Bizhan Micaily

Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma.

Complete responses lasting from 4 to 14 years were documented in 65 of 331 (20%) patients with cutaneous T cell lymphoma treated with topical mechlorethamine (HN2) between 1968 and 1982. Such long-lasting remissions occurred most often, but not invariably, in patients with patch or plaque phase mycosis fungoides without palpable lymphadenopathy (stage Ia or Ib). The likelihood of a continuous remission was enhanced by initiation of treatment before an unequivocal pathologic diagnosis. Despite the long-lasting responses in these patients, however, relapses have been documented in 11 (17%) of these patients, and all relapses occurred within 8 years of discontinuing maintenance topical chemotherapy. Thus, in our experience, a continuous remission lasting 8 or more years provides evidence that cutaneous T cell lymphoma can be eradicated by aggressive topical chemotherapy. This circumstance was observed in 35 patients, representing a cure rate of at least 11% overall. In addition, when compared with the general population of the United States, patients who received topical HN2 were at an 8.6-fold and a 1.8-fold increased risk for the development of squamous cell carcinoma and enhanced for Hodgkins disease and colon cancer but not for systemic cancers known to be induced by systemic administration of alkylating drugs. These results compare favorably with experiences with topical HN2 chemotherapy at other centers but raise questions about the risks associated with long-term administration for maintenance of remissions.

Plaque radiotherapy for retinoblastoma ☆: Long-term tumor control and treatment complications in 208 tumors

OBJECTIVE To evaluate the clinical factors predictive for tumor recurrence and treatment complications in a large series of children who underwent plaque radiotherapy for retinoblastoma. DESIGN Retrospective, noncomparative case series. PARTICIPANTS The participants included 141 children with retinoblastoma who were managed on the Oncology Service at Wills Eye Hospital with plaque radiotherapy between July 1976 and June 1999. MAIN OUTCOME MEASURES Tumor recurrence and treatment complications. RESULTS There were 208 tumors managed with plaque radiotherapy. The mean patient age at plaque treatment was 19 months. Prior treatment to the retinoblastoma of concern was delivered to 148 tumors (71%) and included various combinations of treatments such as intravenous chemoreduction, external beam radiotherapy, laser photocoagulation, thermotherapy, and cryotherapy. For 72 retinoblastomas (35%), more than one therapeutic method had failed to achieve tumor control before the use of plaque radiotherapy. Of the 208 retinoblastomas managed with plaque radiotherapy, Kaplan-Meier estimates of tumor control were 83% at 1 year and 79% at 5 years. Of the 60 tumors treated only with plaque radiotherapy (primary treatment), recurrence at 1 year was 12%. Of the 148 tumors treated after failure of other methods (secondary treatment), specific Kaplan-Meier estimates of tumor recurrence at 1 year was detected in 8% of tumors previously treated with chemoreduction, 25% of tumors previously treated with external beam radiotherapy, 34% tumors previously treated with both chemoreduction and external beam radiotherapy, and 8% of tumors previously treated with laser photocoagulation, thermotherapy, or cryotherapy (methods other than chemoreduction and external beam radiotherapy). Using multivariable analysis, the risks for tumor recurrence included the presence of tumor seeds in the vitreous, presence of subretinal tumor seeds, and increasing patient age. Using Kaplan-Meier estimates, radiation complications at 5 years of follow-up included nonproliferative retinopathy in 27%, proliferative retinopathy in 15%, maculopathy in 25%, papillopathy in 26%, cataract in 31%, glaucoma in 11%, and scleral necrosis in 0%. CONCLUSIONS Plaque radiotherapy for retinoblastoma provides tumor control in 79% of cases at 5 years of follow-up. It is particularly useful for those tumors that fail treatment with chemoreduction, laser photocoagulation, thermotherapy, and cryotherapy. Tumors in young patients without vitreous or subretinal seeding show the best long-term control.

Extracorporeal Photopheresis and Recombinant Interferon Alfa 2b in Sezary Syndrome: Use of Dual Marker Labeling to Monitor Therapeutic Response

The purpose of this pilot study was to evaluate the role of recombinant interferon alfa 2b (rIFN-a) as adjunct immunomodulatory therapy in patients with Sezary syndrome who were considered unlikely to respond to ExP alone. Six patients were treated with rIFN-a in doses ranging from 3 to 20 million units three times weekly in addition to two consecutive photopheresis treatments every 4 weeks. In addition, to better measure the effect of treatment on circulating neoplastic T-cells, cryopreserved lymphocytes were studied by two-color immunofluorescence and flow cytometry, using anti-CD4 combined with anti-CD29, anti-CD45RA, or anti-CD7. Minimal clinical improvement was observed in 4 patients treated with low doses of rIFN-a (3 to 5 million units TIW), and the response was sustained in only 1 patient. However, a clinically significant and sustained improvement did occur in 1 patient after the dose of rIFN-a was increased (20 million units TIW). Although the encountered toxicity profile from combined ExP/rIFN-a therapy was similar to that expected for ExP or comparable doses of rIFN-a given separately, treatment was discontinued in 2 patients because of adverse effects. Three antibody pairs, i.e., CD4+CD7-, CD4+CD29+, and CD4+CD45RA- subsets, appeared to be useful to monitor changes in blood Sezary cells during treatment. We conclude that the combination of ExP and low doses of rIFN-a does not appear to be effective for patients with advanced Sezary syndrome in this small patient series. However, escalation of interferon dose may be beneficial as shown in one patient, but it cannot be discerned whether the response was due to a combination of therapies, or whether the same therapeutic response would have been achieved with the higher doses of rIFN-a alone. Moreover, while none of the antibody pairs is unique for Sezary cells, the CD4+CD7- subset in appropriate patients provided a good objective measure of response and correlated well with visual Sezary cell counts.

Clinical implications of immunologic phenotyping in cutaneous T cell lymphoma

The composition of cutaneous lesions from 158 patients with confirmed cutaneous T cell lymphoma, 91 patients with suspected cutaneous T cell lymphoma, and 145 patients with lymphoid disorders other than cutaneous T cell lymphoma was quantitated in situ with the use of commercially available murine monoclonal antibodies that identify the Pan T, T-helper/inducer (Th), T cytotoxic/suppressor (Ts), and Pan B lymphocyte subsets. On average, cutaneous infiltrates of confirmed cutaneous T cell lymphoma were found to contain significantly more Th and less Ts or Pan B cells compared to benign lymphoid disorders. Moreover, when analyzed in terms of the type of lesion examined by biopsy, the absolute amount of Th cells progressively expands with increasing magnitudes of infiltrate in the dermis while the amount of Ts and Pan B cells remains relatively constant among lesions. A useful diagnostic criterion (anti-Leu 1/4 greater than or equal to 70% and anti-Leu 3a/anti-Leu 2a ratio greater than or equal to 6) correctly discriminated between cutaneous T cell lymphoma and non-cutaneous T cell lymphoma in 87.5% of cases. A positive immunodiagnostic result also may be useful for the prediction of subsequent histopathologic confirmation of cutaneous T cell lymphoma in patients who have suspect lymphoid infiltrates, such as alopecia mucinosis or idiopathic generalized erythroderma, when first seen. With the use of multivariate analysis, stage and possibly the percentage of Th cells within the T cell component in cutaneous infiltrates were covariates with significant relationships to survival in patients with confirmed cutaneous T cell lymphoma. In addition, Ts cells in infiltrates did not correlate significantly with observed responses to topical treatment and subsequent course in pretumorous mycosis fungoides. These results indicate that Ts cells play little biologic role in modifying the natural history of cutaneous T cell lymphoma.

The radiation therapy of early stage cutaneous T-cell lymphoma

Results of different radiotherapy schedules used for early stage (T1-2, N0-1, M0) cutaneous T-cell lymphoma (CTCL) are compared in a series of 45 patients (22 patients treated with high dose total skin electron beam therapy (TSEB) with curative intent, 18 patients treated with palliative radiotherapy, and 5 patients treated with high dose local electron beam). At 3, 5, and 10 years after diagnosis the high dose TSEB treatment group had a probability of overall survival of 91%, 86%, and 75%, respectively, compared with 94%, 88%, and 88% for the palliative treatment group. The complete response (CR) rate for the high dose TSEB treatment group was 82% (18/22), compared with a 57% (4/7) complete response rate for seven patients in the palliative group who received low dose TSEB (less than 25 Gy in 6-7 weeks) followed by daily application of topical mechlorethamine hydrochloride (HN2). However, the probability of continued remission at 3, 5, and 10 years was 44%, 44%, and 33%, respectively, for the high dose TSEB group and 25%, 25%, and 0%, respectively, for the low dose TSEB + HN2 group. The median disease-free survival was 17.5 months for the high dose TSEB group versus 5.5 months for the low dose TSEB + HN2 group. The five patients who were treated with high doses of local electrons to a single local field had an overall survival rate of 80%, a median survival rate of 64 months, and a median length of continued remission of 31 months. These results indicate that high-dose electron beam can result in long-term disease-free survival in patients with localized and limited extent skin involvement with cutaneous T-cell lymphoma.

Innovative techniques in radiation oncology.Clinical research programs to improve local and regional control in cancer

There is a growing importance in failure analysis in cancer management. In these analyses locoregional failure as the cause of death emerges as a significant problem in many tumor sites, e.g., head and neck cancer, gynecologic cancer, genitourinary cancer. Because of these data, the radiation oncology community has attributed high priority to research efforts to improve locoregional control. These efforts include the following: (1) brachytherapy alone or with external beam radiation therapy or surgery; (2) intraoperative radiation therapy; (3) hyperthermia with radiation therapy; (4) particle irradiation (protons, neutrons, stripped nuclei, and pions); and (5) routes of administration of the treatment, including infusional (intravenous) chemotherapy with radiation therapy, intraarterial monoclonal antibodies with radionuclides, and intraarterial chemotherapy with radiation therapy. Each area of investigation is discussed.

The treatment of primary intraocular malignancy

This paper will summarize much of the information derived in an association between The Department of Radiation Oncology of Hahnemann University Hospital and the Oncology Service of Wills Eye Hospital of Thomas Jefferson University, a collaborative effort for the treatment of primary intraocular malignancies that has spanned the last dozen years. In that time we have treated malignant intraocular melanoma by radioactive eyeplaque brachytherapy and have begun to develop a similar program for treatment of recurring retinoblastoma. These experiences will be described.

Brachytherapy for cancer of the female urethra.

Carcinoma of the female urethra is uncommon. The review of literature and our own experience indicates that early distal urethral cancers (squamous and adenocarcinoma) can be treated either with surgery (70-80% 5-year survival) or with radiotherapy (brachytherapy) with excellent results (75% 5-year survival). Early proximal or entire urethral cancers (squamous and adenocarcinoma), if treated surgically, will require exenterative procedures. Alternatively, these cancers can be treated with a combination of external beam and brachytherapy with or without chemotherapy with good results and preservation of organs. Surgery can be used for failures or persistent tumors. Advanced cancers require a multimodality approach, and a combination of radiation and chemotherapy appears to be the optimal way to treat these patients-with surgery to be used for biopsy-proven persistent tumors or recurrences.

Total skin electron beam and total nodal irradiation of cutaneous T-cell lymphoma

Nineteen patients with cutaneous T-cell lymphoma (CTCL) limited to the skin and/or lymph nodes were treated at Hahnemann University with a combination of total skin electron beam and total nodal irradiation (TSEB + TNI). The patients were classified as Stage Ib (1 patient), Stage IIa (8 patients), Stage IIb (5 patients), and Stage IVa (5 patients). Treatment resulted in a complete response in 100% (14/14) of patients with Stage Ib, IIa, and IIb disease, and a CR in 60% (3/5) of patients with Stage IVa disease. The Stage Ib and IIa patients had an overall survival of 100% and a disease-free survival of 44% at 6 years. Four of the five patients with Stage IIb CTCL relapsed within 3 months after completing TSEB + TNI with an overall survival in the group of 40% at 5 years. The Stage IVa patients all relapsed within 7 months and died of their disease within 50 months of completing treatment. The acute effects of TSEB + TNI were well tolerated, but three patients developed second malignancy (lung, kidney and skin) and one patient developed myelodysplasia, possibly the result of radiotherapy.

Concomitant Irradiation and Dose-escalating Carboplatin for Locally Advanced Carcinoma of the Uterine Cervix: An Updated Report

The combination of radiotherapy and carboplatin is associated with high response rates among women who have cervical cancer. To improve control rates for patients who have locally advanced carcinoma of the uterine cervix, oncologists have explored combinations of radiotherapy and chemotherapy. Carboplatin is an analogue of cisplatin, with similar efficacy against cervix cancer and a toxicity profile that is theoretically appealing for this group of patients because it is not nephrotoxic. Fifteen women with International Federation of Gynecology and Obstetrics (FIGO) stages IB2 through IIIB or recurrent carcinoma of the cervix were treated with megavoltage irradiation and weekly intravenous carboplatin (7 women, 60 mg/m2; 8 women, 90 mg/m2). Response was documented among all patients treated at 60 mg/m2 (three complete responses, four partial responses) and in 6 women treated with 90 mg/m2 (four complete responses, two partial responses). The two nonresponders in the series presented with recurrent glassy cell carcinoma of the cervix. All patients completed the planned course of therapy without the need for treatment interruption. At 60 mg/m2, one dose of carboplatin was withheld because of grade 2 thrombocytopenia. At 90 mg/m2, one case of grade 2 leukopenia was documented. The leukocyte counts remained within normal limits for all 3 patients who were irradiated through extended portals that encompassed the paraaortic nodes (2 women, 60 mg/m2; 1 woman, 90 mg/m2). To date, 2 of 7 patients treated at the lower dose level have died of disease (one local progression and distant failure at 11 months, one distant failure alone at 6 months). The remaining patients treated at 60 mg/m2 are alive at a median of 24 months (range, 21-37 months). Among those treated at the higher dose level, 1 patient is alive with local and distant failure at 14 months, and 1 woman succumbed to local and distant disease at 4 months. The remainder are alive at a median follow-up of 6 months (range, 2-10 months). The regimen was unsuccessful in salvaging women with recurrent glassy cell carcinoma. We conclude that the combination of radiotherapy and carboplatin can be safely delivered at both of the chemotherapy schedules studied. The regimen should not be offered to women who have recurrent glassy cell tumors. To prove the efficacy of this approach, phase III testing should be considered that compares the combination of agents to irradiation alone.