High-dose rate intracavitary irradiation for carcinoma of the uterine cervix. The adverse effect of treatment prolongation

AIM: To investigate the adverse effect of treatment prolongation on the local control and survival of the cervical carcinoma of the uterus. PATIENTS AND METHOD: Two hundred and sixteen patients with stage IIB and III cervical carcinoma treated with a combination of external radiation and high-dose rate (HDR) intracavitary irradiation between 1978 and 1989 were retrospectively studied. A multivariate analysis was used to determine the effect of treatment time on local control and survival. RESULTS: Overall treatment time was the most highly significant factors for local control in the multivariate analysis (p = 0.0005). The 5-year cumulative relapse rates were significantly different with the treatment times 35 to 42 days: 9% versus 43 to 49 days: 19% versus 50 to 62 days: 42% (p = 0.001). The second most significant parameter was stage classification (p = 0.02). Concerning relapse-free survival, stage classification (p = 0.0001), overall treatment time (p = 0.0035) and hemoglobin level (p = 0.0174) were the 3 most important prognostic factors, although there was no relationship between treatment time and late complications. CONCLUSION: These results suggest that prolongation of treatment time is associated with decreased local control and survival in patients treated with external radiation and HDR intracavitary irradiation.     

High-dose rate intracavitary radiation therapy for advanced head and neck tumors

Fifty-seven treatments were performed on 27 head and neck pateints with recurrent or residual tumors on a high dose rate, remote controlled afterloading unit: There were 16 cases of maxillary sinus tumors, 6 epipharynx, 3 alveolar ridge, 1 hard palate and 1 floor of mouth. All patients have been followed up more than 2 years except one. Five patients are alive without local recurrence for more than 2 years. In 13 patients local tumors disappeared once and normal mucosa covered the tumor sites. Two patients died from local bleeding. In six patients this method failed to destroy tumors. Our prupose was palliative local control: therefore, in two-thirds of cases treated we were successful with this easy method of nonfractionated acute intracavitary radiation. This result is favorable, considering that all cases treated here were failures following full dose external radiation, although the treatment had to be repeated more than twice in 15 cases. Relief of symptoms is excellent when this therapy is used.     

HDR and MDR intracavitary treatment for carcinoma of the uterine cervix. A prospective randomized study

The multiple goals theory of conflict management (Ohbuchi & Tedeschi, in press) postulated that participants in a conflict pursue to achieve resource goals (economic and personal resources) and social goals (relationship, identity, justice, and power-hostility). The hypotheses based on this theory were examined by the episode method, in which 207 university students were asked to rate their recent experiences of interpersonal conflicts in terms of participants' attributes, goals, and tactics. More than 80% of the subjects answered that they were motivated to achieve multiple goals in their attempts to resolve the conflicts. Social goals were found to be more strongly activated, and economic resource goals were least strongly activated. Regression analyses revealed that the effects of participants' attributes on tactical preference were mediated by goals.     

Dose-volume histogram analysis of high dose rate intracavitary brachytherapy for uterine cervix cancer

PURPOSE: We retrospectively analyzed the relationship between dose distribution and local control using a dose-volume histogram (DVH) in patients with cancer of the uterine cervix treated by definitive radiotherapy including intracavitary brachytherapy. METHODS AND MATERIALS: Twenty-five patients with squamous cell carcinoma of the uterine cervix who underwent definitive radiotherapy between August 1987 and April 1994 were selected for the present study. They included 15 patients with local control and 10 patients with local recurrence. In principle, these patients were treated with 50 Gy of external beam pelvic radiotherapy and a point A dose of 24 Gy, in four fractions, of intracavitary brachytherapy. The DVHs of tumor volumes were calculated by superimposing three-dimensional (3D) dose distributions on computed tomography (CT) images taken before brachytherapy. RESULTS: Differential DVHs revealed a tendency for the portion of the total tumor volume to which the delivered dose was low to be larger in patients with local recurrence. The tumor volumes and the absolute dose volumes of which the absorbed dose was less than 24 Gy [DV (< 24 Gy)] were significantly larger in patients with local recurrence than those in local control patients (p = 0.02 and 0.03, respectively). The percent DV (<24 Gy) was not significantly different in the two groups. In patients with larger tumor volume, the absolute DV (<24 Gy) was also larger and a strong linear correlation was noted between them. CONCLUSIONS: The analysis of dose distribution of brachytherapy using DVH was useful to evaluate the quality of dose distribution quantitatively. The absolute dose volume was considered more important than the percent dose volume for evaluation of the clinical outcome. Our study suggested that unfavorable dose distribution for the tumor volume in brachytherapy was one of the reasons of poor local control in patients with large tumor volume.     

Experience and results of application of remote afterloading system (RALS) optimization program for intracavitary treatment of squamous cell carcinoma of the uterine cervix

An optimization program for a remote after-loading system (RALS) for intracavitary treatment of cancer of the uterine cervix was established in 1982 by Tabushi and his co-workers. This system has been used in our hospital since 1986, using MODULEX. Seventy-three cases of untreated squamous cell carcinoma of the uterine cervix have been treated under RALS, 29 under conventional RALS and 44 under the RALS optimization program. The cumulative 5-year survival rates were obtained for the groups treated under each system by the Kaplan-Meier method. The 5-year survival rate of stage II cases treated under the RALS optimization program was 68.2%, and that of stage III cases 58.5%. On the other hand, that of stage II cases treated under conventional RALS was 56.3%, and that of stage III cases 44.9%. There was no significant difference between these two groups. Local control rates for stage II and III cases were higher than 5 year-survival rates. Among complications, the frequency of grade 2 radiation colitis was 15.9% with the RALS optimization program cases, and that of grade 2 radiation cystitis was 4.5%. We consider the RALS optimization program to be a clinically useful method for the intracavitary treatment of squamous cell carcinoma of the uterine cervix.     

Method for determining optimal intracavitary radiotherapy conditions for carcinoma of the uterine cervix with tumor infiltration of the vaginal wall

Stage III carcinoma of the uterine cervix is occasionally accompanied by tumor infiltration of the vaginal wall. Currently, the vaginal wall has to be irradiated in the same manner as the uterine cervix. The authors have developed a system for determining the optimal irradiation conditions for treating the two regions, uterine cervix and vaginal wall, at the same time. A comparison of two methods is shown in simulation, and then a clinical case is reported. The first method consists of two treatment plans, one for the uterine cervix without tumor infiltration of the vaginal wall, and the other for the vaginal wall without carcinoma of the uterine cervix. The second, newly developed method considers the two regions together. Irradiation times of ovoid sources obtained with the second method are 15-25% less than those of the first method. Isodose curves obtained with the two methods are very different, and thus the uterine cervix and vaginal wall must be considered together in order to determine irradiation conditions.     

Technically accurate intracavitary insertions improve pelvic control and survival among patients with locally advanced carcinoma of the uterine cervix

The purpose of this study was to document whether the technical qualities of a brachytherapy application impacts on the outcome of patients with locally advanced cervix cancer treated by definitive irradiation. A previous report from the patterns of care study demonstrated the importance of brachytherapy in the treatment of locally advanced cervix cancer. Locally advanced disease was defined as FIGO stages Ib (if tumor diameter was < or = 4 cm), IIb (if disease was bilateral or involved the lateral aspect of either parametrium), and III. Localization films from 128 patients with locally advanced squamous cell carcinoma of the cervix were reviewed by a radiation physicist and a radiation oncologist with expertise in gynecologic radiotherapy. All patients received external beam irradiation followed by one brachytherapy application (median point A dose = 8040 cGy; range, 4083-10,020 cGy). Brachytherapy parameters assessed were (a) the distance between the right colpostat source and the distal tandem source, (b) the distance between the left colpostat source and the distal tandem source, and (c) the symmetry of colpostat placement. Implants were scored as "ideal" (n = 8) when all three parameters were deemed satisfactory, "unacceptable" (n = 17) when none of the parameters was deemed satisfactory, and "adequate" (n = 41) in all other cases. Significantly improved 5-year local control was seen when comparing ideal and adequate placements to unacceptable placements (68% vs 34%, P = 0.02). A strong trend toward improved 5-year survival was also noted among the group with ideal and adequate implants as opposed to unacceptable implants (60% vs 40%). Multivariate analysis showed that the technical adequacy of the brachytherapy implant was the most important prognostic discriminant of local control. In conclusion, these analyses demonstrate the direct influence of competent technical implant performance on tumor control and even survival. While only a small fraction of implants for cervical cancer are performed poorly in the United States, there is a need for continued emphasis of the principles for proper implant technique.     

Neuroendocrine differentiated carcinoma of the uterine cervix

Cervical neuroendocrine carcinomas (CNC) are rare tumors. The term includes the cervical carcinoid, the small cell (oat-cell) carcinoma and the primitive neuroectodermal tumor (PNET). Between 1979 and 1993 eight CNC out of 788 cervical carcinomas were identified by conventional light microscopy and immunohistochemistry. Three tumors were small cell carcinomas with positive staining for NSE (6/8 tumors) and chromogranin A (2/8). In one case a PNET was diagnosed by identifying rosette like structures and negative immunohistochemistry for neuroendocrine markers. Two patients (including PNET) died of disease 3.1 (1.3 to 4.8) years after diagnosis. The others showed no evidence of disease after a mean follow up to 4.4 years. Three of them got pelvic radiation postoperatively. Four tumors showed foci of squamous cell carcinoma [3] and adenocarcinoma [2]. There is no evidence, that these foci influence the prognosis on CNC. Therefore, it is important to recognize the neuroendocrine component, as this type of carcinoma requires special therapeutic considerations. The authors favour the metaplastic origin of CNC from a multipotent (endocervical) stem cell.     

A pilot study on concurrent platinum chemotherapy and intracavitary brachytherapy for locally advanced cancer of the uterine cervix

This study aims to evaluate the feasibility, toxicity and efficacy of concurrent chemotherapy with platinum compounds and brachytherapy, for locally advanced carcinoma of the cervix (Stages IIA/B, IIIA). The hypothesis was that synchronous chemo-brachytherapy may be sufficient to cause down-staging of the tumour, to render it operable, and hopefully improve the prognosis. 36 women with locally advanced cervical cancer were treated with concomitant brachytherapy and chemotherapy before surgery and/or definitive external radiotherapy. All patients received two caesium-137 Selectron MDR applications, 1 week apart. The dose calculated to point A for each implant was 20-25 Gy. Chemotherapy consisting of continuous cisplatin infusion (50 mg m2) and of carboplatin (300 mg m-2) was given simultaneously with intracavitary irradiation during the first and second application, respectively. The combined therapy was followed when feasible by radical hysterectomy, pelvic lymphadenectomy and pelvic radiotherapy. Patients deemed ineligible for surgery because of poor response were given full dose external radiotherapy. 31/36 patients were treated by Wertheim hysterectomy of whom 10 had negative lymph nodes and resection margins. Definitive external radiotherapy was given in the remaining five patients. Overall, 83% were disease free at 2.8 years mean follow-up. The most frequent acute side-effects of chemobrachytherapy were nausea and vomiting. No renal toxicity was observed. Thrombocytopenia was seen in five patients and was responsible for delayed surgery in four patients. Concerning late effects, two patients developed grade 2 intestinal sequelae, two mild frequency and two vaginal stenosis. One rectovaginal and one vesicovaginal fistula developed in two patients; and a third patient had a fistula associated with tumour recurrence. Concurrent brachytherapy and chemotherapy with platinum compounds is well tolerated and effective in reducing tumour bulk before definitive local treatment (surgery or external radiotherapy), in patients with locally advanced carcinoma of the uterine cervix.     

Late rectal sequelae following definitive radiation therapy for carcinoma of the uterine cervix: a dosimetric analysis

OBJECTIVE: The structure of the collagen scar during healing of a myocardial infarction is a determinant of the function of the remodeled tissue. We hypothesize that the passive deformations of both scar and normal tissue are related to the underlying collagen uncoiling as the tissue stretches, and that the unloaded tortuosity of the collagen may be a determinant of tissue stiffness at low ventricular pressure. Hence collagen uncoiling and tissue strain were measured during passive loading in normal tissue, and in healing infarct tissue. METHODS: Left ventricles of rats were infarcted by ligation of the left anterior descending artery for 2 weeks. Surface strains were measured during passive inflation in the scar region in one set of excised hearts, and other arrested hearts were fixed at different ventricular pressures, after which collagen tortuosity was measured in the infarcted and normal tissue. RESULTS: Passive loading strains were smaller in the scar in both the fiber and cross-fiber directions. Tortuosity decreased with load in normal and infarcted tissue, with fibrils tending to straighten more in the scar tissue at higher pressures (1.056 +/- 0.009 vs. 1.024 +/- 0.009 at P = 20 mmHg) with similar tortuosities at zero pressure (1.110 +/- 0.012 vs. 1.098 +/- 0.019). The decrease in tortuosity with strain was greater for the infarcted tissue. CONCLUSIONS: The greater stiffness of infarcted tissue at low pressure is not due to 'straightened' collagen fibers, and there may be a different three-dimensional structure of infarct vs. normal coiled collagen fibers which can affect the material properties of these tissues.     

Carcinoembryonic antigen in patients treated with radiation therapy for invasive squamous cell carcinoma of the uterine cervix

Plasma carcinoembryonic antigen (CEA) levels in 75 patients with invasive cervical cancer were measured during and after radiation therapy. Initial CEA levels were elevated in 65% of the patients, the incidence varying with stage of disease. Of the 32 patients followed during therapy, CEA levels rose in 26 (81%). CEA values after therapy in the same 32 patients showed three patterns: (1) decline to normal, associated with a disease-free state; (2) decline but not to normal, associated with heavy cigarette smoking or persistent disease; and (3) decline to normal, followed by a rise to abnormal, associated with tumor recurrence. Elevation of CEA levels preceded recognition of recurrent cervical cancer by as much as 4 months in five of seven patients.     

Race and clinical outcome in patients with carcinoma of the uterine cervix treated with radiation therapy

Epidemiologic and in vitro data have shown that the association of house-dust mite (HDM) allergy and snail allergy in the same patients was due to cross-reactivity between HDM and snail allergenic components. However, the cross-reacting allergen(s) have not yet been identified. In vitro reactivity of seven patients' sera to the various extracts and hemolymph of four different Helix snail species was analyzed by IgE detection and immunodots and Western blots. Cross-reactivity between snails and Dermatophagoides pteronyssinus was assessed by immunodot and ELISA inhibition in two patients. Heterologous inhibition of the snail immunodot and ELISA was observed in one serum. Western blotting showed a specific binding on all four snail species extracts; molecular weights of snail allergens ranged from < 21 to 200 kDa. Marked individual differences were observed in the seven sera under study; most sera demonstrated IgE recognition of multiple bands, illustrating that no single allergen is responsible for cross-reactivity between snail and mite. These results confirm that cross-reactivity exists between snails of the Helix genus and HDM. This cross-reactivity, involving more than a single allergen, may be of clinical significance in atopic patients allergic to D. pteronyssinus. The identity of the cross-reacting allergens remains to be determined. Potential candidates include the thermostable minor allergens of D. pteronyssinus, tropomyosin and hemocyanin.     

Squamous cell carcinoma markers in neoplasms of the uterine cervix

In an extremely well-controlled study, Cohen et al. (1998) add to prior knowledge of stress-illness relationships by showing that self-reports of stress occurrence and duration of 1 month or more, rather than estimates of stressor severity, predict susceptibility to experimentally induced colds (i.e., viral replication and cold symptoms). Although ruling out obvious behavioral and personality factors as causes of the association of stressors to colds, they were unable to identify mediational immune factors, a deficit attributable to the difficulty of assessing the multi-layered, dynamic physiological processes within the bidirectional connections of the nervous (stress) and immune systems. The findings provide an interesting complement to data, showing that people use stressor duration in evaluating the illness implications of somatic symptoms (Cameron et al., 1995), and suggest caution with regard to overestimating the prevalence of stress-induced colds in natural settings.     

Organ preservation in locally advanced carcinoma of the uterine cervix

The purpose of this study was to demonstrate the potential usefulness of the combination of gadolinium and dysprosium to enhance the different between normal and necrotic liver tissue. Small regions of acute necrosis were induced by injecting 200-300 microliters of 95% alcohol into the liver of 26 rats. MRI was performed 24 hours after necrosis induction, before and immediately after injection of one or both contrast agents. Using a mixed T1/T2-weighted sequence, the signal intensity of (SI) of the normal liver was reduced by 70%, whereas the necrotic regions had more than a 50% increase in SI after double contrast. The region that was enhanced corresponded largely with the region of necrosis as observed postmortem. The lesion size, when identified, was largely underestimated using either of the agents along, albeit using the common pulse sequences. The double contrast effect of simultaneous administration of gadolinium and dysprosium allows accurate delineation of liver necrosis.     

The long-term course of carcinoma in situ of the uterine cervix

The malignant potential of carcinoma in situ (CIS) of the uterine cervix has been the subject of great controversy. Despite refinements and additions to knowledge in this area, few reports on the long-term course of the disease have appeared in the past decade. Recent developments in diagnostic and therapeutic techniques coupled with changes in the patient population with this disease have prompted renewed interest in conservative management. Results of long-term observation of a group of patients followed initially without ablative therapy are reported. The data indicate that CIS of the uterine cervix is not the inevitably progressive disease that it has been considered to be. Unequivocal invasive cancer develops in only a small percentage of cases and can be controlled, if not cured, by current therapeutic modalities. The intraepithelial lesion, however, tends to persist despite conization, and eventually requires ablative therapy in most cases. Conservative procedures should be regarded as temporizing, at least until their long-term benefits can be recorded.     

Uterosacral space involvement in locally advanced carcinoma of the uterine cervix

PNU-151774E [(S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate] is a structurally novel anticonvulsant having Na+ channel-blocking and glutamate release-inhibiting properties, as well as being a MAOB inhibitor. Its anticonvulsant activity was evaluated in the maximal electroshock (MES) test and in chemically induced seizures (bicuculline, BIC; picrotoxin, PIC; 3-mercaptopropionic acid, 3-MPA; pentylenetetrazole, PTZ; strychnine, STRYC). Behavioral toxicity was evaluated in the rotorod test with measurements of spontaneous locomotor activity and passive avoidance responding. The anti-MES activity of PNU-151774E in both mice and rats, respectively, produced ED50 values of 4.1 mg/kg and 6.9 mg/kg after i.p. administration or 8.0 mg/kg and 11.8 mg/kg after p.o. administration. Oral anti-MES activity in rats peaked between 1 and 2 h after administration and was evident up to 4 h. This activity was related to brain levels of unchanged drug which peaked at 37 mM within 1 h. Oral ED50 values (mg/kg) effective in blocking tonic extension seizures by chemical convulsants in mice were: BIC (26.9), PIC (60.6), 3-MPA (21.5), STRYC (104.1) and PTZ (26.8). This potency was associated with high therapeutic indices relative to: MES (78.2), BIC (23.3), PIC (10.3), 3-MPA (29.1) and STRYC (6.0). No evidence of tolerance to anti-MES activity after repeated dosing was observed. PNU-151774E did not show anti-absence seizure activity as assessed by i.v. infusion of PTZ. PNU-151774E impaired spontaneous activity in rats only at the oral rotorod ED50 dose of 700 mg/kg p.o. PNU-151774E did not impair passive avoidance responding at doses up to 40 times the oral MES ED50 dose in rats. These results indicate that PNU-151774E is an anticonvulsant effective in various seizure models with a wide therapeutic window, and with a low potential to induce tolerance and locomotor or cognitive side effects.     

Small cell carcinoma of the uterine cervix: a clinicopathological review

Small cell carcinoma of the cervix is rare, with an aggressive natural history. We report on a series of 11 patients treated at the Christie Hospital, Manchester and examine their treatment and survival. Eleven patients with small cell carcinoma of the cervix were identified retrospectively from patient case notes. Treatment was individualised and included a variety of combinations of surgery radiotherapy and chemotherapy. Four patients were disease-free between 21 and 108 months (crude disease-free survival 36%). They presented with earlier disease and were older than the average for the group. They were all initially treated with radical radiotherapy. 7 patients died between 7 and 25 months. Despite combination chemotherapy, survival with advanced disease was poor. Published studies are small and fail to provide definitive answers on the best management of small cell carcinoma of the cervix. Drawing on the experience of small cell carcinoma of the lung however, combination therapy with radiotherapy, chemotherapy and possibly surgery requires careful assessment by an oncologist.