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.     

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.     

Medium-dose-rate brachytherapy of cancer of the cervix: preliminary results of a prospectively designed schedule based on the linear-quadratic model

Purpose: To compare results and complications of our previous low-dose-rate (LDR) brachytherapy schedule for early-stage cancer of the cervix, with a prospectively designed medium-dose-rate (MDR) schedule, based on the linear-quadratic model (LQ).

Methods and Materials: A combination of brachytherapy, external beam pelvic and parametrial irradiation was used in 102 consecutive Stage Ib–IIb LDR treated patients (1986–1990) and 42 equally staged MDR treated patients (1994–1996). The planned MDR schedule consisted of three insertions on three treatment days with six 8-Gy brachytherapy fractions to Point A, two on each treatment day with an interfraction interval of 6 hours, plus 18 Gy external whole pelvic dose, and followed by additional parametrial irradiation. The calculated biologically effective dose (BED) for tumor was 90 Gy₁₀and for rectum below 125 Gy₃.

Results: In practice the MDR brachytherapy schedule achieved a tumor BED of 86 Gy₁₀ and a rectal BED of 101 Gy₃. The latter was better than originally planned due to a reduction from 85% to 77% in the percentage of the mean dose to the rectum in relation to Point A. The mean overall treatment time was 10 days shorter for MDR in comparison with LDR. The 3-year actuarial central control for LDR and MDR was 97% and 98% (p = NS), respectively. The Grades 2 and 3 late complications (scale 0 to 3) were 1% and 2.4%, respectively for LDR (3-year) and MDR (2-year).

Conclusions: LQ is a reliable tool for designing new schedules with altered fractionation and dose rates. The MDR schedule has proven to be an equivalent treatment schedule compared with LDR, with an additional advantage of having a shorter overall treatment time. The mean rectal BED Gy₃ was lower than expected.     

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.     

Radiotherapy alone in the treatment of uterine cervix cancer with telecobalt and low-dose-rate brachytherapy: retrospective analysis of results and variables

PURPOSE: This retrospective analysis aims to report results and variables from patients with cervix cancer treated by radiation therapy alone with telecobalt and low-dose-rate brachytherapy (LDRB). METHODS AND MATERIALS: Between September 1989 and September 1995, 190 patients with histologic diagnosis of cervix carcinoma were treated with telecobalt for external beam radiotherapy (EBR), followed by one or two insertions of LDRB. Stage distribution according to patients was the following: IB, 12; IIA, 4; IIB, 105; and IIIB, 69. Median dose of EBR at whole pelvis was 40 Gy, and median parametrial doses for Stages II and III patients were 50 Gy and 60 Gy, respectively. Median doses of LDRB at point A for patients treated with one and two insertions were 38 Gy and 50 Gy, respectively. RESULTS: Median follow-up time was 70 months (range: 8-127 months). Overall survival, disease-free survival, and 5-year local control of patients at Stages I, II, and III were 83%, 78%, and 46%; 83%, 82%, and 49%; and 92%, 87%, and 58%, respectively. Overall incidence of late complications in the rectum, small bowel, and urinary tract was 15.3% (19/190), 4.2% (8/190), and 6.8% (13/190), respectively. The actuarial 5-year rectal, small bowel, and urinary incidence of late complications was 16.1%, 4.6%, and 7.6%, respectively. Clinical stage was the only significant variable for overall 5-year survival (p = 0.001), for disease-free survival (p = 0.001), and for local control (p = 0.001). Stage II patients more than 50 years old had better disease-free survival and local control at 5 years (p = 0.004). None of the analyzed variables influenced the actuarial 5-year incidence of late complications. CONCLUSIONS: Results of this series suggest that the use of telecobalt equipment for EBR with doses up to 50 Gy at whole pelvis, prior to brachytherapy, is an acceptable technique for radiation therapy alone in the treatment of cervix cancer, especially in developing countries, including Brazil, where telecobalt machines still prevail.     

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.     

The role of brachytherapy in early-stage nasopharyngeal carcinoma

To present the treatment results and assess the optimal radiation dose and the role of brachytherapy in early stage nasopharyngeal cancer (NPC).

One hundred eighty-three patients with Stage I and II (American Joint Committee on Cancer Staging System, 1987) NPC completed the planned radiotherapy in our institution from 1979 to 1991. In 133 patients, radiotherapy was given to the nasopharynx by external beam to 64.8–68.4 Gy. Further boost was done by high dose rate (HDR) brachytherapy for 5–16.5 Gy in one to three fractions. For the remaining 50 patients, a course of external radiotherapy to the nasopharynx for 68.4–72 Gy was given to nasopharynx. Age (>40 or not) sex, neck boost or not, brachytherapy, and irradiation dose were analyzed to determine significant factors that influence the probabilities of local control and actuarial survival.

The 5-year disease-specific survival was 85.8% and local control was 83%. Only the brachytherapy and irradiation dose significantly affected the results. The use of the brachytherapy had significant impact on overall survival and local control. Furthermore, we compared the prognostic effect of various radiation dosage among Group I of 50 patients (<72.5 Gy, no brachytherapy, excluding four patients who received brachytherapy), Group II of 71 patients (72.5–75 Gy; one to two fractions of brachytherapy), and Group III of 58 patients (>75 Gy; three fractions of brachytherapy). Five-year disease-specific survival rates of Group I, Group II, and Group III were 77, 95.5, and 82.4%, respectively. Five-year local control rates were: 73.7, 93.9, and 79.5%. We found that the Group II had the best actuarial survival and local control rate (log-rank test, p < 0.05). Most patients receiving brachytherapy encountered foul odor because of nasopharynx crust; 12 of them had palate or sphenoid sinus floor perforation or nasopharynx necrosis. None of the patients without brachytherapy experienced the same complications.

The optimal radiotherapy dose to the nasopharnyx area in early stage NPC may be within 72.5 to 75 Gy by our treatment protocol. A dose of more than 75 Gy did not have significant local control or survival advantage. The use of brachytherapy to elevate radiation dose had significant local control and survival benefit for early stage NPC patients, but the fractionation size should be decreased to reduce the complications.     

Metastatic melanoma to the brain: prognostic factors after gamma knife radiosurgery

To identify important prognostic factors predictive of survival and tumor control in patients with metastatic melanoma to the brain who underwent gamma knife radiosurgery.

A total of 122 consecutive patients with 332 intracranial melanoma metastases underwent gamma knife radiosurgery over a 5-year period. Of these, 39 (32%) also received whole-brain irradiation (WBI). The median tumor volume was 0.8 cm³ (range: 0.02–30.20 cm³), and the median prescribed dose was 20 Gy (range: 14–24 Gy). Median follow-up was 6.8 months. Univariate and multivariate analyses of survival and freedom from progression were performed using the following parameters: status of systemic disease, intracranial tumor volume, number of lesions, tumor location, Karnofsky performance status, gender, age, and WBI.

Overall median survival was 7.0 months from time of radiosurgery and 9.1 months from the onset of brain metastasis. In multivariate analysis, improved survival was noted in patients with total intracranial tumor volume <3 cm³ (p = 0.003) and inactive systemic disease (p = 0.0065), whereas other parameters studied were of lesser importance (tumor location, p = 0.056, and Karnofsky performance status, p = 0.086), or of no significance (number of lesions, WBI, age, and gender). Freedom from subsequent brain metastasis depended on intracranial tumor volume (p = 0.0018) and status of systemic disease (p = 0.034).

Conclusions: Stereotactic radiosurgery is an effective treatment modality for patients with intracranial metastatic melanoma. Tumor volume and status of systemic disease are good independent predictors of survival and freedom from tumor progression.     

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.     

Postoperative low-pelvic irradiation for stage I-IIA cervical cancer patients with risk factors other than pelvic lymph node metastasis

: To retrospectively investigate whether postoperative low-pelvic radiotherapy (RT) is an appropriate treatment for node-negative, high-risk Stage I–IIA cervical cancer patients.

: A total of 228 Stage I–IIA cervical cancer patients treated by radical surgery and postoperative RT were included in this study. All patients had histopathologically negative pelvic node metastasis, but at least one of the following risk factors: parametrial involvement, positive or close resection margins, invasion depth two-thirds or greater cervical stromal thickness. Seventy-nine patients (35%) received 30–50 Gy (median 44) to whole pelvis and a boost dose to the low pelvis (whole-pelvic RT group); the other 149 patients (65%) received low-pelvic RT only (low-pelvic RT group). For both groups, the total external RT dose to the low pelvis ranged from 40 to 60 Gy (median 50). The potential factors associated with survival, small bowel (gastrointestinal) complications, and leg lymphedema were analyzed, and patients who had a relapse in the upper pelvis were identified.

: The 5-year overall and disease-specific survival rate was 84% and 86%, respectively. After multivariate analysis, only bulky tumor (≥4 cm) and non-squamous cell carcinoma were significantly associated with survival. Parametrial involvement, lymph-vascular invasion, ≤50.4 Gy to the low pelvis, positive or close margins, and low-pelvic RT alone did not significantly affect survival. Grade I–V small bowel complications occurred in 33 patients (15%). Whole pelvic RT and >50.4 Gy to the low pelvis, but not old age and treatment technique (AP-PA vs. box), were significantly associated with gastrointestinal complications. Three patients (2%) in the low-pelvic RT group and 6 patients (8%) in the whole-pelvic RT group were found to have Grade III or higher small bowel complications (p = 0.023). Thirty-one percent of patients developed lymphedema of the leg. A dose to the low pelvis >50.4 Gy and an AP-PA field, but not whole-pelvic RT, old age, or the number of sampled lymph nodes, were associated with lymphedema of the leg. Five patients (3.6%) of the low-pelvic RT group and none of the whole-pelvic RT group developed upper pelvis relapse. Three of these 5 patients had upper pelvic relapse alone.

: Compared with whole-pelvic RT plus low-pelvic boost, low-pelvic RT alone significantly reduces the small bowel complications in node-negative, high-risk, Stage I–IIA cervical cancer patients. Although low-pelvic RT alone increases the incidence of upper pelvic relapse, its effect on survival is not substantial. Low-pelvic RT alone appears to be an appropriate treatment method for this group of patients.     

Role of mitomycin C in the development of late bowel toxicity foloowing chemoradiation for locally advanced carcinoma of the cervix

: To determine if the inclusion of mitomycin C (MMC) in chemoradiation protocols for locally advanced cervical cancer (LACC) significantly enhances the development of serius (Grade 3) late bowel toxicity (SLBT).

: The incidence of SLBT in 154 patients with LACC entered in six consecutive chemoradiotherapy protocols between February 1982 and June 1987 was determined. Fifty-four patients who were treated with MMC, 5-flourouracil (5-FU), and radiation were compated to 100 patients who received similar treatment without MMC. Univariate and multivariate analyses assessed the effect of the following parameters on the development of SLBT: (a) external beam dose, (b) rectal and rectosignoid dose, (c) paraaortic radiation, (d) intracavitary dose and dose rate, (e) volume of tissue irradiated to a total dose od 60 Gy, (f) International Federation of Gynecology and Obstetrics stages, (g) age, (h) number of courses of 5-FU, (i) previous abdominopelvic surgery, (j) split versus continuous radiation, and (k) administration of MMC.

: The overall incidence of SLBT was 15.6%: 14 of 54 (26%) versus 10 of 100 (10%) for patients who did or did not receive MMC, respectively (p = 0.009). Multivariate analysis revealed the administration of MMC as the only factor predictive for the development of SLBT (p = 0.012, odds RATIO = 3.15; 95% confidence interval 1.3–7.7). A significant reduction in SLBT was observed with the elimination of MMC from the chemoradiation protocols despite dose escalation of both radiation and 5-FU. No increase in overall survival was observed in patients receiving MMC, 5-FU, and radiation compared with 5-Fu and radiation alone.

: The inclusion of MMC in these chemoradiation protocols for LACC is associated with significant enhancement in serious late bowel toxicity.     

Salvage radiation therapy for locally recurrent nasopharyngeal carcinoma

Purpose: To study the treatment outcome in patients with locally recurrent nasopharyngeal carcinoma (NPC) and to explore whether a combination of high-dose-rate (HDR) intracavitary brachytherapy and external beam radiation therapy (ERT) could improve the therapeutic ratio.

Methods and Materials: Ninety-one patients with nonmetastatic locally recurrent NPC who were treated with curative intent during the years 1990–1999 were retrospectively analyzed. Eighty-two patients had histologically proven carcinoma. The remaining 9 had clinical and imaging features suggestive of local recurrence. The Ho’s T-stage distribution at recurrence (rT) was as follows: rT1–37, rT2–14, rT3–40. Total equivalent dose (TED) was calculated by the linear–quadratic formula without a time factor correction. For those treated by combined-modality treatment (CMT), the TED was taken as the summation of the equivalent dose by ERT and the absolute dose delivered to floor of the sphenoid by brachytherapy. Eight patients were treated solely with brachytherapy, all receiving 24–45 Gy in 3–10 sessions. Forty-one patients were treated with ERT alone receiving a median TED of 57.3 Gy (range, 49.8–62.5 Gy). Forty-two patients were treated by CMT with a median equivalent dose of 50 Gy (range, 40–60 Gy) given by ERT and 14.8 Gy by brachytherapy (range, 3–29.6 Gy). Multivariate analyses were performed using the Cox regression proportional hazards model.

Results: The 5-year actuarial overall survival rate, disease specific survival rate and local failure-free survival (LFFS) rate for the whole group were 30%, 33.3% and 37.8%, respectively. The 3-year LFFS rates of rT1, rT2, and rT3 diseases were 64%, 61.5%, and 18.4%, respectively (p = 0.001).

Of the 8 patients treated with brachytherapy alone, 4 failed locally. Further analyses were concentrated on the ERT (41 patients) and CMT (42 patients) groups. The 3-year LFFS rates of rT1, rT2, and rT3 diseases were 66.7%, 66.7%, and 18.4%, respectively (p = 0.0008). Better local control for patients who received a TED of 60 Gy or greater was shown. The corresponding 3-year LFFS rates were 29% and 60% (p = 0.0004). Subgroup analysis on the ERT and CMT groups showed a 3-year LFFS rate of 33.5% and 57% (p = 0.003). ERT group had an excess of patients with rT3 disease. Further analysis was performed on the rT1–2 patients showing a trend toward improvement in local control in favor of the CMT group (3-year LFFS rates: CMT, 71.7%; ERT, 54%; p = 0.13). Multivariate analyses showed that rT stage (p = 0.002) and TED (p = 0.01; HR, 0.93; 95% confidence interval, 0.88–0.98) remained significant.

The 5-year major and central nervous system (CNS) complication-free rates were 26.7% and 47.8%. The following factors were found to be significant on univariate analyses for both complications in the ERT and CMT groups: (1) Modality of treatment: more complications with ERT group; and (2) rT stage. Multivariate analyses showed that the rT stage was significant for predicting the occurrence of major (p = 0.004) and CNS complications (p = 0.04).

Conclusion: For rT1–2 local recurrences, CMT with at least 60 Gy TED is recommended. The high incidence of major late complications is of serious concern. Ways of improving the local control of Ho’s rT3 disease and reducing the risk of late complications should be explored.     

Accelerated radiation therapy for locally advanced squamous cell carcinomas of the oral cavity and oropharynx selected according to tumor cell kinetics-A phase II multicenter study

A Phase II multicenter trial testing an accelerated regimen of radiotherapy in locally advanced and inoperable cancers of the head and neck, in patients selected on the basis of 5-bromo-2-deoxyuridine/DNA flow cytometry-derived tumor potential doubling time (T_pot).

From September 1992 to September 1993, 23 patients consecutively diagnosed to have locally advanced, inoperable carcinomas of the oral cavity and the oropharynx, with T_pot of ≤ 5 days, received an accelerated radiotherapy regimen (AF) based on a modification of the concomitant boost technique: 2 Gy/fraction once a day, delivered 5 days a week up to 26 Gy, followed by 2 Gy/fraction twice a day, with a 6-h interval, one of the two fractions being delivered as a concomitant boost to reduced fields, up to 66 Gy total dose (off-cord reduction at 46 Gy), shortening the overall treatment time to 4.5 weeks. A contemporary control group of 46 patients with T_pot of >5 days or unknown was treated with conventional fractionation (CF):2 Gy/fraction once a fay, 5 days a week, up to 66 Gy in 6.5 weeks, with fields skrinkage after 46 Gy.

All patients completed the accelerated regimen according to protocol and in the prescribed overall treatment time. Immediate tolerance was fairly good: 65% of the patients inthe AF group experienced Grade 3 mucositis vs. 45% in thee CF group (p = n.s.). Symptoms related to mucosal reactions seemed to persist longer in AF than in CF patients. The crude proportion of mild (Grades 1 and 2) late effects on skin (p < 0.01) and salivary glands (p < 0.05) was higher in AF than in CF patients, although these reactions dis not exceed the limits of tolerance. Three patients in the AF and 1 in the CF arm experienced a late Grade 4 bone complication. Actuarial estimates of severe (Grade 3 and 4) late complications showed a 2-year hazard of 33.3% in the AF arm and 49.7% in CF (p = NS). The actuarial 2-year local control rate of the AF patients was 49.4%, while actuarial 2-year overall survival for the same patients was 43.5%.

The results suggested that this accelerated regimen is worth testing in a controlled randomized trial to compare different accelerated schedules. Our findings also confirmed the 5-bromo-2-deoxyuridine/DNA flow cytometry technique as a suitable method of evaluating tumor cell kinetics in multicenter clinical studies, on conditions thal all measurements are carried out by one most experienced laboratory.     

Results and prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma

Purpose: To review the results and evaluate the prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma.

Methods and Materials: We reviewed the records of 74 patients with locally recurrent nasopharyngeal carcinoma treated at the University of California, San Francisco between 1957 and 1995. The histologic types included squamous cell carcinoma in 6 (8.1%), nonkeratinizing carcinoma in 48 (64.9%), and undifferentiated carcinoma in 20 (27%) cases. The site of recurrence was in the primary in 46 (62.2%), in the neck nodes in 20 (27%), and in both sites in 8 (10.8%) patients. The recurrent disease was Stage I in 10 (13.5%), Stage II in 16 (21.6%), Stage III in 20 (27%), and Stage IV in 28 (37.9%) patients. Thirty-seven (50%) patients developed recurrence within 2 years and 58 (78.4%) within 5 years after initial treatment. Radiotherapeutic techniques used in the retreatment of primary recurrence consisted of external beam radiotherapy (EBRT), intracavitary brachytherapy, heavy-charged particle beam, and gamma knife, alone or in combination. Reirradiation doses ranged from 18 to 108 Gy, with a median dose of 60 Gy. Treatment of recurrent neck nodes consisted of radical neck dissection (RND) ± intraoperative radiotherapy (IORT), or EBRT ± hyperthermia, or chemotherapy ± hyperthermia. Chemotherapy was used in 22 (30%) patients. Median follow-up was 20 months (range: 2 to 308 months).

Results: The 3-, 5-, and 10-year actuarial overall survival following retreatment were 49, 37, 18%, respectively. Thirty-six patients (49%) were free of further local-regional recurrence after retreatment. The 3-, 5-, and 10-year local-regional progression-free rates were 52, 40, and 38%, respectively. On univariate analysis, histologic type (p < 0.0001), interval to recurrence (p = 0.034), and treatment modality for early-stage disease (p = 0.01) were significant prognostic factors for overall survival, with age being marginally significant (p = 0.053). For local-regional progression-free rate, only histology was significant (p = 0.035). On multivariate analysis, age (p = 0.026), histology (p = 0.015), and interval to recurrence (p = 0.030) were significant for overall survival, and only histology (p = 0.002) and presence of complications (p = 0.016) were significant for local-regional progression-free rate. Of the 64 reirradiated patients, late complications were documented in 29 (45%) patients. The late complications were permanent in 21 (33%) and severe in 15 (23%) patients.

Conclusion: Retreatment using radiotherapy alone or in combination with other treatment modalities can achieve long-term local-regional control and survival in a substantial proportion of patients with locally recurrent nasopharyngeal carcinoma. Age, histology, and interval to recurrence were independent prognostic factors for overall survival, but only histology and presence of complications were significant for local-regional progression-free rate.     

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.     

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.     

Iridium-192 transperineal interstitial brachytherapy for locally advanced or recurrent gynecological malignancies

Purpose: To assess treatment outcome for patients with locally advanced or recurrent gynecological malignancies treated with continuous low-dose-rate (LDR) remote afterloading brachytherapy using the Martinez Universal Perineal Interstitial Template (MUPIT).

Materials and Methods: Between 7/85 and 6/94, 69 patients with either locally advanced or recurrent malignancies of the cervix, endometrium, vagina, or female urethra were treated by 5 different physicians using the MUPIT with (24 patients) or without (45 patients) interstitial hyperthermia. Fifty-four patients had no prior treatment with radiation and received a combination of external beam irradiation (EBRT) and an interstitial implant. The combined median dose was 71 Gy (range 56–99 Gy), median EBRT dose was 39 Gy (range 30–74 Gy), and the median implant dose was 32 Gy (range 17–40 Gy). Fifteen patients with prior radiation treatment received an implant alone. The total median dose including previous EBRT was 91 Gy (range 70–130 Gy) and the median implant dose was 35 Gy (range 25–55 Gy).

Results: With a median follow-up of 4.7 yr in survivors, the 3-yr actuarial local control (LC), disease-specific survival (DSS), and overall survival (OS) for all patients was 60%, 55%, and 41% respectively. The clinical complete response rate was 78% and in these patients the 3-year actuarial LC, DSS, and OS was 78%, 79%, and 63% respectively. On univariate analysis for local control, disease volume and hemoglobin were found to be statistically significant. On multivariate analysis, however, only disease volume remained significant (p = 0.011). There was no statistically significant difference in local control whether patients had received any prior treatment with radiation (p = 0.34), had recurrent disease (p = 0.13), or which physician performed the implant (p = 0.45). The grade 4 complication rate (small bowel obstruction requiring surgery, fistulas, soft tissue necrosis) for all patients was 14%. With a dose rate less than 70 cGy/hour, the grade 4 complication rate was 3% vs. 24% with dose rate ≥ 70 cGy/hour (p = 0.013).

Conclusion: Patients with locally advanced or recurrent gynecological malignancies treated with the remote afterloader LDR MUPIT applicator can expect reasonable rates of local control that are not operator-dependent. Complication rates with this approach are acceptable and appear to be related to the dose rate.     

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.