD was median 4 months mental analyses and prospective clinical trials in a [34]. Several large phase III studies for chemother- large number of patients, are thus needed to confirm apy alone using the combination of paclitaxel and the clear benefits of this regimen. carboplatin for NSCLC have reported a response Promising results have been reported regarding rate of 17–32% and median time to PoD of 3–7 RT plus regional HT using RF-8 for lung can- months [30, 35–37]. Although the comparison of cers [41, 42], however, the disadvantages of an our retrospective small series with the prospective RF-capacitive device for the preferential heating trials is not valid, a response rate of 75% and of the subcutaneous fat tissue are well known, median time to PoD of 9 months was obtained for while Asian patients are considered to be relatively stage IV cases in spite of the mild toxicities with our suitable due to their slender constitution. The exces- therapy using a low dose level of paclitaxel and sive power deposition in the fatty tissue limits the carboplatin with regional HT and HBO. In con- effectiveness of the capacitive technique. In the cur- trast, all aforementioned phase II and III studies rent study, although direct tumor thermometry was included not only stage IV but also IIIB. In not employed, that tumor temperature in most of previous clinical results to identify prognostic our patients might reach, at least, 39–42 C, which factor for the patients with advanced NSCLC demonstrated an improvement in tumor oxyge- treated with carboplatin and paclitaxel, only disease nation, because 41.1 C of the maximum intra- stage of IV (IIIB versus IV) was a significantly worse esophageal temperature was estimated in all the prognostic factor on progression-free survival [38]. patients. Therefore, both HT and HBO might be potentially There are several limitations in this study. First, valuable due to their actions as chemo-sensitizers. because this study was a retrospective case series HBO has been investigated as a radio-sensitizer. report; the patients’ characteristics, such as the Many investigators showed that HBO improved degree of pretreated chemotherapy and whether tumor oxygenation, and treatment with HBO or not they had brain metastases, were variable during or immediately after RT has been shown to and might have influenced the results. A formal 166 T. Ohguri et al. ´ ´ 11. Zoul Z, Filip S, Melichar B, Dvorak J, Odrazka K, Petera J. phase II trial is consequently needed to deter- Weekly paclitaxel combined with local hyperthermia in the mine the efficacy for this combined therapy in the therapy of breast cancer locally recurrent after mastectomy – A patients with advanced NSCLC. Second, this study pilot experience. Onkologie 2004;27:385–388. could not assess the additional value of HBO to 12. 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Journal

International Journal of HyperthermiaTaylor & Francis

Published: Jan 1, 2009

Keywords: Hyperthermia; chemotherapy; hyperbaric oxygen; non-small-cell lung cancer

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