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.     

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.     

Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial

A randomized radiotherapy dose escalation trial was undertaken between 1993 and 1998 to compare the efficacy of 70 vs. 78 Gy in controlling prostate cancer.

A total of 305 Stage T1–T3 patients were entered into the trial and, of these, 301 with a median follow-up of 60 months, were assessable. Of the 301 patients, 150 were in the 70 Gy arm and 151 were in the 78 Gy arm. The primary end point was freedom from failure (FFF), including biochemical failure, which was defined as 3 rises in the prostate-specific antigen (PSA) level. Kaplan-Meier survival analyses were calculated from the completion of radiotherapy. The log-rank test was used to compare the groups. Cox proportional hazard regression analysis was used to examine the independence of study randomization in multivariate analysis.

There was an even distribution of patients by randomization arm and stage, Gleason score, and pretreatment PSA level. The FFF rates for the 70- and 78 Gy arms at 6 years were 64% and 70%, respectively (p = 0.03). Dose escalation to 78 Gy preferentially benefited those with a pretreatment PSA >10 ng/mL; the FFF rate was 62% for the 78 Gy arm vs. 43% for those who received 70 Gy (p = 0.01). For patients with a pretreatment PSA ≤10 ng/mL, no significant dose response was found, with an average 6-year FFF rate of about 75%. Although no difference occurred in overall survival, the freedom from distant metastasis rate was higher for those with PSA levels >10 ng/mL who were treated to 78 Gy (98% vs. 88% at 6 years, p = 0.056). Rectal side effects were also significantly greater in the 78 Gy group. Grade 2 or higher toxicity rates at 6 years were 12% and 26% for the 70 Gy and 78 Gy arms, respectively (p = 0.001). Grade 2 or higher bladder complications were similar at 10%. For patients in the 78 Gy arm, Grade 2 or higher rectal toxicity correlated highly with the proportion of the rectum treated to >70 Gy.

An increase of 8 Gy resulted in a highly significant improvement in FFF for patients at intermediate-to-high risk, although the rectal reactions were also increased. Dose escalation techniques that limit the rectal volume that receives ≥70 Gy to <25% should be used.     

High-dose-rate brachytherapy in the treatment of uterine cervix cancer. Analysis of dose effectiveness and late complications

This retrospective analysis aims to report results of patients with cervix cancer treated by external beam radiotherapy (EBR) and high-dose-rate (HDR) brachytherapy.

From September 1992 to December 1996, 138 patients with FIGO Stages II and III and mean age of 56 years were treated. Median EBR to the whole pelvis was 45 Gy in 25 fractions. Parametrial boost was performed in 93% of patients, with a median dose of 14.4 Gy. Brachytherapy with HDR was performed during EBR or following its completion with a dose of 24 Gy in four weekly fractions of 6 Gy to point A. Median overall treatment time was of 60 days. Patient age, tumor stage, and overall treatment time were variables analyzed for survival and local control. Cumulative biologic effective dose (BED) at rectal and bladder reference points were correlated with late complications in these organs and dose of EBR at parametrium was correlated with small bowel complications.

Median follow-up time was 38 months. Overall survival, disease-free survival, and local control at 5 years was 53.7%, 52.7%, and 62%, respectively. By multivariate and univariate analysis, overall treatment time up to 50 days was the only statistically significant adverse variable for overall survival (p = 0.003) and actuarial local control (p = 0.008). The 5-year actuarial incidence of rectal, bladder, and small bowel late complications was 16%, 11%, and 14%, respectively. Patients treated with cumulative BED at rectum points above 110 Gy₃ and at bladder point above 125 Gy₃ had a higher but not statistically significant 5-year actuarial rate of complications at these organs (18% vs. 12%, p = 0.49 and 17% vs. 9%, p = 0.20, respectively). Patients who received parametrial doses larger than 59 Gy had a higher 5-year actuarial rate of complications in the small bowel; however, this was not statistically significant (19% vs. 10%, p = 0.260).

This series suggests that 45 Gy to the whole pelvis combined with four fractions of 6 Gy to point A with HDR brachytherapy is an effective and safe fractionation schedule in the treatment of Stages II and III cervix cancer if realized up to 50 days. To decrease the small bowel complications, we decreased the superior border of the parametrial fields to the S2-S3 level and the total dose to 54 Gy.     

Fractionation in medium dose rate brachytherapy of cancer of the cervix

: To established an optimum fractionation for medium dose rate (MDR) brachytherapy from retrospective data of patients treated with different MDR schedules in comparison with a low dose rate (LDR) schedule.

: The study population consists of consecutive Stage IB-IIA-IIB patients who received radiotherapy alone with full dose brachytherapy plus external beam pelvic and parametrial irradiation from 1986–1993. Patients also receiving surgery or chemotherapy were excluded. The LDR group (n = 102, median follow-up: 80 months) received a median dose to Point A of 32.5 Gy fractions at 0.44 Gy/h plus 18 Gy of external whole pelvic irradiation. The MDR1 group (n = 30, median follow-up: 45 months) received a mean dose of two 32 Gy fractions at 1.68 Gy/h. An individual dose reduction of 12.5% was planned for this group according to the Manchester experience, but only a 4.8% dose reduction was achieved. The MDR2 group (n = 10, median follow-up: 36 months) received a dose of two 24 Gy fractions at 1.65 Gy/h. The MDR3 group (n = 10, median follow-up 33 months_ received a mean dose of three 15.3 Gy fractions at 1.64 Gy/h. And finally, the MDR4 group (n = 38, median follow-up: 24 months)_received six six 7.7 Gy fractions from two pulses 6 h apart in each of three insertions at 1.61 Gy/h/ The median external pelvic dose to MDR schedules was between 12 and 20 Gy. The linear quadratic (LQ) formula was used to calculate the biologically effective dose (BED) to tumor (BED) to tumor (Gy₁₀) and rectum (Gy₃), assuming T1/2 for REPAIR = 1.5 h.

: The crude central recurrence rate was 6% for LDR (mean BED - 95.4 Gy₁₀) and 10% for MDR4 (mean BED = 77.0 Gy₁₀ (p = NS). The remaining MDR groups had no recurrences. Grade 2 and 3 rectal or bladder complications were 0% for LDR (rectal BED = 109 Gy₃), 83% for MDR1 (BED = 206 Gy₃), and 30% for MDR3 (BED = 127 Gy₃). The MDR2 and MDR4 groups presented no complications (BED, 123 Gy₃, and 105 Gy₃, respectively). The LQ formula appears to correlate with late complications of the different MDR regimens. A BED above 125 Gy₃ was associated with Grade 2+3 rectal complications. Adequate central tumor control may be compromised with a tumor BED below 90–95 Gy₁₀.

: Medium dose rate brachytherapy at 1.6 Gy/h to point A has a marked dose ratre effect. Increased fractionation is the cost of overcoming the less favorable therapeutic ratio for MDR than for LDR. A larger (25%) reduction of brachytherapy dose than previously reported is also necessary. Our most recently developed schedule for Stage I–II patients is three insertions on three treatment days with six 8.0 Gy brachytherapy fractions, two on each treatment day, following or preceding an external whole pelvis dose of 18 Gy, and followed by additional external parametrial dose.     

Early response of lung in breast cancer irradiation: radiologic density changes measured by CT and symptomatic radiation pneumonitis

To quantify radiologic changes in the lung with CT after radiotherapy (RT) for breast cancer (BC) and to study their association with treatment techniques and symptomatic radiation pneumonitis (RP).

CT scans of the lungs were performed before and 4 months after RT in 121 BC patients treated with four different RT techniques. The changes in mean density (MDCs) were analyzed at two lung levels (i.e., the central and apical CT slice). The central CT slice was also analyzed with respect to the MDCs in the anterior third and anterior half of the ipsilateral lung area. In mastectomized patients who received chest wall RT with an en-face electron beam, the maximal depths for a range of isodose curves were measured. The occurrence of mild/moderate symptomatic RP was assessed prospectively 1, 4, and 7 months after RT. Data on covariates with potential confounding effect on RT-induced lung toxicity were also collected prospectively.

In the entire study population, an association between the MDCs in the anterior third of the central CT slice and treatment technique (p <0.001) and symptomatic RP (p <0.001) was found. Among patients with chest wall treatment consisting of an en-face electron beam, the MDCs of the anterior third of the central CT slice correlated with the 35% isodose curve (16–30 Gy) (p = 0.046) and age (p <0.001). No association between post-RT lung density changes and pre-RT chemotherapy, concurrent tamoxifen intake, or smoking habits was found. Among patients treated with locoregional RT, an association was found between the MDCs in the anterior third of the central CT slice and the incidence of RP. MDCs in the apical CT slice, however, were not associated with RP.

The results imply that short-term post-RT lung density changes and symptomatic RP were associated with RT techniques, total doses as low as 16–30 Gy, and increasing age. Structural changes in the central part of lung appeared to be more important for the development of RP than changes in the apex.     

Local excision and postoperative radiotherapy for distal rectal cancer

To assess the outcome following local excision and postoperative radiotherapy (RT) for distal rectal carcinoma.

Seventy-three patients received postoperative radiotherapy following local surgery for primary rectal carcinoma at Princess Margaret Hospital from 1983 to 1998. Selection factors for postoperative RT were patient preference, poor operative risks, and “elective” where conservative therapy was regarded as optimal therapy. Median distance of the primary lesion from the anal verge was 4 cm (range, 1–8 cm). There were 24 T1, 36 T2, and 8 T3 lesions. The T category could not be determined in 5. Of 55 tumor specimens in which margins could be adequately assessed, they were positive in 18. RT was delivered using multiple fields by 6- to 25-MV photons. Median tumor dose was 50 Gy (range, 38–60 Gy), and 62 patients received 50 Gy in 2.5-Gy daily fractions. The tumor volume included the primary with 3–5 cm margins. No patients received adjuvant chemotherapy. Median follow-up was 48 months (range, 10–165 months).

Overall 5-year survival and disease-free survival were 67% and 55%, respectively. Tumor recurrence was observed in 23 patients. There were 14 isolated local relapses; 6 patients developed local and distant disease; and 3 relapsed distantly only. For patients with T1, T2, and T3 lesions, 5-year local relapse-free rates were 61%, 75%, and 78%, respectively, and 5-year survival rates were 76%, 58%, and 33%, respectively. The 5-year local relapse-free rate was lower in the presence of lymphovascular invasion (LVI) compared to no LVI, 52% vs. 89%, p = 0.03, or where tumor fragmentation occurred during local excision compared to no fragmentation, 51% vs. 76%, p = 0.02. Eleven of 14 patients with local relapse only underwent abdominoperineal resection, 8 achieved local control, and 4 remained cancer free. The ultimate local control, including salvage surgery, was 86% at 5 and 10 years. The 5-year colostomy-free rate was 82%. There were 2 patients who experienced RTOG Grade 3 late complications, and 1 with Grade 4 complication (bowel obstruction requiring surgery).

The local relapse rate for patients with T1 disease was high compared to other series of local excision and postoperative RT. Patients with LVI or tumor fragmentation during excision have high local relapse rates and may not be good candidates for conservative surgery and postoperative RT.     

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.     

Late radiation effects to the rectum and bladder in gynecologic cancer patients: the comparison of LENT/SOMA and RTOG/EORTC late-effects scoring systems

To test the correlation of LENT/SOMA and RTOG/EORTC late-effect scales for rectum and bladder, 116 cases with gynecologic malignancies that were treated with radiotherapy were assessed with both scales.

All cases had been treated at least 6 months before the date of assessment with external beam radiotherapy (50–54 Gy to midline) and 1–2 fractions of HDR brachytherapy (2 × 8.5 Gy to point-A for 32 inoperable cases; 1 × 9.25 Gy to 5–9 mm from the ovoid surface for 84 postoperative cases). The patients were questioned with both scales, and the correlation between the two scales was analyzed by Spearman’s rho (rank correlation) test.

There were 64 cases with uterine cervix carcinoma and 52 cases with endometrium carcinoma, The overall (external + brachy) doses to ICRU points were 57.8 ± 3.8 Gy for rectum and 59.3 ± 4.9 Gy for bladder. The statistical analysis of LENT/SOMA and RTOG/EORTC scales revealed a very good correlation for rectum (r = 0.81; p < 0.01) and a good correlation for bladder (r = 0.72; p < 0.01).

The LENT/SOMA system is a further step on the reporting of late radiation effects. Some modifications will improve its precision, and multicentric randomized studies are needed to test its validity.     

Long-term results with radiotherapy for stage I–II follicular lymphomas

Purpose: To analyze the long-term results with radiotherapy (RT) for early-stage, low-grade follicular lymphomas.

Methods and Materials: From 1960 to 1988, 80 patients with Stage I (n = 33) or II (n = 47), World Health Organization Grade 1 (n = 50) or 2 (n = 30) follicular lymphoma were treated with RT. The lymph nodes or spleen were involved in 97% of cases. The maximal tumor sizes ranged from 0.5 to 11.0 cm (median 2.0). The RT fields encompassed only the involved Ann Arbor nodal region (involved-field RT) in 9% of the patients. The fields also included 1–3 adjacent, grossly uninvolved nodal regions (regional RT) in 54% of patients but were smaller than mantle or whole abdominopelvic fields. Mantle or whole abdominopelvic fields encompassing up to 6 grossly uninvolved regions (extended-field RT) were used in the remaining 37% of patients. The total RT doses ranged from 26.2 to 50.0 Gy given in daily 1.0–3.0-Gy fractions.

Results: The follow-up of the surviving patients ranged from 3.5 to 28.7 years (median 19.0). No recurrences were found >17.0 years after RT, with 13 patients free of disease at their last follow-up visit 17.6–25.0 years after treatment. In 58% of cases, death was not from follicular lymphoma. The 15-year local control rate was 100% for 44 lymphomas <3.0 cm treated with only 27.8–30.8 Gy (median 30.0 in 20 fractions). Progression-free survival was affected by the maximal tumor size at the start of RT (15-year rate 49% vs. 29% for lymphomas <3.0 cm vs. ≥3.0 cm, respectively, p = 0.04) and Ann Arbor stage (15-year rate 66% vs. 26% for Stages I and II, respectively, p = 0.006). Ann Arbor stage also affected the cause-specific survival (15-year rate 87% vs. 54% for Stages I and II, respectively, p = 0.01). No significant difference was found in overall survival between those treated with extended-field RT and those treated with involved-field RT or regional RT (15-year rate 49% and 40%, respectively, p = 0.51). The 15-year incidence rate of Grade 3 or greater late complications according to the Subjective, Objective, Management, and Analytical scale in patients treated with 26.2–30.8 Gy vs. 30.9–50.0 Gy was 0% and 6%, respectively.

Conclusions: RT can cure approximately one half of Stage I and one quarter of Stage II, World Health Organization Grade 1 or 2 follicular lymphomas. Follicular lymphomas <3.0 cm can be controlled locally with doses of 27.8–30.8 Gy, and there is a trend toward a higher incidence of late complications with doses of >30.8 Gy. Doses of 25–30 Gy delivered in 15–20 fractions should be examined prospectively in patients with follicular lymphomas of <3.0 cm.     

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.     

Acute effects of irradiation on cognition: changes in attention on a computerized continuous performance test during radiotherapy in pediatric patients with localized primary brain tumors

To assess sustained attention, impulsivity, and reaction time during radiotherapy (RT) for pediatric patients with localized primary brain tumors.

Thirty-nine patients (median age 12.3 years, range 5.9–22.9) with primary brain tumors were evaluated prospectively using the computerized Conners’ continuous performance test (CPT) before and during conformal RT (CRT). The data were modeled to assess the longitudinal changes in the CPT scores and the effects of clinical variables on these changes during the first 50 days after the initiation of CRT.

The CPT scores exhibited an increasing trend for errors of omission (inattentiveness), decreasing trend for errors of commission (impulsivity), and slower reaction times. However, none of the changes were statistically significant. The overall index, which is an algorithm-based weighted sum of the CPT scores, remained within the range of normal throughout treatment. Older patients (age >12 years) were more attentive (p < 0.0005), less impulsive (p < 0.07), and had faster reaction times (p < 0.001) at baseline than the younger patients. The reaction time was significantly reduced during treatment for the older patients and lengthened significantly for the younger patients (p < 0.04). Patients with a shunted hydrocephalus (p < 0.02), seizure history (p < 0.0006), and residual tumor (p < 0.02) were significantly more impulsive. Nonshunted patients (p < 0.0001), those with more extensive resection (p < 0.0001), and patients with ependymoma (p < 0.006) had slower initial reaction times.

Children with brain tumors have problems with sustained attention and reaction time resulting from the tumor and therapeutic interventions before RT. The reaction time slowed during treatment for patients <12 years old. RT, as administered in the trial from which these data were derived, has limited acute effects on changes in the CPT scores measuring attention, impulsiveness, and reaction time.     

Organ preservation in patients with invasive bladder cancer: initial results of an intensified protocol of transurethral surgery and radiation therapy plus concurrent cisplatin and 5-fluorouracil

To assess safety, tolerance, and disease control of transurethral resection of the bladder tumor (TURB) plus concurrent cisplatin, 5-fluorouracil (5-FU), and radiation therapy (RT) with selective organ preservation in patients with bladder cancer.

Forty-five patients with muscle-invading or high-risk T1 (G3, associated carcinoma in situ, multifocality, >5 cm) bladder cancer were entered into a protocol of TURB followed by concurrent cisplatin (20 mg/m²/day, 20-min infusion) and 5-FU (600 mg/m²/day, 120-hour continuous infusion), administered on Day 1–5 and 29–33 of RT (single dose 1.8 Gy, total dose to the bladder 54–59.4 Gy). Response was evaluated by restaging TURB 6 weeks later. In case of invasive residual or recurrent tumor, salvage cystectomy was recommended. Median follow-up was 35 months (range: 8–80 months).

Thirty-nine patients (87%) had no detectable tumor at restaging TURB; 29 patients (64%) have been continuously free of tumor in their bladders. A superficial relapse occurred in 4 patients, a muscle-invasive relapse in 6 patients. Overall survival and survival with preserved bladder was 67% and 54%, respectively, at 5 years. Hematologic Grade 3/4 toxicity occurred in 10%/4%; Grade 3 diarrhea occurred in 9%. Thirty-four patients (76%) completed the protocol as scheduled or with only minor deviations. One patient required salvage cystectomy because of a shrinking bladder.

Conclusion: This protocol of concurrent cisplatin/5-FU and RT has been associated with acceptable toxicity. The complete response rate of 87% and the 5-year survival with intact bladder of 54% are encouraging and compare favorably with our historical control series using RT with carboplatin and cisplatin alone.     

Incorporating biologic measurements (SF(2), CFE) into a tumor control probability model increases their prognostic significance: a study in cervical carcinoma treated with radiation therapy

To assess whether incorporation of measurements of surviving fraction at 2 Gy (SF₂) and colony-forming efficiency (CFE) into a tumor control probability (tcp) model increases their prognostic significance.

Measurements of SF₂ and CFE were available from a study on carcinoma of the cervix treated with radiation alone. These measurements, as well as tumor volume, dose, and treatment time, were incorporated into a Poisson tcp model (tcp_,ρ). Regression analysis was performed to assess the prognostic power of tcp_,ρ vs. the use of either tcp models with biologic parameters fixed to best-fit estimates (but incorporating individual dose, volume, and treatment time) or the use of SF₂ and CFE measurements alone.

In a univariate regression analysis of 44 patients, tcp_,ρ was a better prognostic factor for both local control and survival (p < 0.001 and p = 0.049, respectively) than SF₂ alone (p = 0.009 for local control, p = 0.29 for survival) or CFE alone (p = 0.015 for local control, p = 0.38 for survival). In multivariate analysis, tcp_,ρ emerged as the most important prognostic factor for local control (p < 0.001, relative risk of 2.81). After allowing for tcp_,ρ, CFE was still a significant independent prognostic factor for local control, whereas SF₂ was not. The sensitivities of tcp_,ρ and SF₂ as predictive tests for local control were 87% and 65%, respectively. Specificities were 70% and 77%, respectively.

A Poisson tcp model incorporating individual SF₂, CFE, dose, tumor volume, and treatment time was found to be the best independent prognostic factor for local control and survival in cervical carcinoma patients.     

Cumulative interfraction interval analysis of influence of time and interruptions on radiotherapy results in oral cancers

To present a new approach to analyze the influence of time and interruptions in fractionated radiotherapy, in terms of cumulative interfraction intervals (CIFIs), that is, the interval between nonsuccessive fractions of radiotherapy.

The subjects were 142 patients with epidermoid cancer of the buccal mucosa-gingiva-palate region treated by 60 Gy in 25 fractions during 5 weeks. The influence of CIFI between the first and sixth, eleventh, sixteenth, and twenty-first fractions (CIFI_1–6, CIFI_1–11, CIFI_1–16, and CIFI_1–21, respectively), as well as overall treatment time on local control, was analyzed by Kaplan-Meier calculation of the primary relapse-free survival and Mann-Whitney U testing of the difference in various CIFIs between the tumors that recurred (recurred group) and those that did not (controlled group).

Only CIFI_1–11 influenced local control significantly, with the 5-year primary relapse-free survival rate being 67.9%, 48.4%, and 32.6% in those with CIFI_1–11 of <14, 14, and >14 days (p = 0.0181). The median CIFI_1–11 in the controlled group was significantly lower than that in the recurred group (14 days vs. 15 days; p = 0.0037).

Interruptions during the first 11 fractions, including planned weekend gaps, decrease the effect of radiotherapy, possibly because of successful tumor cell repopulation during the protracted interfraction intervals. The analysis of time in terms of CIFI rather than overall treatment time appears to be a promising area for research.     

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.     

Usefulness of tumor volumetry by magnetic resonance imaging in assessing response to radiation therapy in carcinoma of the uterine cervix

: Clinical evaluation of tumor size in cervical cancer is often difficult, and clinical signs of radiation therapy failure may not be present until well after completion of treatment. The purpose of this study is to investigate early indicators of treatment response using magnetic resonance (MR) imaging for quantitative assessment of tumor volume and tumor regression rate before, during, and after radiation therapy.

: Thirty-four patients with cervical cancer Stages IB [5], IIB [8], IIIA [1], IIIB [14], IVA [3], IVB [1], and recurrent [2] were studied prospectively with four serial MR examinations obtained at the start of radiation therapy, at 2-2.5 weeks (20–24 Gy), at 4–5 weeks (40–50 Gy), and 1–2 months after treatment completion. Tumor volume was assessed by three-dimensional volumetric measurements using T₂-weighted images of each MR examination. The volume regression rate was generated based on the four sequential MR studies. These findings were correlated with local control, metastasis rate, and disease-free survival. Median follow-up was 18 months (range: 9–43 months).

: The tumor regression rate after a dose of 40–50 Gy correlated significantly with treatment outcome. The actuarial 2-year disease-free survival was 88.4% in patients with tumors regressing to <20% of the initial volume compared with 45.4% in those with ≥20% residual (p = 0.007). The incidence of local recurrence was 9.5% (2 out of 21) and 76.9% (10 out of 13), respectively (p < 0.001). Analysis by initial tumor volume showed that this observation was valid in patients with initial volumes between 40 and 100 cm³. Analysis by FIGO stage confirmed this observation in all patients except those with Stage IB.

: Sequential tumor volumetry using MR imaging appears to be a sensitive measure of the responsiveness of cervical cancer to irradiation. Treatment response can be assessed as early as during the course of radiation therapy by measurement of initial tumor volume and regression rate at 40–50 Gy. In patients with large (>40 cm³) and advanced (Stage ≥ IIIA) tumors, this technique may be helpful in supplementing the clinical examination for response assessment. The identification of patients at high risk for treatment failure may ultimately lead to improved clinical outcome.     

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.     

Impact of intensity-modulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies

: To evaluate the impact of intensity-modulated whole pelvic radiotherapy (IM-WPRT) on acute hematologic toxicity (HT) in gynecology patients.

: Between February 2000 and June 2001, 36 patients (24 cervix, 12 uterus) received IM-WPRT. The target consisted of the upper vagina, parametria, uterus, and presacral and pelvic lymph nodes. Using commercially available software, seven or nine coplanar IM-WPRT plans were generated. The planning goals were to irradiate the target while minimizing the dose to the small bowel, bladder, and rectum. Pelvic bone marrow (BM) was not a constraint in the planning process. The variables analyzed included white blood count (WBC), absolute neutrophil count (ANC), platelets, and hemoglobin (Hgb) obtained before and weekly during RT. As a comparison, the HT in 88 patients (44 cervix, 44 uterus) treated to the same target volume and total dose (45 Gy) with conventional four-field WPRT was analyzed. In addition, the medullary spaces within the pelvic bones in 10 women were contoured and the average dose-volume histograms representing the pelvic BM were compared between the two groups.

: IM-WPRT patients had a lower median age (p = 0.008), higher percentage of squamous histologic features (p = 0.04), and were more likely to receive chemotherapy (CTX) (p = 0.02) than were the WPRT patients. No differences were seen in the baseline WBC, ANC, platelet, or Hgb levels between the two groups. Grade 2 or greater WBC, ANC, and Hgb toxicity was seen in 19.4%, 9.1%, and 8.6% of the IM-WPRT patients, respectively. Comparable rates were seen in the WPRT patients (WBC 21.6%, p = 0.79; ANC 8.3%, p = 0.91; Hgb 9.2%, p = 0.94). No Grade 2 or greater platelet toxicity was seen in either group. Significant HT was infrequent in women treated with RT alone and was comparable in the two groups. In contrast, WPRT + CTX patients experienced more Grade 2 or greater WBC toxicity (60% vs. 31.2%, p = 0.08) and developed lower median WBC (2.8 vs. 3.6 μg/dL, p = 0.05) and ANC (1874 vs. 2669, p = 0.04) nadirs than did IM-WPRT + CTX patients. Moreover, CTX was held more often in the WPRT group secondary to HT (40% vs. 12.5%, p = 0.06). Although Grade 2 or greater ANC (23.5% vs. 15.3%) and Hgb (35.2% vs. 15.2%) toxicity were lower in the IM-WPRT + CTX group, these differences did not reach statistical significance (p = 0.58 and p = 0.22, respectively). The comparison of pelvic BM dose-volume histograms revealed that IM-WPRT planning resulted in significantly less BM volume being irradiated compared with WPRT planning, particularly within the iliac crests.

: IM-WPRT has a favorable impact on the risk of acute HT in gynecology patients, particularly in those receiving CTX. Future work is needed to optimize BM sparing in these patients to reduce the risk of significant HT further.