[Surgery and follow-up 131I therapy in patients with differentiated thyroid carcinoma in the south-east of the Netherlands, 1983-1996, compliance with the 1987 consensus guidelines: additional data]. / Chirurgie en 131I-nabehandeling bij patiënten met gedifferentieerde schildklierkanker in Zuidoost-Nederland, 1983-1996, vergeleken met de consensusrichtlijnen uit 1987: aanvullende gegevens.

In a previous study using data from the regional cancer registry of the Comprehensive Cancer Centre South, Eindhoven, The Netherlands, we concluded that in the majority of cases surgical treatment was in accordance with the consensus recommendations, but that about 40% of patients with differentiated thyroid cancer from a number of regional hospitals had not been referred for 131I therapy. However, in a subsequent study using patient data from these hospitals, it became clear that almost all patients had in fact been referred for therapy but to centres outside the 131I therapy region. The conclusion of the study should therefore be altered: the great majority of patients with differentiated thyroid cancer in the south-east of The Netherlands (1983-96) were referred for 131I treatment and therefore the primary surgical and the follow-up treatment complied with the 1987 consensus guidelines.

Feasibility of a randomized trial on adjuvant radio-iodine therapy in differentiated thyroid cancer.

BACKGROUND: Justification for adjuvant radio-iodine (I-131) therapy in differentiated thyroid cancer (DTC) is purely based on retrospective data. This is true for ablative therapy and even more so for high-dosage adjuvant schedules. Randomized trials on the latter application are considered impossible due to anticipated formidable sample sizes required in a disease with an overall excellent prognosis like DTC. OBJECTIVE: To develop and validate a model that could stratify for risk of recurrence, rather than survival, as is usually done in prognostic indices, and secondly, to use this model to estimate the sample size required for a randomized trial. DESIGN, PATIENTS AND RESULTS: From databases of three large Dutch centres, we identified 342 consecutive patients without known residual DTC after (near-) total thyroidectomy. Using Cox proportional hazards analysis, a model was validated that clearly distinguished risk categories of recurrence using commonly available baseline variables. The model included age, N stage at presentation and T stage in papillary carcinoma. According to this stratification, a subset of patients at substantial risk for relapse (30-40%) was identified. They could be eligible for a trial assessing the impact of high-dose adjuvant I-131 on recurrence rates. Assuming a clinically relevant effect of 30% reduction of relapses, 290 patients would have to be entered in either arm (alpha 0.05, power 80%). CONCLUSION: We conclude that even though a randomized trial on this issue will be difficult to design and conduct, sample size is not the main problem.

[Surgery and referral for subsequent 131I therapy for patients with differentiated thyroid carcinoma in the south-east of the Netherlands, 1983-1996, compared to the consensus guidelines from 1987]. / Chirurgie en 131I-nabehandeling bij patiënten met gedifferentieerde schildklierkanker in Zuidoost-Nederland, 1983-1996, vergeleken met de consensusrichtlijnen uit 1987.

OBJECTIVE: To evaluate the treatment of patients with differentiated (papillary or follicular) thyroid cancer in general hospitals in the south-east of the Netherlands during the period 1983-1996, in relation to the 1987 national consensus recommendations. DESIGN: Population-based, retrospective, descriptive. METHOD: For the period 1 January 1983-31 December 1996, data on the histology, TNM-stage and treatment (hospital, specialist, type of operation, referral for 131I therapy) of all 236 patients with differentiated thyroid cancer were obtained from the cancer registry of the Comprehensive Cancer Centre South, Eindhoven, the Netherlands. The treatment was compared with the recommendations from the consensus meeting in 1987. RESULTS: Data on 219 patients (137 papillary, 82 follicular thyroid carcinoma) treated in the general hospitals in the region were studied; the 17 remaining patients had been referred from outside the region. Patients were treated at all hospitals in the region; the number of specialists per hospital able to treat thyroid carcinoma (internist and/or surgeon) was limited. In total 79% of the patients underwent a (near-)total thyroidectomy, half of them in two phases, and in 12% of the cases combined with regional lymph node dissection. In the majority of cases, surgical treatment was in accordance with the consensus recommendations: 65-100% of the cases per hospital. The proportion of patients referred for 131I therapy varied from 17% to 90%; referral was more frequent in the case of larger tumours and/or metastases. Of the 24 patients with a small papillary carcinoma without metastases, 79% were not referred for 131I therapy. CONCLUSIONS: The recommendations laid down in the consensus meeting in 1987 were known and appeared to be followed for surgical treatment but for subsequent 131I therapy they appeared to be interpreted differently. A review of the consensus guidelines seems to be worthwhile.

Trends in treatment and long-term survival of thyroid cancer in southeastern Netherlands, 1960-1992.

Thyroid cancer (TC), comprising less than 1% of all cancers in the Netherlands, has a good prognosis in general. Controversy still remains on the extent of surgical treatment and the indication for additional Iodine-131 (131I) therapy in the management of differentiated TC. The aim of this study was to describe (changes in) the treatment of TC and to determine independent prognostic factors for crude and relative survival of differentiated TC diagnosed in general hospitals. This population-based, retrospective study was based on data from the Eindhoven Cancer Registry, Comprehensive Cancer Centre South (I.K.Z.), Eindhoven, the Netherlands. Data were collected on all 343 TC patients diagnosed from 1 January 1960 to 31 December 1992. All available information on treatment (initial and additional) and survival (on 1 April 1994) were recorded. Initial surgical treatment was defined as limited or extended. Multivariate analysis of crude and relative survival to determine prognostic factors for differentiated TC was performed. Mean follow-up was 7.6 years. The proportion of patients with differentiated TC increased from 60% in 1960-1972 to 84% in 1985-1992. TC patients were treated in all hospitals in the region, approximately 2-4/year. Ninety per cent of all TC patients initially underwent surgical treatment; the extended procedures increasing from 27% in 1960-1974 to 61% in 1985-1992. 131I was also administered increasingly (from 18-44%) to patients with differentiated TC. The relative 5, 10 and 20 year survival rates for all TC were 80, 75 and 75%, respectively. In the first 5 years after diagnosis the crude death ratio was higher with the rise of age and for the follicular type and after 5 years for males and advanced disease. After inclusion of surgical treatment into the model, the estimates of the other death ratios did not change. Patients treated with 131I did better only during the first 5 years. Although the prognosis for TC patients treated in general hospitals in Southeastern Netherlands was similar to that found for patients treated in referral centres, concentration of treatment should be considered.

Short-term results of Na131I treatment of hyperthyroidism evaluated using an extended dosimetric method.

OBJECTIVE: To assess and evaluate the short-term results of radio-iodine treatment using an extended dosimetric method. METHODS: Sixty-five patients with Graves disease (GD) and 32 patients with toxic multinodular goitre (TMG) received a pre-therapeutic dosage of Na123I. The overall indicative radiation dose (Dind) and the indicative dosage (Aind) was calculated for the individual patient using the dosimetric results found. In the therapeutic setting dosimetric measurements were performed again. The quotient of the administered dose (A) and the indicative dosage and the quotient of the absorbed radiation dose (Dabs) and the indicative radiation dose were used to evaluate treatment results after 1 year of follow-up. RESULTS: Clinical outcome after 1 year for GD was 26% hyper-, 48% eu- and 26% hypothyroidism and for TMG 32, 59 and 9%, respectively. Within the percentile range P25-P75 of A/Aind these results were 27, 46 and 27% for GD and 36, 64 and 0% for TMG. Within the percentile range P25-P75 of Dabs/Dind these results were 23, 59 and 18% for GD and 33, 67 and 0 for TMG. Correlation coefficients between pre- and therapeutic dosimetric measurements in GD and TMG were 0.76 and 0.38, respectively. CONCLUSIONS: The short-term outcome after 1 year of follow-up is 48 and 59% euthyroidism for GD and TMG, respectively. Clinical outcome within the percentile range P25-P75 of A/Aind did not change these results. Within the percentile range P25-P75 of Dabs/Dind euthyroidism was achieved in 59% and 67% for GD and TMG, respectively. The pre-therapeutic values inaccurately represent the therapeutic values for GD and even more for TMG.

Radiotherapy for T2 and T3 carcinoma of the bladder: the influence of overall treatment time.

The influence of overall treatment time on local control rate was studied on a group of 147 patients with muscle invasive T2 or T3 transitional cell carcinoma of the urinary bladder. All patients received external radiotherapy at the Catharina Hospital, Eindhoven, The Netherlands between January 1974 and December 1984. Patients treated with overall treatment times shorter than 75 days (n = 92) were irradiated during a continuous course; all but one patient, with overall treatment times of 75 days or more (n = 55), received split-course radiotherapy. Actuarial local relapse-free probability at 3 years (LRFP3) was computed from the onset of radiotherapy. LRFP3 proved to be dependent on overall treatment time. For T2 stage, LRFP3 was 80 +/- 18% (n = 5) and 54 +/- 13% (n = 13) for overall times between 15-44 and 45-74 days, respectively, 36 +/- 14% (n = 11) for overall times between 75 and 104 days and 64 +/- 15% (n = 11) for overall times longer than 105 days. For T3 stage, LRFP3 was 33 +/- 19% (n = 6) and 48 +/- 10% (n = 25) for overall times between 15-44 and 45-74 days, respectively, 25 +/- 14% (n = 12) for overall times between 75 and 104 days and 22 +/- 14% (n = 9) for overall times longer than 105 days. The figures between brackets are numbers of patients relapsing within 3 years or at risk of relapse during at least 3 years. Patients who died without local relapse before 3 years were censored. We have reasons to believe that patient selection bias leads to overestimation of LRFP3 for the split-course radiotherapy in retrospective studies where the 'intention to treat' cannot be recalled. This retrospective study suggests that prolonging overall time of radiotherapy has an effect on local control in T2 and T3 transitional cell carcinoma of the urinary bladder. Local control was the worst for patients treated by split-course radiotherapy with a gap of approximately one month. Local control was not further decreased (and seemed even improved) by longer gaps, but this observation is possibly biased as explained in the discussion section. For patients treated by continuous course radiotherapy we could not find a difference in local control rates between patients treated with overall times of 44 days or less and those treated with overall times of 45-74 days.

Adjuvant postoperative radiotherapy for adenocarcinoma of the rectum and rectosigmoid. A retrospective analysis of locoregional control, survival, and prognostic factors on 178 patients.

Results are presented of a retrospective study on 178 patients receiving adjuvant postoperative radiotherapy after curative surgery for adenocarcinoma of the rectum and rectosigmoid. Tumorstages according to Gunderson-Sosin were B2: 67, B3: 5, C1: 9, C2: 94, and C3: 3. Median total dosage was 50 Gy (range: 10-66 Gy), with a median dose per fraction of 2.0 Gy, 5 fractions per week. The censored overall 5-year survival rate was 42%, and 5-year disease-free survival rate was 37%. The respective rates for stage B2 patients (n = 67) were 59% and 53%, and for stage C2 patients (n = 94), 25% and 25%. Recurrences occurred in 89% within 3 years, 8% in the fourth, and 1% in the fifth year of follow-up. Five-year local relapse rates were 27% for the stage B2 tumors and 40% for the stage C2 tumors. For survival, stage (P = .006), grade (P = .02), fixation at surgery (P = .03), and gender (P = .03) were independent prognostic factors. With local relapse-free probability (LRFP) as endpoint, grade (P < .02) was an independent prognostic factor. Dose of radiation was not of prognostic significance, neither for survival (P = .63) nor for LRFP (P = .61). Since improvement should be made in locoregional control, initiatives are taken to start preoperative radiotherapy; furthermore, the key role of surgery is emphasized.

[Thyroid cancer in Southeastern Netherlands, 1970-1989: trends in incidence, treatment and survival]. / Schildklierkanker in Zuidoost-Nederland, 1970-1989: trends in incidentie, behandeling en overleving.

OBJECTIVE: To describe the (changes in) incidence, treatment and prognosis of thyroid cancer (TC) in the period 1970-89 in the South-east of the Netherlands. SETTING: Eindhoven Cancer Registry, Comprehensive Cancer Centre South (I.K.Z.), Eindhoven. DESIGN: Retrospective. PATIENTS AND METHODS: Data were collected from al TC patients (ICD-O code 193 and non-Hodgkin lymphoma originating from the thyroid) diagnosed in the period 01.01.1970-31.12.1989. Histological, treatment and survival (on 01.07.1991) data were collected. The standardised incidence, prevalence, (relative) survival and mortality were calculated for men and women. RESULTS: The mean age of the 297 TC patients was 52 years; the male-female ratio was 1:2.3. 46% Of the TC patients had papillary TC, 35% follicular TC. The incidence of TC increased from 1.4 to 3.0/100,000/yr for females, the incidence remained unchanged for males (1,1/100,000/yr). The point prevalence (01.07.1991) was 25.6/100,000 for females and 8.2/100.000 for males. TC patients were treated in all hospitals in the region and were increasingly first seen bij an internist. There was a trend to more extensive surgical treatment and iodine-131 treatment in differentiated TC. For all TC patients the crude 10-year survival rate was 61%, the relative 10-year survival rate was 74%. Survival was related with sex, age and histological type. Mortality from TC remained very low. CONCLUSIONS: The incidence and prognosis of TC were similar to the surrounding countries. In general the recommendations from the consensus meetings for treatment of TC in 1985 and 1987 appear to be followed.

Carcinoma of the urinary bladder: long-term results of interstitial radiotherapy.

Between January 1974 and December 1988, 46 patients with cancer of the urinary bladder, stages T1 or T2, and one patient with stage T3, were treated with an interstitial implant at the radiotherapy department of the Catharina Ziekenhuis at Eindhoven, The Netherlands. Prior to implantation, one patient received no external radiotherapy, all other 46 patients were treated by either a low dose (40 patients: 12 Gy median) or an intermediate dose (six patients: 38-40 Gy) of external radiotherapy. Loco-regional relapse was observed in 14/47 (30%) of the patients (1/14 also had distant metastases). The site of loco-regional relapse was the bladder in 11 patients and the immediate vicinity of the bladder in three patients. Only four patients died due to uncontrolled locoregional disease. A salvage cystectomy was performed in five patients. Distant metastases alone were observed in 3/47 (6.4%) of patients. The intercurrent death corrected actuarial 5 and 10-year survival was 79.5% (72.2% for T1; 85.7% for T2). The difference between T1 and T2 tumors was not significant (P = 0.55). During follow-up, 17/47 (36%) patients died. Cause of death was intercurrent disease in eight patients, bladder cancer in eight patients and unknown cause in one patient. For the whole group, seven patients developed second or third malignancies. Multivariate analyses using survival as the endpoint showed no significant prognostic variables, while using relapse-free survival (RFS) as the endpoint (calculated from the date of interstitial implant and with censoring for death from intercurrent disease) the number of TUR before implant (P = 0.01) and the dose of external radiation before interstitial implant (P = 0.045) were of prognostic significance, both being negatively correlated with RFS. As six patients had received an intermediate dose of interstitial radiotherapy, separate multivariate analyses were performed on the subgroup of 41 patients who had received a high dose of interstitial radiation. Using survival as the endpoint, again no prognostic significant factors were found, but in the analyses using local relapse-free period (LRFP) as the endpoint, dose rate (P = 0.026) and duration of implant (P = 0.021) were inversely correlated with LRFP. The higher the dose rate, the better the LRFP, while a long duration of implantation had a negative impact on the LRFP. Information concerning radiotherapy-related complications was not available in one patient, ulceration of the bladder mucosa was observed in 9/46 (19.6%) and bladder stone formation in 3/46 (6.5%) patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Radiotherapy for locoregional relapses of rectal carcinoma after initial radical surgery: definite but limited influence on relapse-free survival and survival.

A group of 95 patients, treated with irradiation for relapse after radical surgery as only initial treatment modality for a rectal carcinoma was studied. The term locoregional relapse relates to evidence of tumor recurrent in the pelvis or the perineal area. Seventy-six patients presented with locoregional relapse only, and 19 patients presented with locoregional relapse and concomitant distant metastases. All patients were irradiated at the site of locoregional relapse. Total dose of irradiation was resp. 44 Gy median (range 6-66 Gy) and 40 Gy median (range 6-50 Gy). In the group of patients with locoregional relapse only, recurrence-free survival and survival after radiotherapy were, respectively, 23% and 61% at 1 year, and 6% and 13% at 3 years. In the group of patients with concomitant distant metastases, survival after radiotherapy was even worse, 33% at one year, and nihil at 3 years. Recurrences after radiotherapy occurred early during follow-up with 75% of the recurrences being recorded during the first year of follow-up. Recurrent or persistent disease inside the irradiation volume was the most important clinical problem in both groups, being documented in, respectively, 43/76 and 7/19 (7/13 if six patients were excluded with a survival of less than 3 months from onset of therapy). In the group of patients with locoregional relapse only, using recurrence-free survival as the endpoint, dose of irradiation (p = 0.01) was a significant multivariate prognostic factor and using survival as the endpoint, dose of irradiation (p = 0.005) and grade of tumor differentiation (p = 0.002) were significant. Potentials of current radiotherapy regimes are limited. Therefore, maximal initial treatment is warranted. In the event of a relapse after initial radical surgery, one should opt for either more aggressive standard therapy, or either new combined modalities approaches should be studied.

T1 and T2 carcinoma of the urinary bladder: long term results with external, preoperative, or interstitial radiotherapy.

Between January 1974 and December 1984, 273 consecutive patients with cancer of the urinary bladder, Stages T1 or T2, any N, M0, were referred to the radiotherapy department of the Catharina Hospital at Eindhoven, The Netherlands and 265 were treated in a non-randomized fashion according to one of the three following schedules: 137 patients (67 T1, 70 T2) received radiotherapy only; 96 (44 T1, 52 T2) had preoperative radiotherapy followed by cystectomy and diversion according to the Bricker technique in 94/96; 32 patients (13 T1, 19 T2) had low total dose (12 Gy median) external radiotherapy followed by an interstitial cesium implant. The external radiotherapy fields included the pelvic structures. Total dose was 64 Gy median in the radiotherapy-only group and 40 Gy median in the preoperative irradiated group. The median follow-up in survivors was 81 months (range: 15-203). Locoregional relapse was observed in 50% in the group treated by external radiotherapy alone versus 17% in the group treated by preoperative radiation plus surgery and 28% of the patients who received cesium implant. During follow-up, 106/137 (77%), 67/96 (70%) and 13/32 (41%) patients died. In the radiotherapy-alone group, 38 died from intercurrent diseases, 36 from bladder cancer, two from therapy-related complications and cause of death was unknown in 30 patients. In the preoperative radiation group, the figures were 17 for intercurrent deaths, 26 related to progressive bladder cancer, 14 died due to perioperative complications and cause of death was unknown in 10. Cause of death was intercurrent in six and due to bladder cancer in seven patients treated by cesium implant. Probability of survival (calculated from the date of histological diagnosis) for the whole group, with censoring death to intercurrent disease was 53% at 5 years (56% for T1; 51% for T2) and 41% (40% for T1; 43% for T2) at 10 years. No significant difference was observed between T1 and T2 (p = 0.76). Survival in the treatment subgroups was, for patients treated by external radiotherapy only: 50% at 5 years and 33% at 10 years; for patients treated by external radiotherapy and surgery: 49% at 5 years and 42% at 10 years; for patients treated by cesium implant: 76% at 5 years and 76% at 10 years. Survival of patients in the cesium implant group was significantly better than in the other groups (p = 0.0001). Following variables were analyzed using the Cox proportional hazards model: age, gender, T1 or T2 stage, grade, cesium implant or not, and surgery or not.(ABSTRACT TRUNCATED AT 400 WORDS)

Long-lasting epidural sensory blockade by n-butyl-p-aminobenzoate in the terminally ill intractable cancer pain patient.

An aqueous suspension of n-butyl-p-aminobenzoate (BAB), a highly lipid-soluble congener of benzocaine, was applied epidurally in terminally ill cancer patients with intractable pain. The suspension consisted of 10% BAB and 0.025% of the nonionic surfactant polysorbate 80 in 0.9% sodium chloride. Twelve consecutive patients received epidural BAB because pain was uncontrollable either by palliative radiotherapy or oral or epidural administrations of analgesics. The catheter or injecting needle was positioned at the segmental level of the pain. Repeated epidural injections were administered. In all patients, long-lasting sensory blockade (segmental analgesia) occurred, accompanied by a marked reduction or even absence of pain. In all patients, treatment with epidural opioids, alone or combined with local anesthetics, was no longer necessary. Five of the 12 patients did not require further administration of oral opioids. Motor, bowel, and bladder function were well preserved. In 6 patients, extensive necropsy of the spinal cord and spinal nerves did not reveal pathomorphologic changes. The outer aspect of the dura showed signs of focal necrosis on microscopy, yet its collagen structure and thickness were unchanged. Epidurally, focal infiltrative reactions were seen. The epidural use of an extremely lipid-soluble--hence hydrophobic--local anesthetic, with an exceptionally low pKa (2.3), formulated in suspension of the base, is conceptually innovative and needs further investigation. The authors conclude that the epidural administration of a BAB suspension may be an effective alternative to the neurolytic agents alcohol and phenol and may replace procedures such as cordotomy. Further investigation to determine the safety of BAB in this patient group appears warranted.

Incompletely resected rectum, recto-sigmoid, or sigmoid carcinoma: results of postoperative radiotherapy and prognostic factors.

Postoperative radiotherapy was given in 40 patients with gross or microscopic pathologically proven residual disease after surgical resection of rectum, recto-sigmoid, or sigmoid carcinoma. The radiotherapy target volume included the pelvis with (9 patients) or without (31 patients) the perineum. Median total dose of radiation was 50 Gy (range 30-60). One patient received 30 Gy, 10 received greater than 30 to 40 Gy, 13 received greater than 40 to 50 Gy, and 16 patients received greater than 50 to 60 Gy. The median follow-up in the survivors (16 patients) was 53 months (range: 16-85). Probability of survival with censoring for death due to intercurrent disease was 36% at 5 years. Survival for patients with microscopic residual disease (21 patients) was 40% at 5 years compared to 12% for those with gross residual disease (19 patients) (p = 0.09). Twenty-five patients relapsed. All but one relapse occurred earlier than 50 months after radiotherapy. Approximately half (12/25) of the relapses were observed within 6 months after radiotherapy. Local relapse inside the radiotherapy portals was observed in 9/40 (22%) patients. Therapy-related urogenital complications occurred in no patient and gastro-intestinal complications in three patients (7%). In one patient they were scored WHO grade 4 and in two patients WHO grade 3. Prognostic factors were analyzed using the Cox proportional hazards model. For survival differentiation, grade (p less than 0.001), stage (p = 0.04), and perineal irradiation (p = 0.03) were independent prognostic factors. With relapse-free survival as the endpoint, only stage (p = 0.003) was a statistically significant prognostic factor. There was a trend toward a better relapse-free survival when the perineum was included in the radiation portals (p = 0.09).

Endometrial carcinoma: high dose-rate brachytherapy in combination with external irradiation; a multivariate analysis of relapses.

From June 1974 to June 1984, 347 women with endometrial carcinoma were referred to the radiotherapy department of the Catharina Hospital, Eindhoven, The Netherlands. Of this total number, 327 patients were considered eligible for analysis; 36 being referred for recurrences of previous surgically treated endometrial carcinoma, and 291 being referred for radiotherapy as part of the initial treatment. The 28% 5-year relapse-free survival (RFS) of the group of 36 patients demonstrated that endometrial carcinoma may behave as a radiosensitive tumour. The remaining 291 had all undergone surgery, except 10. Radiotherapy consisted of high dose-rate brachytherapy applied to the vaginal vault for pathological stage I tumours, well differentiated, and with superficial myometrial invasion. All other patients received external beam irradiation to a pelvic dose of 40 Gy in 4 weeks, followed by brachytherapy (4 fractions of 5 Gy each). The 5-year RFS for pathologically staged patients was: stage I (232 patients) 88%, stage II (27 patients) 68%, stage III and IV (22 patients) 50%. Treatment-related complications were minimal. In-field recurrences were rare: 5% locoregional, 2.2% both loco-regional and distant, versus 9.3% distant failures. Multivariate RFS analysis demonstrated age, stage and tumour differentiation as independent prognostic factors, tumour differentiation being the most important factor.