1004
Letters
Table 1. Four prospective randomised trials comparing surgery (S) versus radiotherapy followed by surgery (RS) in the treatment of cancer of the oesophagus P*..A.. oruuy Nygaard et Launois et Gignoux et Wang et al. al. al. 1981 [l] al. 1987 [2] 1989 [3] (unpublished)
1. Launois B, Delarue D, Campion JP, Kerbaol M. Preoperative radiotherapy for carcinoma of the esophagus. Sura- Gvnecol Obstet _ _ 1981,153;890-692. 2. Gignoux M, Roussel A, Paillot B, et al. The value of preoperative radiotherapy in esophageal cancer: results of a study of the EORTC. Wor~JS& 1987,i1,426-432. 3. Wang M, Gu X-Z, Yin W-B, Huang G-T. Wang L-T. Zhana DW. Randomised ckical trial .on theconkination of preoperkve irradiation and surgery in the treatment of esophageal carcinoma: report on 206 patients. Int 3 Radiat Oncol Biol Phys 1989, 16, 325-327.
S
RS
Patients randomised Operable patients Respectable patients Operative mortality
57 47 33 11
67 62 47 14
114 115 106 97 87 75 19 24
102 104 102 104 87 97 5 5
Patients in survival analysis
26
34
106 102
102 104
3 years Actual survival Number ofresected patients surviving*
-
-
S
-
RS
-
S
RS
S
106 111 79 70 57 57 11 12 91
6% 28/66 35174 -
5 Years 9% 10% Actuarial survival Number ofpatients 1916427177 surviving* Actuarial survival 11.5%9.5% 10% 16% for resected patients Number ofresected 1915726171 patients surviving*
RS 1992.
95
19% -
-
-
-
-
-
Eur_9 Cancer, Vol. .%A, No. 415, pi. 10061005, Pnnred in Greor Brimn 0964-1947l92$5.00 t 0.00 0 1992 Pergmnon Presr Lrd
-
* Denominators are numbers of patients assessable for period stated.
population and in the patients in whom resection was possible, preoperative radiotherapy improved survival. Nevertheless, they indicated that none of the differences was statistically significant at the 5% level. In the trial by Nygaard et al. (Ullevaal Hospital, Oslo, Norway), the radiotherapy dose was 35 Gy and the interval between radiotherapy and surgery was 3 weeks. 217 patients with squamous cell cancer at least 21 cm from the incisors were randomised and survival analyses were based on the 186 treated according to protocol. Actuarial survival rates at 3 years were 6% in the S group and 19% in the RS group. The authors concluded that preoperative radiotherapy significantly improved survival. The results of these four trials might appear contradictory. They could, however, be consistent with a modest but worthwhile improvement in survival when preoperative radiotherapy is given. It is not possible to use the published data in an overview (meta-analysis), combining the results of all the trials, because different methods of analysis have been used and the results have been presented in different ways. To investigate whether preoperative radiotherapy improves survival in oesophageal cancer, we have therefore initiated an overview which aims to collect individual updated survival information from all the patients randomised into all relevant trials. To do this successfully we need to include data from all relevant trials. If readers know of any other such trials, we would be grateful if they could send us details.
Undifferentiated Small Cell Neuroendocrine Carcinoma of the Urinary Bladder Maurizio Amichetti, Sebastiana Boi, Gianni Fellin, Paolo Dalla Palma and Lucia Luciani EXTRAPULMONARYUNDIFFERENTIATED small cell carcinoma
(SCC) has been described in several organs. Primary SCC of the urinary tract is rare but has been increasingly reported [I]. Undifferentiated SCC of the bladder is a rare but aggressive subset of urinary tract neoplasms, frequently showing neuroendocrine differentiation [2]. We report one such case. A 56year-old woman was admitted for gross painless haematuria. Laboratory data and clinical examination were normal. Abdominopelvic computed tomography (CT) showed a right bladder lesion without nodal metastases. Cytoscopic examination revealed a large solid tumour involving the right lateral wall. A transurethral resection was performed. Light microscopy showed an undifferentiated SCC. Immunoperoxidase staining for keratin was positive in 80% of the cells, neuron specific enolase in 70% and neurofilament in 50%; chromogranine was diffusely positive, see Fig. 1. Two courses of a combination of methotrexate, cisplatin and vinblastine were admmistered, followed by radiotherapy (total dose of 64 Gy) combined with three infusions of cisplatin. A cystoscopic examination was negative and random biopsies showed no residual tumour but whole-body CT revealed metastatic diffusion. Therefore cyclophosphamide, epirubicin and vincristine were started. The disease progressed and the patient died 13 months after diag-
nosis. The first case of SCC of the bladder was described in 1981 [3], 63 additional cases have been reported in English to date. Despite extensive and accurate pathological studies, the histogenesis of SCC of the bladder has yet to be defined. Some theories have been proposed. The presence of multipotential epithelial cells capable of differentiation in more than one cell Correspondence to M. Amichetti. M. Amichetti and G. Fellin are at the Oncology Center; S. Boi and P.Dalla Palma are at the Department of Pathology; and L. Luciani is at the Department of Urology, S. Chiara Hospital, USLCS, 38100 Trento, Italy. Revised 27 Sep. 1991; accepted 21 Oct. 1991.
Letters
100s
Eur.?’Cmcer, Vol. 28A, No. 415,pi. IOOS-IW6.1992. Pnnredrn Grear Brimin 0964-1947192$5.00 + 0.W 0 1992 l’ergama Pras Ltd
Severe Complications of 5Fluorouracil and Cisplatin with Concomitant Radiotherapy in Inoperable Non-metastatic Squamous Cell Oesophageal Cancer After Intubation-Early Termination of a Prospective Randomised Trial Fig. 1. SCC of the bladder showing solid sheets of small cells with hypercbromatic nuclei and scanty cytoplasm. (haemotoxyWeosin 10 XL
line is at present the most probable [4], suggested by the frequent finding of other carcinomas with SCC. The diagnosis of neuroendocrine carcinoma of the bladder poses several problems: a vesical metastasis has to be excluded and such lesions have to be differentiated from transitional cell carcinoma, lymphoma, paraganglioma and peripheral nerve neuroblastoma. The incidence of these tumours will probably tend to increase because of the increasing use of immunohistochemical techniques. Since extrapulmonary SCC are rare, standard therapeutic approaches have not been developed, but several treatments have been proposed. Surgery, more or less conservative, and radiotherapy are the preferred treatments, as used in transitional cell carcinoma of the bladder. The usefulness of combining chemotherapy with conventional radiotherapy and surgery has been suggested [5-71. Interpretation of the prognosis of bladder SCC is limited by the small number of well documented cases, but the high malignancy of this neoplasm is demonstrated by the frequent metastatic diffusion of the disease in a short time. Our case confirms the aggressiveness of this tumour.
1. Yu DS, Chang SY. Wang J, et al. Small cell carcinoma of the urinarv tract. Br3 U&1990,66~59&595. WT. Small cell 2. Davis, BH, Ludwig ME, Cole SR, Pastuszak neuroendocrine carcinoma of the urinary bladder: Report of three cases with ultrastructural analysis. Ulnastruct Path01 1983, 4, 197-204. granules in small 3. Cramer SF, Aikawa M, Cebelin M. Neurosecretory cell invasive carcinoma of the urinary bladder. Cancer 1981, 47, 724-730. oat cell 4. Ibrahim NB, Briggs, JC, Corbishley CM. Extrapulmonary carcinoma. Cancer 1984,54, 1645-1661. 5. Podesta AH, True LD. Small cell carcinoma of the bladder. Report of five cases with immunohistochemistry and review of the literature with evaluation of prognosis according to stage. Cancer 1989, 64, 710-714. 6. Blomjous CEM, Vos W, De Voogt HJ, Van der Valk P, Meijer CJLM. Small cell neuroendocrine carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical and ultrastructural study of 18 cases. Cancer 1989,64,1347-1357. 7. Oosterhng JE, Brendler CB, Burgers JK, Marshall FF, Epstein JI. Advanced small cell carcinoma of the bladder. Successful treatment with combined radical cystoprostatectomy and adjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy. Cancer 1990,65, 1928-1936.
A.S. Alberts, W. Burger, F. Greeff, L. Schoeman, D. Friediger, J. Nel, E. Steyn, E.U. Schmid and G. Falkson recent review [l] of 1926 cases of oesophageal cancer in South Africa, it was shown that 77.4% of all cases had stage III AJC disease. Palliative intubation was the treatment most often selected. The median survival of patients with advanced oesophageal cancer in South Africa is 3-4 months[2, 31. Despite the advanced stage of disease some patients will present with good performance status and are potential candidates for more intensive anticancer therapy. Seitz et al. [4] demonstrated considerable activity with concomitant 5-fluorouracil(5FU) and cisplatin in patients with oesophageal cancer. In the present trial the addition of radiotherapy to concomitant S-FU and cisplatin (postintubation) was therefore prospectively evaluated. 20 patients with advanced, inoperable squamous carcinoma of the esophagus and ECOG [5] performance status of 0, 1 or 2, were entered on study. Pretreatment staging was done with barium swallow, computed tomography, and endoscopy. All patients had had placement of either a Celestin or Procter-Livingstone tube and could swallow semi-solid food and maintain adequate nutrition afterwards. Patients with tracheobronchial bulging due to tumour or small mediastinal fistulae were admitted to the study provided that the area was well covered by the tube and no frank trachea-bronchial fistulae were present (Table 1). Patients had to have adequate renal, haematologic and hepatic function. After intubation eligible patients were randomised to no further treatment (observation) or radiotherapy and concomitant S-FU and cisplatin. Radiation thc.apy consisted of 4 Gy fractions daily from day 1-S (20 Gy) and 29-33 (20 Gy). A 3field technique was used with the fields covering at least 5 cm superior and inferior, and 2 cm lateral to the known tumour volume. The chemotherapy consisted of S-FU 600 mg/mZ over 24 h from days 1-5 and 29-33 and cisplatin 15 mg/m* daily from days l-5 and 29-33. IN A
Correspondence to A.S. Alberts. A.S.Alberts, D. Friediger and J. Nel are at the Department of Radiotherapy, University of Pretoria, P.O. Box 667, Pretoria, 0001 South Africa; W. Burger, L.Schoeman and G. Falkson are at the Department of Medical Oncology, and F. Greeff, E. Steyn and E.U.Schmid are at the Department of Surgery, University of Pretoria, Pretoria, South Africa. Revised 16 Sep. 1991; accepted 2 Dec. 199!
Letters
Table 1. Four prospective randomised trials comparing surgery (S) versus radiotherapy followed by surgery (RS) in the treatment of cancer of the oesophagus P*..A.. oruuy Nygaard et Launois et Gignoux et Wang et al. al. al. 1981 [l] al. 1987 [2] 1989 [3] (unpublished)
1. Launois B, Delarue D, Campion JP, Kerbaol M. Preoperative radiotherapy for carcinoma of the esophagus. Sura- Gvnecol Obstet _ _ 1981,153;890-692. 2. Gignoux M, Roussel A, Paillot B, et al. The value of preoperative radiotherapy in esophageal cancer: results of a study of the EORTC. Wor~JS& 1987,i1,426-432. 3. Wang M, Gu X-Z, Yin W-B, Huang G-T. Wang L-T. Zhana DW. Randomised ckical trial .on theconkination of preoperkve irradiation and surgery in the treatment of esophageal carcinoma: report on 206 patients. Int 3 Radiat Oncol Biol Phys 1989, 16, 325-327.
S
RS
Patients randomised Operable patients Respectable patients Operative mortality
57 47 33 11
67 62 47 14
114 115 106 97 87 75 19 24
102 104 102 104 87 97 5 5
Patients in survival analysis
26
34
106 102
102 104
3 years Actual survival Number ofresected patients surviving*
-
-
S
-
RS
-
S
RS
S
106 111 79 70 57 57 11 12 91
6% 28/66 35174 -
5 Years 9% 10% Actuarial survival Number ofpatients 1916427177 surviving* Actuarial survival 11.5%9.5% 10% 16% for resected patients Number ofresected 1915726171 patients surviving*
RS 1992.
95
19% -
-
-
-
-
-
Eur_9 Cancer, Vol. .%A, No. 415, pi. 10061005, Pnnred in Greor Brimn 0964-1947l92$5.00 t 0.00 0 1992 Pergmnon Presr Lrd
-
* Denominators are numbers of patients assessable for period stated.
population and in the patients in whom resection was possible, preoperative radiotherapy improved survival. Nevertheless, they indicated that none of the differences was statistically significant at the 5% level. In the trial by Nygaard et al. (Ullevaal Hospital, Oslo, Norway), the radiotherapy dose was 35 Gy and the interval between radiotherapy and surgery was 3 weeks. 217 patients with squamous cell cancer at least 21 cm from the incisors were randomised and survival analyses were based on the 186 treated according to protocol. Actuarial survival rates at 3 years were 6% in the S group and 19% in the RS group. The authors concluded that preoperative radiotherapy significantly improved survival. The results of these four trials might appear contradictory. They could, however, be consistent with a modest but worthwhile improvement in survival when preoperative radiotherapy is given. It is not possible to use the published data in an overview (meta-analysis), combining the results of all the trials, because different methods of analysis have been used and the results have been presented in different ways. To investigate whether preoperative radiotherapy improves survival in oesophageal cancer, we have therefore initiated an overview which aims to collect individual updated survival information from all the patients randomised into all relevant trials. To do this successfully we need to include data from all relevant trials. If readers know of any other such trials, we would be grateful if they could send us details.
Undifferentiated Small Cell Neuroendocrine Carcinoma of the Urinary Bladder Maurizio Amichetti, Sebastiana Boi, Gianni Fellin, Paolo Dalla Palma and Lucia Luciani EXTRAPULMONARYUNDIFFERENTIATED small cell carcinoma
(SCC) has been described in several organs. Primary SCC of the urinary tract is rare but has been increasingly reported [I]. Undifferentiated SCC of the bladder is a rare but aggressive subset of urinary tract neoplasms, frequently showing neuroendocrine differentiation [2]. We report one such case. A 56year-old woman was admitted for gross painless haematuria. Laboratory data and clinical examination were normal. Abdominopelvic computed tomography (CT) showed a right bladder lesion without nodal metastases. Cytoscopic examination revealed a large solid tumour involving the right lateral wall. A transurethral resection was performed. Light microscopy showed an undifferentiated SCC. Immunoperoxidase staining for keratin was positive in 80% of the cells, neuron specific enolase in 70% and neurofilament in 50%; chromogranine was diffusely positive, see Fig. 1. Two courses of a combination of methotrexate, cisplatin and vinblastine were admmistered, followed by radiotherapy (total dose of 64 Gy) combined with three infusions of cisplatin. A cystoscopic examination was negative and random biopsies showed no residual tumour but whole-body CT revealed metastatic diffusion. Therefore cyclophosphamide, epirubicin and vincristine were started. The disease progressed and the patient died 13 months after diag-
nosis. The first case of SCC of the bladder was described in 1981 [3], 63 additional cases have been reported in English to date. Despite extensive and accurate pathological studies, the histogenesis of SCC of the bladder has yet to be defined. Some theories have been proposed. The presence of multipotential epithelial cells capable of differentiation in more than one cell Correspondence to M. Amichetti. M. Amichetti and G. Fellin are at the Oncology Center; S. Boi and P.Dalla Palma are at the Department of Pathology; and L. Luciani is at the Department of Urology, S. Chiara Hospital, USLCS, 38100 Trento, Italy. Revised 27 Sep. 1991; accepted 21 Oct. 1991.
Letters
100s
Eur.?’Cmcer, Vol. 28A, No. 415,pi. IOOS-IW6.1992. Pnnredrn Grear Brimin 0964-1947192$5.00 + 0.W 0 1992 l’ergama Pras Ltd
Severe Complications of 5Fluorouracil and Cisplatin with Concomitant Radiotherapy in Inoperable Non-metastatic Squamous Cell Oesophageal Cancer After Intubation-Early Termination of a Prospective Randomised Trial Fig. 1. SCC of the bladder showing solid sheets of small cells with hypercbromatic nuclei and scanty cytoplasm. (haemotoxyWeosin 10 XL
line is at present the most probable [4], suggested by the frequent finding of other carcinomas with SCC. The diagnosis of neuroendocrine carcinoma of the bladder poses several problems: a vesical metastasis has to be excluded and such lesions have to be differentiated from transitional cell carcinoma, lymphoma, paraganglioma and peripheral nerve neuroblastoma. The incidence of these tumours will probably tend to increase because of the increasing use of immunohistochemical techniques. Since extrapulmonary SCC are rare, standard therapeutic approaches have not been developed, but several treatments have been proposed. Surgery, more or less conservative, and radiotherapy are the preferred treatments, as used in transitional cell carcinoma of the bladder. The usefulness of combining chemotherapy with conventional radiotherapy and surgery has been suggested [5-71. Interpretation of the prognosis of bladder SCC is limited by the small number of well documented cases, but the high malignancy of this neoplasm is demonstrated by the frequent metastatic diffusion of the disease in a short time. Our case confirms the aggressiveness of this tumour.
1. Yu DS, Chang SY. Wang J, et al. Small cell carcinoma of the urinarv tract. Br3 U&1990,66~59&595. WT. Small cell 2. Davis, BH, Ludwig ME, Cole SR, Pastuszak neuroendocrine carcinoma of the urinary bladder: Report of three cases with ultrastructural analysis. Ulnastruct Path01 1983, 4, 197-204. granules in small 3. Cramer SF, Aikawa M, Cebelin M. Neurosecretory cell invasive carcinoma of the urinary bladder. Cancer 1981, 47, 724-730. oat cell 4. Ibrahim NB, Briggs, JC, Corbishley CM. Extrapulmonary carcinoma. Cancer 1984,54, 1645-1661. 5. Podesta AH, True LD. Small cell carcinoma of the bladder. Report of five cases with immunohistochemistry and review of the literature with evaluation of prognosis according to stage. Cancer 1989, 64, 710-714. 6. Blomjous CEM, Vos W, De Voogt HJ, Van der Valk P, Meijer CJLM. Small cell neuroendocrine carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical and ultrastructural study of 18 cases. Cancer 1989,64,1347-1357. 7. Oosterhng JE, Brendler CB, Burgers JK, Marshall FF, Epstein JI. Advanced small cell carcinoma of the bladder. Successful treatment with combined radical cystoprostatectomy and adjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy. Cancer 1990,65, 1928-1936.
A.S. Alberts, W. Burger, F. Greeff, L. Schoeman, D. Friediger, J. Nel, E. Steyn, E.U. Schmid and G. Falkson recent review [l] of 1926 cases of oesophageal cancer in South Africa, it was shown that 77.4% of all cases had stage III AJC disease. Palliative intubation was the treatment most often selected. The median survival of patients with advanced oesophageal cancer in South Africa is 3-4 months[2, 31. Despite the advanced stage of disease some patients will present with good performance status and are potential candidates for more intensive anticancer therapy. Seitz et al. [4] demonstrated considerable activity with concomitant 5-fluorouracil(5FU) and cisplatin in patients with oesophageal cancer. In the present trial the addition of radiotherapy to concomitant S-FU and cisplatin (postintubation) was therefore prospectively evaluated. 20 patients with advanced, inoperable squamous carcinoma of the esophagus and ECOG [5] performance status of 0, 1 or 2, were entered on study. Pretreatment staging was done with barium swallow, computed tomography, and endoscopy. All patients had had placement of either a Celestin or Procter-Livingstone tube and could swallow semi-solid food and maintain adequate nutrition afterwards. Patients with tracheobronchial bulging due to tumour or small mediastinal fistulae were admitted to the study provided that the area was well covered by the tube and no frank trachea-bronchial fistulae were present (Table 1). Patients had to have adequate renal, haematologic and hepatic function. After intubation eligible patients were randomised to no further treatment (observation) or radiotherapy and concomitant S-FU and cisplatin. Radiation thc.apy consisted of 4 Gy fractions daily from day 1-S (20 Gy) and 29-33 (20 Gy). A 3field technique was used with the fields covering at least 5 cm superior and inferior, and 2 cm lateral to the known tumour volume. The chemotherapy consisted of S-FU 600 mg/mZ over 24 h from days 1-5 and 29-33 and cisplatin 15 mg/m* daily from days l-5 and 29-33. IN A
Correspondence to A.S. Alberts. A.S.Alberts, D. Friediger and J. Nel are at the Department of Radiotherapy, University of Pretoria, P.O. Box 667, Pretoria, 0001 South Africa; W. Burger, L.Schoeman and G. Falkson are at the Department of Medical Oncology, and F. Greeff, E. Steyn and E.U.Schmid are at the Department of Surgery, University of Pretoria, Pretoria, South Africa. Revised 16 Sep. 1991; accepted 2 Dec. 199!
