External Beam Combination Research Articles

Distal Vaginal Recurrences after Vaginal Brachytherapy

Distal Vaginal Recurrences after Vaginal Brachytherapy

Prediction of outcome in buccal cancers treated with radical radiotherapy based on the early tumor response.

Aim was to assess the clinical significance of the rate of tumor regression in carcinoma buccal mucosa undergoing radical radiotherapy. Sixty six patients were enrolled in the study with proven buccal cancers requiring radical radiotherapy, from 1990 to 1996. Radiotherapy was delivered using a combination of external beam and brachytherapy with preloaded cesium 137 needles. The response to the radiation was assessed at the completion of external beam radiation and 6 weeks after brachytherapy. An analysis correlating various parameters influencing the long term disease free survival and overall survival was done. Response assessed at the end of external beam radiation correlated strongly with the overall survival and the disease free interval (P=0.000). No other factor influenced the survival. The rate of the tumor regression can predict the overall outcome in patients with buccal cancers treated with radiation. Completion of the planned course of radiation in patients who do not show a substantial reduction in size by 4.5 weeks of conventional radiation does not improve the results.

Results of hormone therapy as first-line treatment for high-risk prostate cancer

To assess the current place for androgen deprivation therapy as single modality in locally advanced nonmetastatic situations. One standard of care for node negative locally advanced disease is a combination of external beam with androgen deprivation treatment. Several recent randomized trials have confirmed the key role of a local treatment combined to a systemic one in terms of specific and overall survival. The specific morbidity of this combined modality appears to be minimal. Retrospective data also suggest that a local treatment should be considered in case of positive nodes. Finally, the real place of immediate single hormonal treatment has also been clarified. The limited survival benefit has to be balanced with the side-effects. Therefore, this single modality should be limited to the most aggressive situations when no local treatment is planned. Single hormonal treatment for nonmetastatic advanced prostate cancer appears to be limited to the few patients unfit or unwilling for a local treatment and having a high prostate-specific antigen and a short prostate-specific antigen doubling time. In all other situations, it might represent a clear undertreatment.

Feasibility of Composing External Beam Radiotherapy and HDR Brachytherapy of Cervical Cancer Using Deformable Image Registration

Combination of external beam (EB) and intracavitary brachytherapy (IB) are the standard treatment of cervical and medically inoperable endometrioid carcinomas. Integrated dose distributions from EB and IB plans are currently unavailable due to large anatomic changes. This study combined EB and IB plans using deformable image registration.

Radiation-Induced Bowel Complications: Laparoscopic Versus Open Staging of Gynecologic Malignancy

To evaluate whether the type of surgical approach used to stage gynecologic malignancies influences the risk of developing nonrectal radiation-induced intestinal injury (NRRIII) in patients who subsequently receive adjuvant radiotherapy. A prospectively entered database was queried for all women with either primary or recurrent gynecologic malignancy who underwent external-beam radiation therapy±brachytherapy and who had prior abdominopelvic surgery at our institution. Univariate and multivariate analysis of variables potentially affecting the risk of developing significant bowel toxicity (defined as grade 2 or more according to Radiation Therapy Oncology Group scoring) were performed. One hundred fifty-nine patients were identified. The site of primary tumor was the cervix in 61(38%) patients and the corpus uteri in the remaining patients (98, 62%). Treatment was delivered with a combination of external-beam and intracavitary irradiation to 50 (31.4%) patients, and 109 (68.6%) patients received only external-beam irradiation. Staging procedures were performed by open surgery in 93 (58.5%) patients, whereas laparoscopy was the surgical approach of choice in 66 (41.5%) women. Fifteen patients (9.4%) developed grade 2 or greater NRRIII, at median latency of 10months (range 3-64months); six were diagnosed as grade 3 complications requiring surgery, and three developed grade 4 complication. Multiple regression revealed an independent protective effect of pretreatment laparoscopic staging against the risk of developing both grade ≥2 and grade ≥3 NRRIII. Notwithstanding potential limitations of nonrandomized study design, our findings suggest that the benefits of minimal-access surgery used to perform staging procedures may translate into long-term reduction in radiation-induced bowel injury.

WE-E-T-617-04: IMRT and Brachytherapy for Cervical Cancer

Purpose: Radiotherapy of cervical cancer is usually delivered through a combination of external-beam and intracavitary-brachytherapy treatments. A portion of the external-beam treatment is often delivered with a midline block, either straight or tapered at the edges, to avoid overdosing the brachytherapy dose distribution. This study investigates the replacement of the midline block with intensity-modulated-radiation-therapy (IMRT), matching the IMRT dose to the biologically-equivalent brachytherapy dose distribution, while additionally achieving optimized target coverage and minimized critical organ doses. Method and Materials: CT scans of a female pelvic phantom were imported into a commercial treatment planning system (TPS) to calculate the dose distribution of a high-dose-rate (HDR) tandem and ovoid treatment delivering 650cGy to point A. A planning target volume (PTV), the rectum, and the bladder were segmented. The brachytherapy dose distribution was converted to its biologically-equivalent dose distribution, at 180cGy daily fractions, using the linear-quadratic equation and an α/β ratio of 10, by modifying the HDR source's radial-dose function (RDF) values. A set of IMRT fields, at 180cGy/fraction, was planned to deliver a dose of 720cGy to the target for each HDR fraction while accounting for implant dose. The IMRT fields geometry included two scenarios; AP/PA parallel-opposed fields, mimicking the conventional split-field pelvis treatments with a midline block, and a 5-field coplanar beam arrangement that had the potential to improve target coverage and reduce critical-organ doses. Results: The single-source RDF values were successfully modified to compute the biologically-equivalent dose distribution of the HDR treatment. The TPS was able to calculate IMRT field fluence maps, in both scenarios, to obtain dose volume histograms of the target and the critical organs as prescribed. Conclusion: It was demonstrated that IMRT doses distributions for cervical cancer treatment can be biologically matched to brachytherapy dose distributions, thus improving target coverage and sparing critical structures.

Biological effective dose for comparison and combination of external beam and low-dose rate interstitial brachytherapy prostate cancer treatment plans

We report a methodology for comparing and combining dose information from external beam radiotherapy (EBRT) and interstitial brachytherapy (IB) components of prostate cancer treatment using the biological effective dose (BED). On a prototype early-stage prostate cancer patient treated with EBRT and low-dose rate I-125 brachytherapy, a 3-dimensional dose distribution was calculated for each of the EBRT and IB portions of treatment. For each component of treatment, the BED was calculated on a point-by-point basis to produce a BED distribution. These individual BED distributions could then be summed for combined therapies. BED dose-volume histograms (DVHs) of the prostate, urethra, rectum, and bladder were produced and compared for various combinations of EBRT and IB. Transformation to BED enabled computation of the relative contribution of each modality to the prostate dose, as the relative weighting of EBRT and IB was varied. The BED-DVHs of the prostate and urethra demonstrated dramatically increased inhomogeneity with the introduction of even a small component of IB. However, increasing the IB portion relative to the EBRT component resulted in lower dose to the surrounding normal structures, as evidenced by the BED-DVHs of the bladder and rectum. Conformal EBRT and low-dose rate IB conventional dose distributions were successfully transformed to the common “language” of BED distributions for comparison and for merging prostate cancer radiation treatment plans. The results of this analysis can assist physicians in quantitatively determining the best combination and weighting of radiation treatment modalities for individual patients.

The role of irradiation in the management of locally recurrent non-metastatic soft tissue sarcoma of extremity/trunkal locations.

Background: Patients who have had initial curative intent therapy for non-metastatic soft tissue sarcoma, and who subsequently relapse at the initial site without evidence of metastatic disease, have various options regarding local treatment. The treatment options available will be determined by the extent of relapse, previous therapy rendered, and patient characteristics. We reported on a series of 31 patients treated initially with only surgery for extremity/trunkal high-grade soft tissue sarcoma and then seen for recurrence at our institution between 1980 and 1999. Local re-treatment consisted of combined modality therapy, most often aggressive surgical debulking/resection and irradiation, in an effort to reduce the need for amputation and, where anatomically allowable, to maintain a functional limb. We report our results in re-establishing local control, subsequent survival, and complication rates. Methods: Thirty-one patients with locally recurrent, non-metastatic high-grade soft tissue sarcoma, (excluding extraabdominal desmoid) were retrospectively reviewed to determine local control, survival, and complication rates associated with the relapsed disease. All patients had multimodality re-treatment most often utilizing aggressive surgical debulking and irradiation. The irradiation consisted of either external beam alone, brachytherapy alone, or a combination of external beam and brachytherapy. Nine patients also received multi-agent, multi-cycle chemotherapy using various regimens. In addition, the impact of surgical margin at the time of re-resection (gross versus microscopic disease), radiation treatment type, total radiation dose delivered, size of relapse, histological sub-type, sex and age, were evaluated to determine if they had any impact on the re-establishment of local control and subsequent survival. Results: Local control was re-established in 25 of 31 (80.6%) patients. Two additional patients with isolated local relapse after irradiation were salvaged with amputation and remain NED at last follow-up. With these patients a total of 27/31 (87%) are now with local control. At last follow-up, which ranged from 23 to 192 months, 23 of 31 (74%) remained alive. Of the eight patients who have died, four had evidence of local and distant failure. Two additional patients died of distant failure while the treated sites remained in local control and two patients, both NED, died of intracurrent processes. Follow-up for those patients who had re-established local control has ranged from 23 to 192 months (median=60.5 months). Time to local failure following re-treatment ranged between 3 and 72 months following re-treatment (median=12 months). Five patients had significant treatment related complications. Included are two patients in which amputation was required due to local recurrences. Two patients developed a soft tissue necrosis and one patient had a wound healing problem that resolved with conservative management. No statistical significance in the development of local control could be found based on surgical margin status, total dose of irradiation (greater or less than 60 Gy), size of recurrence (greater than 5 cm), histological sub-type, sex, or age (greater than 50 years). There was a trend for negative impact for those patients receiving only external beam irradiation. Conclusion: Selective locally recurrent, non-metastatic soft tissue sarcoma of the extremity/trunkal regions should still be considered eligible for aggressive limb-sparing therapy. Our experience suggests that a majority of patients re-establish local control following aggressive surgical resection/debulking and irradiation and this appears to be durable in its nature. The role of chemotherapy in this group of patients remains investigational. In a surprising finding, one patient re-relapsed in the re-treatment site at 72 months, thus justifying continued strict surveillance not only in the primary site but also for subsequent metastatic disease.

The Role of Irradiation in the Management of Locally Recurrent Non-Metastatic Soft Tissue Sarcoma of Extremity/Trunkal Locations

Background:Patients who have had initial curative intent therapy for non-metastatic soft tissue sarcoma, and who subsequently relapse at the initial site without evidence of metastatic disease, have various options regarding local treatment. The treatment options available will be determined by the extent of relapse, previous therapy rendered, and patient characteristics. We reported on a series of 31 patients treated initially with only surgery for extremity/trunkal high-grade soft tissue sarcoma and then seen for recurrence at our institution between 1980 and 1999. Local re-treatment consisted of combined modality therapy, most often aggressive surgical debulking/resection and irradiation, in an effort to reduce the need for amputation and, where anatomically allowable, to maintain a functional limb. We report our results in re-establishing local control, subsequent survival, and complication rates.Methods:Thirty-one patients with locally recurrent, non-metastatic high-grade soft tissue sarcoma, (excluding extraabdominal desmoid) were retrospectively reviewed to determine local control, survival, and complication rates associated with the relapsed disease. All patients had multimodality re-treatment most often utilizing aggressive surgical debulking and irradiation. The irradiation consisted of either external beam alone, brachytherapy alone, or a combination of external beam and brachytherapy. Nine patients also received multi-agent, multi-cycle chemotherapy using various regimens. In addition, the impact of surgical margin at the time of re-resection (gross versus microscopic disease), radiation treatment type, total radiation dose delivered, size of relapse, histological sub-type, sex and age, were evaluated to determine if they had any impact on the re-establishment of local control and subsequent survival.Results:Local control was re-established in 25 of 31 (80.6%) patients. Two additional patients with isolated local relapse after irradiation were salvaged with amputation and remain NED at last follow-up. With these patients a total of 27/31 (87%) are now with local control. At last follow-up, which ranged from 23 to 192 months, 23 of 31 (74%) remained alive. Of the eight patients who have died, four had evidence of local and distant failure. Two additional patients died of distant failure while the treated sites remained in local control and two patients, both NED, died of intracurrent processes. Follow-up for those patients who had re-established local control has ranged from 23 to 192 months (median=60.5 months). Time to local failure following re-treatment ranged between 3 and 72 months following re-treatment (median=12 months). Five patients had significant treatment related complications. Included are two patients in which amputation was required due to local recurrences. Two patients developed a soft tissue necrosis and one patient had a wound healing problem that resolved with conservative management. No statistical significance in the development of local control could be found based on surgical margin status, total dose of irradiation (greater or less than 60 Gy), size of recurrence (greater than 5 cm), histological sub-type, sex, or age (greater than 50 years). There was a trend for negative impact for those patients receiving only external beam irradiation.Conclusion:Selective locally recurrent, non-metastatic soft tissue sarcoma of the extremity/trunkal regions should still be considered eligible for aggressive limb-sparing therapy. Our experience suggests that a majority of patients re-establish local control following aggressive surgical resection/debulking and irradiation and this appears to be durable in its nature. The role of chemotherapy in this group of patients remains investigational. In a surprising finding, one patient re-relapsed in the re-treatment site at 72 months, thus justifying continued strict surveillance not only in the primary site but also for subsequent metastatic disease.

High-dose-rate brachytherapy boost following concurrent chemoradiotherapy for esophageal carcinoma

Purpose: To assess the efficacy, toxicity, and the optimum dose of high-dose-rate brachytherapy following chemoradiotherapy (CRT) compared with a historical group of patients treated with a combination of external beam and brachytherapy (RT alone).Methods and Materials: Fifty-three patients with localized esophageal cancer received concurrent chemoradiotherapy followed by brachytherapy. The chemotherapy regimen was a combination of cisplatin 60 mg/m2 on day 1 and fluorouracil 600 mg/m2 continuous infusion from days 1–4 during the first and last week of external irradiation. Radiotherapy consisted of external irradiation to a total dose of 40–61 Gy (median 50 Gy) and brachytherapy to 8–24 Gy (median 16 Gy) in 2–4 fractions.Results: Acute toxicity was well tolerated. A fistula occurred in one patient 1 week after completion of external irradiation. Local control was achieved in 32/53 (60%) compared with 42% of the RT group (p = 0.029). Local control rates of the CRT group were significantly better than those of the RT group in Stages II and III. Late toxicity (esophageal ulceration and strictures) occurred in 18 (34%) of the CRT group compared with 12% in the RT group (p = 0.013). Severe late toxicity (RTOG/EORTC criteria Grade 3–4) occurred in six patients (15%) whose chemotherapy was followed by 16–24 Gy via brachytherapy compared with 2.5% in the RT group (p = 0.010).Conclusion: Combined chemoradiotherapy and brachytherapy boost achieved better local control than radiotherapy alone. However, a high level of severe late toxicity was observed especially with 16–24 Gy via brachytherapy.

Patterns of radiotherapy practice for patients with squamous carcinoma of the uterine cervix: patterns of care study

Purpose: To determine the impact of research findings and evolving technology on the patterns of radiotherapy practice for patients with carcinoma of the uterine cervix. Methods and Materials: Sixty-two radiation therapy facilities participated in the study after having been selected from a random sample, proportionally stratified according to practice type, of all United States facilities. Each facility submitted a list of patients treated during 1992–1994 with radiation for squamous carcinoma of the cervix. Cases for review were randomly selected from each institution after excluding those of patients who had distant metastases or initial hysterectomy. A total of 471 patients’ records were reviewed in the treating institutions to obtain information about patients’ characteristics, diagnostic evaluation, tumor extent, treatment approach, and radiotherapy techniques. Results: Of the 61 facilities that treated eligible cases of intact cervical cancer during the 3-year survey period, 35 (57%) treated fewer than three eligible patients per year. Thirty-four (83%) of 41 non-academic facilities vs. 1 (5%) of 20 academic facilities treated fewer than three patients per year. FIGO stages were I, II, III, and IV in 32%, 40%, 24%, and 3% of patients, respectively. Computed tomography (CT) was the most common method of lymph node evaluation, but surgical evaluation, which was performed in 76 (16%) patients, had increased from previous surveys. Fields were designed using a dedicated simulator in 95% of patients; a dedicated CT unit was used for treatment planning in 119 (30%) cases. External beam irradiation was most often given using a four-field technique at 180 cGy per day on a 10–20 MV linear accelerator. The average daily fraction size had decreased from previous surveys, and 13% of patients were treated with daily doses of 170 cGy or less. Most patients were treated with a combination of external beam and low dose-rate (LDR) intracavitary irradiation. Of 425 patients who had treatment with curative intent that included brachytherapy, 362 (85%) had LDR brachytherapy, 45 (11%) had high dose-rate (HDR) brachytherapy, 3 had a combination of HDR and LDR, and 15 had incomplete information about the brachytherapy dose-rate. Forty-six (23%) of 197 patients with Stages I–IIA disease were treated with radiation followed by extrafascial hysterectomy. Of 111 patients treated with curative intent for Stage III–IV disease, 72 (65%) had a combination of external beam and intracavitary radiation therapy, 22 (20%) had external beam plus interstitial brachytherapy, and 17 (15%) were treated with external beam irradiation only. For patients who completed treatment with curative intent and did not have adjuvant hysterectomy or HDR brachytherapy, the median total dose at point A was 82.5 Gy. For all patients who completed treatment with radiation alone, the median total duration of treatment was 63 days; more than 70 days were taken to complete treatment in 33% of cases. Twenty-nine percent of patients received chemotherapy, usually concurrent with their radiation therapy. Only 27% of these patients were on investigational protocols. Conclusions: Greater participation in well-designed prospective trials might help clinicians address important clinical questions and reduce current inconsistencies in the use of adjuvant treatments. Radiation oncologists should take steps to avoid unnecessary treatment protraction and to improve patient compliance. Future studies will be needed to determine whether the small number of cases being treated in most nonacademic facilities will influence the outcome for patients with invasive cervical carcinoma.

Combined low-dose-rate brachytherapy and external beam radiation for cervical cancer: experience over ten years.

Cervical cancer was treated with a combination of external beam and intracavitary radiation during a 10-year period at Wayne State University. Data were collected for 216 patients treated radically with external beam radiation (EBRT) and low-dose-rate brachytherapy for cervical cancer between 1980 and 1991 at Wayne State University. Patient distribution by stage was IB, 20.8%; IIA, 7.4%; IIB, 26.9%; IIIA, 1.8%; IIIB, 40.7%; and IVA, 2.3 %. Survival curves were constructed using Kaplan-Meier methods and differences between groups were tested for significance using the log-rank test. Multivariate analysis was done using the Cox proportional hazards model. With a median follow-up of 114 months, actuarial disease-free survival for all patients was 60% at 5 years and 55% at 10 years. Actuarial 5-year survival for Stage IB was 79%; for Stage II, 59%; and for Stage III, 53%. There were 14/216 (6%) of patients with severe late complications. On univariate analysis, race was found to be statistically significant, with Caucasian patients having better survival than African American (P = 0.03). The survival for patients treated in shorter overall times was significantly higher (P<0.001), especially with treatment completion in under 58 days. The stepwise Cox multivariate analysis provided the following significant results: race (African American vs. Caucasian; P = 0.04, RR = 1.6), Stage (II vs. I, P = 0.004, RR = 2.6), Stage (III vs. I; P = 0.004, RR = 2.5), and overall treatment time (P = 0.006, RR = 1.62). Rates of local control, survival, and complications among women treated with combined external beam and intracavitary radiation for cervix cancer were similar to those of prior retrospective studies.

Conservative treatment of anorectal tumors.

To evaluate the results of interstitial radiotherapy of anorectal tumors. From 1972 to 1993, one of the authors treated 45 patients by an interstitial implant for anorectal tumors. Of these, 33 patients suffered from primary tumors, 19 from squamous carcinoma, 2 from basaloid carcinoma of the anus and the other 12 from primary adenocarcinoma of the rectum. Of 12 patients treated for local recurrence, 10 had adenocarcinoma and 2 squamous cell carcinoma. Of the 33 patients with primary tumors, 27 received a course of external-beam radiotherapy before the implant. The median follow-up was 35 months. Local response depended on the tumor volume treated. All 21 anal tumors showed complete response, 5 patients developed local recurrence and 4 distant metastases: 3 died from their disease. Of 12 rectal adenocarcinomas, 9 responded completely, 4 patients developed local recurrence and 4 distant metastases; 6 died from active disease. In the last group of 12 patients who were treated for recurrent tumors, 7 responded completely. One patient developed local recurrence and 9 distant metastases, only 4 are alive. A combination of external-beam and interstitial radiotherapy is a relatively simple, non-mutilating, but well-tolerated and very effective method of treatment for early carcinoma of the lower rectum and anus.

Tumor Size, Irradiation Dose, and Long-Term Outcome of Carcinoma of Uterine Cervix

Purpose: To assess the impact of tumor size and extent, and dose of irradiation on pelvic tumor control, incidence of distant metastases, and disease-free survival in carcinoma of the uterine cervix. Methods and Materials: Records were reviewed of 1499 patients (Stages IA–IVA) treated with definitive irradiation (combination of external beam plus two intracavitary insertions to deliver doses of 65–95 Gy to point A, depending on stage and tumor volume). Follow-up was obtained in 98% of patients (median 11 years, minimum 3 years, maximum 30 years). The relationship between outcome and tumor size was analyzed in each stage. Pelvic tumor control was correlated with total doses to point A and to the lateral pelvic wall. Results: The 10-year actuarial pelvic failure rate in Stage IB was 5% for tumors <2 cm, 15% for 2.1–5 cm, and 35% for tumors >5 cm ( p = 0.01); in Stage IIA, the rates were 0%, 28%, and 25%, respectively ( p = 0.12). Stage IIB unilateral or bilateral nonbulky tumors <5 cm had a 23% pelvic failure rate compared with 34% for unilateral or bilateral bulky tumors >5 cm ( p = 0.13). In Stage IIB, pelvic failures were 18% with medial parametrial involvement only, compared with 28% when tumor extended into the lateral parametrium ( p = 0.05). In Stage III, unilateral parametrial involvement was associated with a 32% pelvic failure rate versus 50% for bilateral extension ( p < 0.01). Ten-year disease-free survival rates were 90% for IB tumors <2 cm, 76% for 2.1–4 cm, 61% for 4.1–5 cm, and 47% for >5 cm ( p = 0.01); in Stage IIA, the rates were 93%, 63%, 39%, and 59%, respectively ( p ≤ 0.01). Patients with Stage IIB medial parametrial involvement had better 10-year disease-free survival (67%) than those with lateral parametrial extension (56%) ( p = 0.02). Stage III patients with unilateral tumor extension had a 48% 10-year disease-free survival rate compared with 32% for bilateral parametrial involvement ( p ≤ 0.01). The presence of endometrial extension or tumor only in the endometrial curettings had no significant impact on pelvic failure. However, in patients with Stage IB disease, the incidence of distant metastases was 31% with positive curettings, 15% with negative curettings, and 22% with admixture ( p ≤ 0.01). In Stage IIA, the corresponding values were 51%, 33%, and 18% ( p = 0.05). The 10-year disease-free survival rates in Stage IB were 67% with positive curettings, 81% for negative curettings, and 77% for admixture ( p = 0.02); in Stage IIA, the rates were 45%, 66%, and 67%, respectively ( p = 0.14). Because this is not a prospective Phase II dose-escalation study, the correlation of doses of irradiation with pelvic tumor control in the various stages and tumor size groups is not consistent. Nevertheless, with Stage IB and IIA tumors <2 cm in diameter, the pelvic failure rate was under 10% with doses of 70–80 Gy to point A, whereas for larger lesions even doses of 85–90 Gy resulted in 25% to 37% pelvic failure rates. In Stage IIB with doses of 70 Gy to point A, the pelvic failure rate was about 50% compared with about 20% in nonbulky and 30% in bulky tumors with doses >80 Gy. In Stage III unilateral lesions, the pelvic failure rate was about 50% with ≤70 Gy to point A versus 35% with higher doses, and in bilateral or bulky tumors it was 60% with doses <70 Gy and 50% with higher doses. Conclusions: Clinical stage and size of tumor are critical factors in prognosis, therapy efficacy, and evaluation of results in carcinoma of the uterine cervix. The doses to point A suggest that for lesions <2 cm, doses of 75 Gy result in ≤10% pelvic failures, whereas in more extensive lesions, even with doses of 85 Gy, the pelvic failure rate is about 30%; and in Stage IIB–III tumors, doses of 85 Gy result in 35–50% pelvic failures. Refinements in brachytherapy techniques and/or use of agents to selectively sensitize the tumors to irradiation will be necessary to improve the present results in invasive carcinoma of the uterine cervix.

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.

Carcinoma of the uterine cervix. II. Lack of impact of prolongation of overall treatment time on morbidity of radiation therapy

Purpose :Several reports document a negative impact of prolongation of overall treatment time in a course of irradiation on tumor control and survival. A correlation has been documented of incidence of significant treatment sequelae with increasing does of irrdiation, volume of the specific organ, and dose per fraction. However, no data were found on the potential correlation of overall irradiation treatment time with significant sequelae. Records were reviewed of 1269 patients with carcinoma of the cervix (Stage IB to III) treated with definitive irradiation (combination of external beam and two intracavitary insertions). Follow-up was obtained in 97% of patients (median, 12 years; minimum, 3 years; maximum, 28 years). The relationships between overall treatment time and time of brachytherapy and incidence of treatment sequelae were analyzed for each stage. Results :Overall incidence of Grades 2 (moderate) sequelae was 7% and of Grade 3 (severe) sequelae, 11%. There was no significant correlation of various incidences of Grade 2 and 3 sequelae with overall treatment times (8% in patients treated in less than 7 weeks, 9% in 7.1 to 9 weeks, and 12% when treatment time was longer than 9 weeks) ( p = 0.08). In patients with Stage IB and IIA tumors, incidence of rectal toxicity (mostly proctitis) was comparable in patients treated in less than 7 or 7.1 to 9 weeks (4.1 and 6%, respectively) and slightly higher in those treated in longer periods (11.5%) ( p = 0.24) In patients with Stage IIB and III, the incidence of Grade 2 and 3 small bowel morbidity was 2% in those treated in less than 7 weeks, 6% for 7.1 to 9 weeks, and 4.9% for longer times ( p ⩽ 0.001). This increased morbidity was also correlated with total dose of irradiation to the lateral pelvic wall: 5 of 257 (2%) for less than 60 Gy and 21 of 438 (4.8%) for higher doses ( p ⩽ 0.01). There was no significant correlation between the timing of brachytherapy (usually two low dose rate intracavitary insertions performed within 4.5 to 6.5 weeks of initiation of external beam therapy) and significant treatment sequelae. Conclusion : We observed a varied average incidence of Grade 2 and 3 morbidity in the bladder, rectum, and small intestine with different overall treatment times, without a definite pattern to suggest an impact of prolongation of treatment time on morbidity. Likewise, there was no significant correlation with the timing of intracavitary inertions and morbidity of therapy. Because prolongation of the overall treatment time has a well-documented detrimental effect on pelvic tumor control and survival in carcinoma of the cervix with no significant impact on morbidity, it is imperative to deliver radiation therapy in the shortest possible time and without schedule interruptions.

1181 10 year results of external beam and HDR intracavitary irradiation in the primary treatment of cancer of the uterine cervix

From August 1980 to December 1990, 303 patients with cancer of the uterine cervix underwent primary irradiation in a combination of external beam and HDR intracavitary treatment at the Department of Radiation Oncology at the Sisters of Mercy Hospital in Linz, Austria. All patients were classified according to the FIGO rules: Stage I 54 patients, stage II 171, stage III 75 and stage IV 3 patients. 8 patients were lost to follow up. The mean follow up time of survivors is 110 months. A complete remission could be achieved in 282 patients, which is 93%; persistent turnout was found in 21 patients at the first follow up check 3 to 5 months after completion of irradiation. The actuarial overall survival probability for all patients at 5 and 10 years is 62% and 42% respectively, the disease specific survival probability is 68% and 64%. The local control rate at 5 and 10 years is 73% and 72% respectively. According to stage, disease specific survival lies at 90% for stage I, 69% for stage II, and 48% for stage III and IV at 5 years, and at 10 years 87%, 66% and 41% respectively. The actuarial local control probability for stages I, II, and III/IV is 90%, 74%, 60% respectively at 5 years, and 88%, 74%, and 56% at 10 years. (Kaplan-Meier calculations). From all 303 patients 34 suffered from 40 severe and moderate side effects (glossary of Chassagne and Sismondi). The rate for grade II complications is 10% and for grade III 3%. We conclude that HDR after loading in addition to external beam radiotherapy is a very effective tool for primary irradiation of cervical cancer, and a safe one in experienced hands.

Carcinoma of the uterine cervix. I. Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy

Purpose : Some studies have described pelvic tumor control and survival rates in invasive carcinoma of uterine cervix when the overall time in a course of definitive irradiation is prolonged. We attempt to confirm or deny these observations and evaluate the impact of timing of brachytherapy on outcome. We also explore the hypothesis that more extensive tumors technically require prolongation of the course of irradiation; thus decreased tumor control and survival in these patients may not necessarily be the result of time/dose factor. Methods and Materials : Records of 1224 patients (Stage IB to III) treated with definitive irradiation (combination of external beam and two intracavitary insertions to deliver doses of 70 to 90 Gy to point A) were reviewed. Follow-up was obtained in 97% of the patients (median, 12 years; minimum, 3 years; maximum, 28 years). The relationship between outcome and overall treatment and time of intracavitary insertions was analyzed in each stage and according to tumor size/extent. Results : There was strong correlation between overall treatment time (OTT) and tumor stage (≤ 7 weeks: 81% for Stage IB; 74% for Stage IIA; 52% for Stage IIB; and 47% for Stage III). Interuptions of therapy accounting for prolongation of treatment time ocurred in 25–30% of patients, most frequently because of holidays and weekends and side effects of therapy. Overall treatment time had a major impact on pelvic tumor control in Stages IB, IIA, and IIB; in Stage IB 10-year actuarial pelvic failure rates were 7% with OTT ≤ 7 weeks, 22% with 7.1 to 9 weeks, and 36% with >9 weeks ( p ≤ o.01). For Stage IIA the corresponding values were 14%, 27% and 36% ( p = 0.08), and in Stage IIB pelvic failure rates were 20%, 28%, and 34%, respectively ( p = 0.09). In Stage III, pelvic failure was 30%, 40%, and 505 respectively ( p = 0.08). There was also a strong correlation between OTT and 10-year cause-specific survival (CSS); in Stage IB rates were 86% with OTT of ≤7 weeks, 78% for 7.1 to 9 weeks, and 55% for ≥9 weeks ( p < 0.01). The corresponding rates in Stage IIA were 73%, 41%, and 48% ( p ≤ 0.01). For patients with Stage IIB, CSS rates were 72% for OTT ≤7 weeks, 60% for 7.1 to 9 weeks, and 70 for >9 weeks ( p = 0.01). Patients with Stage III disease had 45% to 10-year CSS when treatment was delivered in 9 weeks or less and 36% for longer overall ( p = 0.16). In multivariate analysis of patients with Stage IB and IIA, OTT and clinical stage were the most important prognostic factors for pelvic tumor control, disease-free survival, and CSS. Tumor size was a prognostic factor for CSS. In Stages IIB and III, OTT, clinical stage, unilateral or bilateral parametrical invasion, and dose to point A were significant prognostic factors for pelvic tumor control, disease-free survival, and CSS. Prolongation of time had a significant impact on pelvic tumor control and CSS regardless of tumor size, except in Stage IB tumors ≤3 cm. Regression analysis confirms previous reports that prolongation of OTT results in decreased pelvic tumor control rate of 0.85% per day for all patients, 0.37% per day in Stages IB and IIA, 0.68% per day in Stage IIB, and 0.54% for Stage III patients treated with ≥85 Gy to point A. Performance of all intracavity insertions within 4.5 weeks from initiation of irradiation of yeilded decreased pelvic failture rates in some groups of patients (8.8 vs. 18% in Stage IB and IIA tumors ≤4 cm and 12.3 vs. 35% in Stage IBB) ( p ≤ 0.01). Conclusions : Prolongation of treatment time in patients with Stage IB, IIA, IIB, and III carcinoma of the uterine cervix has a significant impact on pelvic tumor control and CSS. The effect of OTT was present regardless of tumor size except in Stage IB tumors ≤3 cm. This may be related to biologic factors such as cell repopulation and increased proliferation resulting from treatment interruptions, in addition to initial clonogenic cells burden. Irradiation for patients with invasive carcinoma of the cervix should be delivered in the shortest possible overall time.

The adverse effect of treatment prolongation in cervical carcinoma

Purpose : Proliferation of surviving tumor clonogens during a course of protracted radiation therapy may be a cause of local failure in cervical carcinoma. The effect of total treatment time was analyzed retrospectively in relation to pelvic control and overall survival for squamous cell carcinomas of the uterine cervix. Methods and Materials : Two hundred and nine patients (Stage IB-IIIB) treated with a combination of external beam and low dose rate intracavitary irradiation were evaluable for study. Multivariate analysis and Kaplan-Meier statistical methods were used to determine the effect of treatment time on pelvic control and survival at 5 years. Results : The median treatment duration was 55 days. For all stages combined, the 5-year survival and pelvic control rates were significantly different with treatment times < days vs. ≥ 55 days 65 and 54% ( p = 0.03), 87 and 72% ( p = 0.006), respectively. By stage, a shorter treatment duration (i.e., < 55 days vs. ≥ 55 days) was significant for 5-year overall survival and pelvic control for Stages IB/IIA and III, but not for Stage IIB: Stage IB/IIA (81 and 67%, and 84%), Stage III disease (52 and 42%, 76 and 55%) and Stage IIB (43 and 50%, 74 and 80%, respectively). Survival decreased 0.6%/day and pelvic control decreased 0.7%/day for each additional day of treatment beyond 55 days for all stages of disease. Additionally, significantly late complications were not influenced by treatment time. Conclusion : These results that prolongation of treatment time is associated with decreased local control and survival in patients with cervical carcinoma. This is consistent with emerging data from other institutions. Therapeutic implications include avoidance of unnecessary treatment breaks, the design of fractionation schemes that decrease treatment duration, and possibly the use of tumor cytostatic drugs during conventional radiation.

Treatment of endometrial carcinoma with radiation therapy alone

Purpose : To review the results of treatment with radiotherapy alone in 152 patients with adenocarcinoma of the endometrium who had medical or surgical contraindications to hysterectomy. Methods and Materials : We reviewed the records of all patients who were treated with radiotherapy alone for uterine carcinoma at The University of Texas M. D. Anderson Cancer Center between 1960 and 1986. One hundred fifty-two cases were analyzed. Most patients had multiple medical problems. One hundred sixteen patients were treated with intracavitary radiotherapy alone. A combination of external beam and intracavitary radiotherapy was used for 10 patients with Stage I disease who had unusually large uterine cavities, 10 patients with Stage II disease, and 13 of 15 patients with Stage III or IV disease. Histologic material was reviewed in 91 cases. Results : Ten years after treatment, these patients were twice as likely to have died of intercurrent illness as of uterine cancer. The 5-year disease-specific survival rate of patients with Stage I disease was 87%. The disease-specific survival of patients with Stage II disease was 88%, which was not significantly different from that of Stage I patients. Stage III and IV patients had a significantly poorer disease-specific survival rate of 49% at 5 years. Intrauterine recurrence occurred in 14% of the patients with Stage I or II disease. Salvage treatment was attempted in 5 of the 10 patients who had isolated intrauterine recurrences of Stage I disease and was successful in all cases. Extrauterine pelvic recurrence developed in only 3% of Stage I and II patients. Of 82 Stage I and II carcinomas that were available for pathologic review, 17 (21%) were clear-cell or papillary serous variants. The disease-specific survival rate of patients with Stage I or II papillary serous carcinomas was 43%, significantly poorer than that of patients with endometrioid carcinomas. Seven patients experienced acute anesthesia-related complications; none were fatal. Five patients had serious late complications of radiation therapy. Conclusion : Radical radiotherapy achieved acceptable DSS and local control rates in patients with medically or surgically inoperable uterine carcinoma. However for patients with localized disease, such treatment is justified only when the operative risk exceeds the 10–15% uterine recurrence rate expected with radiation alone.