Effect of low-dose radiation therapy when combined with surgical resection for Ewing sarcoma.

BACKGROUND: As an alternative to high-dose irradiation, limited surgery and low-dose irradiation have been investigated as a means to achieve local control. We retrospectively examined the clinical characteristics, treatment, and outcome for 25 patients with Ewing sarcoma treated with limited surgery and low-dose irradiation. PROCEDURE: The records of 25 patients (age 4-48 years) were reviewed who were treated between 1979 and 1996 at Memorial Sloan-Kettering Cancer Center. At the time of diagnosis, 21 of the 25 patients had prognostically unfavorable tumors including the presence of metastatic disease (n = 12), an axial primary (n = 17), and a tumor measuring greater than 8 cm (n = 18). The primary tumor was completely resected (wide local excision) in 13 patients, incompletely resected (marginal excision) in 7 patients, and biopsied only in the remaining 5 patients. The median dose of irradiation to the primary site was 30 Gy. RESULTS: With a median follow-up of 67 months (range 16-189 months) for the surviving patients, 28% failed distantly, and an additional 28% suffered from the progression of previously established metastatic disease. No patient failed locally. The median overall survival was 43 months. The actuarial overall survival at 5 years was 39% (+/-11%) for all patients and 60% (+/-14%) for patients with localized disease. CONCLUSIONS: Limited surgery and postoperative irradiation are one strategy that promises to balance the goal of achieving local control with the goal of diminishing late effects. Apart from the scenario in which radiation therapy is absolutely unnecessary, low-dose irradiation may be appropriate after considering the risk for local recurrence and overall prognosis.

The employment status of 1995 graduates from radiation oncology training programs in the United States.

PURPOSE: To quantify the employment status of 1995 graduates of radiation oncology training programs in the United States. METHODS AND MATERIALS: All senior residents (149) and fellows (36) who completed training in 1995 were mailed an employment survey questionnaire by the Association of Residents in Radiation Oncology (ARRO). Telephone follow-up of nonrespondents achieved a 100% response rate. Twenty graduates who chose to continue training and five who returned to their home countries were removed from the study. Of the 160 who attempted to enter the U.S. workforce, 106 were men and 54 were women. Initial job status and job status at 6-8 months following graduation were determined. RESULTS: Unemployment was 6.9% at graduation and 4.4% at 6-8 months. Underemployment (part-time employment) was 10.6% at graduation and 11.9% at 6-8 months postgraduation. Of those working part-time 6-8 months after graduation, 63% (12 of 19) did so involuntarily after unsuccessfully seeking full-time employment. For the 20 graduates who chose to continue training with fellowships, seven (35%) did so solely to avoid unemployment, four (20%) were partially influenced by the job market, and nine (45%) were not influenced by the job market. Adverse employment search outcome was defined as being either unemployed as a radiation oncologist or involuntarily working part-time. Excluding those who chose to work part-time, a total of 19 (11.9%) graduates at 6-8 months following graduation, compared to 22 (13.8%) at graduation, were either unemployed or involuntarily working part-time. In terms of gender, this represented 18.5% (10 of 54) of females and 8.6% (9 of 105) of males. In terms of geographic restrictions in the job search, 56% of males and 70% of females with an adverse employment outcome limited their job search to certain parts of the country. This compares to 62% of all graduates in this study with geographic restrictions in their job search. In terms of perceptions of the workforce and employment opportunities, 95% of all graduates believed there was an oversupply of radiation oncologists and 95.5% believed the job market was worse than what they had anticipated on entering training. Only 42.8% of all graduates were satisfied with the job opportunities available to them. A significant number of private practice positions (41%) did not offer a partnership track, and those that did so had an increased median employment period before partnership (3.25 years) compared to previous years. CONCLUSION: This is the only employment survey for any specialty in which a 100% response rate was achieved. Upon graduation, a significant number of residents and fellows were either unemployed or involuntarily underemployed. The job market absorbed only a fraction of them at 6-8 months. Most graduates, including those employed full-time, were not satisfied with the practice opportunities available to them during their job search. Many private-sector jobs did not offer a partnership track, and those that did required an increased employment period. A higher rate of involuntary part-time employment was seen for female graduates. Geographic restrictions in job search alone could not account for graduates being unemployed or underemployed, and could not account for gender differences. An overwhelming majority of 1995 radiation oncology graduates believed that the job market had deteriorated and that there was an oversupply of radiation oncologists. As one of two major studies tracking the employment status of radiation oncology graduates, we believe this study to be superior in methodology. We also believe this study presents data in a manner useful to medical students, training program directors, and healthcare policymakers.

Radiation therapy for relapsed CNS germinoma after primary chemotherapy.

PURPOSE: To retrospectively evaluate the ability of radiation therapy to salvage patients with CNS germinoma who relapsed after treatment with primary chemotherapy on a multiinstitution trial that included carboplatin, etoposide, and bleomycin (PEB). PATIENTS AND METHODS: Eight patients with CNS germinoma received carboplatin, etoposide, and bleomycin as their only nonsurgical treatment following their initial diagnosis. At the time of relapse each patient received high-dose cyclophosphamide (one to three cycles) followed by craniospinal irradiation (25.2 to 36 Gy) and a boost to the site of recurrent disease (45 to 54 Gy). Six of eight patients had disease at relapse that was more extensive than at diagnosis. One patient had magnetic resonance imaging (MRI) evidence of leptomeningeal enhancement in the cauda equina although CSF cytology was negative, and one patient had cytologic evidence of CSF involvement. The median time to relapse following primary chemotherapy was 17 months. RESULTS: Although myelosuppression was prolonged following the administration of preirradiation chemotherapy, all patients completed a continuous course of radiation therapy. With a median follow-up after radiation therapy of 32 months (range, 16 to 47 months), no failures have occurred. CONCLUSION: Radiation therapy has a proven record of efficacy in the treatment of intracranial germinoma and it remains the standard therapy with which others are compared for treatment response, local control, and overall survival. Arguments can be made for alternative approaches when patients face hormonal or neurocognitive dysfunction as a result of radiation therapy; however, any reduction in late effects will have to be weighed against the probability of survival if alternative approaches prove to be inferior.

High-dose rate intraoperative radiation therapy for pediatric solid tumors.

BACKGROUND: Sixteen pediatric patients with solid tumors received treatment on a protocol designed to test the feasibility and safety of high-dose rate intraoperative radiation therapy (IOHDR) via a remote afterloader. PATIENTS AND METHODS: Patients with Ewing's sarcoma (n = 5), rhabdomyosarcoma (n = 3), synovial cell sarcoma (n = 2), Wilms tumor (n = 2), osteosarcoma, immature teratoma, desmoplastic small round cell tumor, and inflammatory fibrosclerosis were included. IOHDR was used in the initial management of nine patients and at the time of recurrence in seven. Indications for treatment included gross residual disease in 5 and suspected microscopic disease in 11. The general sites treated were the abdomen (n = 3), chest-wall/thoracic cavity (n = 7), and pelvis (n = 6). All of the patients received multiagent chemotherapy prior to the IOHDR procedure, and 5 had been previously treated with external beam radiation therapy. Separate from the procedure during which IORT was performed, 9 patients underwent an attempt at resection at the time of their initial presentation. A dose of 1200 cGy was prescribed to a depth of 0.5 cm from the surface of a multichannel tissue-equivalent applicator. Complications ascribed to IOHDR included an abscess, delayed wound healing, and cytopenia. Four patients received supplemental external beam radiation therapy to the IOHDR site. At the time of IOHDR, 3 patients had disseminated disease within the pleural cavity and one had pulmonary metastases. RESULTS: With a median follow-up of 18 months, the actuarial rates of local control, metastasis-free, and overall survival at 2 years were 61%, 51%, and 54%, respectively. The patterns of failure were local (n = 1), distant (n = 1), and local + distant (n = 1). Two patients are alive with active disease. Nine are alive with no evidence of disease and the remaining 5 are dead from disease (n = 2), other causes (n = 1), or treatment (n = 2). CONCLUSIONS: The potential to improve local control with high doses of radiation should be balanced against the risk of late effects. The ability to confine the dose of radiation to the primary site and decrease the dose to normal tissues makes IOHDR an important adjunct to external beam radiation therapy. IOHDR can be a safe and integral component in the management of pediatric solid tumors.

Offering the option of randomized clinical trials to cancer patients who overestimate their prognoses with standard therapies.

We have shown that cancer patients' routine (and understandable) overestimations of their prognoses with standard therapy may inhibit their accrual to randomized clinical trials for which standard therapies are the alternative. Patients' appreciation of the rationale for a trial, and the potential benefit of trial participation, can only be enhanced if they understand their prognoses with standard therapy. However, clinical investigators may be reluctant to provide specific information that deflates patients' estimates of their prognoses. The routine withholding of information regarding the modest benefits of standard therapies may avoid patient distress, but such physician behavior is paternalistic and may deleteriously affect trial accrual. On the other hand, the routine communication of prognostic information will cause significant distress among patients and will perhaps be destabilizing to that minority of patients who would otherwise shun this information or truly cannot psychologically tolerate it. A middle ground between these extremes is the stepwise disclosure of potentially distressing information, wherein specific prognostical information is offered by physicians to patients and actually provided or communicated only after patients first understand the nature of it and then indicate their interest in receiving it. A practical disadvantage of this approach is its additional demand on physicians' time. Therefore, if impracticality is to be avoided and yet the approach fostered, clinical investigators might consider developing trial-specific, written or audiovisual materials for patient education about general background information. These could be employed prior to patient-physician dialogue and so enable physicians to focus on more sensitive subjects, such as prognosis with standard therapy.

Pollen wall formation in Lilium: The effect of chaotropic agents, and the organisation of the microtubular cytoskeleton during pattern development.

Using a combination of electron-microscopic and immunocytochemical techniques the behaviour of the microtubular cytoskeleton has been followed throughout microsporogenesis in Lilium henryi Thunb. Cells treated with colchicine at specific stages and then permitted to develop to near maturity were used to investigate any participation by microtubules in the regulation of pollen wall patterning. The microtubular cytoskeleton assumes four principal forms during the meiotic process; in pre-meiosis it resembles that characteristic of meristematic somatic cells, during meiotic prophase it becomes associated with a nuclear envelope and, perhaps, with the chromosomes and, as the nuclear and cell divisions commence, it takes the form of a normal spindle apparatus. In the young microspores, microtubules assume a radial organisation extending from sites at the nuclear envelope to the inner face of the plasma membrane. No firm evidence was found linking any one of these forms of cytoskeleton with the generation of patterning on the cell surface. Experiments with colchicine revealed that the drug would readily dislocate the colpus, but did not affect the general reticulate patterning. The radial cytoskeleton was present during the deposition of the early primexine, but evidence from these and other studies (J.M. Sheldon and H.G. Dickinson 1983, J. Cell. Sci. 63, 191-208; H.G. Dickinson and J.M. Sheldon, 1984, Planta 161, 86-90) indicates patterning to be imprinted upon the plasma membrane prior to the appearance of this type of cytoskeleton. These results are discussed in terms of a recent model proposed to explain pattern generation on the surface of Lilium pollen grains, based on the "self-assembly" of patterning determinants within the plasma membrane.

A radial system of microtubules extending between the nuclear envelope and the plasma membrane during early male haplophase in flowering plants.

The angiosperm male meiocyte is unusual among plant cells in that during early development ordered cellulosic microfibrils are not deposited at the protoplast surface. Instead, a complex series of events takes place which leads to the formation of the pollen wall 'primexine'. The use of immuno-cytochemistry, electron microscopy and experiments with an inhibitor have revealed this cell to contain no cortical microtubules, and its cytoskeleton to be radially organised with microtubules extending from the nucleus to the plasma membrane. It is proposed that these microtubules, perhaps organised from the nuclear envelope, play a part in orientation of the nucleus and in the transport of materials to the cell surface.

Determination of patterning in the pollen wall of Lilium henryi.

Centrifugation of living pollen mother cells of Lilium henryi has permitted the modifications of complex walls developed on the four daughter microspores. This experimental approach has not only provided an insight into the mechanism by which patterning is established, but has also identified the stages in cell development when wall determinants are present. These determinants can be first detected late in the meiotic prophase, but are not necessarily active at the cell surface at this early stage. The fact that treatment during cytokinesis may affect subsequent wall formation, combined with the obvious interference of the colpus with the spore patterning, indicates pattern determination to be a lengthy process, commencing during late prophase and reaching completion in the young tetrad. The study of walls formed on enucleate cell fragments suggests that neither the spindle nor the cytoskeleton is intimately involved in formation of the basic reticulate patterning. It is proposed that material is inserted into the mosaic of the plasma membrane and is reorganized biophysically to form contiguous 'plates', which then modify the properties of the membrane in such a way that the cytoplasmic protrusions that constitute the first stages of wall formation only develop in the interstices between them. Changes in the plasma membrane have been detected over this period and it seems that a population of coated vesicles is closely involved in these events. Examination of the cytoskeleton of the young spore suggests that microtubules play a critical rôle in the positioning of the colpus, and reveals ways by which only small changes in this skeleton could give rise to multicolporate grains.