B e h a n d l u n g Die Wechselwirkungen zwischen Anti-epileptika und anderen Medikamenten Zugabe der so genannten enzyminduzierenden Medikamente (be-schleunigen den Abbau von Medikamenten in der Leber) unterein Unter Wechselwirkungen zwischen Medikamenten (so genannte Interaktionen) versteht man eine gegenseitige Beeinflussung ihrer ander zu einer Wirkungsabschwächung. Bei diesen
Doi:10.1016/s1572-1000(04)00039-0Photodiagnosis and Photodynamic Therapy (2004) 1, 157—171
Photodynamic therapy for chest wall recurrence
from breast cancer
R.R. Allison, MD, C. Sibata, T.S. Mang, V.S. Bagnato,
G.H. Downie, X.H. Hu, R. Cuenca
a Radiation Oncology Department, Brody School of Medicine, East Carolina University, b PDT Center, Brody School of Medicine, East Carolina University, Greenville, NC, USA c School of Dental Medicine, State University of New York at Buffalo, Buffalo, NY, USA d Physics Department, University of S˜ao Paulo—S˜ao Carlos, S˜ao Carlos, SP, Brazil e Pulmonary and Critical Care Medicine, Brody School of Medicine, East Carolina University, f Physics Department, Thomas Harriot College of Arts and Sciences, East Carolina University, g Surgical Oncology Department, Brody School of Medicine, East Carolina University, Greenville, NC, USAAvailable online 13 September 2004 KEYWORDS
Breast cancer is common with over 230,000 new cases diagnosed each year in North America alone. While great strides have been made to achieve excel- lent cancer control and survival, a signiﬁcant minority of patients fail locally. While initial salvage to regain disease control is of the utmost importance, it is not univer- sally successful. This leads to a therapeutic quagmire. Additional surgery, radiation and chemo-hormonal therapy are possible, but they are usually highly morbid with low success rates. Photodynamic therapy appears to be an underutilized salvage modality for this unfortunate patient population. This report analyzes and reviews the role of photodynamic therapy for patients with chest wall re-recurrence from 2004 Elsevier B.V. All rights reserved.
Natural history of chest wall lesions . 159 * Corresponding author. Tel.: +1 252 744 2900; fax: +1 252 744 2812.
E-mail address: email@example.com (R.R. Allison).
1572-1000/$ — see front matter 2004 Elsevier B.V. All rights reserved.
PDT for chest wall recurrence/re-recurrence from breast cancer. 160 Reported outcomes from clinical trials . 161 Introduction
ation is modiﬁed radical mastectomy For pa- tients who fail mastectomy full course radiation Dramatic advances have occurred in the early de- therapy is employed to the chest wall and regional tection and treatment of breast cancer. However, lymphatics. Fortunately in both situations salvage even with 90% or higher local control rates re- therapy is generally successful with minimal acute ported at 5-year follow up, a considerable num- morbidity for most patients. Salvage in these situ- ber of women still suffer local regional failure ations usually incurs risk of arm edema as the most Potentially, in North America alone, this translates common chronic side effect. Overall, several large to nearly 20,000 of the 230,000 new breast cancer series show that nearly 90% of patients undergo- cases diagnosed each year requiring salvage ther- ing salvage will regain local control For apy for local-regional failure. Further, it is well doc- lumpectomy and radiation patients with isolated umented that local failure increases with longer recurrence at the initial tumor site survival is nearly follow-up. Eventually more than 15% of these pa- equivalent to similar patients who did not recur.
tients will require local salvage by 15 years post- Most patients who experience recurrence will un- treatment despite ‘‘curative’’ therapy dergo additional chemotherapy though no random- Generally initial salvage for patients who fail ized series exist to examine this important question breast-conserving therapy of lumpectomy and radi- Photodynamic therapy for chest wall recurrence from breast cancer Given the large number of patients diagnosed and edema. The quality of life for these individuals with breast cancer, the real risk of local failure, and their caretakers can become poor. As lesions and the fact that local control from salvage does progress uncontrollably, psychological and physio- not approach 100%, a signiﬁcant minority of breast logical distress occurs as might be expected from cancer patients will re-recur loco-regionally. These individuals watching their cancers grow in front of individuals will most likely have already undergone their eyes. Some patients will succumb due to the one or more major surgical procedures for local combination of infected wound, pain and tumor control, full dose radiation and multi-agent chemo- hormonal therapy. Clearly, additional salvage op- tions with these modalities are limited. Photody- Salvage for re-recurrence: options
namic therapy (PDT) had considerable suc- cess in the treatment of cutaneous primary and metastatic malignant lesions and should be con- sidered for these unfortunate individuals. PDT has With the extensive dermal lymphatic involvement the additional beneﬁt of being a potentially pain- of the skin, a local approach to excision virtually less outpatient procedure that is repeatable. PDT always fails As it is impossible in many pa- can work in combination with other salvage regi- tients to obtain clear margins, which would allow mens or as a stand-alone therapy. In a simplistic for wound healing, further surgery must be ap- overview, PDT has three main components: ﬁrst a proached cautiously. Even highly selected patients sensitizing agent, which preferentially accumulates who have been deemed candidates for chest wall in malignant/pre-malignant tissues and/or clears resection often followed by additional radiation and faster from surrounding normal tissue; second, a chemotherapy generally fail at the margins of re- source of intense illumination, which at the ap- section Further, these patients have fairly propriate wavelength will activate the sensitizer.
high morbidity even in the best surgical hands This leads to the third component of PDT, oxy- It would be clinically more efﬁcacious to excise and gen, which in the course of the photodynamic re- close wounds in a sterilized ﬁeld than to leave a tu- action is transformed into singlet oxygen. The gen- mor infested wound and expect healing. Should the eration of singlet oxygen allows for the rapid cyto- tumor bed be sterilized, for example by PDT, a va- toxic/vasculotoxic activity associated with PDT. We riety of plastic surgery grafts could be employed will analyze and review the PDT literature, based to close defects, if needed. In this situation, as on published peer reviewed papers, concerning this no viable tumor would prevent healing, potentially one could expect excellent clinical and cosmetic Radiation
Natural history of chest wall lesions
Radiation is a highly effective modality for patients Once tumor cells have invaded dermal lymphatics, diation has the beneﬁt of treating the recurrent they appear free to travel extensively in this cuta- ﬁeld and regional lymphatics with excellent clini- neous system As these lymphatics are without cal and cosmetic outcomes Patients with re- direction, due to lack of valves, metastasis originat- currence post-radiation are extremely difﬁcult to ing from the chest wall can spread to the contra- re-irradiate. This is due to the well-established tol- lateral chest, abdomen and even the back. This ex- erances of tissue to radiation. After a ﬁrst course of tensive spread explains the virtual complete failure radiation therapy, the lung, soft tissue, ribs, lym- of nidusectomy, attempted at what appears to be phatics and nerves in the prior radiation ﬁeld are a solitary metastasis. As these lesions grow, they near tolerance levels. An additional course of radia- often cause intensive signs and symptoms. Com- tion to recurrent disease will likely bring these crit- monly, patients report an unrelenting itching which ical normal structures beyond tolerance. This can is not relieved by topical steroids or shots. Many pa- have severe clinical complications in terms of symp- tients report pain from these lesions as well as mo- tomatic pneumonitis, arm edema, plexopathies, ﬁ- tion limitation due to discomfort. Eventually, the lesions begin to weep and bleed causing further dis- tress. Open tumor inﬁltrated wounds and infections Chemo-hormonal therapy
that are poorly controlled follow. Lesions may im- Re-recurrent lesions often bode for systemic fail- pinge on the brachial plexus and remaining axillary ure. Most patients should undergo additional stag- nodes leading to additional neurologic difﬁculties ing for extent of disease work-up. This includes chest, abdomen, pelvic CT and bone scan. Tu- mor markers may be of beneﬁt. Patients with structures. Those tried in breast cancer treat- widespread and progressing systemic disease may ment included hematoporphrin derivatives (HPD; not need local treatment in as urgent a fash- Photofrin®), aminolevulinic acid (ALA) — a pro- ion as they need systemic therapy. Most patients drug which stimulates the production of the nat- who have chest wall re-recurrence have already urally occurring photosensitizer Protoporphyrin IX failed primary and salvage chemo-hormonal treat- (PPIX) — and the synthetic porphyrin TPPS4. An open ring porphyrin based texaphyrin, Lutex, has courses of chemotherapy as well. It is rare for third- also been examined. Chlorophyll based compounds line treatments to effectively control chest wall have also been explored including Foscan® (MTHPC) failure for any prolonged period. Further, no clear and HPPH, which are chlorines and Purlytin (SnET2), data exists that correlates systemic response with a purpurin, which is a degradation product of chlo- chest wall response for these patients. Even in the rin. As yet, no dye has been tested for this indica- face of systemic improvement, local re-control can tion and reported in peer reviewed literature.
be poor. This may be due to the poor hematologic delivery of chemotherapeutic agents to the chest wall as its blood supply may be compromised due Illumination
to surgery and radiation, most likely on several oc- casions. It is recognized that certain chemother- Appropriate illumination should allow for activa- apy agents are potentially radiation sensitizers and tion of the photosensitizer. The longer the wave- perhaps PDT sensitizers. This may complicate the length of light, the deeper the penetration into and treatment of chest wall disease. It may also in- through the skin. As most chest wall lesions can ap- proach 1cm or more in depth, one generally will require an activation wavelength to readily pene- trate this deep. Photofrin® and ALA/PPIX activate As currently practiced, PDT involves a photosensi- around 630 nm. This allows for at least 1 cm light tizing agent that is activated optimally by a par- penetration and should be adequate for most situ- ations. ALA has a lesser penetration depth because results in a photodynamic reaction. The reaction it is applied locally, and the drug only diffuses to a creates highly cytotoxic and vascular toxic free few mm depth. Deeper lesions may require inter- radicals leading to tumor cell death and immuno- stitial therapy; however, even lesions approaching modulation. As PDT has been employed to a wide 2 cm were successfully treated by superﬁcial means variety of cutaneous neoplasms with excellent using Photofrin®Purlytin’s (660 nm) and clinical and cosmetic outcome, it is reasonable Foscan®’s (652 nm) should behave similarly to to hypothesize that chest wall lesions would be Photofrin® in depth penetration. Lutex with 732 nm amenable to this therapy. As PDT works well even treatment wavelength may have deeper penetra- in operated upon and radiated ﬁelds, this would be tion. Illumination to activate the photosensitizers a means for additional salvage options. We will re- can be by multi-wavelength light or more efﬁciently view the treatment and outcome results in the pub- by monochromatic light at the appropriate wave- lished literature for each photosensitizer.
length. This can be generated by intense white light with ﬁlters or more accurately by laser light at the speciﬁc wavelength. Light is transmitted from the PDT for chest wall
source (i.e. laser) by ﬁberoptics for illumination.
recurrence/re-recurrence from breast
The illumination may be done using a diffusing ﬁber for multi-directional illumination, which is good for interstitial and intraluminal work, or a micro lens, which like a ﬂashlight projects in a single forward Photosensitizers
direction. Many other types of ﬁbers also exist. All lesions are more selectively activated by using a mi- Photosensitizers are substances that transfer and cro lens aimed at the treatment ﬁeld. This will illu- translate light energy into a type II photodynamic minate a circular ﬁeld, and appropriate light block- reaction The oxygen-based reaction creates ing can be added. By blocking light from surround- toxic singlet oxygen species for tumor ablation.
ing or reﬂected surfaces, one will minimize normal Photosensitizers may be natural or synthetic. In tissue toxicity. Inappropriate blocking of light may general the three main families for photosensi- block illumination of tumor. One should avoid light tization are porphyrin based, chlorophyll based ﬁeld junctions over tumor beds to minimize light Photodynamic therapy for chest wall recurrence from breast cancer inhomogeneity due to gap or overlap of the light ﬁeld is illuminated twice (e.g. ﬁeld junctions). Low- ﬁelds. This could allow for under-dosage in the tu- dose Photofrin® is very forgiving in these situations mor bed and treatment failure. Overlapping light likely due to photobleaching (see below).
ﬁelds can allow for over light dosage and severe morbidity, particularly to normal tissue. Light emit- Fluorescence
ting diodes can also be used as a substitute for the laser in the treatment of superﬁcial lesions. One ad- A major issue in any treatment is where the tar- vantage is that they can be manufactured to treat get is located. Clearly symptomatic lesions are easy a large area in one setting, making the treatment to identify and response to PDT can be accurately shorter and more comfortable to the patient. The gauged both clinically and by biopsy. Less clear are efﬁcacy of the LED as a replacement for a laser has subtle lesions and areas at risk. In these cases, been studied by Ferreira et al. (Lasers Med Sci 2004, clinical experience is required. It would be better to have a reproducible ability to detect and de- PDT reaction
It is here that most photosensitizers can shine as most photosensitizers also ﬂuoresce. By vi- sual means or by more sophisticated techniques, it While it has been demonstrated that most photo- is hoped that ﬂuorescence can be used to better de- sensitizers induce PDT by a photodynamic reaction, ﬁne treatment ﬁelds and outcome. This is an area the location of this reaction may be of clinical con- of active research, but results are preliminary. The- sequence. Photofrin® accumulates at the outer cell oretically the change in ﬂuorescence could also be membrane and upon activation may induce apopto- used as a real time dosimeter. Potentially, sensitiz- sis as well as cell death by cell membrane destruc- ers that ﬂuoresce could be used to optically biopsy tion. This may then lead to cytokine release and immune system activation. Clearly this may bene- ately and deﬁne a successful therapy without bias.
ﬁt patients with systemic disease. Other sensitizers are more selective in their location of concentra- Photobleaching
tion and may cause mitochodrial destruction lead- ing to apoptosis without systemic immune activa- Clinically, one can exploit photobleaching to en- tion since they don’t destroy the cell membrane hance tumor response and minimize normal tissue leading to cytokine release. This may well avoid toxicity Higher photosensitizer drug dose immune stimulation and have clinical ramiﬁcations appears to minimize selectivity in PDT response be- tween tumor tissue and normal tissue This may be explained by photobleaching kinetics. In clinical Dosimetry
photobleaching, as little photosensitizer as possible is employed to destroy tumor. Since sensitizers con- Ideally real time dosimetry would exist to assist in centrate to a certain degree higher in tumor than therapy. Accurate dosimetry would allow optimiza- normal tissue then one should have more PDT in tion for an appropriate light dose to destroy ma- tumor. Using as little sensitizer as possible spares lignancy with minimal or no normal tissue damage.
normal tissue by minimizing PDT at that location.
Optimally, the dosimetry system would inform the If more sensitizer is infused than needed, more will user that adequate treatment had been delivered.
go to both tumor and normal tissue. Even though No such system exists today, although progress have more sensitizer is still in tumor than normal tissue been reported on photosensitizer photobleaching enough sensitizer is still in normal tissue to create (see photobleaching section below) and other PDT signiﬁcant PDT. Therefore, by infusing as little sen- effects as an indication of treatment efﬁcacy.
sitizer as is needed to destroy tumor beds one can Therefore therapeutic decisions are made with the minimize normal tissue toxicity and enhance selec- rather empirical use of drug and light dose. This would explain why some treatments are more suc- cessful than others based mainly on clinical skill and judgment rather than accurate information. Until Reported outcomes from clinical trials
accurate dosimetry is available, clinicians will need to be highly cautious when using extremely active Photofrin®
sensitizers or, when high concentrations of less ac- tive sensitizers are employed. Low-dose Photofrin® Photofrin®, a hematoporphyrin derivative, is a can be successful even when part of the treatment member of the porphyrin family which has been was threshold for breast PDT but likely exploited dition to highly variable drug dose, light dose and photobleaching to minimize normal tissue toxic- drug to light interval time, dissimilar patient pop- ity. Since Photofrin® for breast metastasis accu- ulations also appear to exist. Complicating mat- mulates a bit more in malignancy than normal tis- ters even more, the reporting of response varies sue, the 0.8 mg/kg allows for tumor destruction, from series to series, sometimes including lesions but the 0.8 mg/kg is not enough to allow for sig- response rates, patient response, and volume re- niﬁcant PDT in surrounding normal tissue. Due to sponse among others. These varying endpoints of normal tissue morbidity found at 2 mg/kg, illumi- analysis and treatment techniques make it difﬁ- nation ﬁelds in the Roswell Park report were very cult to compare the published data. As Photofrin® tight around lesions. This led to many patients ex- has the longest history of availability, it is not sur- periencing recurrence at the rim of the illumination prising that this photosensitizer has the most clin- ﬁeld which would require additional salvage treat- ical reporting. Many of the early works included ment. Patients treated at 0.8 mg/kg on this series drug dose, light dose and drug to light interval also had very tight light ﬁelds leading to rim recur- time variations which are, based on today’s 20—20 hindsight, clearly inadequate. However, each series Based on photobleaching and the concept that added to our knowledge, and taken as a whole, 0.8 mg/kg with 150 J/cm2 were near optimal for tu- truly give us impressive insight into appropriate mor control with minimal morbidity larger illumina- tion ﬁelds were employed in a more recent publi- cation Here margins well beyond the tumor 0.6 mg/kg to 4 mg/kg for breast patients. Illumina- nodule at risk were illuminated. Rim recurrence tion has ranged from 20 to 360 J/cm2. Generally, was not generally seen and virtually all lesions were drug to light interval was about 48 h, but could eliminated. Overall, it appears that 98% of the time range to 1 week. Complicating matters further is chest wall lesions could be stopped from growing or that current micro lens construction appears more eliminated. Despite all patients having undergone amenable to therapy than older ﬁbers and may extensive surgery, high dose radiation and multiple offer more homogeneous illumination. Despite chemo-hormonal therapies, cosmetics was judged all of this, complete response rates of 100% with to be excellent. Using the same parameters, the minimal morbidity is possible. It is also possible East Carolina University (ECU) experience was re- to overdose normal tissue with drug or light and cently published Patients, including those with induce serious morbidities. These morbidities to large conﬂuent lesions, who had failed all salvage normal tissue can present with pain, ﬁbrosis, including radiation were illuminated with wide mar- scarring and altered pigmentation causing serious gins. Drug dose was 0.8 mg/kg with illumination at cosmetic concerns among others. Since most 48 h by 630 nm light at 150 J/cm2. All lesions re- patients treated for chest wall recurrence have sponded and 9 of 14 patients had total elimina- tissues injured by prior salvage, healing is of great tion of chest wall disease. Five of 14 patients had concern. That is why it is appropriate to analyze most lesions cleared, but remained with some ar- data to reveal which techniques offer the best eas of non-growing tumors and were called par- tial responders. Overall out of 500 lesions treated, In an elegant series from Roswell Park, infusions more than 90% were complete response. As all pa- of Photofrin® from 0.57 to 2.5 mg/kg with illumi- tients were followed closely, it became apparent nation from 30—350 J/cm2 at 48 h were reported that even wider margins of illumination are needed in patients with chest wall metastasis. Several pa- 244 J/cm2 light was seen. This shows a minimum tients failed beyond the edge of the illumination threshold for response. Further patients infused at ﬁeld which generally already included 2 cm mar- 2 mg/kg had much higher treatment related mor- gin. With the drug/light dose employed larger mar- bidity than patients infused with 1 mg/kg. Partic- gins of illumination were possible without addi- ularly, individuals infused at 2 mg/kg illuminated tional normal tissue toxicity. Perhaps larger mar- with light doses greater than 72 J/cm2 were at gins will be required to be illuminated to further in- greatest risk. Interestingly 6 patients infused at crease control rates. High response rates have also 0.75 mg/kg and illuminated at 140—182 J/cm2 had been reported with 2—3 mg/kg of Photofrin® and excellent response with minimal normal tissue tox- light doses of 100 J/cm2 Of note, however, icity. Similar response was also seen in patients is the signiﬁcantly higher morbidity seen includ- with high light and drug dose, but morbidity in ing wound healing difﬁculties, ﬁbrosis and treat- those patients was much more severe. This we feel ment related pain. These drug/light doses also do demonstrates a drug and light dose that not only not seem to offer the selectivity in PDT between Photodynamic therapy for chest wall recurrence from breast cancer normal and tumor tissue requiring tight illumina- and illuminated with 150 J/cm2. Interestingly ﬂu- tion borders. This would also increase the chance ence rates varied by up to 70% in the treatment ﬁeld, which may have contributed to the limited reported high normal tissue toxicity with high drug CR rates as well as morbidity This study also and/or light doses, again pointing the way toward revealed that treatment 3-h post-infusion is asso- lower drug concentrations for these particular pa- ciated with minimal selectivity and excess toxicity tients. Chemotherapy agents may interact syner- while treatment beyond 24 h was without photo ac- gistically with PDT to potentially enhance response of tumors, however, normal tissues may be sensi- tized as well leading to enhanced toxicity of normal tissues The net result may not be of clinical While many different Photofrin® drug/light dose In a phase I study of the chlorin, mono-l-aspartyl schedules can offer high tumor response, normal tissue toxicity can be signiﬁcant. Further, as der- patients with recurrent chest wall lesions who mal invasion leads to widespread disease, wide bor- failed prior salvage. In this dose—light ﬁnding study ders of illumination to seemingly normal appearing 0.5—3.5 mg/kg of Npe6 were intravenously applied but tumor-containing tissue is needed. By exploit- to the patients. Approximately 4 h later, lesions ing photobleaching, low-dose Photofrin® appears to were illuminated from 25 to 100 J/cm2 at 662 nm.
offer excellent tumor response with minimal nor- Tumor regression and eschar formation were al- mal tissue toxicity. Even heavily operated upon and ways noted, but patients always failed within this radiated ﬁelds respond well. Low-dose Photofrin® treatment ﬁeld at doses of drug ≤1.65 mg/kg. Pa- PDT has also allowed for surgical graft placement tients infused with 2.5 or 3.5 mg/kg and illumi- in a wound defect in the center of a ﬁeld sterilized nated at 100 J/cm2 allowed for 66% complete re- by PDT This clearly offers select patients even mission (CR) rate. However, at drug dose of 2.5 mg or above no normal tissue selectivity was seen For patients treated with Photofrin®, the actual in the treatment ﬁelds. While the PDT treatment illumination procedure appears relatively painless.
was tolerated all patients were photosensitive for Some series report a slight stinging towards the end of each ﬁeld illumination. Most patients have minimal post-PDT related pain as well. Overall, it appears to be a well tolerated procedure. When 2 mg/kg of Photofrin® is used, patients must main- Another chlorin family member, MTHPC, Foscan® tain direct sunlight precautions for a minimum of 4 weeks. At doses of 0.8 mg sunlight sensitization tients with chest wall recurrence underwent PDT in 11 sessions. Most patients had failed radiation, but some did not undergo radiation salvage post- mastectomy. Three patients underwent 0.1 mg/kg Lutetium texaphyrin
infusion followed by illumination at 48 h at 5 J/cm2.
Eight treatments on ﬁve patients occurred follow- Lutetium Texaphyrin (Lu-Tex), a member of the ing 0.15 mg/kg infusion with illumination at 96 h texaphyrin family of sensitizers has also been at 10 J/cm2. All illumination was at 652 nm. Nor- examined in patients with locally recurrent breast mal tissue was covered by plaster with a hole cut out for the illumination ﬁeld. Six of seven patients cluding radiation therapy, were infused with vary- had PDT related pain. This pain generally lasted ing drug doses of 0.6—7.2 mg/kg, 3—96 h prior for 2 weeks post-treatment. Narcotic analgesia was to illumination. Illumination at 732 nm generally needed for several patients. One patient, who had at 150 J/cm2 was then employed. At dose above undergone prior radiation treatment, had extreme 5.5 mg/kg, treatment could not be completed due pain develop within her radiation ﬁeld. Another pa- to pain during illumination. Dysesthesia in light ex- tient suffered photosensitivity from a reading light.
posed areas also occurred. A 27% CR was reported.
While all 89 lesions appeared to have CR it is inter- Additional patients were treated with 1—3 mg/kg.
esting to note that 4 of 7 patients needed addi- Most patients experienced pain at the treatment tional PDT due to recurrences bordering the prior site during therapy. Response rates were marginally PDT ﬁelds. This rim like recurrence appears to be better. As part of this study dosimetry was exam- due to the normal tissue toxicity noted in the illu- ined for patients infused with either 4 or 5 mg/kg minated ﬁelds requiring the physicians to treat as small a skin volume as possible. The authors report Even when introduced systemically (orally or intra- treatment areas greater than 12 cm2 cause delayed venous) ALA/PPIX has limited depth penetration. It slough off of necrotic tissue. Tissue healing time also loses a signiﬁcant amount of tumor versus nor- for areas treated greater than 12 cm2 was greater mal tissue selectivity as compared to topical appli- than 3 months. While obviously a very potent and cation. This would explain the very poor response successful treatment for chest wall patients the rates for breast metastasis, which are usually nodu- optimal use of this photosensitizer for this indi- lar Conceivably ALA could be used via a multi- cation is far from known. The very limited treat- visit regimen of repeated topical applications and ment ﬁelds possible with the drug—light doses used illumination, but would lose its convenience. It is clearly allowed for failure in skin bordering illumi- nation ﬁelds. This is not unlike some of the earlier reports on Photofrin®, where drug/light dose com- binations were employed and were not optimized.
Patients were also sunlight and dark light sensitive for 2 weeks post-infusion. This may have more qual- ity of life limitations than 4 weeks of sunlight pho- sulphophenyl porphin (TPPS4) has also been was found to be neurotoxic on systemic applica- tion. An alternate use has been by intra-lesional Purlytin
injection, without the reported neurotoxicity. In 9 patients who failed initial salvage, including Purpurins, derivatives of chlorines also have been radiation, TPPS4 was introduced into each lesion tested. Purlytin, tin ethyl etiopurpurin, was exam- at 0.15 mg or 0.3 mg via injection. Illumination ined on eight patients who had failed conventional began 45 min later at 630 nm with ﬂuence of salvage regimens including radiation The drug 150 J/cm2. Only 33% CR rates were reported with was infused at 1.2 mg/kg and illumination was un- follow-up of 6—8 months. Of note, most lesions dertaken 24 h later at 660 nm with 200 J/cm2 via required an average of 12 injections/illuminations micro lens. A complete response rate of 92% with to achieve this result. Clearly, this is not a very partial response rate of 8% was reported. No pa- convenient treatment regimen for patient or tient had lesion re-growth within the illumination ﬁelds and cosmetic results were excellent. Good wound healing without ﬁbrosis was noted. Therapy Summary of trials
was always as outpatient and with minimal discom- fort. Good selectivity was noted within illumina- tion ﬁeld. Margins of illumination of at least 1 cm The results and parameters of the clinical studies were used. No rim recurrences at the borders of the illuminated ﬁelds were seen. No sunlight pho- Photofrin® and other photosensitizers. PDT is ac- tosensitivity was reported and sunlight precautions tive and potentially has an excellent outcome as a were employed for 2 weeks post-infusion. Similar salvage tool even in heavily pretreated tissue. The good outcomes were published in case report form drug can accumulate in tissue damaged by surgery, radiation and chemotherapy. Even with illumina- tion lethal enough to destroy tumors, normal tissue can heal without intervention. Particularly note- ALA/PPIX
worthy is that the healed skin is not ﬁbrotic, and has excellent cosmetic results. It is also very clear ALA, 5-aminolaevulinic acid is a pro-drug that Photofrin®, with its long clinical history, and Introduction of ALA overloads the heme synthetic its published data for this population of patients, pathway and lead to excess Protoporphyrin IX, an can be clinically successful with minimal morbid- active photosensitizer. This member of the por- ity. While many drug/light doses can bring success, phyrin family activates around 630 nm and has had some appear to have higher side effects. Our expe- excellent response on superﬁcial malignant and rience shows that low-dose Photofrin® at 0.8 mg/kg pre-malignant skin lesions. However, ALA is gen- and illumination at 150 J/cm2 gives a reliable and erally applied as a superﬁcial cream, which while greatly convenient, is sub-optimal for nodular le- Other sensitizers are also able to offer good re- sion therapy. The wavelength of light should al- sponse, but the patient population so far exam- low for deep enough tissue penetration, but the ined is small and follow-up is short. Many of these cream itself must not be able to diffuse far enough.
sensitizers are not always commercially available Table 1 Clinical Studies for Chest Wall PDT.
Number of Number Number of Drug dose Wavelength Fluence MorbidityPhotosensitivity Follow-up Reference a Drug infusion to light illumination interval.
e Morbidity for Photofrin® includes: severe Tx pain, wound healing problems, scar; morbidity for other drugs includes: severe Tx pain, wound healing problems, scar, normal tissue ∗ 91% (465/511 lesions); 9/14 patients with CR, 5/14 with PR.
∗∗ Highly active version of photofrin, potentially equivalent to 3 mg/kg.
∗∗∗ Isolated nodules <1 cm.
∗∗∗∗ Minimal response to nodules >1 cm.
and appropriate wavelength light sources may not ﬁrst and which last. One does not want to treat be available either. Clearly, the potential for these the asymptomatic lesions, cause them to become photosensitizers to outperform Photofrin® is possi- tender, and thus prevent treatment of symptomatic ble, but has not yet been reliably shown. Only larger anatomy. With patients requiring multiple planes of multi-institutional clinical trials will be able to as- illumination and multiple anatomical regions (i.e.
chest wall, abdomen, shoulder, etc.) considerable One also should be cautious about the pa- treatment planning must be done prior to patient tient population examined. Most of the published positioning, otherwise therapy will not be able to literature was for patients with recurrent chest wall disease. However, some studies included a re-recurrent patient population. These individu- Illumination
als have undergone multiple surgeries, radiation courses, and chemotherapies. They are more likely As critical as patient positioning, and deciding susceptible to normal tissue morbidity but excel- which anatomical region is to be treated in which sequence, is the ability to deliver homogeneous il- lumination. It is important that the light source be incident to the anatomy, otherwise over and under Treatment techniques
light dosage could occur in each ﬁeld. Further, the light sources must be able to reach each anatomi- cal area, thus light source mobility and location is Patient positioning
part and parcel of patient set-up. Since it is im- portant not to overlap light ﬁelds (i.e. over illu- Unlike many patients who undergo PDT, patients minate) it is critical that accurate placement of with chest wall disease pose certain unique con- ﬁbers be maintained throughout therapy. As patient siderations. First and foremost patients generally anatomy varies dramatically it is easy to over and have numerous lesions requiring therapy. Since ide- under dose. Further, patients may move during il- ally each lesion should be treated appropriately, lumination and a means to re-position patient/and a system of identifying the lesion and ensuring it or light in real time is critical. It is also critical that is illuminated is essential. As some individuals will illumination ﬁelds not cut through or partially illu- have 50 treatment ﬁelds, memory will not sufﬁce.
minate tumor beds for this will potentially under We recommend an anatomical drawing to be used dose lesions. As palpable lesions only represent the in conjunction with patient coordinates and land- tip of the iceberg, it is also critical that generous il- marks. The suprasternal notch and tip of xyphoid lumination margins around disease be used. In con- process are easily deﬁned and can serve as refer- sideration of the added uncertainty of patient mo- ence, as can the clavicle. Surface marking by ink at tion, we suggest at least 2 cm margin. If indicated, even intervals can assist. This grid will allow for sys- following illumination, an ice patch applied to the tematic rather than haphazard treatment and avoid treatment ﬁelds while the next treatment ﬁeld is geographic misses as well as treatment of the same being illuminated will usually eliminate any acute anatomy twice by mistake. Additionally, patients who have numerous lesions will require comfort- The indications for interstitial illumination are able positioning to minimize movement during illu- unclear as the majority of reports employ only sur- mination. Since chest wall PDT is accomplished in a face illumination. Even lesions approaching 2 cm fully conscious outpatient setting we recommend a depth can be successfully treated with surface il- very comfortable treatment couch or bed. Follow- lumination when Photofrin® is employed. Photo- ing along these lines, setting up for illumination is sensitizers such as Foscan and Lutex theoretically time consuming so making the most efﬁcient use can treat even thicker lesions from the surface. In of the micro lens set-up is important. Stands that general interstitial implants are done for bulky le- allow for easy adjustment of the light are needed.
sions greater than 2 cm in depth. The implanted il- Mobile stands that can be rapidly moved and locked lumination source is usually placed at the base of into place for the next illumination are very im- the lesion, close to the skin to ensure deep light portant. Critically, patients who have widespread penetration. Implanted ﬁbers should be about 1 cm lesions may need to be turned over or around to apart. The use of small amounts of local anesthetic reach treatment sites. As PDT can give rapid ther- may help to ease placement pain. Some anesthetics apeutic outcome with treatment lesions becoming can impede blood ﬂow, which may alter photosen- very tender or weeping, one must use considerable sitizer concentration. Bleeding may absorb treat- forethought deciding which lesions will be treated Photodynamic therapy for chest wall recurrence from breast cancer Speciﬁc precautions
With ALA and Foscan® illumination all patients ex- Photosensitivity
Photofrin®. In cases where pain occurs an ice patch to the affected area generally works. Numbing the All sensitizers will offer sunlight photosensitivity skin prior to therapy has been tried, but failed.
For Photofrin® at 2 mg/kg, 4—8 weeks of We suggest patients be dispensed narcotic or non- precautions are needed. At 0.8 mg/kg we have narcotic pain pills prior to illumination to minimize found sunlight photosensitivity rare after 4 weeks.
Purlytin patients were sensitive for 2 weeks Many patients have painful chest wall lesions that impact on their quality of life. PDT is often sunlight precautions apply only to sunlight or simi- able to offer pain control via successful therapy. De- lar intense light. Patients’ skin must be covered and pending on the photosensitizer and treatment pa- wrap around sunglasses as well as a wide brim hat rameters, the actual PDT can be painless or painful.
is recommended. Reﬂected light, for example from In general excellent pain control from lesion dimin- a car window, can cause photosensitivity reaction.
ishment can be seen within 2 weeks of the PDT In general, room light is safe. Foscan® patients may session. During this time, however, we recommend be sensitive even at minimal light levels and reports continued narcotic or non-narcotic analgesia, as exist of toxicity occurring from sitting near a light bulb or ﬁreplace. As most patients with chest wall Photosensitivity reaction
recurrence have undergone multiple surgeries, ra- diation and chemotherapies, they are well versed in toxicity. We have found in our practice, that the A photosensitivity reaction occurs when normal tis- sunlight precautions have not prevented any pa- sue is exposed to enough light to activate the photo- tient from signing informed consent for therapy.
sensitizing agent As each sensitizer has its own However, if you encounter a patient unable to, or characteristic activation energy and half-life, the unwilling to accept this precaution, they should not ability to have a photosensitivity reaction is sen- sitizer dependent. In general, this reaction is sim- ilar but more rapid to develop and more intense Illumination
than a sunburn. Even a few moments of sunlight to a powerful photosensitizer such as Foscan® can induce this reaction. Patients complain of pain in Depending on the photosensitizer and its treatment the exposed area and swelling with burn can occur.
parameters, morbidity to normal tissue during illu- The severity of signs and symptoms will depend on mination is possible. Foscan® patients must have the intensity of light exposure and amount of sen- non-illuminated regions heavily blocked from scat- sitizer remaining. Treatment to each burn is rec- ter of light As this drug is so active, scattered ommended with ice/cold compress, steroids, ele- light is often enough to initiate PDT. While employ- vation and pain control. If critical structures such ing Foscan®, one must use signiﬁcant effort to en- as airway, neck, orbits, etc. are exposed and begin sure no scatter to tissue you do not wish to treat.
swelling, emergency treatment may be required, It is also very important to not overlap illumination perhaps as an inpatient. It should be emphasized ﬁelds as tissue necrosis may occur. Similarly, when that patients are photosensitive starting from infu- 2 mg/kg of Photofrin® is employed one also must be sion (not treatment). An ounce of sunlight preven- extremely careful concerning illumination overlap to prevent serious morbidity. Interestingly, likely To enhance elimination of the photosensitizer due to photobleaching, when low-dose Photofrin® from the skin one can employ the following pro- (0.8 mg/kg) is employed, no additional morbidity is cedure, if indicated. We suggest waiting at least 1 clinically noted during illumination overlap. Indeed week post-treatment to try this. The fully covered as micro lens illumination is circular and few tumor patient can carefully expose a 1 cm2 area of skin beds are circular, the ability to overlap illumination (forearm placed in a brown bag with a hole in it) at ﬁelds without undue morbidity is the great advan- sunset for a minute or two, but should pain occur, this procedure should then be abandoned. If at 24 h minimal sensitivity occurs, the patient can expose Pain control
more forearm skin for a bit longer and repeat this several more times. By progressively increasing the Depending on the sensitizers and treatment vari- amount of skin exposed to limited amounts of twi- ables, pain may or may not occur during therapy.
light sunshine, the photosensitizer can be bleached out fairly rapidly. Do not attempt this with Foscan® In sterilized ﬁelds, the rare non-healing defect and do not try it at other times of the day.
caused by very large tumors necrosing can be closed by ﬂaps. This should only be attempted by Post-treatment
All patients’ post-therapy should undergo several Retreatment
days of steroids with taper. This minimizes local re- action and swelling. Oral narcotic and non-narcotic As recurrent lesions invade dermal lymphatics, they analgesia for 1—2 weeks is generally useful, though have a propensity for wide cutaneous spread and some patients do not actually need these medica- clinical re-occurrence. The PDT literature shows tions. We suggest a 1-week course of antibiotics patients are readily able to undergo multiple treat- such as keﬂex or Augmenten. Patients are also en- ment sessions and chest wall lesions are no excep- couraged to drink plenty of liquids. Every patient tions. New lesions outside prior illumination ﬁelds must be reminded of sunlight precautions at this as well as the rarer rim progression can generally be treated with the same drug/light parameters as accomplished on the ﬁrst session. Similar good outcomes are expected. For the rarer in ﬁeld re- Patient selection
currence, more intense illumination should be con- sidered. However, it is likely that the in-ﬁeld re- This is a key issue. One must ultimately ask how lo- currence was due to under-dosage of light during cal control of the chest wall will impact patients.
the initial PDT sessions. Several reports indicate For patients with highly symptomatic chest wall le- that re-treatment is well tolerated with excellent sions, even in the face of widespread disease, an improved quality of life might be possible. How- treating patients on a case-by-case basis. Those ever, should PDT create open wounds that will not individuals with an isolated small recurrence may heal in the patient’s lifetime, no obvious beneﬁt is beneﬁt from a short course of radiation rather than to be gained. Given the natural history of recurrent PDT induced photosensitivity. Also, as normal tissue lesions to be poorly controlled and to grow, local migration is required for wound healing, one might control and symptom prevention is an important not want to re-treat until the initial PDT treatment consideration. The timing of intervention is vari- ﬁelds have virtually healed. This will prevent the able; however, larger PDT ﬁelds take longer to heal development of excessive open wounds.
as does treatment of larger lesions. It is our pref- erence to intervene with PDT prior to the patient’s back being against the wall. We have found that Conclusion
many patients will not participate in any social ac- tivity due to the physical and psychological prob- lems associated with growing, visible tumors. Suc- PDT can reliably salvage individuals with chest wall cessful PDT for these individuals is able to provide recurrence despite fragile tissues from surgical, extraordinary improvement in quality of life.
radiation and chemotherapeutic intervention. PDT can not only control chest wall recurrence, but of- fer the potential for superior cosmetic results. This Wound healing
is particularly noteworthy as these patients are all too often denied any additional salvage, and are left with daily growing reminders of their mortal- progressing non-healing lesions with sterilized wounds that can heal with excellent cosmetics Local treatment may have an impact on survival, For lesions less than 1 cm in diameter and particularly if infected open tumor wounds can be isolated, healing time is measured in weeks. Larger healed. In general survival is a function of control treatment ﬁelds can require months to heal.
of systemic spread. This is why most patients with Thicker and larger lesions often form eschars, recurrent disease, even if thought to be contained which we have found to be protective, painless and on the chest wall are initiated on systemic therapy.
infection free. It is our recommendation that PDT No study of PDT for this patient population has been ﬁelds be kept clean with as minimal intervention large enough to analyze for improved survival. Even as possible. Biopsy and wound surgery should be if PDT may not signiﬁcantly improve survival it can avoided. In virtually all cases, lesions will close and improve the quality of life by eliminating obvious heal. Time to healing is delayed by chemotherapy.
signs and symptoms of disease. PDT also offers ex- Photodynamic therapy for chest wall recurrence from breast cancer cellent pain control and by this criteria alone should based radiation. One can only hope that this review will help stimulate interest in answering these im- Even with limited dosimetry, patients with chest wall recurrence can be reliably salvaged by a va- riety of photosensitizing agents used in a variety of treatment paradigms. Each agent and treatment References
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Sommario Rassegna Stampa del 29-06-2013 29-06-2013 Il Gazzettino (Vicenza) TEATRO POPOLARE Stasera, alle 21.15, nella corte di Casa Guggin a Montecchio M., per la rassegna. . 29-06-2013 Il Giornale di Vicenza Senza titolo . 2 29-06-2013 Il Giornale di Vicenza S'inventano la rapina In tre verso il processo . 3 29-06-2013 Il Giornale di Vicenza FURTO ALL'EMISFERO GIOVANE BLOCCATA . 4 2