BACKGROUND

 

 

Malignant tumors of the musculoskeletal system, as many other solid tumors, require a true and wide surgical resection for their complete removal. The term wide margins currently used by orthopaedic and surgical oncologist refers to the margins of normal tissue surrounding a visible tumor mass, usually a few centimeters in thickness. However, such resection does not guarantee cure as microscopic disease is left throughout the surgical field beyond this wide cuff of tissue.

 

Adjuvant treatments for surgery are, therefore, required, and patients who undergo resection of malignant musculoskeletal tumors are usually referred for treatment with radiation therapy and/or chemotherapy upon their recovery from surgery. These adjuvant treatment modalities were shown to be effective in lowering the likelihood of local tumor recurrence. However, they are associated with a most considerable rate of complications, local and systemic, as they are not tissue specific and harm healthy tissues and organs as well.

 

 

INDICATIONS

Photodynamic ablation (PDA) allows specific tumor kill and therefore may provide a treatment option for the microscopic disease remaining in the surgical field following tumor removal. It is defined as the administration of a nontoxic drug or dye, known as a photosensitizer (PS), either systemically, locally, or topically to a patient bearing a tumor. The PS has specific affiliation to the tumoral tissue, and following its accumulation within the tumor cells, the tumor site is illuminated with a visible light, which excites the PS to generate cytotoxic species and consequently cause tumor cell death and destruction of tumor.

The realization that the combination of nontoxic dyes and visible light could kill cells was first made by Oscar Raab, a medical student working with Professor Herman Von Tappeiner in Munich in 1900. While investigating the effects of acridine dyes on the protozoa that causes malaria, he made an incidental

discovery that the combination of acridine red and light resulted in protozoal death.12 He postulated that the effect was caused by the transfer of energy from light to the chemical, similar to the process of photosynthesis seen in plants after the absorption of light by chlorophyll. This discovery led to the first therapeutic medical application in which topical eosin, combined with white light illumination, were used to treat various skin tumors. It was soon realized that oxygen is required to allow this chain of reactions, and the term photodynamic action was used to describe this phenomenon.

 

ANATOMIC CONSIDERATIONS

 

Over the last few decades, PDA has been studied and used in a large variety of tumors. However, the use of PDA in the field of orthopaedic oncology was practiced only by a small group of enthusiastic surgeons.

 

Matsubara et al10 reported on eight patients who had either bone or soft tissue sarcomas of the forearm and underwent intralesional resection of their tumor followed by PDA using topical administration of acridine

orange (AO). Destruction of the microscopic disease that was left in the surgical field was done in three consecutive steps:

1. The surgical field is illuminated with blue light, which excites the AO within the residual tumoral tissue to emit green fluorescence. The tissue emitting this green fluorescence is detected with a designated surgical microscope and removed using an ultrasonic surgical scalpel.

2. Illumination of the surgical field with unfiltrated light from a xenon lamp

3. Single session of radiation therapy at a dose of 5 Gy, given immediately after surgery

 

 

This group of 8 patients was compared to another group of 10 patients who underwent wide tumor resection with adjuvant radiation therapy. The rates of local tumor recurrence were 12.5% and 20%, respectively, and patients who underwent marginal tumor resection with PDA had considerably better

function.2

 

We are currently studying the use of PDA with 5-aminolevulinic acid (5-ALA) in the management of desmoid tumor and other benign and malignant soft tissue tumors, which have fibrous element in their structure.

Desmoid tumors, also known as fibromatoses, are locally aggressive, soft tissue lesions. Extra-abdominal lesions appear between puberty and the sixth decade of life, with the peak incidence between 25 and 35 years of age. These lesions are located in a variety of anatomic sites, with the shoulder girdle, chest wall,

back, and thighs being the most frequent locations in descending order.7 Although desmoid tumors do not metastasize, they are locally infiltrative and their propensity for local recurrence following wide resection is well documented. Although wide local resection still remains the treatment of choice for the majority of patients, the postoperative local recurrence rates were reported to be as high as 30% and 33% at the 5- and 10-year

posttreatment follow-ups, respectively.1 Rock et al13 reported 194 patients with desmoid tumor who were treated at the Mayo Clinic, of whom 132 (68%) had a local tumor recurrence. Positive margins of the resection are considered a strong predictor for local tumor recurrence.1,6

 

 

A locally recurrent desmoid tumor is a devastating clinical event. It usually requires extensive surgery for its removal and usually mandates adjunctive treatment (radiation therapy and/or chemotherapy). It is also associated with a

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considerable loss of function and impaired quality of life. Because recurrence rates are so closely related to residual tumor tissue and positive margins of the resection, elimination of the microscopic disease left in the surgical field following wide tumor resection is key to lowering these high rates of tumor recurrence (FIG 1).

 

 

 

FIG 1 • Recurrent tumors are related to the presence of microscopic disease left in the surgical field following wide resection of the main tumoral mass.

 

 

The formation of 5-ALA from glycine and succinyl coenzyme A (CoA) is the first step of the heme biosynthetic pathway, which ends with the incorporation of iron into protoporphyrin IX (PpIX). Due to enzymatic abnormalities occurring along this pathway in some tumors, exogenous administration of 5-ALA results in the

accumulation of PpIX, which is an efficient PS (FIG 2).11 When cells and tissue specimens that had been photosensitized with 5-ALA-induced PpIX are exposed to blue light at a wavelength of 420 nm, pink fluorescence can be detected—a finding which allows intraoperative identification and enhanced resection of

these tumors.11 This effect was used to improve the margins of resection in ovarian carcinomas and glioblastomas.8,14 Furthermore, exposure of cells that have accumulated PpIX to red light (635 nm) achieved a

cytotoxic effect, which can be exploited for photodynamic therapy (FIG 3).11 This 5-ALA characteristic has already been implemented in the management of skin tumors, bladder cancer, tumors of the oral cavity, and high-grade dysplasias and carcinomas of the esophagus.3,4,5,9

 

 

 

FIG 2 • Due to enzymatic abnormalities, exogenous administration of 5-aminolevulinic (5-ALA) to tumor cells results in intracellular accumulation of protoporphyrin IX (PpIX), a potent PS. GLY, Glycine; SCoA, Succinyl-Coenzyme A; PBG, Porphobilinogen; URO, Uroporphyrinogen; PROTO, Protoporphyrinogen; COPRO, Coproporphyrinogen.

 

 

 

FIG 3 • Exposure of intracellular protoporphyrin IX (PpIX) to blue light at a wavelength of 420 nm results in pink fluorescence. Its exposure to red light (635 nm), however, induces a cytotoxic effect, which can be exploited for photodynamic therapy.

 

OUTCOMES

The results of our recent pilot clinical study revealed that preoperative administration of 5-ALA (20 mg/kg) to five patients diagnosed as having desmoid tumor resulted in a considerable intracellular accumulation of PpIX. Pink fluorescence was clearly evident in all the study patients upon the illumination of the resected tumor with a blue light. Pink fluorescence, however, was not evident within the surgical field probably due to the microscopic size of the residual disease. At their most recent follow-up, all study patients had local tumor recurrence. The results of this study were presented at several international meetings.

Based on our earlier findings, we applied for approval to run a second clinical study with the aim of

 

treating desmoid tumors with 5-ALA-based photoablation. Briefly, the proposed study protocol includes oral administration of 5-ALA (60 mg/kg) 3 hours before surgery (FIG 4). The tumor is resected according to standard procedures. After tumor removal, the surgical specimen is illuminated with blue light (420 nm) to verify the presence of PpIX within the tumoral tissue (FIG 5). The surgical field is then illuminated with

 

red light (635 nm, light dose of 150 J/cm2), which induces the killing of the remaining microscopic disease (FIGS 6,7 and 8).

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FIG 4 • 5-ALA (60 mg/kg) is given orally 3 hours before surgery.

 

 

 

FIG 5 • The resected tumor is illuminated with blue light (420 nm) to verify the presence of PpIX within the tumoral tissue.

 

 

 

FIG 6 • The surgical field is illuminated with red light (635 nm, light dose of 150 J/cm2) to induce the killing of the remaining microscopic disease.

 

 

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FIG 7 • A. Magnetic resonance scan showing desmoid tumor of the lateral arm. B. Intraoperative photograph showing the surgical field following resection of the tumoral mass; the humeral diaphysis is exposed. C. The tumor is opened to expose the neoplastic tissue. D. A strong pink fluorescence is evident following illumination with blue light. E. A designated red light source is positioned in front of the

surgical field. F. The surgical field is illuminated with red light (635 nm, light dose of 150 J/cm2) for approximately 30 minutes to induce the killing of the remaining microscopic disease.

 

 

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FIG 8 • A,B. Medium-grade fibrosarcoma of the right flank. C. The tumor is opened to expose the neoplastic tissue. D. A strong pink fluorescence is evident following illumination with blue light. As in the case shown in FIG 7, following the detection of pink fluorescence in the resected tumor, the surgical field was illuminated with red light.

 

 

The use of 5-ALA-based photoablation of desmoid tumor is an ongoing study, the preliminary results of which will be published in 2 years. We similarly use 5-ALA-based photoablation in the management of chondromyxoid fibroma, dermatofibrosarcoma protuberans, solitary fibrous tumors, and fibrosarcomas.

 

REFERENCES

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2. Blume JE, Oseroff AR. Aminolevulinic acid photodynamic therapy for skin cancers. Dermatol Clin 2007;25:5-14.

    

    

3. Denzinger S, Burger M, Walter B, et al. Clinically relevant reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acid-induced fluorescence diagnosis: 8-year results of prospective randomized study. Urology 2007;69:675-679.

    

    

4. Fan KF, Hopper C, Speight PM, et al. Photodynamic therapy using 5-aminolevulinic acid for premalignant and malignant lesions of the oral cavity. Cancer 1996;78:1374-1383.

    

    

5. Gossner L, May A, Sroka R, et al. Photodynamic destruction of high-grade dysplasia and early carcinoma of the esophagus after the oral administration of 5-aminolevulinic acid. Cancer 1999;86; 1921-1928.

    

    

6. Gronchi A, Casali PG, Mariani L, et al. Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution. J Clin Oncol 2003;21:1390-1397.

    

    

7. Hosalkar HS, Torbert JT, Fox EJ, et al. Musculoskeletal desmoid tumors. J Am Acad Orthop Surg 2008;16:188-198.

    

    

8. Löning M, Diddens H, Küpker W, et al. Laparoscopic fluorescence detection of ovarian carcinoma metastases using 5-aminolevulinic acid-induced protoporphyrin IX. Cancer 2004;100:1650-1656.

    

    

9. Mackenzie GD, Dunn JM, Selvasekar CR, et al. Optimal conditions for successful ablation of high-grade dysplasia in Barrett's esophagus using aminolaevulinic acid photodynamic therapy. Laser Med Sci 2009;24:729-734.

    

    

10. Matsubara T, Kusuzaki K, Matsumine A, et al. Clinical outcome of minimally invasive surgery using acridine orange for musculoskeletal sarcomas around the forearm, compared with conventional limb salvage surgery after wide resection. J Surg Oncol 2010;102:271-275.

     

     

11. Peng Q, Warloe T, Berg K, et al. 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges. Cancer 1997;79:2282-2308.

     

     

12. Raab O. Uber die wirkung fluoreszierender stoffe auf infusorien. Z. Biol 1900;39:524-526.

     

     

13. Rock MG, Pritchard DJ, Reiman HM, et al. Extra-abdominal desmoid tumors. J Bone Joint Surg Am 1984;66:1369-1374.

     

     

14. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomized controlled multicenter phase III trial. Lancet Oncol 2006;7:392-401.