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Introduction

Radiotherapy is considered to be a good therapeutic strategy for the local treatment of tumors (1–3). Due to the improvement in diagnostic methods, the use of radiotherapy for the treatment of recurrent malignancies and/or distant metastases that are limited to a single site/organ (oligometastasis) has increased in recent years (1–3). However, the use of radiotherapy presents a number of disadvantages (4–8). In radiotherapy, a linear accelerator generates high-energy X-rays and electron beams that are generally used for tumor treatment (4–8). However, these are low-linear energy transfer (LET) forms of radiation, and thus exert relatively weak biological effects on tumors that contain numerous hypoxic cancer cells and/or large quantities of antioxidative enzymes (4–8), including malignant melanoma, various types of sarcoma, glioblastoma multiforme and the majority of tumors that measure more than several centimeters in their long diameter (4–8). Previous studies have examined the efficacy of increasing tissue oxygen concentration to promote the oxidation of radicals produced by low-LET irradiation to cancer cells/tissue, but limited therapeutic advantages have been observed thus far (9–20). In addition to increasing the tissue oxygen concentration, it is important to inactivate antioxidative enzymes such as peroxidase and catalase, which protect cancer cells from oxidative stress (4–8). Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II) was developed for the treatment of malignant tumors that contain numerous hypoxic cancer cells and/or large quantities of antioxidative enzymes (4–8). The concepts underlying this novel enzyme-targeting radiosensitization treatment are represented in Fig. 1. Hydrogen peroxide is the only agent known to be capable of inactivating antioxidative enzymes and producing oxygen when applied topically to tumor tissues (4–8).

Figure 1. Concepts underlying the mechanism of action of KORTUC II, a novel enzyme-targeting radiosensitization treatment. With KORTUC II treatment, radioresistant tumors become radiosensitive. KORTUC II, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II.

In a previous report, the effectiveness of KORTUC II for the treatment of supraclavicular lymph node metastases was demonstrated (7). The purpose of the present study was to evaluate the safety and effectiveness of KORTUC II in patients with recurrent breast cancer.

Materials and methods

Patients

The present study was performed from February 2006 to June 2014. The institutional ethics committee of Kochi University (Kochi, Japan) approved the use of KORTUC II in combination with radiation therapy for the treatment of recurrent breast cancer. A total of 20 patients with recurrent breast cancer were enrolled in the present study upon providing written informed consent. All patients underwent complete surgical removal of the primary breast cancer, but recurrent breast cancer was observed during the follow-up examination by positron emission tomography (PET)-computed tomography (CT) (Discovery STE; GE Healthcare, Tokyo, Japan). The details of the recurrent lesions are shown in Table I. Patients' age ranged from 39.0 to 84.0 years (average, 66.4 years). The majority of patients underwent neoadjuvant chemotherapy. The most frequent chemotherapy regimens administered prior to radiosensitization treatment were adriamycin (Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan) + cyclophosphamide (CPA; Shionogi & Co., Ltd., Osaka, Japan) + 5-fluorouracil (5-FU; Kyowa Hakko Kirin Co., Ltd.), CPA + docetaxel (Elmed Eisai Co., Ltd., Tokyo, Japan), CPA + epirubicin (EPI; Nippon Kayaku, Tokyo, Japan), CPA + 5-FU + methotrexate (Pfizer Inc., New York, NY, USA), CPA + 5-FU + tetrahydropalmatine (Daiichi Sankyo Healthcare Co., Ltd, Tokyo, Japan), EPI + 5-FU, gemcitabine (Yakuruto Co., Ltd., Tokyo, Japan) + herceptin (HER; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan), HER + paclitaxel (PTX; Nippon Kayaku), HER + vinorelbine (Kyowa Hakko Kirin Co., Ltd.) and PTX. All chemotherapies were administered every 3 weeks.

Table I. Details of the recurrent lesions.

Table I.

Details of the recurrent lesions.

		Hormone receptor
Patient	Age (years)	ER	PgR	HER2	Treated site (RT field)	Exposure dose (Gy)	Imaging examination	FDG accumulationa	Tumor size (mm)	Therapeutic effect
1	61	(+)	(−)	(2+)	Parasternal	X 44.0	PET-CT	12.0 → 3.6	41.0 → 26.0	PR
2	83	(+)	(−)	(1+)	Lt. breast	X 44.0+E 9.0	PET-CT	3.1 → disappearance	10.0 → disappearance	CR
3	46	(−)	(+)	(1+)	Lt. breast	E 40.0	PET-CT	4.4 → 1.9	23.0 → disappearance	CR
		(−)	(+)	(1+)	Lt. rectus abdominis muscle	E 48.0	PET-CT	8.9 → disappearance	33.0 → disappearance	CR
4	51	(+)	(+)	(3+)	Rt. breast	E 40.0	PET-CT	3.0 → disappearance	9.0 → disappearance	CR
5	64	(−)	(−)	(3+)	Lt. breast	E 40.0	PET-CT	4.3 → disappearance	23.0 → disappearance	CR
6	80	(+)	(+)	(1+)	Rt. breast	E 32.0	MRI	No data	9.0 → disappearance	CR
7	80	(+)	(+)	(1+)	Lt. axilla	X 49.5	MRI	No data	7.0 → disappearance	CR
8	59	(+)	(+)	(2+)	Rt. axilla	X 49.5	PET-CT	7.0 → disappearance	18.0→ disappearance	CR
9	58	(+)	(−)	(−)	Rt. supraclavicular LN	E 48.0	PET-CT	10.7 → 2.5	26.0 →14.0	PR
		(+)	(−)	(−)	Rt. cervical LN	E 40.0	PET-CT	9.7 → 4.0	31.0 →18.0	PR
10	66	(+)	(+)	(−)	Rt. supraclavicular LN	E 48.0	PET-CT	1.5 → 4.9	15.0 →30.0	PD
11	69	(−)	(−)	(−)	Lt. supraclavicular LN	X 49.5	PET-CT	9.3 → disappearance	54.0 → disappearance	CR
12	63	(−)	(−)	(3+)	Lt. supraclavicular LN	E 48.0	PET-CT	3.6 → disappearance	13.6 → disappearance	CR
13	39	(−)	(−)	(−)	Lt. pectoralis major muscle	X 49.5	PET-CT	7.0 → 5.0	27.0 →20.0	PR
14	66		Unclear		Lt. supraclavicular LN	E 48.0	PET-CT	No data	25.0 → disappearance	CR
15	61	(−)	(−)	(3+)	Rt. supraclavicular LN	E 48.0	PET-CT	9.3 → 3.5	16.0 → disappearance	CR
		(−)	(−)	(3+)	Lt. cervical LN	E 48.0	PET-CT	6.5 → 3.3	15.0 → disappearance	CR
16	52		Unclear		Lt. breast	X 44.0+E 9.0	PET-CT	3.0 → disappearance	10.0 → disappearance	CR
17	76		Unclear		Lt. breast	E 48.0	PET-CT	5.7 → disappearance	12.0 → disappearance	CR
18	59	(+)	(+)	(3+)	Rt. axilla	X 49.5	PET-CT	12.5 → 5.3	24.0 → 10.0	PR
		(+)	(+)	(3+)	Rt. breast	E 48.0	PET-CT	8.0 → disappearance	23.0 → disappearance	CR
19	52	(+)	(−)	(−)	Skin of sinciput	E 48.0	PET-CT	No data	10.0 → disappearance	CR
20	84		Unclear		Rt. breast	X 44.0+E 9.0	PET-CT	No data	8.0 → disappearance	CR

a Measured as the maximum standardized uptake value. HER (1+), <10% cells exhibit positive membrane staining; HER (2+), 10–30% cells exhibit positive membrane staining; HER (3+), >30% cells exhibit positive membrane staining; ER, estrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor 2; RT, radiation therapy; Rt., right; Lt., left; LN, lymph node; X, X-ray; E, electron beam; PET, positron emission tomography; CT, computed tomography; MRI, magnetic resonance imaging; FDG, fluorodeoxyglucose; CR, complete response; PR, partial response; PD, progressive disease.

However, since the sizes of the tumors were not conspicuously reduced, the patients were diagnosed as being resistant to these chemotherapies. Therefore, it was decided to use the novel radiosensitizer KORTUC II. The basic criterion for case selection was that the patients and/or their family wanted the patient to receive KORTUC II treatment and did not wish the patient to undergo surgery. In addition, further criteria included the absence of metastases to brain, lung or liver, and life expectancy >3 months.

Radiation therapy to recurrent breast cancer consisted of 2.75 Gy/fraction, 5 fractions/week, for a total of 16–18 fractions, with a total radiation dose of 44.00–49.50 Gy (X-ray irradiation), or 4.00 Gy/fraction, 3 fractions/week, for a total of 10–12 fractions, with a total radiation dose of 40.00–48.00 Gy (electron beam irradiation; EXL-20TP linear accelerator; Mitsubishi Electric Co., Ltd., Tokyo, Japan). Electron beam irradiation was performed for patients who had received postoperative irradiation (2.75 Gy/fraction, 16 times, total 44.00 Gy) at the treatment site of the primary breast cancer, or in those cases where the recurrence involved superficial lesions. In the case of X-ray irradiation for patients with locally recurrent lesions who did not receive postoperative radiotherapy following the treatment of the primary breast cancer, boost irradiation (3 Gy/fraction, 3 times) was added. For locally recurrent lesions, tangential irradiation was administered, whereas for other sites, various forms of irradiation (including one-field irradiation, two opposed-fields irradiation, multiple-field irradiation and intensity-modulated radiation therapy) were administered, according to the depth and location of the target lesion. Based on the radiodermatitis of the treated area, the dose of radiation was adjusted to the aforementioned number of times and exposure dose. The X-ray energy level was 4 MV, while the energy of the electron beam was selected for individual patients according to the depth of the target lesion. Injection of 3–6 ml KORTUC II (consisting of 0.83% w/v sodium hyaluronate and a 0.5% w/v solution of hydrogen peroxide) was initiated at the sixth radiation fraction, and was performed twice/week (on Mondays and Thursdays) under ultrasonographic guidance (High Vision 900; Hitachi, Ltd., Tokyo, Japan), in order to maintain a high concentration of oxygen in the tumor, since the addition of hyaluronic acid to the hydrogen peroxide solution delays the decomposition of hydrogen peroxide, which enables to maintain a high concentration of oxygen in the tumor for >24 h (4–8). The injection rate of the radiosensitizer was adjusted according to the tumor size, and the total number of injections was 5–6. Patients' data and therapeutic effects of KORTUC II are described in Table I. Following radiotherapy with KORTUC II, hormonal therapy and/or chemotherapy with denosumab (Daiichi-Sankyo Co., Ltd., Tokyo, Japan), letrozole (AstraZeneca, London, UK) or taxane (Sanofi, Co., Ltd., Tokyo, Japan) was administered to the patients to prevent recurrence.

Assessment of therapeutic response

The majority of the 20 patients enrolled in the study underwent PET-CT examinations prior to and 1–7 months following KORTUC II treatment. The therapeutic effects were evaluated by comparing the results of the PET-CT examinations of the treated regions prior and subsequent to treatment. Those patients who did not undergo PET-CT examinations were examined by magnetic resonance imaging (MRI) prior and following irradiation therapy in order to evaluate the therapeutic effect of the treatment. Patients underwent PET-CT or MRI examinations every 6 months thereafter, if possible. The final therapeutic response of the lesion was assessed according to the revised Response Evaluation Criteria in Solid Tumors guidelines version 1.1 (21), and patient monitoring and tumor assessment were performed monthly. Treatment-associated complications were assessed in detail to evaluate the feasibility of the KORTUC II approach, according to the Common Terminology Criteria for Adverse Events [CTCAE; version 4.0 (22)]. Patients were followed-up for ≥15 months.

Formulation example

A 2.5-ml syringe of hyaluronic acid preparation (Kaken Pharmaceutical Co., Ltd., Tokyo, Japan) with a 1% w/v concentration of sodium hyaluronate (ARTZ Dispo®; Seikagaku Corporation, Tokyo, Japan) was used, which contained 25.0 mg sodium hyaluronate, 2.5 mg L-methionine, sodium chloride, potassium phosphate, crystalline sodium dihydrogen phosphate and an isotonizing agent. The preparation was a colorless, transparent, viscous, aqueous solution with a pH of 6.8–7.8, a specific osmotic pressure of 1.0–1.2 (relative to physiological saline) and an average molecular weight of 600,000–1.2 million Da. To prepare the final radiosensitizer solution, 0.5 ml of a 3% w/v solution of hydrogen peroxide (Oxydol; Ken-ei Pharmaceutical Co. Ltd., Osaka, Japan) was added immediately prior to use, and the solution was mixed well. This final radiosensitizer preparation had a concentration of sodium hyaluronate and hydrogen peroxide of 0.83 and ~0.50%, respectively. The constituents of the radiosensitizer were the same as those used previously for the treatment of chemotherapy-resistant supraclavicular lymph node metastases (7).

Results

The treatment was well tolerated with minimal adverse effects, since 18 patients (90%) exhibited local pain or flare at the injection site, 1 patient (5%) experienced soreness and hair loss at the treated part, and 1 patient (5%) presented worsening of edema as an acute phase complication. All patients were cured by local treatment, and evaluated as displaying grade I complications, according to the CTCAE criteria version 4.0. One patient (5%) also exhibited tumor collapse fever (an acute systemic syndrome caused by abundant cancer cell death following chemo- or radiotherapy) that resolved with symptomatic treatment (fluid therapy and antibiotic medication), and was evaluated as presenting grade II complications, according to the aforementioned CTCAE criteria. No patients displayed chronic phase complications.

Of the 24 lesions, 18 (75%) exhibited complete response, 5 (21%) exhibited partial response, 0 (0%) exhibited stable disease and 1 (4%) exhibited progressive disease. The response rate was 96%. The overall survival rate was 100% at 1 year and 95% at 2 years, since 19 out of 20 patients survived for 2 years following treatment. No obvious recurrences were observed at the treated sites.

The treatment outcomes were satisfactory, and the adverse events were within the acceptable range. Representative PET-CT and MRI examinations are depicted in Figs. 2–4. The mean follow-up period was 51 months, and the disease-free survival was 28 months at the end of June 2014. At the time of writing, 16 patients were alive.

Figure 2. Therapeutic response of patient 1 in Table I, a 61-year-old woman with recurrent breast cancer at the sternum, as evaluated by positron emission tomography-CT examination (A) prior to and (B) 3 months following treatment with Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II. The maximum standardized uptake value of fluorodeoxyglucose accumulation at the sternum decreased from 12.0 to 3.6. The minor axis of the target lesion decreased from 41.0 to 26.0 mm on CT. The therapeutic effect was assessed as partial response. CT, computed tomography; PET, positron emission tomography.

Figure 4. Therapeutic response of patient 11 in Table I, a 69-year-old woman with recurrent breast cancer at the left supraclavicular lymph node, as evaluated by positron emission tomography-CT examination (A) prior to and (B) 2 months following treatment with Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II. Following treatment, the maximum standardized uptake value of fluorodeoxyglucose accumulation at the left supraclavicular lymph node decreased from 9.3 to unmeasurable, and the minor axis of the target lesion decreased from 54.0 mm to unmeasurable on CT. The therapeutic effect was assessed as complete response. No obvious recurrences were observed at the treated site following treatment. CT, computed tomography.

Discussion

Improved diagnostic methods have resulted in earlier detection of recurrent tumors and/or distant metastases when they are limited to a single site/organ (oligometastasis) (1–3). For these cases, radiotherapy is considered to be a reliable method of treatment (1–3). Previous studies have indicated that re-irradiation plus hyperthermia for recurrent breast cancer may be more effective than radiotherapy alone (23–25). Oldenborg et al (23) reported that, with re-irradiation plus hyperthermia, the 3-year survival rate was 66%, and the 3 and 5-year local control rates were 78 and 65%, respectively, in patients with high-risk recurrent breast cancer. Thus, the therapeutic effect of re-irradiation plus hyperthermia was observed to be better than radiotherapy alone, which was confirmed by further studies (24,25).

Despite the differences in the evaluation method and timing, the therapeutic effect of KORTUC II in the present study was equally excellent to that of re-irradiation plus hyperthermia. Furthermore, KORTUC II is administered more easily than re-irradiation plus hyperthermia. In the present study, the response rate (96%) and the overall survival rates at 1 (100%) and 2 years (95%) observed for KORTUC II treatment were considered satisfactory. Therefore, KORTUC II may constitute an excellent therapeutic approach for cancer patients. The present authors hypothesize that the majority of patients with oligometastasis and local recurrence may achieve complete remission by combining radiotherapy with KORTUC II.

Using animal models, Tokuhiro et al (8) identified that sodium hyaluronate was the most effective supporting agent for hydrogen peroxide in maintaining a high concentration of oxygen in tumor tissues. KORTUC II consists of 0.83% w/v sodium hyaluronate and a 0.5% w/v solution of hydrogen peroxide, which are inexpensive and widely available reagents (4–8). Thus, the novel radiosensitizer KORTUC II could be used for the treatment of local cancer worldwide. Regarding the use of this agent, it is essential to avoid its direct injection into blood vessels, and to confirm an even distribution of oxygen microbubbles throughout the tumor tissue under ultrasonographic or CT guidance (4–7).

In conclusion, the treatment of recurrent breast cancer with radiotherapy and KORTUC II in the present study was well tolerated with minimal adverse effects. At present, the treatment outcomes for this agent are satisfactory, and the adverse events are within the acceptable range. In addition, the cost of this type of therapy is much lower than that of the molecular-targeted therapies currently used for the treatment of recurrent breast cancer, such as cetuximab (20). However, both the number of patients treated with KORTUC II thus far and the follow-up period are insufficient to draw definitive conclusions. Therefore, well-designed, prospective, randomized, clinical trials are required to establish the therapeutic efficacy of KORTUC II.

Acknowledgements

The present study was partially supported by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Tokyo, Japan; no. 25461916).

References