Endometrial carcinoma: the current role of adjuvant radiation.

Endometrial cancer is the most common gynaecological malignancy in the USA, expected to account for over 40,000 new cases and 7,400 deaths in 2008. Risk factors for local-regional recurrence after surgery have been identified in surgical-pathological studies as well as prospective randomised trials. While most women with early stage, low risk disease do well without adjuvant therapy, those in higher risk groups frequently recur both locally and distantly. The use of adjuvant radiation therapy has been controversial since randomised trials have demonstrated improvement in local control, without a clear impact on survival. The magnitude of potential benefit is dependent on combinations of risk factors. In this review, we use the available data to help guide the selection of patients for whom radiotherapy may be beneficial, and provide recommendations regarding treatment volumes and methods of delivery.

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.

Quantitative analysis of three-dimensional conformal radiotherapy techniques for posterior fossa treatment in children.

Numerous beam directions using 3-D conformal techniques can be employed in treating tumors in the posterior fossa, each with characteristic normal tissue exposure along the entrance and exit trajectory. A representative variety of beam configurations were modeled in a modern computer planning system initially with the entire posterior fossa as the target. These beams were quantitatively scored using criteria based on integral doses for both low dose and high dose effects encompassing a variety of critical normal structures, thus identifying strengths and weaknesses of each beam. By blocking portions of a particular beam accounting for unfavorable scores, a map of "zones" within the posterior fossa ideally treated by a certain beam or beams could be constructed. No universally ideal photon beam arrangement for the entire posterior fossa target could be identified. However, using single beam analysis, the strengths and weaknesses of particular strategies could be quantified. For example, vertex beams treating the cerebellar hemispheres allow the greatest sparing of cochlea and hypothalamus but at the cost of increased low to moderate dose to the supratentorial brain. Using the constructed maps identifying "zones" appropriately treated by a given beam or beams, three-dimensional conformal treatment plans with favorable dose-volume statistics can be designed based on previously defined normal tissue tolerance considerations. It is shown how this approach can be individualized based on specific patient characteristics (e.g., age). We conclude that radiotherapy directed to the posterior fossa can be optimized based on systematic assessment of individual beam contributions to normal tissues. This technique allows fast selection of treatment beams based on known normal tissue anatomical and tolerance information. Further studies will be required regarding long term effects of various radiation doses on specific volumes of normal tissue in order to individualize beam selection. When treating children, knowledgeable consideration of these beam characteristics can help avoid late effects.

Relapse in the skull after myeloablative therapy for high-risk neuroblastoma.

Patterns of relapse were determined for 20 high-risk neuroblastoma patients treated with chemotherapy, surgery, primary and metastatic site radiation (21 Gray), myeloablative chemotherapy, peripheral blood stem cell rescue, and 13-cis-retinoic acid. The median follow-up duration after transplant is 21 months (range, 8-34 months). The event-free survival and overall survival at 2 years were 45 and 75%, respectively. There were 2 primary site recurrences. Metastatic sites that became MIBG-scan negative on induction chemotherapy were not irradiated. Four patients relapsed in irradiated metastatic sites, 3 in the skull, 1 in the liver. Failure also occurred at 2 skull sites treated with chemotherapy only, and at 5 new sites: 1 skull, 2 distant lymph nodes, and 2 bones other than skull. Eight of 20 patients had skull metastasis at presentation; 6 were irradiated and 3 were controlled. Skull metastasis warrants more aggressive evaluation and treatment.

Neurons in the periaqueductal gray are critically involved in the neuronal network for audiogenic seizures during ethanol withdrawal.

The periaqueductal gray (PAG) is implicated in the network subserving audiogenic seizures (AGS). AGS are seen during ethanol withdrawal (ETX), and the present study examined effects of focal NMDA receptor blockade in PAG during ETX and PAG neuronal firing changes associated with ETX. Bilateral cannulae or microwire electrodes were chronically implanted into PAG. Ethanol was administered intragastrically at 8-h intervals for 4 days, resulting in AGS susceptibility during ETX. Microinjection of a competitive NMDA receptor antagonist, DL-2-amino-7-phosphonoheptanoic acid (AP7) (2 and 5 but not 1 nmol/side), into the PAG suppressed AGS, in part, reversibly. In microwire experiments spontaneous and acoustically evoked PAG neuronal responses in behaving rats were reduced significantly 1 h after initial administration of ethanol. During ETX, when the animals were susceptible to AGS, significant increases in spontaneous and acoustically evoked PAG neuronal firing occurred. PAG neurons exhibited burst firing 2-4 s prior to the tonic-clonic phase of AGS and tonic repetitive firing during this seizure phase, which ceased during post-ictal depression. Increased NMDA receptor function in PAG may be important to the aberrant PAG neuronal firing in AGS, since previous studies observed upregulation of NMDA receptors during ETX, and the present study observed that focal microinjection of a NMDA antagonist into PAG blocked AGS.

Modulation of audiogenically kindled seizures by gamma-aminobutyric acid-related mechanisms in the amygdala.

Repetitive induction of audiogenic seizures (AGSs) ("AGS kindling") results in expansion of the AGS neuronal network from the brainstem to forebrain structures. AGSs in kindled genetically epilepsy-prone rats (GEPR-9s) exhibit a significant increase in the duration of posttonic clonus (PTC). The amygdala (AMG) does not appear to be a required network component before AGS kindling, but this structure is implicated in the seizure network after AGS kindling. gamma-Aminobutyric acid (GABA) is a major neurotransmitter in AMG, and histamine receptor activation is also reported to stimulate GABA release. The present study examined the effect on audiogenically kindled seizures of focal microinjections into the AMG of GEPR-9s. AGS kindling involved induction of 14 AGSs in GEPR-9s. Bilateral microinjection of a GABA(A) agonist, muscimol (0.3 nmol/side), into the AMG significantly reduced the duration of PTC, starting 0.5 h after drug infusion, with recovery by 24 h. Microinjection of histamine (60 nmol/side) suppressed PTC at 0.5 h, with total blockade at 24 h, but the seizure pattern did not revert to that observed before kindling until 120 h. This long duration suggests that mechanisms in addition to modulation of GABA function may be involved in the effect of histamine. The wild running and tonic components of AGS were never affected by microinjection of these agents into the AMG. These findings confirm previous work suggesting that the AMG is not a required nucleus in the AGS neuronal network before kindling. However, the AMG becomes critical in expansion of the seizure network during AGS kindling, and audiogenically kindled seizures are negatively modulated by increased GABA function.

A technique for inguinal node boost using photon fields defined by asymmetric collimator jaws.

A technique is described for treating inguinal nodes when using radiotherapy in the control of pelvic malignancies. A posterior photon field treats the pelvis. A wider anterior photon field treats pelvis and inguinal nodes. An anterior photon boost to nodes is delivered using asymmetric collimator jaws moved across center line. Advantages of this technique include simplicity of setup and treatment (a single isocenter is retained, and no transmission block is needed), minimal dose inhomogeneity, reduced dose to femoral necks reducing the risk of femoral fracture, low risk of nodal underdose, and elimination of dosimetric difficulties inherent in electron beam boosts.

Integrating radiation therapy in the curative management of ovarian cancer: current issues and future directions.

Although important advances in surgery, chemotherapy (CT), and radiation therapy (RT) have been made, overall survival for patients with ovarian cancer (OC) has not changed significantly. Despite its long history in the treatment of OC and its proven curative role in patients with microscopic or minimal residual disease, the proper role of RT in the management of OC is not clearly established. Although the use of primary adjuvant RT (whole abdominal irradiation) has declined in the last 15 years, there has been a resurgence of interest in RT as part of a combined modality approach and as salvage therapy for patients with small-volume persistent disease after primary cytoreductive surgery and platinum-based CT. This article reviews the evidence supporting the use of RT alone or combined with chemotherapy as primary adjuvant therapy or in the salvage setting. Current issues in the radiotherapeutic management are discussed along with ideas for future clinical research directions.

Radiotherapy in epithelial ovarian cancer: state of the art.

Modern advances in surgery, chemotherapy (CT) and radiotherapy (RT) have not, unfortunately, impacted the overall survival for patients with ovarian cancer (OC). Despite its long history in the treatment of OC and its proven curative role in patients with microscopic or minimal residual disease, the proper role of RT in the management of OC is controversial and not clearly established. Similarly, the potential roles of RT in the consolidative treatment and as salvage therapy following CT failure remain controversial. In the present review current issues in the radiotherapeutic management are discussed along with possible future clinical research directions.

Neurons in the deep layers of superior colliculus play a critical role in the neuronal network for audiogenic seizures: mechanisms for production of wild running behavior.

Recent investigations suggest that the deep layers of superior colliculus (DLSC) play a role in the neuronal network for audiogenic seizures (AGS). The present study examined DLSC neuronal firing and convulsive behavior simultaneously in freely-moving genetically epilepsy-prone rats (GEPR-9s) using chronically implanted microwire electrodes. An abrupt onset of acoustically-evoked firing at approximately 80-90 dB was observed in DLSC neurons of GEPR-9s, which was significantly above the normal threshold. DLSC neurons began to exhibit rapid tonic burst firing 1-2 s prior to the onset of the wild running behavior at the beginning of AGS. As the tonic phase of the seizure began, DLSC firing ceased, and only returned towards normal following post-ictal depression. These neuronal mechanisms may be relevant to other seizure models in which the DLSC is implicated. The temporal pattern of neuronal firing during AGS is specific to DLSC and differs markedly from those observed elsewhere in the AGS neuronal network. The temporal firing pattern suggests that the DLSC plays a primary role in the generation of the wild running phase of AGS. Previous studies indicate that the inferior colliculus is dominant during AGS initiation, and the pontine reticular formation is dominant during the tonic extension phase of AGS. Taken together these data suggest that the neurons in the neuronal network undergo a dominance shift as each specific convulsive behavior of AGS is elaborated.

New techniques in the radiotherapeutic treatment of gynecological malignancies.

The management of patients with gynecological malignancies serves as a prominent example of the importance of multi-modality oncologic therapy. Optimal treatment of these patients requires the skillful implementation of surgery, radiation therapy and chemotherapy. The decision to use simple versus combined modality therapy is crucial and best carried out in centers in which an experienced and coordinated multidisciplinary team is available. In this article, we have reviewed the most recent data regarding the role of radiation therapy in gynecological malignancies and have pointed out those areas where additional confirmatory studies are needed.

Adenocarcinoma of the fallopian tube: results of a multi-institutional retrospective analysis of 72 patients.

PURPOSE/OBJECTIVE: To determine the prognostic factors for predicting outcome of patients with adenocarcinoma of the fallopian tube and to evaluate the impact of treatment modalities in managing this uncommon disease. MATERIALS AND METHODS: A retrospective analysis of the tumor registries from 6 major medical centers from January 1, 1960 up to March 31, 1995 yielded 72 patients with primary adenocarcinoma of the fallopian tube. The Dodson modification of the FIGO surgical staging as it applies to carcinoma of the fallopian tube was utilized. Endpoints for outcome included overall and disease-free survival. Univariate analysis of host, tumor, and treatment factors was performed to determine prognostic significance, and patterns of failure were reviewed. RESULTS: The median age of the study cohort was 61 years (range 30-79 years). Stage distribution was 24 (33%) Stage I; 20 (28%) Stage II; 24 (33%) Stage III; and 4 (6%) Stage IV. Adjuvant chemotherapy was administered to 54 (75%) patients, and postoperative radiotherapy was employed in 22 (31%). In the latter treatment group, 14 (64%) had whole pelvic external beam irradiation, 5 (23%) whole abdominal radiotherapy, 2 (9%) P-32 instillation, and 1 (4%) vaginal brachytherapy alone. Chemotherapy was used in 67% of Stage I and in 79% of Stages II/III/IV disease (not significant); radiotherapy was more commonly employed in Stage I than in Stages II/III/IV (46% vs. 23%, p = 0.05). The 5-, 8-, 15-year overall and disease-free survival for the study patients were 44.7%, 23.8%, 18.8% and 27.3%, 17%, 14%, respectively. Significant prognostic factors of overall survival included Stage I vs. II/III/IV (p = 0.04) and age < or = 60 years vs. > 60 years at diagnosis (p = 0.03). Only Stage I vs. II/III/IV (p = 0.05) was predictive of disease-free survival. Patterns of failure included 18% pelvic, 36% upper abdominal, and 19% distant. For all patients, upper abdominal failures were more frequently found in Stages II/III/IV (29%) than in Stage I (7%) (p = 0.03). Relapses solely outside of what would be included in standard whole abdominal radiotherapy portals occurred for only 15% of patients (6 of 40) with failures. Furthermore, patients having any recurrence, including the upper abdomen, were more likely (p = 0.001) to die (45%) than those without any type of relapse (18%). CONCLUSION: This retrospective, multi-institutional study demonstrated the importance of FIGO stage in predicting the overall and disease-free survival of patients with carcinoma of the fallopian tube. Future investigations should consider exploring whole abdominal irradiation as adjunctive therapy, particularly in Stage II and higher.

Advances in gynecologic radiation oncology.

Radiation therapy is an important modality in the curative and palliative management of patients with gynecologic malignancies. However, the specific roles of radiation therapy continue to evolve in terms of specific indications, volumes treated, techniques, and integration with other modalities. Retrospective assessments of outcome and prospective clinical trials are necessary to answer questions, generate additional hypotheses, and guide further refinements in the application of radiation therapy. This article focuses on recent literature and ongoing clinical trials in this disease group.

Chemotherapy, early surgical reassessment, and hyperfractionated abdominal radiotherapy in stage III ovarian cancer: results of a gynecologic oncology group study.

PURPOSE: To determine outcomes and treatment toxicities in patients with optimal (< or = 1 cm residual) Stage III ovarian carcinoma treated with three courses of cisplatin-cyclophosphamide, surgical reassessment (SRA), and hyperfractionated whole abdominal irradiation (WAI). METHODS AND MATERIALS: Forty-two eligible patients entered this prospective Phase II study conducted by the Gynecologic Oncology Group (GOG). Disease characteristics were as follows: age range, 32-76 years (median 58); Stage IIIA (n = 1, 2%), IIIB (n = 2, 5%), IIIC (n = 39, 93%); histology-serous papillary (n = 21, 50%); other (n = 21, 50%); Grade 1 (n = 1, 2%); 2 (n = 14, 33%); 3 (n = 27, 54%); residual disease after initial surgery (present: n = 23, 55%; absent: n = 19, 45%). Five patients progressed while on chemotherapy, could not be effectively cytoreduced, and were not eligible for WAI. Of the remaining 37 patients, 35 received WAI. Surgical reassessment was not performed in five patients. RESULTS: Of 37 patients with known SRA status after chemotherapy, 21 (57%) were grossly positive, 4 (11%) were microscopically positive, and 12 (32%) were negative. Based on measurements recorded following initial laparotomy and surgical reassessment, progression during chemotherapy was noted in 40%, stage disease in 37%, and objective response in 23%. Toxicity during hyperfractionated WAI was limited and reversible. No patient beginning WAI failed to complete or required a significant treatment break. Following WAI, six patients underwent laparotomies for abdominal symptoms; five had recurrent disease. Five additional patients were managed conservatively for small bowel obstruction (SBO) or malabsorption, of whom three subsequently developed recurrence. Twenty-two patients having pelvic boosts were significantly more likely to require management for gastrointestinal morbidity (p = 0.0021). Considering all eligible patients, median disease-free and overall survivals were 18.5 and 39 months, respectively. Considering patients completing chemotherapy and WAI, median disease-free and overall survivals were 24 and 46 months, respectively. CONCLUSIONS: (a) Disease progression occurred within three cycles of cisplatin and cyclophosphamide chemotherapy in 40% of patients with optimal (< or = 1 cm residual) Stage III ovarian carcinoma. (b) Following limited chemotherapy, hyper-fractionated WAI was acutely well tolerated. (c) Late radiation-related toxicity was observed in only three patients (8.6%) in the absence of recurrent disease. Late gastrointestinal morbidity was significantly associated with the administration of a pelvic radiotherapy (RT) boost. (d) Short duration chemotherapy followed by SRA and hyperfractionated WAI without a pelvic boost is a promising management option for patients with optimal Stage III ovarian cancer. A Phase III trial will be necessary to determine how this treatment strategy compares with chemotherapy or RT alone in this patient population.

The efficacy of cranial irradiation in ovarian cancer metastatic to the brain: analysis of 32 cases.

OBJECTIVE: To determine the role of irradiation in the management of brain metastases from epithelial ovarian cancer. METHODS: Tumor registries from five university cancer centers were searched to identify ovarian cancer patients with brain metastases. During a 30-year period (1965-1994), 4027 ovarian cancer patients were evaluated, 32 of whom were found to have cerebral metastases. Each received fractionated whole-brain irradiation (median dose 30 Gy, range 20-52.5). Five patients received concomitant chemotherapy with whole-brain irradiation. RESULTS: The median survival time for the whole population was 4 months. For the entire series, symptomatic response (complete response and partial response) was achieved in 23, 16 of whom were palliated until death. Patients with higher Karnofsky performance status (70 or above versus below 70) were more likely to derive a palliative response and attained a statistically significant survival advantage. No other factor predicted the likelihood of deriving a palliative response or a survival advantage after treatment. CONCLUSIONS: In this large review of patients with cerebral metastases from ovarian cancer, we found that most of those treated with whole-brain irradiation achieved palliation until death. Nearly all women with high performance status derived durable palliation from cerebral irradiation. Whole-brain irradiation was an effective means of palliating ovarian cancer metastatic to the brain and provided a favorable alternative to other means of management.

Pontine reticular formation neurons exhibit a premature and precipitous increase in acoustic responses prior to audiogenic seizures in genetically epilepsy-prone rats.

The genetically epilepsy-prone rat (GEPR-9) exhibits elevated seizure sensitivity and audiogenic seizures (AGS). The pontine reticular formation (PRF) is implicated in the neuronal network for AGS in the GEPR-9. The present study examined PRF neuronal firing and convulsive behavior simultaneously in the GEPR-9. Chronically implanted microwire electrodes in PRF allowed single neuronal responses and behavior to be examined in freely-moving rats. PRF neurons in the GEPR-9 exhibit precipitous intensity-evoked increases at a significantly lower (approx. 15 dB SPL) intensity than normal Sprague-Dawley rats. PRF neurons in the GEPR-9 also exhibit increased auditory response latencies. At the onset of AGS (wild running) the firing rate of PRF neurons increased, and the rate of PRF firing increased dramatically as the tonic phase of the seizure began. During post-ictal depression the rate of PRF neuronal firing slowed, gradually returning to normal. This pattern of PRF periseizural neuronal firing changes differ dramatically in pattern and temporal characteristics from those previously observed in inferior colliculus (IC). The IC serves as the AGS initiation site. IC neurons show extensive firing increases prior to and during the initial wild running, silence during the tonic and post-ictal phases, and gradual recovery of responses thereafter. The changes in PRF neuronal firing pattern suggest that the PRF may play a major role in the generation of the tonic phase of AGS. The premature onset of the precipitous rise in PRF neuronal firing suggests that the influence of the IC on PRF neurons may be magnified in association with AGS susceptibility. The PRF neuronal firing increases observed in the present study coupled with previous observation of AGS blockade by PRF microinjections in the GEPR-9 further support an important role of the PRF in the propagation of AGS in the GEPR-9. The mechanisms of PRF firing elevation may also be relevant in other seizure models in which the brain-stem reticular formation is implicated.

Brachytherapy: criteria for case selection.

Brachytherapy has an established role in the management of a number of malignancies. Contributing to successful application of brachytherapy techniques are proper planning, technical sophistication, and meticulous execution. Equally important, presumably, is proper case selection although conditions favoring brachytherapy utilization are not well described. To facilitate discussion of this topic, a semiquantitative system of brachytherapy case selection is proposed. Variables considered include the natural history of the malignancy, risks involved in the procedure, accessibility of implant site, and results obtainable with other treatment modalities. Brachytherapy Case Selection Scores (0-8) were generated for a number of malignancies. Higher scores were found for sites in which the use of brachytherapy is generally accepted and practiced, implying that the clinical factors considered in this system are clinically relevant, and that such a system could be useful when considering the use of brachytherapy in individual cases. Additional critical analysis regarding brachytherapy case selection is desirable.

Whole abdominal radiotherapy versus combination chemotherapy with doxorubicin and cisplatin in advanced endometrial carcinoma (phase III): Gynecologic Oncology Group Study No. 122.

Although localized endometrial cancer is effectively treated with surgery and radiation therapy, the treatment of advanced disease remains problematic. With increasing utilization of primary surgical staging and therapy, the early identification of patients with tumor spread beyond the uterus is becoming routine. The impact of adjuvant radiotherapy and/or chemotherapy in these patients remains to be demonstrated. In several institutions, whole abdominal radiation therapy has been used with some success as adjuvant treatment in selected patients with advanced disease. The Gynecologic Oncology Group (GOG) has completed a phase II trial of the whole abdominal radiotherapy in this patient population. Although data analysis is not complete, the regimen employed appears to be tolerable and shows some evidence of efficacy. In previous GOG trials, cisplatin and doxorubicin have shown single-agent activity in patients with measurable, advanced endometrial cancer. Subsequently, the response rate with the combination of cisplatin and doxorubicin was found to be superior to that with doxorubicin alone. Because approximately 30%-50% of patients with extrauterine disease have systemic failure, the evaluation of combination chemotherapy with doxorubicin and cisplatin in the adjuvant setting seemed warranted. The current ongoing prospective, randomized trial (GOG No. 122) compares the survival and the progression-free interval and treatment failure patterns in patients with endometrial carcinoma of stage III or IV with up to 2 cm of residual disease when treated with either whole abdominal radiotherapy or a combination of doxorubicin and cisplatin. The incidence and type of acute and late adverse events observed with the two treatment regimens were determined and compared.

Prognostic factors and treatment outcome for patients with locally recurrent endometrial cancer.

BACKGROUND: Women who do not receive adjuvant irradiation after hysterectomy for endometrial carcinoma (EC) are at risk for developing a pelvic recurrence. Disease- and treatment-related factors were examined for their impact on disease-specific survival (DSS) and pelvic control (PC) in patients with locoregional recurrences to whom salvage radiotherapy was administered. METHODS: Forty-five patients with pelvic/vaginal recurrences of EC were treated at a single institution between 1973 and 1991. The median follow-up period was 89 months. Multiple patient-, disease-, and treatment-related factors were examined with univariate and multivariate analysis for their impact on DSS and PC. Kaplan-Meier methods were used to estimate outcomes. RESULTS: Overall DSS and PC was 51 and 54% at 5 years, respectively. Univariate analysis revealed the following factors to impact on outcome (P < or = 0.05): age (DSS, PC), vaginal stage of recurrence (DSS, PC), size of recurrence (DSS, PC), time interval from hysterectomy (DSS, PC), initial grade (DSS), location of recurrence (PC), and radiation boost technique (PC). CONCLUSION: Women in whom endometrial cancer recurrences develop can be salvaged with aggressive radiotherapy consisting of external beam therapy followed by a radiation boost. Close follow-up after the initial hysterectomy is important because patients with low-volume recurrence limited to the vagina have the best outcome.