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 DOI: 10.1177/1534735409343693

2009 8: 283Integr Cancer TherXiaohuai Wang, Weimin Zhang, Zhiyong Xu, Yifan Luo, Doug Mitchell and Ralph W. Moss

Sonodynamic and Photodynamic Therapy in Advanced Breast Carcinoma: A Report of 3 Cases  

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Sonodynamic and Photodynamic Therapy in Advanced Breast Carcinoma: A Report of 3 Cases

Xiaohuai Wang, Weimin Zhang, Zhiyong Xu, Yifan Luo, Doug Mitchell, and Ralph W. Moss1

Abstract

Photodynamic therapy (PDT) is an established therapeutic method, first approved by the FDA for certain kinds of cancer in 1998. There are also increasing data to show that a related procedure, sonodynamic therapy (SDT), is a promising new modality for cancer treatment. Here, the authors report clinical results in 3 advanced refractory breast cancer patients who were treated using a combination of sonodynamic and photodynamic therapy (SPDT), along with conventional therapies. All 3 patients had pathologically proven metastatic breast carcinoma. These widely disseminated carcinomas had ultimately failed to respond to conventional therapy. A new sensitizing agent, Sonoflora 1™ (SF1) was administered sublingually; then, after a 24-hour delay, patients were treated with a combination of light and ultrasound. All patients had significant partial or complete responses. SPDT is a promising new therapeutic combination for the treatment of breast cancer.

Keywords

sonosensitizer, photosensitizer, sonodynamic therapy, photodynamic therapy, chlorophyll derivatives, breast cancer

1Liu Hua Qiao Hospital, Guangzhou 510010, People’s Republic of China, Chemistry and Environment College, Southern China Normal University, Guangzhou, People’s Republic of China, Science Group, Melbourne, Australia, Cancer Decisions, Inc, Lemont, PA, USA

Corresponding Author:Xiaohuai Wang, Department of Oncology, Liu Hua Qiao Hospital, 111 Liu Hua Road, Guangzhou 510010, People’s Republic of China. Email: wangxhgz@163.com

IntroductionSince the 1990s, photodynamic therapy (PDT) has been increasingly used for the treatment of various human tumors. However, the successful application of this method has been limited to superficial lesions because of the limited penetra-tion of laser light into tumor tissues.1,2 Sonodynamic therapy (SDT) has been developed as a complementary or alternative therapy to PDT.3-9 There are data to show that an additive effect might be obtained if SDT is combined with PDT.10 There are also data showing that PDT is synergistic with che-motherapeutic agents.11 In SDT treatment, patients first ingest a sonosensitizer, a drug that can be activated by ultrasound. This drug is then activated through the use of low-intensity ultrasound, producing a cascade of endogenous cytotoxic agents. The therapy is thus similar to PDT, except that the sensitizer is activated by ultrasound rather than by light. The body transmits ultrasound much more efficiently than light, and this is a decisive advantage when treating deeper tumors.

So far, not much clinical data on SDT have been pub-lished. One reason is the difficulty in finding a drug suitable for clinical use. Such a drug would need the following 5 characteristics:

1. No significant toxicity2. High tumor selectivity

3. High clearance rate from normal tissues4. High sonosensitivity5. A stable chemical composition

In recent years, a novel sonosensitizer was developed by the late Donald Burke, MD, of Advanced Technologies, Boston, USA. He named this Sonoflora 1™ (SF1). This agent is a chlorophyll derivative with very high sonodynamic as well as photodynamic activity. The absorption peak is a wavelength of 636 nm. SF1 basically fulfills all the above desiderata. Embryonic zebra fish assay data provided by Advanced Technologies show no evidence of toxicity. Our own animal studies demonstrate that SDT with SF1 inhibits the growth of mouse S-180 sarcoma, even when the tumor is covered by a bone.12

Here, we report initial clinical data using SF1 for sonody-namic and photodynamic therapy (SPDT) in advanced breast

Integrative Cancer Therapies8(3) 283–287© The Author(s) 2009Reprints and permission: http://www. sagepub.com/journalsPermissions.navDOI: 10.1177/1534735409343693http://ict.sagepub.com

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284 Integrative Cancer Therapies 8(3)

carcinoma. For this study, SF1 was supplied by Advanced Technologies, Boston, MA, and by its successor company, SonneMed LLC, Marlborough, NH.

Case PresentationTreatment MethodFrom 2005 to 2007, we consecutively treated 3 advanced breast carcinoma patients using SPDT. All these carcinomas were pathologically proven, and all patients had failed con-ventional therapies. SF1 was given to patients through lin-gual absorption for 2 or 3 days. Then, 24 h after taking the last dose of agent, a red LED light, 630 nm and 20 mW/cm2, was used to irradiate the tumor area or the whole body for 30 minutes (Figures 1A and 1B, and Figure 2). After this, a portable ultrasound device was applied to treat each tumor area for 20 minutes at a 1 MHz frequency and power of 2.0 W/cm2 (Figure 2 and Figure 3B). The light and ultrasound treatments were performed daily for 3 days. Based on each patient’s situation, 1 or 2 weeks later, the next cycle of treatment was carried out. Two light designs were used in this study—a handheld device and a light bed. The handheld light was for local treatment (Figure 1A and Figure 2), and the light bed was for whole body treatment, provided that the patient was strong enough to get in the device (Figure 1B). Cases 1 and 2 were given SDT using a conductive gel on the skin (Figure 2). Case 3 was given SDT in a water bath (Figure 3B). Water conducts ultrasound almost as well as gel, but it is much easier to carry out SDT under water, and this can be used for whole body treatment.

Case 1, woman, aged 43. She had a resection of her left breast carcinoma in March, 1997. Pathological examination confirmed this to be carcinoma, T2N2M0, with Her-2[++], P53[-], ER[+++], PR[+++], EGFR[−]. After surgery, she received 6 cycles of chemotherapy (cyclophosphamide + doxorubicin + 5-fluorouracil, CAF), radiation therapy (DT:

50 Gy/25F), and then tamoxifen. The cancer recurred in 1999 and spread throughout her body. She then had radia-tion therapy and 6 cycles each of paclitaxel and 5-fluorouracil (TF), vinorelbine + trastuzumab, capecitabine, and hormonal therapy with goserelin and letrozole. She also had 2 courses of 89Sr treatment. All these treatments ulti-mately failed.

A PET/CT scan in March 2005 showed that the tumor had spread to the bones, lungs, liver, and abdomen. The metastases in the neck had already destroyed the cervical vertebra and had involved the spinal cord (Figure 4A). By May 2005, the patient had high-level paraplegia, respiratory failure, heart failure, lung infections, high fever, and no feeling in the limbs. Her heart rate was 150 to 170 per minute, and she was put on a respirator to

Figure 1. Case 1, breast carcinoma, further treatment: A, the picture shows her second cycle of treatment with sonodynamic and photodynamic therapy (SPDT) in the ICU. She was able to stop the use of the respirator that had been necessary to maintain breath. B, the picture shows the third cycle of treatment of SPDT in a LED red light bed. Her symptoms were already much improved. C, comparison of PET/CT scans before and after 3 cycles of SPDT treatment: PET/CT on August 4, 2005, shows positive partial response, especially in the neck

Figure 2. Case 2, woman, 49 years. The picture shows case 2 in treatment by light for axillary lymph nodes and by ultrasound for primary breast tumor

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Figure 3. Case 3, woman, 36 years. A, PET/CT taken before sonodynamic and photodynamic therapy treatment showing right breast cancer with multiorgan metastases, including lung, bones, liver, and abdominal lymph nodes. B, the picture of a water bath used for ultrasound treatment in case 3

Figure 4. Case 1, breast carcinoma, woman, 42 years: A, PET/CT scan on March 25, 2005, showed that the tumor had spread widely in the patient’s body, and the metastases in the neck had already destroyed the cervical vertebra and involved the spinal cord (see arrow). B, a picture showing case 1 treated in the ICU. The patient was unable to talk, move, feel, eat, or even breathe. She had to use a respirator to maintain breath

maintain her breath. The patient was deemed terminally ill, and her tumors could no longer be treated with conventional meth-ods. She was transferred from the ICU of another hospital to our hospital for SPDT on May 16, 2005 (Figure 4B). The next day, she was treated with SPDT using 30 mg of SF1 plus a half dose of chemotherapy consisting of dicycloplatinum (DCP) and hydroxycamptothecin. DCP, which is little known in the West, is approved in China for use in clinical trials. After 1 cycle of treatment, the patient’s breathing was much improved and feeling in the limbs was restored (Figure 1A). After 2 cycles, the tumor in the patient’s neck had shrunk from

13 × 6 cm2 to 5 × 3 cm2. The heart rate was now <100 per minute, and she could breathe without a respirator (Figure 1B). After 3 cycles, her symptoms further improved, and her limbs could be moved with aesthesis. The respiratory, gastric, and urine catheters were all removed. PET-CT scans in August 2005 showed a partial response, especially in the neck (Figure 1C). She only had reversible grade 2 hematological toxicities. She was moved out of the ICU into a general ward. However, from 3 to 6 months after the treatments, the patient’s neck gradually shortened by about 5 cm because of the destruction wrought by her cancer. In November 2005, the patient died from respiratory failure, heart failure, and lung infections.

Case 2, woman, aged 49. The patient found a small mass on her left breast in July 2005. A needle biopsy proved this to be a breast carcinoma, which was ER− and PR+. The PET/CT scan showed left breast carcinoma with multiorgan metasta-ses to the axillary lymph nodes, bones, liver, and abdominal lymph nodes (Figure 5A). From July to August, 2005, the patient was treated with 3 cycles of chemotherapy (first 2 cycles with taxol 240 mg + hydroxycamptothecin 30 mg + DCP 600 mg and the third cycle with 4-epi-adriamycin 80 mg, cyclophosphamide 0.8 mg, and DCP 600 mg). In September 2005, a PET/CT scan showed no significant change in the primary tumor, with new metastases suspected. Immediately thereafter, high-intensity-frequency ultrasound (HIFU) was used to destroy a large mass in the patient’s left liver lobe, and 125I radioactive seeds were implanted into masses in the right liver lobe and in the breast primary tumor.

In October and November 2005, she had 2 cycles of SPDT with SF1 60 mg per cycle (Figure 2). A PET/CT scan in December 2005 showed a very positive PR. This included improvement in the tumors in the vertebra, sternum, and abdominal lymph nodes. These had not been treated by HIFU and radio seeds (Figure 5B). A PET/CT taken 28 months after SPDT treatment failed to detect any tumor activity whatso-ever (Figure 5C).

Case 3, woman aged 36. In April, 2003, the patient’s right breast and axillary lymph nodes were surgically removed. Pathology confirmed a T1N1M0 carcinoma with ER++, PR+++, P53+, PCNA+++, C-erbB2−. After surgery, she had radiotherapy (TD: 60 Gy/F30) and chemotherapy (3 cycles of CAF and 3 cycles of TAX/EPI). Her hematological toxici-ties were grade 2 to 4. Then she started hormone therapy. A March 2007 PET/CT scan showed metastases in the liver, lungs, and in many bones (Figure 3A). She was considered too ill to receive conventional chemotherapy. She was then admitted to this hospital, where she received 3 cycles of 125I radio-seed implantation combined with local chemotherapy for the tumors in her chest, liver, lumbar vertebra, sacrum, and pelvis. Her CEA (carcinoembryonic antigen) dropped from 39.7 µg/L to 4.90 µg/L and CA153 from 5000 U/L to 1500 U/L. However, her marrow function deteriorated, presumably as a result of radioactive seeds and local

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chemotherapy in the lumbar vertebra, sacrum, and pelvis. On April 22, 2007, her white blood cell count was 2.0 × 109/L; HGB (hemoglobin), 72 × 109/L; and PLT (platelet) 48 × 109/L. In May, she received 2 cycles of SPDT with SF1 60 mg per cycle. The ultrasound treatment was performed in a water bath (Figure 3B). After this treatment, her symptoms were much improved. She had less pain, a more active lifestyle, and better appetite. A PET/CT scan in June 2007 showed signifi-cant tumor inhibition in both the tumors treated with radio seeds and local chemotherapy as well as in those only treated with SPDT (Figure 6B). Tumor markers and blood routine tests had improved to CEA, 5.81 µg/L; CA153, 306.05 U/L; white blood cell count, 3.9 × 109/L; HGB, 98 × 109/L; and PLT, 80 × 109/L. They were even better than before SPDT.

DiscussionFrom 2005 to 2007, we consecutively treated 3 patients with advanced breast carcinoma using SPDT along with conven-tional therapies.

Case 1 was safely and effectively treated with SPDT plus a small dose of chemotherapy. Although chemotherapy was used, in our opinion, the good response in this case was mainly a result of SPDT. The patient had 24 cycles of chemo-therapy, but all chemotherapy ultimately failed. During the first 3 cycles, the patient was so ill that we had to treat her in the ICU and give the SPDT mainly on her neck tumors, which were the most dangerous manifestation of the cancer. After 2 cycles of treatment, the tumors in her neck shrank very significantly (from 13 × 6 cm2 to 5 × 3 cm2), and PET/CT scan after 3 cycles showed a positive response, especially on the neck.

We obtained positive results in case 2 and case 3 using 2-step therapy—first the debulking of larger tumors and then SPDT. To debulk larger tumors we used 125I radio-seed implantation and HIFU. Both these methods have few adverse effects and are able to destroy local tumors very efficiently. In general, the above local treatment reduces the tumor load but cannot effectively treat widespread metastases. For a given amount of sensitizer, the fewer living tumor cells will absorb more sensitizer, enhancing the SPDT therapeutic effect. In case 2 we mainly used SPDT to treat undebulked tumors in the vertebra, sternum, and abdominal lymph nodes and obtained very good results. In case 3, the patient still had many untreated metastases in her cervical and thoracic verte-brae and elsewhere after tumor debulking. We used a water bath for SDT treatment for almost her whole body (Figure 6B). Ultrasound conducts very quickly and effectively in water. We believe that SDT delivery through water contrib-uted to this patient’s excellent results, and we now routinely use this method of ultrasound delivery.

In all 3 cases, SPDT with SF1 was well tolerated. Unlike chemotherapy and radiation therapy, SPDT has almost no toxic effects, nor has it affected marrow and gastrointestinal function, or damaged important organs such as the spinal cord, heart, lungs, liver, or kidney. All 3 patients had metas-tases in the spine, and for case 1, tumors in the neck had already involved the spinal cord. In our experience, SPDT is even safer than conventional PDT. The 3 cases did not have photosensitive dermatitis and did not require interventional procedures to introduce optical fibers into the body or tumors, as is often necessary with conventional PDT.

Pain in the tumor regions was the main side effect of SPDT. If the handheld ultrasound probe is left in one

Figure 5. Case 2, PET/CT scans: A, before sonodynamic and photodynamic therapy (SPDT); B, after SPDT—PET/CT shows a highly satisfactory outcome of therapy; C, after SPDT—PET/CT taken 28 months later shows no signs of tumor in the body

Figure 6. Case 3. PET/CT scans: A, before sonodynamic and photodynamic therapy (SPDT); B, after SPDT—PET/CT on June 27, 2007, shows a highly satisfactory outcome of therapy

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position, the energy can accumulate in the deep organs, espe-cially in the bone. This causes pain. The problem can be largely avoided by using pulsed ultrasound or by constantly moving the ultrasound probe. SPDT-induced tumor break-down can also induce local pain and make patients feel weak and tired. This is not a severe problem, and in our experience, patients recover in a few days.

In case 1, 3 to 6 months after SPDT treatments, the patient’s neck gradually shortened by about 5 cm, but her neck tumors did not enlarge. We believe that cervical vertebra collapse, resulting in repression of the respiratory center on the cervical spine caused or contributed to her death. Before SPDT, her cervical vertebra had already been seriously destroyed by tumor (Figure 4A). The SPDT shrank the tumors, but the bone could not be adequately restored.

In summary, SPDT with Sonoflora is well tolerated and had significant therapeutic benefits for some patients with advanced breast cancer. SPDT with Sonoflora has significant merit for further investigation.

AcknowledgmentsThe authors wish to acknowledge the scientific contributions and intellectual leadership of the late Don Burke, MD, in the con-duct of this research. Lucy Qing Li, PhD, and Mr Jiangan Su, as officers of EEC Bio-Tech (Guangzhou) Co, Ltd, supported this project in providing funding, equipment, information, and organiza-tional skills.

Declaration of Conflicting Interests

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding

The authors received no financial support for the research and/or authorship of this article.

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