Small-field fractionated radiotherapy with or without stereotactic boost for vestibular schwannoma

Purpose: To assess the efficacy and toxicity of small-field fractionated radiotherapy with or without stereotactic boost (SB) for vestibular schwannomas.

Methods and materials: Thirty-nine patients with vestibular schwannoma were treated with irradiation between March 1991 and February 1996. Extra-meatal tumor diameters were under 30 mm. Thirty-three patients received small-field fractionated radiotherapy followed by SB. Basic dose schedule was 44 Gy in 22 fractions over 5 1/2 weeks plus 4 Gy in one session. Six patients received small-field fractionated radiotherapy only (40–44 Gy in 20–22 fractions over 5–5 1/2 weeks or 36 Gy in 20 fractions over 5 weeks).p>Results: Follow-up ranged from 6 to 69 months (median, 24 months). Tumors decreased in size in 13 cases (33%), were unchanged in 25 (64%), and increased in one (3%). The actuarial 2-year tumor control rate was 97%. Fifteen patients had useful hearing (Gardner–Robertson class 1–2) and 25 patients had testable hearing (class 1–4) before irradiation. The 2-year actuarial rates of useful hearing preservation (free of deterioration from class 1–2 to class 3–5) were 78%. The 2-year actuarial rates of any testable hearing preservation (free of deterioration from class 1–4 to class 5) were 96%. No permanent facial and trigeminal neuropathy developed after irradiation. The 2-year actuarial incidences of facial and trigeminal neuropathies were 8% and 16%, respectively.

Conclusions: Small-field fractionated radiotherapy with or without SB provides excellent short-term local control and a relatively low incidence of complications for vestibular schwannoma, although further follow-up is necessary to evaluate the long-term results.     

Radiotherapy after high-dose chemotherapy and peripheral blood stem cell support in high-risk breast cancer

To assess the toxicity and efficacy of radiotherapy with respect to locoregional control after adjuvant high-dose chemotherapy for patients with breast cancer. At first, radiotherapy was withheld because of toxicity concerns, but it was introduced in 1995 because of reported high locoregional relapse rates.

Between 1992 and 1998, 40 patients with Stage II–III high-risk breast cancer received adjuvant high-dose chemotherapy consisting of thiotepa, mitoxantrone, and cyclophosphamide and peripheral blood stem cell support after four cycles of induction chemotherapy. The chest wall or breast, as well as the supraclavicular nodes, were irradiated with electrons and photons to a median dose of 50.4 Gy in 20 patients. Six additional patients received only supraclavicular irradiation to a median dose of 50.4 Gy. Acute toxicity was scored clinically. Pulmonary function tests were performed in 14 irradiated patients before high-dose chemotherapy and 1.1–4.4 years (median 1.6) after irradiation. The median follow-up time of living patients was 33 vs. 67 months in irradiated (n = 26) and nonirradiated (n = 14) patients, respectively.

G2 and G3 hematologic toxicity occurred in 1 patient each. No clinical pneumonitis or clinical impairment of lung function was observed. After 1–2 years, the lung function tests showed only minor changes in 4 patients. The 3-year locoregional control rate was 92% in the irradiated patients vs. 58% in the nonirradiated patients (p = 0.049, actuarial analysis).

In this series, adjuvant radiotherapy after adjuvant chemotherapy for breast cancer appeared well tolerated, with improved local regional control and without significant side effects. Longer follow-up and more patient accrual, as well as Phase III trials, are necessary for confirmation.     

Radiation-induced myelopathy in long-term surviving metastatic spinal cord compression patients after hypofractionated radiotherapy: a clinical and magnetic resonance imaging analysis

Background and purpose: Hypofractionated radiotherapy is often administered in metastatic spinal cord compression (MSCC), but no studies have been published on the incidence of radiation-induced myelopathy (RIM) in long-term surviving patients. Our report addresses this topic.

Patients and methods: Of 465 consecutive MSCC patients submitted to radiotherapy between 1988 and 1997, 13 live patients (seven females, six males, median age 69 years, median follow-up 69 months) surviving for 2 years or more were retrospectively reviewed to evaluate RIM. All patients underwent radiotherapy. Eight patients underwent a short-course regimen of 8 Gy, with 7 days rest, and then another 8 Gy. Five patients underwent a split-course regimen of 5 Gy ×3, 4 days rest, and then 3 Gy ×5. Only one patient also underwent laminectomy. Full neurological examination and magnetic resonance imaging (MRI) were performed.

Results: Of 12 patients submitted to radiotherapy alone, 11 were ambulant (eight without support and three with support) with good bladder function. In nine of these 11 patients, MRI was negative; in one case MRI evidenced an in-field relapse 30 months after the end of radiotherapy, and in the other, two new MSCC foci outside the irradiated spine. In the remaining patient RIM was suspected at 18 months after radiotherapy when the patient became paraplegic and cystoplegic, and magnetic resonance images evidenced an ischemic injury in the irradiated area. The only patient treated with surgery plus postoperative radiotherapy worsened and remained paraparetic. Magnetic resonance images showed cord atrophy at the surgical level, explained as an ischemic necrosis due to surgery injury.

Conclusions: On the grounds of our data regarding RIM in long-term surviving MSCC patients, we believe that a hypofractionated radiotherapy regimen can be used for the majority of patients. For a minority of patients, more protracted radiation regimens could be considered.     

Serum PSA evaluations during salvage radiotherapy for post-prostatectomy biochemical failures as prognosticators for treatment outcomes

Serum prostate specific antigen (PSA) levels have proved to be sensitive markers for the diagnosis of prostate cancer. In addition, PSA levels are useful for detecting and monitoring prostate cancer progression after radiotherapy. Serum PSA evaluations during radiotherapy, however, have not been well documented. In this study, we investigate the prognostic value of PSA evaluations during salvage radiotherapy for prostatectomy failures.

Forty-one patients with biochemical failures after prostatectomy treated with salvage radiotherapy consented to have their serum PSA levels evaluated at 30 Gy and 45 Gy of irradiation. All 41 patients had negative metastatic workup and pathologically uninvolved pelvic lymph nodes at the time of referral for salvage radiotherapy. Radiation therapy was delivered with 10–25 MV photons, with doses of 59.4–66.6 Gy. No patients received hormonal ablation therapy before irradiation.

The mean follow-up for all patients was 30.9 months. At last follow-up, 28/41 patients (68.3%) were free from biochemical failure, with 20 of 41 patients (48.8%) expressing undetectable PSA levels. Serum PSA evaluations at 30 Gy did not significantly predict for either biochemical (p = 0.0917) or clinical (p = 0.106) disease-free outcome. However, serum PSA evaluations at 45 Gy significantly predicted for both biochemical (p = 0.0043) and clinical (p = 0.0244) disease-free outcomes, with PSA elevations at 45 Gy significantly associated with poor outcomes. On univariate analysis of prognosticators for biochemical failures, the following were significant: an elevation in serum PSA levels at 45 Gy, detectable serum PSA immediately after prostatectomy, Gleason score 7–10, and serum PSA level >1 ng/ml before salvage radiotherapy.

Evaluation of serum PSA level at 45 Gy of salvage radiotherapy for biochemical relapses after prostatectomy may serve as a significant prognosticator for both biochemical and clinical disease-free outcomes.     

Conformal technique dose escalation for prostate cancer: Biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen ≥10 ng/ml

: Conformal radiation technology results in fewer late complications and allows testing of the value of higher doses in prostate cancer.

: We report the biochemical freedom from disease (bNED) rates (BNED) failure in Prostate Specific Antigen (PSA) ≥ 1.5 ng/ml and rising) at 2 and 3 years for 375 consecutive patients treated with conformal technique from 66 to 79 Gy. Median follow-up was 21 months. Biochemical freedom from disease was analyzed for patients treated above and below 71 Gy as well as above and below 73 Gy. Each dose group was subdivided by pretreatment PSA level (<10, 10–19.9, and ≥20 ng/ml). Dose was stated to be at the center of prostate gland.

: There was significant improvement in bNED survuval for all patients divided by a dose above or below 71 Gy (p = 0.007) and a marginal improvement above or below 73 Gy (p = 0.07). Subdividing by pretreatment PSA level showed no benefit to the PSA < 10 ng/ml group at the higher dose but there was a significant improvement at 71 and 73 Gy for pretreatment PSA 10–19.9 ng/ml (p = 0.03 and 0.05, respectively) and for pretreatment PSA ≥ 20 ng/ml (p = 0.003 and 0.02, respectively).

: Increasing dose above 71 or 73 Gy did not result in improved bNED survuval for patient with pretreatment PSA < 10 ng/ml at 2 or 3 years. Further dose escalation studies may not be useful in the patients. A significant improvement in bNED survuval was noted for patients with pretreatment PSA ≥ 10 ng/ml treated above 71 of 73 Gy; further dose escalation studies are warranted.     

Localized aggressive non-Hodgkin’s lymphoma of the nasal cavity: a survey by the Japan Lymphoma Radiation Therapy Group

Purpose: To clarify the role of radiotherapy and chemotherapy in the treatment of patients with localized aggressive non-Hodgkin’s lymphomas (NHL) originating in the nasal cavity.

Methods and Materials: The survey, administered at 25 Japanese institutes in 1998, enabled us to collect the clinical data for 787 patients with localized aggressive NHL who were treated between 1988 and 1992.

Results: There were 42 patients (5%) with nasal lymphomas. Twelve of these patients received radiotherapy alone, and 30 were treated with a combination of radiotherapy and chemotherapy. The median radiation dose was 47 Gy (22–66). Twelve patients were reviewed histopathologically according to REAL (Revised European-American Classification of Lymphoid neoplasms) classification. T-cell or natural killer (NK) cell lymphomas were detected in 9 patients (75%), and diffuse large B-cell lymphomas in 3 (25%). The 5-year overall and disease-free survival (DFS) rates of all patients were 57% and 59%, respectively. The 5-year DFS rate for the 30 patients treated with the combined therapy was 64% and that for the 12 patients treated with radiotherapy alone was 46% (p = 0.021). For the 34 patients with stage-modified International Prognostic Index (m-IPI) 0–1, the 5-year DFS rates of those treated with the combined therapy and radiotherapy alone were 68% and 45%, respectively (p = 0.020), but there was no difference in DFS rate among the two groups of patients with m-IPI 2–3. The 5-year local control rates of the patients who received >46 Gy (n = 22) and ≤46 Gy (n = 20) were 95% and 76% (p = 0.087), respectively. There was no significant difference among the 5-year DFS rates (62% vs. 67%) and local control rates (87% vs. 100%) of the patients with T-cell or NK-cell lymphoma and diffuse large B-cell lymphoma.

Conclusions: Patients with nasal lymphomas (m-IPI 0–1) should be treated with combined therapy. For the patients with high risk (m-IPI 2–3), the effectiveness of combined therapy was not clarified because of the small number of the patients. A high radiation dose >46 Gy may need to be used to achieve good local control.     

Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer

To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC).

Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m²/day)/carboplatinum (70 mg/m²) on days 1–5 and 29–33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 μg, days 15–19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1–3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors).

This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: ± G-CSF, p = 0.0072).

With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.     

The influence of the radicality of resection and dose of postoperative radiation therapy on local control and survival in carcinomas of the upper aerodigestive tract

Purpose: To evaluate dose concepts in postoperative irradiation of carcinomas of the upper aerodigestive tract according to the radicality of resection.

Patients and Methods: In a retrospective analysis, the charts of 257 patients with histologically-proven carcinoma of the upper aerodigestive tract (40 T1, 80 T2, 53 T3, 84 T4 tumors, with nodal involvement in 181 cases) were reviewed according to the radicality of resection and dose of irradiation administered. Sixty-four patients had tumor-free resection margins (> 3 mm), 66 patients had close resection margins (< 3 mm), and 101 patients had R1 resections, and 26 patients had R2 resections. A median dose of 56 Gy was applied to the primary tumor bed and the cervical lymphatics (2 Gy/fraction, 5 fractions/week). In cases of R1 or R2 resection, or of close margins (< 3 mm), the tumor bed or, respectively, tumor residuals were boosted with doses up to a median of 66 Gy. Locoregional tumor control and survival was investigated by uni- and multivariate analyses according to T-, N-stage, grade of resection, total dose of radiation, and presence or absence of extracapsular tumor spread and lymphangiosis carcinomatosa.

Results: An overall 3- and 5-year survival rate of 60% and 45%, respectively, was achieved. Rates for freedom from locoregional recurrence were 77% and 72% at 3 and 5 years, respectively. The survival rates according to the grade of resection at 5 years were 67% for patients resected with tumor-free margins, 59% for patients resected with close margins, 26% for patients with R1 resection, and 27% for patients with R2 resection. Within a median follow-up period of 4.7 years for living patients, a total of 67 recurrences (26%) were observed (in 9% of patients resected with tumor-free margins, in 27% with close margins, in 37% of R1 resected, and in 19% of R2 resected patients). Freedom from locoregional recurrence at 3 years was achieved in 100% of the patients resected with tumor-free margins, in 92% of patients resected with close surgical margins, in 87% of R1 and 69% of R2 resected patients. In multivariate Cox-regression analysis, the variables grade of resection (p = 0.00031) and total dose of irradiation (p = 0.0046) were found as factors influencing locoregional control. Variables influencing survival according to multivariate analysis are T-stage (p = 0.0057), N-stage (p = 0.024), grade of resection (p = 0.000015), total dose of irradiation (p < 0.000000). Extracapsular tumor spread and lymphangiosis carcinomatosa are factors of borderline significance (p = 0.055, p = 0.066).

Conclusion: In postoperative radiotherapy of head and neck carcinomas, doses adapted to the risk of locoregional recurrent disease should be applied. Patients with R1 and R2 resections should be treated with doses of more than 68 Gy (2 Gy/fraction, 5 fractions/week) (with close margins [< 3 mm] more than 66 Gy) to achieve an improvement in locoregional control and survival.     

Retreatment of the spinal cord with palliative radiotherapy

We conducted this retrospective review of patients whose spinal cord was irradiated twice to evaluate the outcome in terms of palliation and long-term side effects.

Eight patients (4 females, 4 males; median age: 67 years) were identified whose spinal cord had been irradiated twice between July 1990 and July 1997, usually for the management of bone metastases. All patients were followed up until their death from progressive disease. The Karnofsky performance score at the time of retreatment ranged from 20% to 90%. Total dose for the first treatment ranged from 29 to 50 Gy (median: 38 Gy) with single doses 1.25–3 Gy; the total dose for the retreatment ranged from 29 to 38 Gy (median: 30 Gy) with a single dose 1.8–4 Gy. The cumulative dose ranged from 59 to 88 Gy (median: 67.5 Gy). The overlap in the site of retreatment consisted of 1–3 segments, whereas in one patient, 2 single segments were treated twice. The outcome in terms of progressive disease, the palliative effects, and the development of myelopathy was assessed retrospectively.

The median interval to reirradiation was 30 months (range: 6–63 months), and the median follow-up after the last treatment was 16 months (range: 5–44 months). After reirradiation, 4/7 patients experienced complete pain relief, 2/7 patients experienced minor pain relief, and only 1 patient showed no change. Two patients with paraparesis experienced complete recovery. All patients tolerated retreatment very well. No serious acute side effects requiring any therapy were seen. During follow-up, no patient showed treatment-induced neurologic abnormalities affecting motor and sensory function, and all patients were able to walk and were continent for stool and urine.

On the basis of the findings in this limited number of patients, it is not possible to give clear and general recommendations concerning the optimal total dose and fraction size that will have maximal palliative effects and minimal side effects. However, for the purpose of palliation, retreatment within the dose range used at our institution should be considered, taking the patient’s expected life span and clinical symptoms into account.     

Spinal cord planning risk volumes for intensity-modulated radiation therapy of head-and-neck cancer

PURPOSE: To assess planning organ at risk volume (PRV) margins of the spinal cord in intensity-modulated radiotherapy (IMRT) of oropharyngeal cancers, by modeling the effect of geometric uncertainties to estimate the probability of the spinal cord receiving a particular dose. METHODS AND MATERIALS: Five patients with oropharyngeal cancer were treated by IMRT with simultaneous doses of 66 Gy (gross disease) and 54 Gy (subclinical disease) in 30 fractions. Spinal cord doses were limited to 45 Gy. The probability, due to random and systematic patient positioning uncertainties (3-mm standard deviation), of the cord receiving a particular dose was determined. The effect of an on-line setup correction protocol was also modeled. RESULTS: The mean probability of a maximum spinal cord dose of 45 Gy was 1%, with a 6-mm PRV margin. The mean probability of a maximum dose exceeding 40 Gy was 37% (range, 13-77%); this probability is reduced with a setup correction protocol. CONCLUSION: A spinal cord PRV generated with a 6-mm margin leads to a 99% probability of maintaining the maximum spinal cord dose below 45 Gy. The application of an on-line setup correction protocol reduces the cord dose by approximately 5 Gy.     

Effectiveness of accelerated radiotherapy for patients with inoperable non-small cell lung cancer (NSCLC) and borderline prognostic factors without distant metastasis: a retrospective review

Purpose: The standard treatment for patients with unresectable or medically inoperable non-small cell lung cancer (NSCLC) and good prognostic factors (e.g., weight loss [WL] ≤5% and Karnofsky performance status [KPS] ≥70) is induction chemotherapy followed by definitive radiotherapy to the primary site at 1.8–2.0 Gy per fraction with a total dose of 60–63 Gy to the target volume. Patients with poor prognostic factors usually receive radiotherapy alone, but the fractionation schedule and total dose have not been standardized. To attempt to optimize irradiation doses and schedule, we compared the effectiveness of accelerated radiotherapy (ACRT) alone to 45 Gy at 3 Gy per fraction with standard radiation therapy (STRT) of 60–66 Gy at 2 Gy per fraction in regard to tumor response, local control, distant metastasis, toxicity, and survival.

Methods and Materials: Fifty-five patients treated with radiation for NSCLC at The University of Texas M. D. Anderson Cancer Center between 1990 and 1994 were identified. All 55 patients had node-positive, and no distant metastasis (N+, M0) of NSCLC. Two cohorts were identified. One cohort (26 patients) had borderline poor prognostic factors (KPS less than 70 but higher than 50, and/or WL of more than 5%) and was treated with radiotherapy alone to 45 Gy over 3 weeks at 3 Gy/fraction (ACRT). The second cohort (29 patients) had significantly better prognostic factors (KPS ≥70 and WL ≤5%) and was treated to 60–66 Gy over 6 to 6 weeks at 2 Gy per fraction (STRT) during the same period.

Results: In the first cohort treated by ACRT, the distribution of patients by AJCC stage was IIB 8%, IIIA 19%, and IIIB 73%. Sixty-two percent had KPS <70, and 76% had a WL of >5%. The maximum response rate as determined by chest X-ray was 60% among 45 of 55 patients who were evaluable for response: combined complete responses (20%) and partial responses (40%). Overall survival in these patients was 13% at 2 and 5 years, with a locoregional control rate of 42% and a freedom from distant metastasis rate of 54%. The ACRT cohort treated with 3 Gy per fraction had significantly lower KPS scores (p = 0.003) and greater WL (p = 0.063) than the cohort STRT treated with 2 Gy per fraction. However, treatment results and toxicity were not significantly different between the two cohorts in spite of significantly better prognostic factors in the STRT cohort.

Conclusions: Despite having worse prognostic factors, the cohort treated with radiotherapy alone to 45 Gy at 3 Gy per fraction over 3 weeks (ACRT) had response rates, locoregional control, and overall survival comparable to those in the cohort treated by a total dose of 60–66 Gy at 2 Gy per fraction over 6 to 6 weeks (STRT). Given that accelerated treatment schedules decrease treatment time and cost less, these may, in the current health care environment, be important factors for health care providers to consider in treating patients who have locally advanced NSCLC and borderline poor prognostic factors.     

Planning and delivering high doses to targets surrounding the spinal cord at the lower neck and upper mediastinal levels: static beam-segmentation technique executed with a multileaf collimator

Background and purpose. It remains a technical challenge to limit the dose to the spinal cord below tolerance if, in head and neck or thyroid cancer, the planning target volume reaches to a level below the shoulders. In order to avoid these dose limitations, we developed a standard plan involving Beam Intensity Modulation (BIM) executed by a static technique of beam segmentation. In this standard plan, many machine parameters (gantry angles, couch position, relative beam and segment weights) as well as the beam segmentation rules were identical for all patients. Materials and methods. The standard plan involved: the use of static beams with a single isocenter; BIM by field segmentation executable with a standard Philips multileaf collimator; virtual simulation and dose computation on a general 3D-planning system (Sherouse's GRATIS®); heuristic computation of segment intensities and optimization (improving the dose distribution and reducing the execution time) by human intelligence. The standard plan used 20 segments spread over 8 gantry angles plus 2 non-segmented wedged beams (2 gantry angles). Results. The dose that could be achieved at the lowest target voxel, without exceeding tolerance of the spinal cord (50 Gy at highest voxel) was 70–80 Gy. The in-target 3D dose-inhomogeneity was ≈25%. The shortest time of execution of a treatment (22 segments) on a patient (unpublished) was 25 min. Conclusions. A heuristic model has been developed and investigated to obtain a 3D concave dose distribution applicable to irradiate targets in the lower neck and upper mediastinal regions. The technique spares efficiently the spinal cord and allows the delivery of higher target doses than with conventional techniques. It can be planned as a standard plan using conventional 3D-planning technology. The routine clinical implementation is performed with commercially available equipment, however, at the expense of extended execution times.     

32例妇科恶性肿瘤术后调强适形放射治疗分析

目的 探讨调强适形放射治疗（IMRT）在妇科恶性肿瘤患者术后治疗中的效果及价值。方法 32例子宫颈癌、子宫内膜癌术后患者（KPS≥70）在放疗前均行1～3个周期的化疗,而后给予全程IMRT。其中17例为术后、化疗后预防性照射,15例为术后、放疗和（或）化疗后腹膜后淋巴结转移和（或）盆腔壁复发的放疗。结果 32例患者均完成全程放射治疗,预防性照射的计划靶区（PTV）中位剂量为56．8Gy;腹膜后淋巴结转移、盆壁复发的胛V中位剂量为60．6Gy,90％的等剂量曲线可以覆盖99％以上的肉眼肿瘤靶区（GTV）体积。小肠、膀胱、直肠、肾脏和脊髓的中位剂量分别为21．3Gy、37．8Gy、35．3Gy、8．5Gy和22．1Gy。14例患者出现Ⅰ～Ⅱ级消化道反应,其中Ⅱ级反应者3例,I级反应者11例;5例出现Ⅰ～Ⅱ度骨髓抑制;12例出现Ⅰ级皮肤反应。1年生存率为100％。预防性照射的2、3年生存率均为100％;腹膜后淋巴结转移和（或）盆腔壁复发患者的2、3年生存分别为5／7和3／6。结论 IMRT对妇科恶性肿瘤术后患者的预防性照射和复发患者的放疗均可获得理想的剂量分布,邻近危险器官得到保护,临床近期疗效满意。     

Linac radiosurgery for cerebral arteriovenous malformations: results in 169 patients

Purpose: To present the SALT group results using Linac radiosurgery (RS) for AVM in 169 evaluable patients treated from January 1990 thru December 1993.

Methods and Materials: Median age was 33 years (range 6–68 years). Irradiation was the only treatment in 55% patients. Other treatment modalities had been used prior to RS in 45%: one or more embolizations in 36%, surgery in 6%, and embolization and surgery in 3% patients. Nidus were supratentorial in 94% patients, infratentorial in 6% patients. Circular 15 MV x-ray minibeams (6–20 mm) were delivered in coronal arcs by a GE-CGR Saturne 43 Linac. Patient set-up included a Betti arm-chair, a Talairach frame. Prescribed peripheral dose was 25 Gy on the 60%–70% isodose (max dose 100%). Arteriographic results were reassessed in December 1997 at 48 to 96 months follow-up.

Results: The overall obliteration rate (OR) was 64% (108/169). AVM volumes ranged from 280 to 19,920 mm³, median 2460 mm³. OR was 70% for AVM ≤ 4200 mm³ vs. 51% for AVM > 4200 mm³ (p = 0.02). The largest nidus dimension ranged from 8 to 51 mm, median 22 mm. OR was 70% for nidus ≤ 25 mm vs. 54% for nidus > 25 mm (p = 0.04). OR was 71%, in the absence of embolization, vs. 54% for previously embolized nidus (p = 0.03). OR was 71% for monocentric RS vs. 54% for multi-isocenters (p = 0.03). Peripheral doses (Pd) ranged from 15 to 28Gy, median 25 Gy, OR was 52% in patients receiving Pd ≤ 24.1 Gy or > 25.9 Gy and 70% for 25 Gy (NS). Peripheral isodoses ranged from 50%–90%, median 70%: OR was 67% for peripheral isodoses of 65% and 70% vs. 61% for peripheral isodoses of 50%–60% (NS). The mean lesion doses (MLd) ranged from 14 to 36 Gy, median 29 Gy: OR was 72% for MLd > 28 Gy vs. 55% for values ≤ 28 Gy (p = 0.02). The mean lesion isodoses (MLi) ranged from 53 to 90 Gy, median 79%: OR was 75% for MLi > 79% vs. 57% for lower values (p = 0.03). The minimum lesion doses (mLd) ranged from 3.6 to 23, median 16 Gy: OR was 69% for mLd > 17 Gy, vs. 59% for mLd ≤ 16 Gy (p = 0.05). The minimum lesion iodoses (mLi) ranged from 9%–65%, median 45%: OR was 71% for mLi > 40%, vs. 54% for mLi ≤ 40% (p = 0.05). The coverage ratio (CR) ranged from 33%–100%, median 85%: OR was 68% for CR > 85% vs. 60% for CR ≤ 84% (NS). For patients treated according to our protocol, i.e., 24–26 Gy on the 60%–70% isodoses, OR was higher (68%) than for other patients (47%) (p = 0.02). After multivariate analysis, absence of previous embolization and mono isocentric-irradiation were independent factors predicting obliteration. Complications were: recurrent hemorrhage, 4 patients (1 patient died); brain necrosis on MRI, 2 patients; subsequent epilepsy, 4 patients; other subsequent neurologic deficits, 3 patients.

Conclusion: Overall OR was 64% (48–96 months follow-up). After monovariate analysis higher ORs were associated with smaller volumes ≤ 4200 mm³, smaller nidus size ≤ 25 mm, absence of prior embolization, monoisocentric RS, higher values for mean and minimum lesion doses and compliance to our protocol. Higher values for the peripheral dose and isodose tended to give better results. Multivariate analysis showed that the absence of prior embolization and monoisocentric irradiation were independent factors predicting successfull irradiation.     

A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients

To evaluate the role of adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma (NPC) patients, we conducted a randomized Phase III trial comparing radiotherapy (RT) followed by adjuvant chemotherapy to RT alone in patients with advanced NPC.

Between November 1994 and March 1999, 157 patients with Stage IV, M₀ (UICC/AJCC, 1992) advanced NPC disease were randomized to receive standard radiotherapy, as follows: 35–40 fractions, 1.8–2.0 Gy/fraction/day, 5 days/week, to a total dose 70–72 Gy with or without 9 weekly cycles of 24-h infusional chemotherapy (20 mg/m² cisplatin, 2,200 mg/m² 5-fluorouracil, and 120 mg/m² leucovorin) after RT. Of 157 patients enrolled, 154 (77 radiotherapy, 77 combined therapy) were evaluable for survival and toxicity analysis.

With a median follow-up of 49.5 months, the 5-year overall survival and relapse-free survival rates were 60.5% vs. 54.5% (p = 0.5) and 49.5% vs. 54.4% (p = 0.38) for the radiotherapy-alone group and the combined radiotherapy and adjuvant chemotherapy group, respectively. The Cox regression showed that the hazard rates ratio of combined treatment to RT alone was 0.673 (p VALUE = 0.232); the 95% confidence interval was 0.352 and 1.288, respectively. Patients who received combined treatment had a lower systemic relapse rate than radiotherapy-alone patients, according to relapse pattern analysis. The incidence of leukopenia (≥ Grade 3) occurred in 17 out of 819 (2.1%) cycles of weekly chemotherapy. No patient developed moderate to severe mucositis (≥ Grade 3).

We conclude that adjuvant chemotherapy after RT for patients with advanced NPC has no benefit for overall survival or relapse-free survival.     

Predictive value of linear-quadratic model in the treatment of cervical cancer using high-dose-rate brachytherapy

: To determine whether a dose-response relationship exists between the biologic effective dose (BED) at Point A and the bladder and rectum and the clinical outcomes in our experience with external beam radiotherapy (EBRT) and high-dose-rate brachytherapy in the treatment of cervical carcinoma.

: This was a retrospective study. A total of 49 patients with cervical cancer were treated with a combination of EBRT (median 45 Gy, range 41.4–50.4) and high-dose-rate brachytherapy (median 18 Gy; range 18–19, in two fractions). Twenty-three patients received concomitant cisplatin-based chemotherapy. The cumulative BEDs were calculated at Point A (BED10) and at bladder and rectal reference points (BED3) using the linear-quadratic equation. The BED10 values, after incorporating a time factor (BED10tf) in the formula, were also calculated.

: In patients treated with RT alone, the local failure rate was 10% (1 of 10) and 19% (3 of 16) in patients receiving a BED10 >89 Gy10 or <89 Gy10 to Point A, respectively (p = 0.2). The corresponding local failure rates were 20% (3 of 15) and 0% (0 of 8) in patients treated with concomitant chemotherapy (p = 0.3). In patients treated with RT alone, the local failure rate was 7.7% (1 of 13) and 23% (3 of 13) in patients with a BED10tf >64 Gy10 or <64 Gy10 (p = 0.1), respectively. The median BED3 values at the rectal and bladder point was 95.5 Gy3 and 103.6 Gy3, respectively. Only 1 case of Grade 2 late rectal toxicity (2%) and no late bladder toxicity occurred.

: In patients treated with RT alone, a BED10 >89 Gy and a BED10tf >64 Gy indicated a trend toward a better local control rate. This difference was not observed in patients receiving chemotherapy. A BED3 <100 Gy3 was associated with negligible late toxicity. Although the BED10 in our study was about 10–15 Gy10 less than that in the published data, the 4-year local control rate of 80% and 83% and disease-free survival rate of 75% and 70% with and without chemotherapy, respectively, compare well with the rates in other studies in the literature.     

Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients

Background and purpose: Amifostine has been shown to protect against xerostomia induced by radiotherapy for head and neck cancer, but its impact on the therapeutic index is unknown. This is the first report focusing on amifostine related adverse effects leading to discontinuation of amifostine treatment.

Patients and methods: Thirty-nine patients from two centers irradiated for head and neck cancer received i.v.-infusions of amifostine prior to each radiation fraction. In a phase III study, two daily amifostine doses, 200 mg/m² (n=21) and 340 mg/m² (n=18), were compared for protection against radiation induced toxicity. Total radiation dose was 60–70 Gy (2 Gy per fraction), nine patients received concurrent chemotherapy with cisplatin/5-FU. amifostine was usually discontinued after >1 episode of serious toxicity during subsequent treatment sessions.

Results: In 16/39 patients (41%) amifostine was discontinued due to severe adverse effects, which led to discontinuation of the phase III study. In four of 16 patients radiotherapy was delayed due to amifostine related adverse effects for 1–3 days. Discontinuation occurred more often in patients receiving chemotherapy. The results led to a literature review for amifostine treatment during radiotherapy in head and neck cancer patients. Regarding our series and published series using an amifostine schedule comparable to ours, total discontinuation rate was 27% (57/214). Discontinuation was significantly influenced by chemotherapy (P=0.007), but not by amifostine dose (P=0.156).

Conclusion: Daily i.v. administration of amifostine during radiotherapy in head and neck cancer is associated with a high rate of serious adverse effects leading to discontinuation of amifostine treatment and sometimes delay of radiotherapy.     

Pathologic downstaging of T3-4Nx rectal cancer after chemoradiation: 5-fluorouracil vs. Tegafur.

Purpose: To describe downstaging effects in locally advanced rectal cancer induced by 2 fluopirimidine radiosensitizing agents given through different routes in conjunction with preoperative radiotherapy.

Methods and Materials: From March 1995 to December 1999, two consecutive groups of patients with cT_3–4N_x rectal cancer (94% CT scan, 71% endorectal ultrasound) were treated with either (1) 45–50 Gy (1.8 Gy/day, 25 fractions) and 5-fluorouracil (5-FU) (500–1,000 mg/m² by 24-h continuous i.v. infusion on Days 1–4 and 21–25) or (2) oral Tegafur (1,200 mg/day on Days 1–35, including weekends). Surgery was performed 4 to 6 weeks after the completion of chemoradiation.

Results: The total T downstaging rate was 46% in the 5-FU group and 53% in the Tegafur group. Subcategories were downstaged by the sensitizing agents (5-FU vs. Tegafur) as follows: pT_0–1, 14% vs. 23%; pT₂, 32% vs. 32%; pT₃, 49% vs. 37%; pT₄, 5% vs. 7%; and N₀, 74% vs. 86%. Analysis of residual malignant disease in the specimen discriminated mic/macsubgroups (mic: <20% of microscopic cancer residue), with evident superior downstaging effects in the Tegafur-treated group: pTmic 23% vs. 58% (p = 0.002).

Conclusions: When administered concurrent with pelvic irradiation, oral Tegafur induced downstaging rates in both T and N categories superior to those induced by intermediate doses of 5-FU by continuous i.v. infusion. In this pilot experience, oral Tegafur reproduced the characteristics of downstaging described previously when full doses of 5-FU have been combined with radiotherapy.     

Consequences of voice impairment in daily life for patients following radiotherapy for early glottic cancer: voice quality, vocal function, and vocal performance

Purpose: To assess consequences of voice impairment in daily life for patients following radiotherapy for early glottic cancer, by means of a multidimensional analysis protocol including voice quality, vocal function, and vocal performance measures.

Methods and Materials: A total of 60 men treated with radiotherapy (66 Gy/33 fractions, 60 Gy/30fractions, 60 Gy/25fractions) for early T1 glottic cancer and 20 matched control speakers filled in questionnaires on vocal performance. Furthermore, perceptual analyses of voice quality and stroboscopic measures of vocal function were performed. There was a longitudinal group of 10 patients from whom data were collected before, as well as 6 months and 2 years after, radiation. Furthermore, data were collected on 5 separate groups of 10 patients each: before, 6 months after, 2 years after, 3–7 years after, and 7–10 years after radiation.

Results: High correlations were found between self-ratings of vocal performance and several voice measures. Patients before radiotherapy experienced poor voice characteristics that improved 6 months to 10 years after treatment, and became comparable to vocal performance of control speakers in 50% of the patients. Following radiotherapy, deviant voice characteristics and consequences in daily life occurred significantly more often for patients in whom initial diagnosis consisted of stripping the vocal cord instead of biopsies and for patients who continued smoking after treatment.

Conclusion: Voice characteristics of patients diagnosed with early glottic cancer improved after radiotherapy, and became normal in half of our patients. Stripping the vocal cord for initial diagnosis and continued smoking after treatment decreased deviant voice characteristics.     

Dose optimization of fractionated external radiation and high-dose-rate intracavitary brachytherapy for FIGO stage IB uterine cervical carcinoma

: To determine the optimal dose combination scheme of external beam radiotherapy (EBRT) and high-dose-rate (HDR) intracavitary radiation (ICR) for maximizing tumor control while conferring an acceptable late complication rate in the treatment of Stage IB uterine cervical cancer.

: We retrospectively analyzed 162 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB squamous cell carcinoma of the uterine cervix who received definitive RT between May 1979 and December 1990. Before HDR-ICR, all patients received EBRT to a total dose of 40–46 Gy (median 45), administered during 4–5 weeks to the whole pelvis. HDR-ICR was given 3 times weeks to a total dose of 24–51 Gy (median 39) at point A, using a dose of 3 Gy/fraction. Central shielding from EBRT was begun after the delivery using 20–45 Gy (median 40) of the external dose. The total dose to point A, calculated by adding the EBRT biologically effective dose (BED) and the ICR BED to point A, was 74.1–118.1 Gy (mean 95.2). The rectal point dose was calculated at the anterior rectal wall at the level of the cervical os. The local control rate, survival rate, and late complication rate were analyzed according to the irradiation dose and BED.

: The initial complete response rate was 99.4%. The overall 5-year survival rate and 5-year disease-free survival rate was 91.1% and 90.9%, respectively. The local failure rate was 4.9%, and the distant failure rate was 4.3%. Late complications were mild and occurred in 23.5% of patients, with 18.5% presenting with rectal complications and 4.9% with bladder complications. The mean rectal BED (the sum of the external midline BED and the ICR rectal point BED) was lower in the patients without rectal complications than in those with rectal complications (125.6 Gy vs. 142.7 Gy, p = 0.3210). The late rectal complication rate increased when the sum of the external midline BED and the rectal BED by ICR was ≥131 Gy (p = 0.1962). However, 5-year survival rates did not increase with the external midline BED (p = 0.4093). The late rectal complication rate also increased, without a change in the survival rate, when the sum of the external midline BED and the ICR point A BED was >90 Gy.

: In treating Stage IB carcinoma of the uterine cervix with HDR-ICR, using fractions of 3 Gy, it is crucial to keep the point A BED at ≤90 Gy to minimize late rectal complications without compromising the survival rate. To achieve this goal, appropriate central shielding from EBRT is needed.