Adriana Micheli

Radiation therapy in the management of symptomatic bone metastases: the effect of total dose and histology on pain relief and response duration

PURPOSE In order to better define variables and factors that may influence the pain response to radiation, and to look for a radiation regimen that can assure the highest percentage and the longest duration of pain relief, we performed a prospective, although not randomized, study on patients with bone metastases from various primary sites. METHODS AND MATERIALS From December 1988 to March 1994, 205 patients with a total of 255 solitary or multiple bone metastases from several primary tumors were treated in our radiotherapy center with palliative intent. Irradiation fields were treated with three main fractionation schedules: (1) Conventional fractionation: 40-46 Gy/20-23 fractions in 5-5.5 weeks; (2) Short course: 30-36 Gy/10-12 fractions in 2-2.3 weeks; (3) Fast course: 8-28 Gy/1-4 consecutive fractions. Pain intensity was self-assessed by patients using a visual analogic scale graduated from 0 (no pain) to 10 (the strongest pain one can experience). Analgesic requirement was assessed by using a five-point scale, scoring both analgesic strength and frequency (0 = no drug or occasional nonopioids; 1 = Nonopioids once daily; 2 = Nonopioids more than once daily; 3 = Mild opioids (oral codeine, pentazocine, etc.), once daily; 4 = Mild opioids more than once daily; 5 = Strong opioids (morphine, meperidine, etc.). Complete pain relief meant the achievement of a score < or = 2 in the pain scale or 0 in the analgesic requirement scale. Partial pain relief indicated a score of 3 to 4 or of 1 to 2 on the former and latter scale, respectively. RESULTS Total pain relief (complete + partial) was observed in 195 (76%) sites, in 158 of which (62%) a complete response was obtained. Metastases from NSC lung tumors appeared to be the least responsive among all primary tumors, with 46% complete pain relief in comparison to 65% and 83% complete relief in breast (p = 0.04) and in prostate metastases (p = 0.002), respectively. A significant difference in pain relief was detected among the several ranges of total dose delivered to the painful metastases, with 81%, 65%, and 46% complete relief rates in the 40-46 Gy, 30-36 Gy (p = 0.03), and 8-28 Gy (p = 0.0001) dose ranges respectively. A straight correlation between total dose and complete pain relief was confirmed by the curve calculated by the logistic model which shows that doses of 30 Gy or more are necessary to achieve complete pain relief in 70% or more of bone metastases. This correlation holds also for the duration of pain control, as shown by the actuarial analysis of time to pain progression. Multivariate analyses, with complete pain relief and time to pain progression as endpoints show a highly significant effect of radiation dose (p = 0.0007) and performance status (p = 0.003), with lower rates of complete pain relief and shorter time to pain progression observed after smaller radiation total doses or higher Eastern Cooperative Oncology Group (ECOG) scores. CONCLUSION Although single-dose or short course irradiation is an attractive treatment in reducing the number of multiple visits to radiotherapy departments for patients with painful bone metastases, it is nevertheless clear that aggressive protracted treatments seem to offer significant advantages especially for patients in whom the expected life span is not short.

The responsiveness of bone metastases to radiotherapy: The effect of site, histology and radiation dose on pain relief

281 patients with a total of 463 symptomatic osseous metastases treated for palliation between 1975 and 1985 have been retrospectively analysed. The most frequent primary sites were breast (50.1%) prostate (16.6%) and lung (11%), accounting for more than three fourths of all metastatic areas. Other primaries were represented by bladder, kidney, colorectal, uterus (corpus and cervix) melanoma and thyroid tumors, and by cancer from unknown origin. Palliation was evaluated only on a subjective pain score. Complete response meant complete pain relief, and partial response meant more than 50% and less than complete pain relief in all treated sites. Complete response rates were similar independently from the primary site, except for the adenocarcinomas of the kidney and for non-small cell carcinomas of the lung in which the response tended to be lower. A correlation was also found between the incidence of pain relief and the site of bone metastases, in that a lower response was shown in limb localizations. Also, the number of metastatic sites did not influence the complete response rate. As expected, the response rate in all cases seemed to be dependent on total absorbed dose while, surprisingly, it could not be shown to be affected by the fraction size. A similar trend was shown for the pain recurrence.

Definitive radiation therapy for localized prostatic adenocarcinoma

From 1974 to 1987, a total of 199 patients with prostatic carcinoma localized to the pelvis were treated with definitive external beam radiation therapy at the Istituto Medico e di Ricerca Scientifica. The median follow-up for all 126 surviving patients was 60 months. Actuarial 5-(and 10-) year overall survival rates for U.I.C.C. clinical Stage T1-2, T3 and T4 disease were 76.1% (58.5), 66% (42.5), and 27.6%, respectively. The corresponding 5- and 10-) year disease-specific survival rates were 81.7% (73), 72.5% (57.4), and 36.2%. The corresponding values of disease-free survival were 81.3% (76.8), 59.2% (57), and 17%, respectively. In 120 patients with more than 5 years of follow-up, local failure was seen alone in eight patients (6.6%) and associated with distant metastases in 19 patients (15.8%). In 28 patient (23.3%), distant metastases were observed alone. The median survival from the first evidence of metastases was 20 months, with no patient surviving beyond 5 years. The incidence of complications was acceptable. Serious complications, consisting of stenosis of both ureters and sigmoid colon requiring both urinary and intestinal diversion, occurred in two patients (1.3%). This study reveals that external radiotherapy is an efficacious and safe modality for locoregional control of prostate cancer.

Radiotherapy with or without androgen deprivation in the treatment of localized adenocarcinoma of the prostate.

This study analyzes the results of disease relapse and survival in two series of patients treated between 1974 and 1991 with definitive irradiation, with or without early androgen deprivation, for carcinoma of the prostate localized to the pelvis. All 264 patients were irradiated to the prostate and pelvic lymph nodes with a dose of 50 to 54 Gy in 25 to 27 fractions, followed by a 16- to 20-Gy boost in 8 to 10 fractions to the prostate and periprostatic region. Ninety percent of patients received a total dose to the prostate (pelvis + boost) of 70 Gy. Ninety-nine of the 264 patients underwent early androgen deprivation. The endocrine manipulation program was initiated 0 to 9 months before the beginning of the radiotherapy course and was continued for 2 or more years or until disease progression. All patients who relapsed after radiotherapy alone received late hormonal manipulation. After a median follow-up of 100 months, no difference in the incidence of local and distant failure rate and cancer-specific mortality was detected between the two treatment groups. The local and distant failure rates were, respectively, 19% and 40% in patients who had undergone radiotherapy and early androgen deprivation and 20% and 36% in patients who received radiotherapy alone. Cancer mortality was similar, with 35% and 30% of deaths in the former and latter group, respectively. Death for intercurrent disease, however, was significantly more frequent (p = 0.03) in patients treated with radiotherapy and hormones (19%) than in those who received radiotherapy alone (8%). Actuarial analysis of both metastasis-free and disease-free survival detected no difference between the two treatment groups, with 10-year rates of 53.3% and 42.5%, respectively, in the radiation-alone group and 45.5% and 47%, respectively, in the radiation-plus-androgen deprivation group. A statistically significant difference (p = 0.03) in overall survival in favor of patients treated with radiotherapy alone was noted, with a 10-year rate of 47%, compared with 26% observed in the radiotherapy-plus-androgen deprivation group. In conclusion, results of our study confirm numerous reports based on retrospective analyses that failed to show any benefit of hormonal management adjuvant to a definitive irradiation. The disappointing finding was the significantly better overall survival in patients who underwent radiotherapy alone.

Prognostic impact of transurethral resection on patients irradiated for localized prostate cancer

The prognosis for irradiated patients with localized prostatic carcinoma following transurethral resection of the prostate (TURP) has been debated. Controversy centers upon whether or not TURP has an adverse effect on the outcome. A retrospective analysis of 264 patients treated during 1974-1991 with radical external beam radiotherapy was performed. Ten patients who were irradiated postoperatively were excluded. One hundred and nine patients with urinary obstruction underwent TURP. In another 155 patients, pathological diagnosis was made by needle aspiration or tru-cut biopsies. One hundred and one patients received endocrine manipulation, 58 (40%) in the needle biopsy group, and 43 (39.5%) in the TURP group. Lymph node staging by pelvic lymphadenectomy (20 cases), lymphangiography (15 cases), and CAT and/or NMR (113 cases) was performed in 148 patients. Nodal metastases were found in 38 patients, 19 in the needle biopsy group, and 19 in the TURP group. Disease-related, disease-free and metastasis-free survivals were calculated for all stages and within each tumor stage and histological grade for both groups. Correlation of pretreatment factors with clinical outcome was evaluated by multivariate analysis. Overall, disease-related survival was significantly higher (P = 0.05) in patients undergoing needle biopsy than in those who had TURP (58% vs. 38% at 10 years). This difference was more significant in the subset of patients with well differentiated tumors (P < 0.01). However, no difference could be observed between the two groups in histological grade 2 and 3 tumors or by stage comparison.(ABSTRACT TRUNCATED AT 250 WORDS)

Conservative surgery and radiotherapy in early stage breast cancer: a comparison between tumourectomy and quadrantectomy

BACKGROUND AND PURPOSE This study analyses and compares the results of local regional control, distant metastases and survival in two series of patients irradiated from 1986 to 1992 in our radiation oncology centre following quadrantectomy or tumourectomy for early stage breast cancer. MATERIALS AND METHODS The quadrantectomy group consisted of 152 women, 109 (72%) with T1 and 43 (28%) with T2 tumours. Axillary nodes in this group were positive in 51 (33%) patients. The tumourectomy group included 123 women, 71 (58%) with T1 and 52 (42%) with T2 tumours. Positive axillary nodes were found in 56 (46%) of these patients. All quadrantectomy and tumourectomy patients received a dose of 50 Gy in 5 weeks to the whole breast, followed by a 10-16 Gy electron boost. Node positive patients in the tumourectomy group also received 50 Gy to the axillary apex and supraclavicular region. In both surgical groups, node positive premenopausal and postmenopausal patients received adjuvant CMF or tamoxifen therapy, respectively. RESULTS After a median follow-up of 58 months, 89% of women in the tumourectomy group and 87% in the quadrantectomy group were alive and 80 and 73%, respectively, were free of disease. Breast and nodal failures were detected in 4.9 and 0.8% of cases, respectively, in the tumourectomy group, as compared to 5.9 and 3.3% of cases, respectively, in the quadrantectomy group. Distant relapses were observed in 16 and 18% of patients in the former and latter groups, respectively. Actuarial overall and disease-free survival was similar in the two series, with 5-year rates of 90 and 72%, respectively, in the tumourectomy group, and of 91 and 78%, respectively, in the quadrantectomy group. The differences in survival are not statistically different. CONCLUSIONS Our findings show that tumourectomy and quadrantectomy, followed by adequate radiotherapy, provide comparable results in terms of local-regional control and survival.

A pilot study of concomitant protracted venous infusion 5-fluorouracil and hyperfractionated radiotherapy in rectal tumors

It has recently been shown that postoperative radiotherapy combined with 5-fluorouracil (5FU) resulted in an increase of survival and local control in patients with rectal cancer. However, hematological and intestinal toxicity were also increased. Experimental and clinical studies showed an increased radiation effect with an acceptable toxicity by delivering 5FU via a continuous intravenous infusion. From July 1988, 38 patients radically operated on for stages B2-C rectal cancer were irradiated in our hospital with 3 fractions per day of 100 cGy to a total dose of 5,600 cGy. Of these 38 patients, 13 underwent postoperative radiotherapy alone, and 25 received postoperative radiotherapy combined with concomitant protracted infusion of 5FU at doses of 250 and 300 mg/m2 per day. In addition, 14 patients with inoperable, locally advanced tumors or postoperative recurrences, were treated with the same combination schedule of 5FU and radiotherapy to a total radiation dose of 6,500 cGy. After a median follow-up of 43 months, the actuarial 3-year overall and disease-free survival rates in the postoperative group of patients were 68% and 68%, respectively, in the combined modality group, as compared to 51% and 36%, respectively, in the radiation alone group. Patients with inoperable tumors exhibited 3-year overall and disease-free survival rates of 24% and 32%, respectively. The main toxicity was rectal tenesmus, diarrhea, dysuria, and, less frequently, leukopenia. These symptoms were responsible for a treatment delay of more than 5 days in 2 of 6 and in 7 of 33 patients who received 5FU doses of 300 and 250 mg/m2 per day, respectively, as compared to 2 of 13 patients treated with radiotherapy alone.