Effect of photodynamic therapy on recurrent pituitary adenomas: clinical phase I/II trial--an early report

Pituitary adenomas, although histologically benign, are not always curable by surgery alone, principally because of dural infiltration, as well as their peculiar anatomical location. Radiotherapy has been employed as an adjuvant therapy to address residual disease with favourable results. This approach is, however, not without side effects, and it cannot be repeated. We are therefore investigating the effectiveness of photodynamic therapy (PDT) on recurrent pituitary adenomas in humans. This study details the protocol applied to 12 patients with recurrent pituitary adenomas, which involved systemic administration of photosensitizer (Photofrin) followed, after a period of 24-48 h, by intraoperative illumination of the tumour bed using 630 nm laser light. The primary end points were visual, endocrine and radiological improvement. The incidence of side effects was also monitored. The longest follow-up is 2 years. Most patients suffering from visual acuity or field defects have shown improvement when followed for 12 months or more. Three patients showed complete recovery of their visual fields. All those who presented with functional adenomas have shown reduction in their hormone levels. Tumour volume, relative to the preoperative size, was 122, 87, 66, 60 and 46% at 4 days, and 3, 6, 18 and 24 months, respectively. One patient developed severe skin photosensitization due to early exposure to direct sunlight and three others displayed minor skin reactions. There was no treatment-related mortality or morbidity. One patient (operated transcranially) developed hemiparesis postoperatively, which recovered completely. We think this is unrelated to the treatment. This prospective study demonstrates that PDT may be safely applied to the pituitary fossa by the trans-sphenoidal route and indicates the need for a randomized, controlled trial in order to establish its therapeutic potential.     

A preliminary experimental in vivo study of the effect of photodynamic therapy on human pituitary adenoma implanted in mice

As surgery alone may prove inadequate to effect a cure for invasive pituitary adenomas, photodynamic therapy (PDT) was investigated as a possible adjuvant treatment for this group of tumours. Different subtypes of human pituitary adenoma cells were implanted subcutaneously into nude mice to study the in vivo effect of PDT on such lesions. The photosensitizer used in this study was polyhaematoporphyrin at a dose of 10 mg/kg b.w., followed by light irradiation at a wavelength of 630 nm with varying light doses between 10 and 75 J/cm2. Histopathological examination of the treated implants consistently showed tumour vascular changes with acute inflammatory reaction, interstitial haemorrhage, and evidence of cell death at higher doses of light. These changes were absent in the control groups. These findings indicate that the cytotoxic effect of PDT demonstrated in vitro in previous studies, is also present in vivo.     

Neo-adjuvant hormonal therapy

Abstract:  Neo-adjuvant endocrine therapy has opened new alternatives for locally advanced breast cancer. Such therapy, which has permitted us to expand the treatment role of neo-adjuvant therapies, may be of great benefit to patient groups such as the elderly, those not suited for chemotherapy, and those whose response may not be optimal. This therapy also may be able to help us identify agents that could improve outcomes in the adjuvant setting as well as possible biologic predictors for outcome. The latest generation of endocrine therapy for breast cancer, aromatase inhibitors, has proved superior to tamoxifen in terms of toxicity and efficacy in the adjuvant setting and is currently being studied in other clinical trials. Current findings indicate that these agents are less toxic and better tolerated than neo-adjuvant chemotherapy and that third-generation anti-hormomal therapy offers improved tumor response compared with tamoxifen, which has resulted in increased breast conserving surgery. Biomarker findings of improved response in tumors that are both estrogen receptor positive and HER-2 positive as well as progesterone receptor positivity only will be important for planning future selective treatment and clinical trials.     

Selective necrosis in hamster pancreatic tumours using photodynamic therapy with phthalocyanine photosensitization.

Photodynamic therapy (PDT) is often thought to be able to effect selective tumour necrosis. This therapeutic selectivity, based on transient differences in tumour: normal tissue photosensitizer concentration ratios, is rarely useful clinically in extracranial tumours, although PDT itself may be of value by virtue of the nature of the damage produced and healing of normal tissue by regeneration. This report describes the effects of PDT on normal pancreas and chemically induced pancreatic cancers in the hamster, where a different mechanism of selective necrosis may be seen. Photosensitizer distribution in normal and neoplastic pancreas was studied by chemical extraction and fluorescence microscopy. Correlation of distribution studies with necrosis produced by PDT shows that the photodynamic dose (product of tissue concentration of sensitizer and light dose) threshold for damage is seven times as high for normal pancreas as for pancreatic cancer. Tumour necrosis extended to the point where tumour was invading normal areas without damaging the normal tissue. In rat colonic cancer, photodynamic dose thresholds in tumour and normal tissue are similar and so such marked selectivity of necrosis is not possible. The reason for this selectivity in the pancreas is not clear, but recent evidence has suggested a difference in response to PDT between normal and neoplastic pancreatic cell lines and the presence of a singlet oxygen scavenger in normal pancreas is postulated. Furthermore, the present fluorescence microscopy studies suggest that tumour stroma contains the highest level of photosensitizer and thus receives the highest photodynamic dose during PDT. These results suggest a possible role for PDT in treating small pancreatic tumours or as an adjuvant to other techniques, such as surgery, that reduce the main bulk of tumours localized to the pancreas.     

Vascular and other non-tumour applications of photodynamic therapy

Photodynamic therapy is being investigated as a cancer therapy. As a cytotoxic treatment, it may also have therapeutic benefits in certain non-tumour conditions. The mechanism of photodynamic therapy is discussed in relation to its cancer therapy. The literature on non-tumour applications of photodynamic therapy is subsequently reviewed, highlighting its vascular applications in particular.Arterial angioplasty restenosis has proved resistant to all treatments tried thus far. Because fibrocellular intimal hyperplasia arising from the proliferation of vascular medial smooth muscle cells forms the pathological basis of restenosis, photodynamic therapy has been considered in its prevention. The literature on two second-generation photosensitizers (5-aminolaevulinic acid and phthalocyanine) which are likely to achieve clinical application are reviewed with regard to their photodynamic effects on fibrocellular intimal hyperplasia.This review concludes that photodynamic therapy shows enough promise for the inhibition of fibrocellular intimal hyperplasia for large animal studies to be pursued.     

胃肠道肿瘤的光动力治疗及其进展

光动力疗法是一种新型的肿瘤治疗方法,与传统治疗比,其优势在于高选择性和低毒性。目前光动力疗法已用于胃癌、结直肠癌、肛管鳞癌等胃肠道肿瘤,且部分患者疗效显著,但仍缺少大样本量的临床随机对照研究。笔者就近年来国内外光动力疗法治疗胃肠道肿瘤的文献进行综述,为临床治疗及科研提供参考。     

Photodynamic therapy.

The preliminary data suggest that red-light whole-bladder photodynamic therapy is safe and effective in the treatment of Tis and may be useful in the prophylactic management of superficial bladder cancer. Theoretically, whole-bladder photodynamic therapy has the advantage of higher efficacy after a single treatment than most conventional modalities for superficial bladder cancer. In patients with Tis, the complete response rate is 88%, and 25% have recurrences during a mean follow-up of 20 months (range 12-60). In patients undergoing prophylaxis, the recurrence rate is 31% and the median time to recurrence is 18 months. Importantly, none of the high-risk patients treated with whole-bladder photodynamic therapy has developed disease progression in stage or grade at the time of recurrences. Whole-bladder therapy also has the potential advantage of repeat treatment without increased tumor resistance or increased morbidity. Data from the present phase II-III clinical trials involving a large number of patients will define the role of photodynamic therapy in the management of superficial bladder cancer.     

Effect of radiation therapy and Photofrin® on tissue response in a rat model

Treatment of advanced carcinomas of the head and neck may benefit from adjuvant photodynamic therapy and brachyradiotherapy. To date, however, there has been no controlled study to evaluate whether high-dose irradiation can be safely accomplished without major tissue reaction in the presence of high circulating doses of Photofrin, the photosensitizing agent used in photodynamic therapy. Thirty adult male white rats were involved in the study. Fifteen rats received Photofrin 5 mg/kg intravenously, and 15 rats received the same volume of sterile saline intravenously. At 48 hours following injection, each rat received 1,000 cGy of radiation to a 3 × 5 cm area of dorsal skin using a cobalt linear accelerator unit. Skin changes postradiation were observed for degree of erythema, blistering, necrosis, and sloughing. Five rats from the Photofrin and control radiation groups were sacrificed on days 2, 7, and 21 postradiotherapy. Skin changes in each animal were identical with mild erythema lasting from 10–14 days postradiotherapy. There was no evidence of blistering, necrosis, or sloughing of skin in any of the animals studied. Histologic evaluation of the irradiated skin after sacrifice demonstrated no difference between the Photofrin and saline-irradiated groups. As well, the histologic recovery from acute radiation injury was also identical. This controlled study demonstrates that radiation therapy may be safely administered without increased morbidity when tissue concentrations necessary to perform photodynamic therapy are present. © 1993 Wiley-Liss, Inc.     

Porfimer sodium photodynamic therapy for management of Barrett's esophagus with high-grade dysplasia

Porfimer sodium photodynamic therapy (ps-PDT) for Barrett's esophagus is a powerful endoscopic treatment that can eliminate high-grade dysplasia (HGD) and Barrett's mucosa and reduce the risk of development of cancer in these patients. Ps-PDT typically results in destruction of Barrett's esophagus in the majority of the treated area. However, residual small island of Barrett's mucosa may persist after PDT. Therefore, adjuvant thermal ablation should be available during follow-up endoscopies for ablation of residual islands of Barrett's mucosa. PDT should be applied concurrent with effective proton pump inhibitor therapy. This article provides a practical guide for application of porfimer sodium balloon PDT for management of Barrett's esophagus with HGD. Recommendations are provided for patient selection and screening, delivery of PDT to include light dosimetry, methodology for follow-up endoscopies, as well as discussing the potential side effects and complications.     

Systemic therapy of renal cell carcinoma

Systemic therapy of metastatic renal cell carcinoma has completely changed in the last 5 years. Although a cure for the disease is still not achieved with systemic treatment in the majority of cases immunotherapy is no longer used. The therapeutic regiments are mainly based on angiogenic inhibitors such as sunitinib, sorafenib, pazopanib, everolimus and temsirolimus as well as the combination of bevacizumab with interferon. This article gives an overview of these treatment options and the clinical setting for their usage. To achieve a prolonged progression-free survival, a continuous therapy based on the new drugs is necessary. The major goal of the treatment remains to keep the disease stable as complete remission is only seen in 2-4% of cases. With these lengthy treatment regimes a schedule for sequenced administration of drugs is necessary for most of the patients. The optimal treatment sequence is unknown and should be chosen based on the individual course of the disease and the side effects as well as comorbidities. The role of neoadjuvant and adjuvant therapies remains unclear.     

Laser therapy of colorectal carcinoma.

A plethora of literature is available demonstrating the efficacy of Nd:YAG laser therapy for obstructing or bleeding colorectal cancers. The in-hospital mortality and morbidity rates can be reduced when Nd:YAG laser therapy is used to avoid operative diversion prior to resection and anastomosis. The Nd:YAG laser used to control bleeding or obstruction in those patients with either widely metastatic or unresectable locoregional disease has been successful in the majority of patients and has been associated with minimal morbidity and mortality rates. This laser may be the only treatment modality that may substitute for operative diversion in hopeless clinical situations such as hemorrhage or obstruction in patients with advanced disease. The utility of photodynamic therapy for colorectal cancer will require definition in further controlled trials.     

Radiation therapy and photodynamic therapy for biliary tract and ampullary carcinomas

The purpose of radiation therapy for unresectable biliary tract cancer is to prolong survival or prolong stent patency, and to provide palliation of pain. For unresectable bile duct cancer, there are a number of studies showing that radiation therapy is superior to the best supportive care. Although radiation therapy is used in many institutions, no large randomized controlled trials (RCTs) have been performed to date and the evidence level supporting the superiority of this treatment is low. Because long-term relief of jaundice is difficult without using biliary stenting, a combination of radiation therapy and stent placement is commonly used. As radiation therapy, external-beam radiation therapy is usually performed, but combined use of intraluminal brachytherapy with external beam radiation therapy is more useful for making the treatment more effective. There are many reports demonstrating improved response rates as well as extended survival and time to recurrence achieved by this combination therapy. Despite the low level of the evidence, this combination therapy is performed at many institutions. It is expected that multiinstitutional RCTs will be carried out. Unresectable gallbladder cancer with a large focus is usually extensive, and normal organs with high radio sensitivity exist contiguously with it. Therefore, only limited anticancer effects are to be expected from external beam radiation therapy for this type of cancer. The number of reports on ampullary cancer is small and the role of radiation therapy in this cancer has not been established. Combination treatment for ampullary cancer consists of either a single use of intraoperative radiation therapy, postoperative external beam radiation therapy or intraluminal brachytherapy, or a combination of two or three of these therapies. Intraoperative radiation therapy is superior in that it enables precise irradiation to the target site, thereby protecting adjacent highly radiosensitive normal tissues from irradiation. There are reports showing extended survival, although not significant, in groups undergoing intraoperative or postoperative radiation therapy compared with groups without radiation therapy. To date, there are no reports of large RCTs focusing on the significance of radiation therapy as a postoperative adjuvant treatment, so its usefulness as a postoperative adjuvant treatment is not proven. An alternative treatment is photodynamic therapy. There is an RCT demonstrating that, in unresectable bile duct cancer, extended survival and improved quality of life (QOL) have been achieved through a combination of photodynamic therapy and biliary stenting, compared with biliary stenting alone. Results from large RCTs are desired.     

Photodynamic therapy in the management of malignant gliomas: a review

Interest in photodynamic therapy in the treatment of malignant gliomas began in the 1950s. Following the publication of papers showing that haematoporphyrin was excluded from the intact blood-brain barrier and that glioma cells grown in culture and subcutaneously could be killed by a combination of light and haematoporphyrin, a number of clinical trials was started, none of which has shown any measurable improvement in patient survival. The reason for this may relate to a lack of understanding of the mechanisms of photodynamic therapy and a lack of the scientific data needed to optimize photodynamic selectivity. This review discusses the potential role of photodynamic therapy in glioma treatment, and reviews the current clinical and experimental work in the field.     

An in vitro study of the effect of photodynamic therapy on human meningiomas.

Despite being benign CNS tumours, meningiomas are not always curable and the likelihood of recurrence depends upon the completeness of initial removal. Adjuvant therapy for incompletely resected meningiomas is generally unsatisfactory and such lesions continue to pose difficult management problems. Photodynamic therapy (PDT) has been employed in the management of recurrent cerebral gliomas but its activity against meningiomas has not been specifically studied. An in vitro study of the effects of PDT against a variety of meningiomas was therefore conducted. It was found that PDT using haematoporphyrin derivative as a photosensitizing drug showed dose-dependent activity against a variety of histological subtypes of meningioma. The activity of PDT against meningiomas should be investigated further and may eventually provide a useful form of adjuvant therapy for incompletely resected lesions.     

Role of photodynamic therapy in unresectable esophageal and lung cancer

The incidence of esophageal cancer has increased dramatically in the Western population in the last two decades. Many of these patients tend to present late in the disease course with symptoms of dysphagia and malnutrition. Thus a majority of patients at presentation may require palliation of their symptoms. Lung cancer is the most common cause of cancer related mortality in the United States. Similar to esophageal cancer, many patients present in advanced stages where surgical resection for cure may not be an option. Endobronchial obstruction from both primary and metastatic neoplasm causes significant morbidity. The modalities, which are currently available for palliation of symptoms include surgery, photodynamic therapy, dilation, external beam radiation, stents, Nd:YAG laser therapy, and brachytherapy. Each of these modalities has their specific advantages and drawbacks. In this article, we discuss the role of photodynamic therapy in the palliation of esophageal and lung cancer.     

胃肠间质瘤在靶向治疗时代面临的挑战

虽然靶向药物治疗延长了胃肠间质瘤fGIST）患者的生存期．但在治疗方面仍存在一些困难与争议：（1）伊马替尼辅助治疗时间仍有争议：（2）c—kit外显子9突变、野生型患者辅助治疗是否获益亦尚未确定：（3）转移性GIST患者酪氨酸激酶抑制剂与手术的合理结合能否改善预后．仍缺乏前瞻性随机对照研究;（4）舒尼替尼治疗相关不良反应中的患者教育与密切监测、东西方GIST人群种族与体质量的差异对给药方式的影响以及伊马替尼与舒尼替尼耐药后的治疗选择等均面临挑战：（5）kit下游基因是否能成为新的治疗觏点以及多个靶点药物的联合应用仍存在较多困难。本《通过剖析这些问题,以期达成共识并寻求未来发展方向。     

Adjuvant therapy for locally advanced gastric cancer

D2 gastrectomy is now the globally accepted surgical standard for locally advanced gastric cancer. However, since 2000, different evidence has emerged regarding the efficacy of adjuvant chemoradiation, perioperative adjuvant chemotherapy, and postoperative chemotherapy for locally advanced gastric cancer. This review summarizes the background, current status, and future perspectives of adjuvant therapy for locally advanced gastric cancer. The Intergroup 0116 study was the first to show the significant overall survival benefits of adjuvant (chemoradiation) therapy for gastric cancer. The second study was the MAGIC trial, which showed the efficacy of perioperative adjuvant chemotherapy. Although the findings from the Intergroup 0116 study and the MAGIC trial were positive, recent studies, such as the ARTIST and EORTC 40954 studies, found no survival benefit for patients who had undergone D2 gastrectomy for gastric cancer. Regarding the adjuvant chemotherapy strategy, two pivotal phase III trials: the ACTS-GC and the CLASSIC, demonstrated the efficacy of postoperative adjuvant chemotherapy following D2 gastrectomy. However, more intensive chemotherapy is necessary to improve the survival rate. Several studies have analyzed the effectiveness of molecular-targeted therapy against metastatic gastric or gastroesophageal junction carcinoma. Further studies should focus on the survival benefit of more-intensive adjuvant therapy with D2 resection, or with concurrent molecular-targeted therapy.     

Safe use of pulse oximetry during verteporphin therapy

IMPLICATIONS: Pulse oximetry may produce skin damage after the administration of photosensitizing chemotherapeutic drugs. Surgery must often be performed in near darkness during photodynamic therapy. Limiting the duration of pulse oximetry and rotating sites allowed successful use of pulse oximetry in a long anesthetic during which verteporphin was administered.