Photodynamic therapy: mechanism of action and role in the treatment of skin disease.

The combination of lesion ablation with excellence in cosmetic outcome has allowed photodynamic therapy (PDT) an ever increasing role in the treatment of diseases of the skin. As currently practiced, PDT employs a photosensitizing agent that when activated by light energy creates a photodynamic reaction that is cytotoxic and vasculotoxic. The relative simplicity of therapy with its ability to achieve high response rates has brought PDT to a worldwide audience not only for oncologic indications but far more commonly to non oncologic indications. This paper will review the mechanism of action for PDT and highlight the versatile clinical outcomes reported from the peer reviewed literature.

Toward endobronchial Ir-192 high-dose-rate brachytherapy therapeutic optimization.

A number of patients with lung cancer receive either palliative or curative high-dose-rate (HDR) endobronchial brachytherapy. Up to a third of patients treated with endobronchial HDR die from hemoptysis. Rather than accept hemoptysis as an expected potential consequence of HDR, we have calculated the radial dose distribution for an Ir-192 HDR source, rigorously examined the dose and prescription points recommended by the American Brachytherapy Society (ABS), and performed a radiobiological-based analysis. The radial dose rate of a commercially available Ir-192 source was calculated with a Monte Carlo simulation. Based on the linear quadratic model, the estimated palliative, curative and blood vessel rupture radii from the center of an Ir-192 source were obtained for the ABS recommendations and a series of customized HDR prescriptions. The estimated radius at risk for blood vessel perforation for the ABS recommendations ranges from 7 to 9 mm. An optimized prescription may in some situations reduce this radius to 4 mm. The estimated blood perforation radius is generally smaller than the palliative radius. Optimized and individualized endobronchial HDR prescriptions are currently feasible based on our current understanding of tumor and normal tissue radiobiology. Individualized prescriptions could minimize complications such as fatal hemoptysis without sacrificing efficacy. Fiducial stents, HDR catheter centering or spacers and the use of CT imaging to better assess the relationship between the catheter and blood vessels promise to be useful strategies for increasing the therapeutic index of this treatment modality. Prospective trials employing treatment optimization algorithms are needed.

Photodynamic therapy of the intact breast.

As breast cancer is diagnosed in over a million patients a year it is a significant oncological issue. Treatment paradigms have shifted to emphasize breast preservation protocols. However, due to a lack of equipment and facilities this option is only rarely offered to poverty stricken patients and those in the developing world. Photodynamic therapy may play a role in allowing for greater breast conservation based in part on the emerging success of partial breast radiation. This paper will review the rationale behind and technical aspects for intact breast photodynamic therapy.

PDT experience in Brazil: A regional profile.

The success of PDT and its establishment into the existent hall of therapeutic modalities depends on the collection of reported experiences from around the world. In that sense, it is important to report approaches taken by different countries and what their views are on the future of PDT. Following this idea, we present our clinical experience in photodynamic therapy (PDT) in Brazil, as well as the experimental advances coming up in parallel with clinical implementation. This report is a consequence of pioneering work in a collaborative program involving the Physics Institute in São Carlos, São Paulo State (SP), Brazil, the Medical School of the University of São Paulo, Ribeirão Preto, SP, Brazil and the Cancer Hospital Amaral Carvalho, Jaú, SP, Brazil. This collaborative program, begun in 1997, with the first patient treated in 1999, has treated over 400 patients by late 2004. About 80% of lesions were located in the head and neck or skin, but experience is being built in esophagus, bladder, gynecology, and cutaneous recurrence of breast cancer, among others. The overall results have shown to be compatible with previously reported data. Modifications, whose goal is to improve patient benefit and optimize results, are being implemented as we gain experience. In parallel with the clinical development, several laboratories have started studying experimental whose purpose is to analyze the clinical results and to contribute to the worldwide effort to bring PDT to the forefront of therapies offered to patients. We present the overall results of our 5 years experience as well as the whole implementation process.

Clinical photodynamic therapy of head and neck cancers-A review of applications and outcomes.

As local control is tantamount to cure in head and neck cancer, an aggressive regimen of surgery and radiation remains the standard of care for most patients. Despite significant technical advances, these treatments are highly morbid. Further, patients who fail treatment have limited salvage options. Photodynamic therapy (PDT) and photodiagnosis (PD) of head and neck cancer offer significant potential for improved outcomes in a myriad of clinical indications ranging from in situ to recurrent disease. However, despite promising results, these modalities remain at the fringe of head and neck treatment options. Photofrin(®), Photosan and Foscan(®) are photosensitizers used clinically in head and neck PD/PDT. In addition, aminolevulinic acid (ALA), which gives origin to Protoporphyrin IX, an endogeneous photosensitizer, is also used for PD/PDT. We review the clinical literature on these photosensitizers to assist in the integration of these important modalities into the mainstream of head and neck oncological therapy.

PD/PDT for gynecological disease: A clinical review.

The evolution of diagnostic and interventional procedures for gynecologic disease has led to organ, sexual and reproductive sparing treatments. Photodiagnosis (PD) and photodynamic therapy (PDT) may play a great role for gynecological patients as both offer the potential to achieve these goals. PD/PDT for a wide variety of diagnostic and therapeutic interventions have shown potential for excellent clinical outcomes. However, significant limitations remains, both clinically and dosimetrically, that prevent consistent results. When those limitations are resolved PD/PDT could move to the forefront of gynecological therapy. This clinical review highlights the outcomes and shortcomings of PD/PDT through the peer reviewed literature for gynecological sites.

Radiation and chemotherapy improve outcome in oligodendroglioma.

PURPOSE: Oligodendroglioma is a rare central nervous system tumor which may occur in pure or mixed histology. This scarcity results in difficulty in defining optimal management, mainly due to a lack of outcome analysis. Results are further complicated because the reported series include patients treated before megavoltage radiation or computed tomographic (CT) scan development. This makes extrapolation of outcome difficult to apply to modern-era patients. We report results obtained by current treatment and evaluation. METHODS AND MATERIALS: Outcome of all 38 patients (age 5-70 years) pathologically diagnosed between 1975 and 1993 were reviewed. Pure lesions were seen in 14 cases, of which three were anaplastic. The remainder had mixed tumors, of which six contained anaplastic astrocytic elements. Each patient had undergone maximal debulking surgery, but all remained with residual disease on postoperative CT. RESULTS: For nonanaplastic lesions, no local failure was seen in any patient receiving postoperative radiation (60 Gy) and chemotherapy (vincristine, procarbazine, and carmustine). Follow-up ranged from 28 to 240 months (median 125; N = 6). No postoperative therapy or chemotherapy alone resulted in local failure in all nine patients at risk [time to failure (TTF): 2-40 months; median 25]. Radiation alone in doses of 50 Gy at 2 Gy per day resulted in all six patients failing (TTF: 12-52 months; median 36). Achieving 60 Gy at 2 Gy a day allowed five of eight patients to remain disease free (disease-free survival: 24-160 months; median 66), with three failing at 26, 40, and 60 months. All lesions containing anaplastic elements underwent postoperative radiation therapy (60 Gy) and chemotherapy, with five of nine patients alive and well (median disease-free survival: 48 months; range 28-120). CONCLUSION: The combination of radiation and chemotherapy increases local control of oligodendroglioma whether they contain pure, mixed, or anaplastic histology. Radiation alone may offer good local control as long as 60 Gy is delivered. Chemotherapy alone appears to delay TTF and may be useful for pediatric patients.

If you 'watch and wait,' prostate cancer may progress dramatically.

PURPOSE: Observation has been proposed as an option for localized prostate cancer. However, most series reporting on 'watch and wait' include patients treated by TUR or hormones that may affect results. We retrospectively reviewed the natural history of truly untreated prostate cancer and report the outcome for these patients. METHODS AND MATERIALS: From 1976 to 1992, 34 patients of median age 70 years (range 56-88) with biopsy proven localized adenocarcinoma of the prostate refused therapy. All had negative bone scan and none underwent TUR or hormone treatment. No patient was lost to follow-up (median 76 months). Failure patterns and survival were analyzed. RESULTS: At diagnosis 27 patients had palpable nodules (T2), of which 13 were well differentiated and 14 moderately differentiated. Seven had moderately differentiated T3 lesions. Mild prostatitis including nocturia, hesistancy, and urgency were reported in 16 T2 and 6 T3 patients. Within 36 months, local progression requiring therapy occurred in all T3, all T2 moderate and 5 of 13 T2 well-differentiated patients. Systemic progression occurred in 6 of 7 T3, 9 of 14 T2 (mod), and 2 of 13 T2 (well) patients. Overall 59% are alive, 26% succumbed to prostate carcinoma and 15% to other causes. CONCLUSION: Observation results in a high rate of local progression requiring intervention (77%) and excessive systemic disease development (50%) for patients with clinically palpable disease. Perhaps this strategy is viable for earlier stage lesions detected by PSA but it must be tested in a rigorous fashion before accepted.

Clinical PD/PDT in North America: An historical review.

The healing properties of light have been appreciated for thousands of years. However, the harnessing of light energy to create a rigorous and reliable means to diagnose and treat human disease is only a relatively recent phenomenon. Despite outstanding results from ancient history and subsequent reemergence and refinement of this knowledge over the last 100 years, it took again the hand of serendipity to open the modern age of Photodiagnosis and Photodynamic Therapy. Based on the prescience and perseverance of a handful, the under appreciated observations of tumor fluorescence and photodynamic action have been brought to a worldwide audience. This review highlights the development of clinical Photodiagnosis and Photodynamic Therapy, emphasizing the significant events and milestones taking place in North America.

Photodynamic therapy for chest wall recurrence from breast cancer.

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 excellent 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 universally 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 breast cancer.

Photodynamic therapy for the treatment of nonmelanomatous cutaneous malignancies.

Photodynamic therapy (PDT) is a modality whose concept is not new to dermatologists. PDT has gained regulatory approval in the United States for the treatment of esophageal and lung malignancies. The field has grown over the last decade, and now phase II/III clinical trials using second generation drugs for the treatment of nonmelanoma skin cancers, palliation of metastases to the skin, and Kaposi's sarcomas have been introduced. These new sensitizers tend to reduce the one side effect of PDT, namely persistent generalized cutaneous photosensitivity. PDT has shown efficacy in (1) patients who have failed conventional therapies, and for whom local treatment options are limited (2) patients in whom surgery would result in cosmetic disfigurement, and (3) patients prone to developing multiple lesions as in Gorlins syndrome. Dosimetry is based on well-understood treatment matrices that have optimized light delivery with known photosensitizer administrations. The advantages of PDT for cutaneous malignancies include the ability to treat numerous lesions in one setting, in a noninvasive manner without any apparent concern for the development of carcinogenicity.

Bio-nanotechnology and photodynamic therapy--state of the art review.

Photodynamic therapy (PDT) and bio-nanotechnology (NT) show striking similarities in clinical design and mechanistics. The PDT paradigm of photosensitizer application, light activation and singlet oxygen generation does in fact occur on the nanoscale level as does the resultant outcomes. NT has the ability to explain as well as modify each of the critical steps of PDT particularly photosensitizer design and delivery, light source miniaturization and optimization, location and intensity of the photodynamic reaction as well as offering a far greater insight into dosimetry and mechanisms of action. This review will explore the current and potential future interactions and modifications NT may have on PDT.

Multimodality salvage for patients with persistently elevated postprostatectomy PSA.

A persistently elevated postprostatectomy prostate-specific antigen (PSA) is a therapeutic dilemma for which optimal management is undefined. We evaluated the salvage efficacy of whole-pelvis radiation with hormonal blockade in a subset of patients with persistently elevated postprostatectomy PSA. Within 180 days after surgery, 14 men with elevated postprostatectomy PSA (0.9-18 ng/ml; mean 4.8) and negative metastatic work-up began whole-pelvis radiation (4500 cGy / 25 fractions), which was directly followed by prostate-bed boost (2000 cGy / 10 fractions). Concomitant with radiation, 6 months of LHRH agonist was prescribed. No patients have been lost to follow-up. Chronic morbidity from radiation and hormone treatment was not noted and all 10 patients whose salvage was initiated when PSA was <5.0 ng/ml remain with undetectable PSA at follow-up (36-56 months; median 44 months). Of the four patients with PSA levels >5.0 ng/ml at salvage initiation, none remain with undetectable follow-up PSA. Postprostatectomy salvage initiated at PSA levels < or =5.0 ng/ml with the combination of whole-pelvis external-beam radiation and hormone blockade offers excellent diminishment of PSA for prolonged follow-up periods. Patients with postprostatectomy PSA of >5 ng/ml likely require salvage regimens with greater emphasis on systemic treatment. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 331-335 (2000).

Stereotactic neurosurgical biopsy is an underutilized modality.

The objective of this study was to ascertain if stereotactic neurosurgical biopsy (SNB) optimizes the therapy of undefined CNS masses. The design was of retrospective treatment and outcome analysis and the setting was a large general hospital. We studied a total of 141 patients with undefined, space-occupying CNS lesions detected between 1991-1997, with whom we used SNB to define the lesions. We sought to correlate empiric and histological diagnostics and their impact on medical management. The stereotactic biopsy produced a diagnostic yield for each patient. Management was altered in 57 cases (40%) due to histology and, of these, malignancy was found in 39. Morbidity was ten asymptomatic hemorrhages on post-biopsy CT scans and two cases of clinical deterioration. Our conclusions were that SNB produces high yield with low morbidity. In the community setting, a wide variety of diagnoses can be made with improvements in medical management. SNB should be employed to guide therapy of CNS lesions where complete excision is not possible or when diagnostic questions arise.

Response of primary colon cancer cells in hybrid spheroids to 5-fluorouracil.

We have measured the clonogenic survival of cells isolated directly from colon cancer surgical specimens and treated with 5-fluorouracil (5-FU). Enzymatically disassociated cells were incorporated into hybrid spheroids, consisting predominantly of nonproliferating HeLa feeder cells. Aliquots were exposed for 1.5 hr to a range of concentrations of 5-FU. From the decrease in clonogenic survival, as deduced from the frequency of colony formers among hybrid spheroids after chemical treatment, we were able to construct survival curves in 50% of the surgical specimens tested. A striking revelation was the presence of a resistant plateau in the survival curves, reminiscent of the solid tumor response to treatment with 5-FU. This resistance was absent in monolayer cultures. Evidence is presented that this resistance is due to the absence of, or delay in, cell cycle progression of cells residing in hybrid spheroids.

Symptomatic acute mucositis can be minimized or prophylaxed by the combination of sucralfate and fluconazole.

Mucositis is a common and often serious acute morbidity when radiation is delivered to portals encompassing the oral cavity, pharynx, or esophagus. In an effort to minimize this side effect, the combination of sucralfate and fluconazole was prescribed to 40 patients. Half were given sucralfate, 1 g in suspension q.i.d. from the first week to the completion of radiation with fluconazole 100 mg., q.d. for 14 days initiated during the fourth week. The remaining individuals were placed on the same dosages of the two drugs dispensed simultaneously after symptoms appeared. For both cohorts the combination of sucralfate and fluconazole was effective in diminishing oral discomfort and pain associated with radiation and chemotherapy. When medication was delivered from the first week of therapy, all patients could achieve the prescribed radiation dose without treatment interruption and be maintained on a regular diet. The combination of drugs was also effective in minimizing symptoms once they appeared.