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10.1245/ASO.2004.03.025
Annals of Surgical Oncology 11:322-327 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Breast Cancer With Chest Wall Progression: Treatment With Photodynamic Therapy

Rosa E. Cuenca, MD, Ron R. Allison, MD, Claudio Sibata, PhD and Gordon H. Downie, MD, PhD

From the Photodynamic Therapy Program, Leo Jenkins Cancer Center, Departments of Surgery (REC), Radiation Oncology (RRA, CS), and Medicine (GHD), The Brody School of Medicine, East Carolina University, Greenville, North Carolina.

Correspondence: Address correspondence and reprint requests to: Rosa E. Cuenca, MD, Department of Surgery, 600 Moye Blvd., PCMH TA-202, Greenville, NC 27858; Fax: 252-744-5775; E-mail: cuencar{at}mail.ecu.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Chest wall progression of breast carcinoma affects up to 5% of breast cancer patients and is a major source of their pain. Treatment options are limited or may not be offered to these patients. Low-dose Photofrin-induced photodynamic therapy (PDT) offers an excellent clinical response with minimal morbidity. We report our continued experience with PDT in this setting.

Methods: Fourteen patients with more than 500 truncal metastases were treated with PDT. All received off-label Photofrin (.8 mg/kg) IV and light treatment at 630 nm from a diode laser with a microlens at a fluence of 1800 mW and a total light dose of 150 to 200 J/cm2 at 48 hours. One patient required re-treatment because of extensive disease.

Results: Follow-up was at least 6 months, and several extended to >24 months. All patients demonstrated tumor necrosis, with 9 of 14 complete responses, including with lesions >2 cm in thickness. Disease progression occurred outside of the treatment field. Several patients had initial regression of untreated lesions. Wound care, especially with disease in the deep tissues, was an issue.

Conclusions: Low-dose Photofrin-induced PDT offers patients with chest wall progression a treatment option with an excellent clinical response. To date, the response is prolonged and offers good local control. Surgical oncologists have an active role in this treatment option.

Key Words: Breast carcinoma • Chest wall recurrence • Photodynamic therapy • Photofrin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Breast cancer recurrences after mastectomy pose a therapeutic challenge with few surgical options. If disease is localized, surgical excision can be attempted. However, these lesions often are widespread throughout the chest wall or involve heavily irradiated tissue. Many patients have received aggressive chemotherapy with little to no local response and have exhausted most avenues for local control. Multiple studies show that photodynamic therapy (PDT) provides good tumor kill for primary cutaneous malignancies1–4 and suggest its effectiveness in ablating dermal lymphatic recurrences of breast cancer. Food and Drug Administration (FDA)-approved uses for PDT include lung and esophageal lesions,5–7 but treatment of bladder, head and neck, and other tumor sites with novel approaches has been reported.6,8,9

PDT exploits the accumulation of photosensitizers into the tumor, which then is locally excited with visible light. Selectivity of treatment comes from the excretion of drug from normal tissue over time, promoting a concentration gradient within the tumor plus the location of the activating light.7 Treatment depth varies with the wavelength of light that activates the sensitizer used. The singlet oxygen that is produced during the transfer of energy from light source to drug disrupts plasma, nuclear, and mitochondrial cell membranes, resulting in apoptosis.6 Local edema and perivascular stasis occur rapidly, within hours of treatment. Tumor necrosis can be evident within 2 to 24 hours. Photofrin (dihematoporphyrin ether; Axcan Scandipharm, Birmingham, AL) is the only FDA-approved photosensitizer available for the treatment of cancer. The light source used to activate Photofrin (630 nm) is topically delivered via lasers by using diffusing catheters and is focused on skin surfaces by using a microlens.8,10 This modality has been previously reported in a small number of breast cancer patients with chest wall recurrence, with good responses.11 We report our continued encouraging experience with PDT in 14 patients with chest wall recurrences of their breast cancer.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between March 2000 and December 2002, 33 women with chest wall recurrences of their breast cancer were screened and 14 were treated by the multidisciplinary PDT team at the Leo Jenkins Cancer Center at East Carolina University. All had cutaneous lesions involving their previous mastectomy sites, and all had received systemic chemotherapy, as well as chest wall irradiation, with continued disease. None was actively receiving chemotherapy while being evaluated for PDT.

Patients were assessed for evidence of systemic disease, Karnofsky performance status, and comorbidities. Local factors that were assessed included local skin integrity, extent of surface area to be treated, evidence of underlying bony involvement, and associated lymphedema. Cutaneous lesions were identified as visible or palpable intradermal nodularities with or without pigmentation. Dermal biopsy samples were obtained from all patients for histological diagnosis. Patients were categorized as having stable local recurrence (with an attempt at cure) or as having aggressive disease (with an attempt at palliation). All patients referred for PDT were discussed in the multidisciplinary PDT conference. Patients with localized, asymptomatic distant disease and aggressive chest wall lesions were not excluded from treatment, whereas patients with both aggressive local disease and symptomatic systemic disease were not offered treatment. Those with a Karnofsky performance status <50% were not treated. Photosensitivity precautions were reinforced at all visits.

Patients were given off-label IV Photofrin .8 mg/kg on day 1 in a short outpatient procedure. On day 3, they received PDT via a fiberoptic microlens (Fibersdirect.com) delivery: 630 nm of red light at 150 to 200 J/cm2 with a diode laser light source (Diomed Corp., Andover, MA) at 1800 mW of fluence. Fields were planned during treatment, and 4- to 5-cm-diameter spot deliveries were the norm. Tumor thickness ranged from .1 to 20.0 mm. All areas treated had palpable or visual tumor within the dermis (maculopapular changes consistent with dermal disease). All treatment was performed on an outpatient basis (Fig. 1), and next-day treatment (day 4) was reserved for patients who required extensive surface area treatment. Patients were followed up on a routine basis at 24 hours, 3 days, 1 week, 4 weeks, and every 3 months and as needed for assessment of clinical response and wound care needs. Digital photography and physical examination were routinely used for objective response parameters. Objective response parameters included partial response (PR; necrosis of at least 50% of visible or palpable lesions) and complete response (CR; necrosis of all visible or palpable lesions). Response was assessed at 2 and 4 weeks after treatment, and CR or PR status was assigned. The disease-free interval was defined the duration, in months, of no evidence of chest wall disease from PDT treatment in this cohort (March 2000 to December 2002). The clinical course of disease was documented for success of local control only and not for the development or progression of distant disease.



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  		FIG. 1. Outpatient treatment of chest wall lesions with diode lasers.

 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
More than 500 lesions in fourteen women, aged 38 to 67 years, with biopsy-proven breast cancer recurrence to the chest wall were treated with PDT between March 1, 2000, and December 31, 2002, at the Leo Jenkins Cancer Center. All had reached maximum therapeutic responses with chemotherapy and radiation. Many had extensive surface-area lesions of varying thicknesses, and all had recurrences in irradiated sites. All patients were followed up for at least 6 months, and none of the CRs was lost to follow-up. Follow-up was achieved with weekly immediate posttreatment visits and then monthly visits for local patients, and photographic follow-up was performed by frequent e-mail with out-of-state or international patients (n = 2). All patients received treatment on day 3, and one patient required staged treatment in two doses because a very large surface of disease. All treatment was performed on an outpatient basis, and there were no admissions to the hospital for wound management, sepsis, or pain control. One patient whose central chest wound did not contract after 3 months required a local flap closure. Three patients’ chest wounds are still actively healing.

A CR was seen in 9 (64%) of the 14 patients, with tumor necrosis and re-epithelialization of treated areas (Table 1). Tumor necrosis was seen within the first 24 to 48 hours (in some, 2–4 hours after treatment), with vascular collapse in the dermal vessels (Fig. 2). A thick eschar was seen at 3 to 6 weeks, and this slowly contracted and lifted, yielding new dermis underneath (Figs. 3 and 4Go). No delayed closures were attempted as long as the wound was contracting and healing. One patient, at 3 months, had a large 5 x 6 cm central chest wound that was not contracting, and a flap closure that was performed after biopsy showed no evidence of residual tumor. She had a CR and had no evidence of tumor 6 months later. All patients with CRs have healed wounds except for one, whose 1 x 1 cm central chest wound did not re-epithelialize over the sternum. This was in the center of a heavily irradiated bed. The wound causes her minimal discomfort. She had no recurrent disease at 14 months after treatment.


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  		TABLE 1. Clinical course of 14 patients treated with photodynamic therapy (PDT): March 2000 to December 2002a
 


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  		FIG. 2. Chest wall 6 days after photodynamic therapy. Note the early intradermal vascular collapse and early tumor necrosis.

 


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  		FIG. 3. Same chest wall 110 days after photodynamic therapy. Eschar formation and peripheral epithelial regrowth are noted, requiring only dry dressing.

 


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  		FIG. 4. Chest wall 190 days after photodynamic therapy. Eschar has sloughed, with new skin growth noted. There is no evidence of disease.

 
The median disease-free interval for the CR group was 6 months (range, 3–17 months). In patients who reached only a PR, tumor necrosis was seen in all five, but total tumor ablation was not reached; this was evident within 2 weeks of treatment. All patients with CR are alive to date, and five of these have no systemic disease; three have locally controlled systemic disease. Three of the patients with PR are dead of disease. Five recurrences seen in the patients with CR were out-of-field recurrences, and one was an in-field recurrence. Two of the nine patients with CR required repeat PDT 17 and 6 months after CR was reached. These two patients have locally controlled disease to date. One patient, whose disease recurred as very small areas outside the treatment sites, had electron beam topical treatment, with good local control and no need for repeating PDT. Of the complete responders, five (35.7% of patients treated) are without disease to date. Wounds have totally healed in eight of nine CR patients; one received a local flap closure at 3 months, and one has a residual 1 x 1 cm granulating central chest wound 14 months later that requires minimal care. All patients with PR who are still living have continued chest wall disease.

The median follow-up was 8 months (range, 6–33 months), but two of our patients were those previously treated with PDT more than 24 months before presentation. They had good initial responses but experienced recurrence and were re-treated at our facility. Their current outcomes were measured as reported here. One continues to have good local control more than 3 years from the initial PDT, and the other is alive with local and distant disease. Of all the posttreatment recurrences, only one has recurred inside the treatment field.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Local recurrence in the chest wall after mastectomy is not rare. Locoregional recurrence in the National Surgical Adjuvant Breast and Bowel Project B-04 trial was 5% to 8%.12 Chest wall recurrence may be secondary to inadequate margins at mastectomy, lymphangitic spread through the dermis, or hematogenous metastasis to the wound. Although patients with isolated lesions are able to undergo surgical therapy, many have extensive disease that cannot be controlled surgically. Systemic chemotherapy and radiation are the recommended regimens for these cases, but failure rates for these regimens are between 30% and 55%.13–16 The stage of first disease and the disease-free interval may be important prognostic factors for survival after chest wall recurrence.13,17 Many patients have systemic disease either at the time of their cutaneous recurrence or soon after, some may manifest disease only at the dermal site of disease, and a few are cured with aggressive treatment. The disease is often painful, unsightly, and tedious to attend, often weeping and bleeding and requiring frequent dressings. Cutaneous recurrence causes tremendous anxiety, because the patients are visually witnessing their tumor progression and, thus, their own demise.

PDT is not a new technology. In 1960, Lipson and Schwartz5a identified the fluorescence of neoplastic cells exposed to a hematoporphyrin derivative.5 Purification of this derivative led to the current drug Photofrin. Canada was the first country, in 1993, to approve PDT with Photofrin for the treatment of bladder cancer. The next approvals were in The Netherlands and France for esophageal and lung cancers. The results of a US phase III trial5 for esophageal cancer comparing PDT with neodymium:yttrium-aluminum-garnet laser treatment led to US FDA approval in 1995. Off-label uses for PDT have been numerous. The favorable results with PDT for nonmelanoma skin malignancies prompted its use for breast cancer recurrence. An initial phase II/III trial using tin ethyl etiopurpurin demonstrated clinical responses in eight patients, with a 92% CR rate.10 An earlier report of PDT in nine patients with chest wall recurrence treated with Photofrin showed that 89% of the lesions treated responded.11

The response rate seen in our cohort of patients was 9 of 14 CRs. All patients had different surface areas treated, making comparisons difficult. Several CRs occurred in patients with a very large skin surface involved with tumor. Tumor thickness in these patients also varied. Most had variable thicknesses to be treated—from bulky, fungating lesions to thin, subdermal macules. Depth of the PDT effect was expected to be at most up to 10 mm, but thicker lesions did have an effect, and this may be in some part secondary to the vascular collapse caused by the photoactivation of drug within feeder vessels. The anticipated effect of PDT on bulky, bleeding, or weeping lesions was a drying or topical necrosis. Patients with PR had tumor necrosis, but this occurred in <50% of their lesions. However, their tumor necrosis, where a response was noted, was quite brisk. Native skin pigmentation did not seem to affect the response rate, because there were very pigmented patients within the CR group. Predictability of outcome was difficult, but thicker, more pigmented, or bleeding lesions did respond to PDT. Lesions deep within the dermis had more treatment failure than those extending through the dermis. Several patients had out-of-field failure at the edge of our treatment field, suggesting that microscopic nonpalpable lymphatic spread was present. We have subsequently expanded our treatment field at least 1 to 2 cm beyond visible or palpable spread.

The immune-modulating effects of PDT have been described. PDT-generated tumor-sensitized lymphocytes have been harvested in vivo after treatment.7,18 In our cohort, several lesions that were not within the treatment field regressed within 4 to 6 weeks of treatment. Given the immune responses reported, a possible immune mechanism at these disease sites is hypothesized.

Immediate treatment side effects, aside from the vascular collapse seen, were itching or tingling, edema, erythema, and, rarely, pain at the treatment fields. The edema often extended to the contralateral breast, if present, and onto the abdominal wall. These side effects were modulated by the use of ice packs both during and after treatment, as needed. The use of anti-inflammatory drugs, which included nonsteroidal anti-inflammatory drugs and corticosteroids, was initiated 24 hours after treatment and continued for 7 days.

Wound care was a major focus of the post-PDT treatment. Most patients had brisk tumor necrosis that required topical dressings and emollients. All patients received empirical antibiotics for 7 days. Prolonged antibiotic use was never necessary. Special attention was given to the heavily irradiated areas, because these were the most tenuous for epithelial regrowth. Aggressive debridement was avoided to allow all opportunity for epithelialization. Surgical involvement from the onset of treatment optimizes the foresight and attention needed to address these wounds. Itching with wound healing was a frequent complaint but was managed with topical wound care and emollients. None of these patients required hospitalization for any complications, and all treatment was performed on an outpatient basis.

The ability to repeat treatment is another advantage of PDT, as opposed to radiation, which has limits to its dosage. Three of our patients have been re-treated (two >24 months before presentation). Re-treatment occurred without compounded side effects or resistance. Patients with chest wall recurrence of breast cancer who experience treatment failure with surgery, chemotherapy, and radiation have very few options for control of their disease. Their pain is compounded by the daily observance of the progression of tumor, which often bleeds, weeps, and is unsightly. PDT offers good local control for many patients, often rapidly contracting and drying the tumor surface and reducing wound care issues. Wound closure, once complete, gives good cosmesis. Outpatient treatment makes this modality more feasible and cost-effective; PDT should be offered to these patients. The applicability of PDT to challenging malignancies such as breast cancer chest wall recurrence demands a good understanding of tumor behavior, expected outcomes, and complex wound management. Because of this, surgical oncologists should be actively involved with this technology. Its use as only a last resort treatment option should be questioned, because its response rates are equal or superior to those of other accepted modalities.

In conclusion, PDT for chest wall recurrence of breast carcinoma allows opportunities for good long-term local tumor control. Therapy is well tolerated on an outpatient basis, with few complications and high response rates.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.

The authors thank Nora Wooten, RN, and Karen Fletcher for assistance with this manuscript.


   FOOTNOTES
 
Photodynamic therapy (PDT) for chest wall recurrence of breast carcinoma allows opportunity for good long-term local tumor control. Therapy is well tolerated, as outpatient, with few complications and high response rates.

Received for publication March 7, 2003. Accepted for publication October 22, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Pennington DG, Waner M, Knox A. Photodynamic therapy for multiple skin cancers. Plast Reconstr Surg 1987; 82: 1067–71.
  2. Wilson BW, Mang TS, Cooper MC, et al. Use of photodynamic therapy for the treatment of extensive basal cell carcinomas. Facial Plast Surg 1990; 6: 185–9.
  3. Dougherty TJ. Photosensitization of malignant tumors. Semin Surg Oncol 1986; 2: 24–7.[Medline]
  4. Allison R, Mang TS, Wilson BD. Photodynamic therapy for the treatment of non melanomatous cutaneous malignancies. Semin Cutan Med Surg 1998; 17: 153–63.[CrossRef][Medline]
  5. Dougherty TJ, Gomer CJ, Henderson BW, et al. Photodynamic therapy. J Natl Cancer Inst 1998; 90: 889–905.[Abstract/Free Full Text]
  6. Dougherty TJ, Henderson B. Historical perspective: Schwartz S, Winkelman JW, Lipson RL. In: Henderson BW, Dougherty TJ, editors. Photodynamic therapy. New York: Marcel Dekker Inc., 1992: 1–15.
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  8. Dougherty TJ, Marcus SL. Photodynamic therapy. Eur J Cancer 1992; 28A: 1734–42.
  9. Schweitzer VG. Photofrin-mediated photodynamic therapy for treatment of early stage oral cavity and laryngeal malignancies. Lasers Surg Med 2001; 29: 305–13.[CrossRef][Medline]
  10. Downie GH, Cuenca RE, Allison RR, McIlroy BW. A comparison of interstitial and superficial light delivery for photodynamic therapy of intraluminal neoplasms. J Bronchol 2002; 9: 193–6.[CrossRef]
  11. Mang TS, Allison R, Hewson G, Snider W, Moskowitz R. A phase II/III clinical study of tin ethyl etiopurpurin (Purlytin)-induced photodynamic therapy for the treatment of recurrent cutaneous metastatic breast cancer. Cancer J Sci Am 1998; 4: 378–84.[Medline]
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