- Email: [email protected]
Radiotherapy for Chronic Lymphatic Leukaemia
82
tracranial lesions.27 Lead-pipe rigidity of muscles has been recorded with fentanyl as with other opiates, but is not common. Potent synthetic analgesics have been administered repeatedly to many thousands, perhaps even millions, of patients with chronic pain, with no suspicion of harm to the liver. Because of its brevity of action, fentanyl is not likely to be used for chronic pain relief, but the chemically related compounds, pethidine, anileridine, and phenoperidine have a clean bill. This safety record is cheering in view of INMAN and MUSHlN’S new analysis of reports of jaundice after halothane, which seems to confirm the risk of liver damage after repeat exposure to this very versatile anaesthetic agent. 28 Hypersensitivity, another troublesome problem in clinical anæsthesia,-29 has not been reported with fentanyl and probably not with any form of neuro-
leptanxsthesia. There is certainly an impetus to explore the potential of analgesic supplementation of anaesthesia, and high-dose fentanyl is worthy of further study. More detailed work on technique is needed, with investigations on the role of physostigmine in reversal of its action,30 31 and other combinations such as diazepam/pentazocine should not be forgotten. Besides their possible advantages to patients, non-volatile anxsthetic agents offer an attractive answer to operating-theatre pollution.
Radiotherapy for Chronic Lymphatic Leukaemia DAMESHEK’S description of chronic lymphatic leukaemia (C.L.L.) as an "accumulative disorder of immunologically incompetent lymphocytes"’ is still valid today, though we now recognise that the disease has proliferative features as well. Moreover, the abnormal cells are not completely inert: the use of immunological markers shows that the great majority of cases are characterised by monoclonal populations of lymphocytes of B lineage,3 although T-cell
C.L.L.
also
occurs.
The accumulation of these
morphologically mature-looking lymphocytes gradually obliterates the normal lymphoreticular network, with a blood and marrow lymphocytosis, lymphadenopathy, hepatosplenomegaly, and (eventually) involvement of extralymphatic tissues.4 The source within the lymphoreticular system of this abnormal clone probably varies, but once estab27.
Miller, R., Tausk,
H.
C., Stark,
D. C. C. Can. Anœsth. Soc.
the extremely variable natural history of the disorder and the difficulties encountered in assessing the relative merits of various therapies. Most studies of c.L.L. report median survivals of from 3 to 6 years from the start of therapy or the onset of symptoms,’8 though when survival proves to be short, physical and laboratory findings at diagnosis tend to be more abnormal than those in longer survivors. RAI9 and RUNDLES10 have attempted a comprehensive staging of the disease, based on a combination of clinical and laboratory data. Thus, patients who had only bone-marrow and blood lymphocytosis were deemed to have stage-0 disease and those who also had lymphadenopathy, stage I; patients with stage-11 disease had, in addition, an enlarged spleen or liver, or both; while in stage III, anxmia was present, and stage-IV patients had thrombocytopenia which was always an ominous feature, irrespective of other clinical signs. BINET and his colleaguesll have proposed a slightly different staging protocol which accords special significance to a group of patients with lymphocytosis and splenomegaly, in whom the disease is relatively benign. Classifications of this type correlate well with prognosis:9 thus in RAI’S series, although the median survival for the whole group was 71 months, for those with grade-III and grade-IV disease it was only 19 months-considerably worse than the survival of many patients with acute lymphoblastic leukaemia. The aims in the treatment of c.L.L. have, hitherto, been control of the disease and its epiphenomena rather than radical cure; indeed one view is that, as in chronic myeloid leukaemia, survival is little influenced by therapy. 12 " In some patients death is due to immune deficiency-and immune deficiency is rarely improved by palliative therapy designed to reduce the mass of leukæmic cells. Since the introduction of chlorambucil and prednisolone over 20 years ago, radiotherapy has been largely relegated to a secondary role in the treatment of resistant splenomegaly, large nodal masses, or those producing obstructive symptoms.
J. 1975, 22,
502. 28. 29.
lished it leads to profound changes in lymphocyte circulations and in immunological homoeostasis, of which hypoimmunoglobulinaemia and a propensity to autoimmune disorders are the most obvious clinical features. The kinetics of this abnormal lymphopoiesis, and the severity of immune depression, differ from one patient to another,6 and this helps to explain
Inman, W. H. W., Mushin, W. W. Br. med. J. 1978, ii, 1455. Watkins, J., Ward, A. M. Adverse Responses to Intravenous Drugs. London,
1978. 30. Brebner, J., Hadley, L. Can. Anœsth. Soc. J. 1977, 23, 547. 31. Thompson, D. E. A. ibid. 1976, 23, 582. 1. Dameshek, W. Blood, 1967, 29, 566. 2. Theml, H. D., Love, R., Begemann, H. A. Rev Med. 1977, 28, 131. 3. Brouet, J. C., Seligmann, M. Clins Hemat. 1977, 6, 169. 4. Sweet, D. L., Golomb, H. M., Ultmana, J E. ibid. p. 185.
5. Stryckmans, P. A., Debusscher, L., Collard, E. ibid. p. 159 6. Lopez-Sandoval, R., Moayeri, H , Sokal, J. E Cancer Res. 1974, 34, 146 7. Huguley, C. M. Yb Med. 1970, p. 317. 8. Huguley, C. M. Cancer Treat. Rev. 1977, 4, 261 9. Rai, K. R., Sawitsky, A , Cronkite, E. P., et al Blood, 1975, 46, 219 10. Rundles, R. W., Moore, J. O. Cancer, 1978,42, suppl p. 941. 11. Binet, J. L., Leporrier, M., Dighiero, G., et al. Cancer, 1977, 40, 855 12. Silver, R. T Semin. Hœmat. 1969, 6, 344 13. Boggs, D. R., Sofferman, S. A., Wintrobe, M M., Cartwright, G. E Am. J Med. 1966, 40, 243.
83
OSGOOD14 and others acquired a large experience in the use of radioactive phosphorus in the management of the disease in the 1940s and 1950s, but this agent, too, was superseded by chemotherapy when
long-term studies showed that chlorambucil (in most hands) gave better control of the disease and was easier to use.’ Extracorporeal irradiation sometimes controls the disease when
chemotherapy
failed, and partial remissions with this type of therapy have been recorded. Again, intensive leucapheresis and splenectomy are of value in the odd patient who responds poorly to conventional drugs. Despite initial responses of between 60 and 80% with single-agent chemotherapy, hxmatological toxicity almost always limits the use of alkylating agents and disease resistance is common; probably no more than 10% of patients have a complete has
remission. In view of these results with corticosteroids and alkylating agents it is not surprising to see
radiotherapy being advocated as a primary treatBoth JOHNSON,ts-17 using total body irradiation, and RICHARDS et al.,18 19 using mediastinal and thymic irradiation, claim "complete remissions" in as many as 60% of previously untreated patients. Complete remissions in c.L.L. have been variously defined, but generally imply resolution of lymphadenopathy, splenomegaly, and hepatomegaly, and ment.
of the blood-count and bone-marrow morphology to normal, with less than 20% small lymphocytes in the marrow aspirate. Though not generally regarded as a criterion of complete remission, return of immunoglobulin levels to normal would be important corroborative evidence. Such immunological improvement, seen only rarely after chemotherapy or steroids, was detected in 80% of JOHNSON’S patients who had abnormally low immunoglobulins before therapy.17 RICHARDS et al.19 did serial immunoglobulin assays in a smaller proportion of patients, and about 40% of those with abnormal values showed a return to normal. The patients with the best results in these studies had stage-0 disease on the RAI classification; only 10% of those with stage-III or stage-IV disease achieved full remission. Results were also less good in patients who had had previous chemotherapy. although RICHARDS noted 3 full remissions in one _group of 13_such patients. return
One of the difficulties with whole-body or mediastinal irradiation in patients who have previously had prolonged chemotherapy is their poor marrow
sounded 14 15 16
17 18
reserve.
by
Thus,
a
cautionary
SAWITZKY and his
note
was
colleagues2O
who
Osgood, E. E Blood, 1960,16, 1104 Johnson, R E Cancer,1970, 25, 523. Johnson, R E ibid. 1976, 37, 2691
Johnson, R.E Clins Hemat.1977, 6, 237. Richards, F, Spurr, C. L, Pajak, T. F., Blake, D. D , Raben, M. Am J. Med 1974, 57, 862. 19. Richards, F., Spurr, C. L , Ferree, C., Blake, D. D., Raben, M. ibid. 1978, 64,947 20 Sawitsky, A , Rai, K R , Aral, I., et al. ibid. 1976, 61, 892.
recorded severe myelosuppression in 11 of 31 patients treated with only modest doses of mediastinal radiotherapy; 7 of these died. In this study there were no complete remissions. Preliminary indications from JOHNSON’S17 work suggest that complete remission does improve overall survival. However, until a prospective randomised study, with stratification of cases according to the stage of the disease, is achieved, the case will be unproven. It is also obviously desirable to compare the results of various types of radiotherapy with those of intensive chemotherapy and of combined radiotherapy and chemotherapy. In this respect there is much interest in the results of PHiLLiPS and his colleagues 21 with a five-drug regimen originally devised for myeloma. 22 They reported an overall response of 70%, with 15% achieving complete remission, though the total numbers in the trial were small. Clearly, there is a need for a new approach to the treatment of C.L.L., with a goal of cure in selected patients rather than temporary palliation in all. Now that criteria for staging the disease are available, clinical trials should not be difficult to devise; the Medical Research Council is at present organising a trial which explores several therapeutic protocols, including splenic irradiation. Follow-up of these patients will necessarily be long, especially in patients with early-stage disease in whom median survival is at present 10 years or so. Moreover, the advantages of radical cure of a leukaemia which mainly affects elderly patients must be balanced against the risks of radiotherapy and intensive chemotherapy in this age-group.
LABORATORY WORK ON SMALLPOX VIRUS
photographer who worked in the anatomy department of Birmingham University Medical School and who died of smallpox on Sept. 11 was infected with a strain of virus used in the smallpox laboratory in the medical school. The report of an investigation under the chairmanship of Prof. R. A. Shooter condemns working conditions in the laboratory: they were such that the THE
virus could have become airborne or could have been deposited on surfaces in both the smallpox room and the outer animal-pox room. The most probable route of infection was through a duct in the outer room to a room immediately above. The infected photographer (who had not been vaccinated against smallpox since 1966) made almost exclusive use of this room and during the relevant period she was on the telephone there several times every day. When at the telephone she would have been close to an ill-fitting inspection panel of the duct. Investigations had shown that tracers liberated outside the safety cabinet in the smallpox room reached the main corridor outside the pox-virus laboratory suite, so if the patient had visited the inquiry office or the dark21. Phillips, E. A., Kempin, S., Passe, S., Hemat. 1977, 6, 203. 22. Case, D. C., Lee, B. J., Clarkson, B. D.Am.
Mike, V., Clarkson,
B. D. Clins
J.Med 1977, 63, 897.
tracranial lesions.27 Lead-pipe rigidity of muscles has been recorded with fentanyl as with other opiates, but is not common. Potent synthetic analgesics have been administered repeatedly to many thousands, perhaps even millions, of patients with chronic pain, with no suspicion of harm to the liver. Because of its brevity of action, fentanyl is not likely to be used for chronic pain relief, but the chemically related compounds, pethidine, anileridine, and phenoperidine have a clean bill. This safety record is cheering in view of INMAN and MUSHlN’S new analysis of reports of jaundice after halothane, which seems to confirm the risk of liver damage after repeat exposure to this very versatile anaesthetic agent. 28 Hypersensitivity, another troublesome problem in clinical anæsthesia,-29 has not been reported with fentanyl and probably not with any form of neuro-
leptanxsthesia. There is certainly an impetus to explore the potential of analgesic supplementation of anaesthesia, and high-dose fentanyl is worthy of further study. More detailed work on technique is needed, with investigations on the role of physostigmine in reversal of its action,30 31 and other combinations such as diazepam/pentazocine should not be forgotten. Besides their possible advantages to patients, non-volatile anxsthetic agents offer an attractive answer to operating-theatre pollution.
Radiotherapy for Chronic Lymphatic Leukaemia DAMESHEK’S description of chronic lymphatic leukaemia (C.L.L.) as an "accumulative disorder of immunologically incompetent lymphocytes"’ is still valid today, though we now recognise that the disease has proliferative features as well. Moreover, the abnormal cells are not completely inert: the use of immunological markers shows that the great majority of cases are characterised by monoclonal populations of lymphocytes of B lineage,3 although T-cell
C.L.L.
also
occurs.
The accumulation of these
morphologically mature-looking lymphocytes gradually obliterates the normal lymphoreticular network, with a blood and marrow lymphocytosis, lymphadenopathy, hepatosplenomegaly, and (eventually) involvement of extralymphatic tissues.4 The source within the lymphoreticular system of this abnormal clone probably varies, but once estab27.
Miller, R., Tausk,
H.
C., Stark,
D. C. C. Can. Anœsth. Soc.
the extremely variable natural history of the disorder and the difficulties encountered in assessing the relative merits of various therapies. Most studies of c.L.L. report median survivals of from 3 to 6 years from the start of therapy or the onset of symptoms,’8 though when survival proves to be short, physical and laboratory findings at diagnosis tend to be more abnormal than those in longer survivors. RAI9 and RUNDLES10 have attempted a comprehensive staging of the disease, based on a combination of clinical and laboratory data. Thus, patients who had only bone-marrow and blood lymphocytosis were deemed to have stage-0 disease and those who also had lymphadenopathy, stage I; patients with stage-11 disease had, in addition, an enlarged spleen or liver, or both; while in stage III, anxmia was present, and stage-IV patients had thrombocytopenia which was always an ominous feature, irrespective of other clinical signs. BINET and his colleaguesll have proposed a slightly different staging protocol which accords special significance to a group of patients with lymphocytosis and splenomegaly, in whom the disease is relatively benign. Classifications of this type correlate well with prognosis:9 thus in RAI’S series, although the median survival for the whole group was 71 months, for those with grade-III and grade-IV disease it was only 19 months-considerably worse than the survival of many patients with acute lymphoblastic leukaemia. The aims in the treatment of c.L.L. have, hitherto, been control of the disease and its epiphenomena rather than radical cure; indeed one view is that, as in chronic myeloid leukaemia, survival is little influenced by therapy. 12 " In some patients death is due to immune deficiency-and immune deficiency is rarely improved by palliative therapy designed to reduce the mass of leukæmic cells. Since the introduction of chlorambucil and prednisolone over 20 years ago, radiotherapy has been largely relegated to a secondary role in the treatment of resistant splenomegaly, large nodal masses, or those producing obstructive symptoms.
J. 1975, 22,
502. 28. 29.
lished it leads to profound changes in lymphocyte circulations and in immunological homoeostasis, of which hypoimmunoglobulinaemia and a propensity to autoimmune disorders are the most obvious clinical features. The kinetics of this abnormal lymphopoiesis, and the severity of immune depression, differ from one patient to another,6 and this helps to explain
Inman, W. H. W., Mushin, W. W. Br. med. J. 1978, ii, 1455. Watkins, J., Ward, A. M. Adverse Responses to Intravenous Drugs. London,
1978. 30. Brebner, J., Hadley, L. Can. Anœsth. Soc. J. 1977, 23, 547. 31. Thompson, D. E. A. ibid. 1976, 23, 582. 1. Dameshek, W. Blood, 1967, 29, 566. 2. Theml, H. D., Love, R., Begemann, H. A. Rev Med. 1977, 28, 131. 3. Brouet, J. C., Seligmann, M. Clins Hemat. 1977, 6, 169. 4. Sweet, D. L., Golomb, H. M., Ultmana, J E. ibid. p. 185.
5. Stryckmans, P. A., Debusscher, L., Collard, E. ibid. p. 159 6. Lopez-Sandoval, R., Moayeri, H , Sokal, J. E Cancer Res. 1974, 34, 146 7. Huguley, C. M. Yb Med. 1970, p. 317. 8. Huguley, C. M. Cancer Treat. Rev. 1977, 4, 261 9. Rai, K. R., Sawitsky, A , Cronkite, E. P., et al Blood, 1975, 46, 219 10. Rundles, R. W., Moore, J. O. Cancer, 1978,42, suppl p. 941. 11. Binet, J. L., Leporrier, M., Dighiero, G., et al. Cancer, 1977, 40, 855 12. Silver, R. T Semin. Hœmat. 1969, 6, 344 13. Boggs, D. R., Sofferman, S. A., Wintrobe, M M., Cartwright, G. E Am. J Med. 1966, 40, 243.
83
OSGOOD14 and others acquired a large experience in the use of radioactive phosphorus in the management of the disease in the 1940s and 1950s, but this agent, too, was superseded by chemotherapy when
long-term studies showed that chlorambucil (in most hands) gave better control of the disease and was easier to use.’ Extracorporeal irradiation sometimes controls the disease when
chemotherapy
failed, and partial remissions with this type of therapy have been recorded. Again, intensive leucapheresis and splenectomy are of value in the odd patient who responds poorly to conventional drugs. Despite initial responses of between 60 and 80% with single-agent chemotherapy, hxmatological toxicity almost always limits the use of alkylating agents and disease resistance is common; probably no more than 10% of patients have a complete has
remission. In view of these results with corticosteroids and alkylating agents it is not surprising to see
radiotherapy being advocated as a primary treatBoth JOHNSON,ts-17 using total body irradiation, and RICHARDS et al.,18 19 using mediastinal and thymic irradiation, claim "complete remissions" in as many as 60% of previously untreated patients. Complete remissions in c.L.L. have been variously defined, but generally imply resolution of lymphadenopathy, splenomegaly, and hepatomegaly, and ment.
of the blood-count and bone-marrow morphology to normal, with less than 20% small lymphocytes in the marrow aspirate. Though not generally regarded as a criterion of complete remission, return of immunoglobulin levels to normal would be important corroborative evidence. Such immunological improvement, seen only rarely after chemotherapy or steroids, was detected in 80% of JOHNSON’S patients who had abnormally low immunoglobulins before therapy.17 RICHARDS et al.19 did serial immunoglobulin assays in a smaller proportion of patients, and about 40% of those with abnormal values showed a return to normal. The patients with the best results in these studies had stage-0 disease on the RAI classification; only 10% of those with stage-III or stage-IV disease achieved full remission. Results were also less good in patients who had had previous chemotherapy. although RICHARDS noted 3 full remissions in one _group of 13_such patients. return
One of the difficulties with whole-body or mediastinal irradiation in patients who have previously had prolonged chemotherapy is their poor marrow
sounded 14 15 16
17 18
reserve.
by
Thus,
a
cautionary
SAWITZKY and his
note
was
colleagues2O
who
Osgood, E. E Blood, 1960,16, 1104 Johnson, R E Cancer,1970, 25, 523. Johnson, R E ibid. 1976, 37, 2691
Johnson, R.E Clins Hemat.1977, 6, 237. Richards, F, Spurr, C. L, Pajak, T. F., Blake, D. D , Raben, M. Am J. Med 1974, 57, 862. 19. Richards, F., Spurr, C. L , Ferree, C., Blake, D. D., Raben, M. ibid. 1978, 64,947 20 Sawitsky, A , Rai, K R , Aral, I., et al. ibid. 1976, 61, 892.
recorded severe myelosuppression in 11 of 31 patients treated with only modest doses of mediastinal radiotherapy; 7 of these died. In this study there were no complete remissions. Preliminary indications from JOHNSON’S17 work suggest that complete remission does improve overall survival. However, until a prospective randomised study, with stratification of cases according to the stage of the disease, is achieved, the case will be unproven. It is also obviously desirable to compare the results of various types of radiotherapy with those of intensive chemotherapy and of combined radiotherapy and chemotherapy. In this respect there is much interest in the results of PHiLLiPS and his colleagues 21 with a five-drug regimen originally devised for myeloma. 22 They reported an overall response of 70%, with 15% achieving complete remission, though the total numbers in the trial were small. Clearly, there is a need for a new approach to the treatment of C.L.L., with a goal of cure in selected patients rather than temporary palliation in all. Now that criteria for staging the disease are available, clinical trials should not be difficult to devise; the Medical Research Council is at present organising a trial which explores several therapeutic protocols, including splenic irradiation. Follow-up of these patients will necessarily be long, especially in patients with early-stage disease in whom median survival is at present 10 years or so. Moreover, the advantages of radical cure of a leukaemia which mainly affects elderly patients must be balanced against the risks of radiotherapy and intensive chemotherapy in this age-group.
LABORATORY WORK ON SMALLPOX VIRUS
photographer who worked in the anatomy department of Birmingham University Medical School and who died of smallpox on Sept. 11 was infected with a strain of virus used in the smallpox laboratory in the medical school. The report of an investigation under the chairmanship of Prof. R. A. Shooter condemns working conditions in the laboratory: they were such that the THE
virus could have become airborne or could have been deposited on surfaces in both the smallpox room and the outer animal-pox room. The most probable route of infection was through a duct in the outer room to a room immediately above. The infected photographer (who had not been vaccinated against smallpox since 1966) made almost exclusive use of this room and during the relevant period she was on the telephone there several times every day. When at the telephone she would have been close to an ill-fitting inspection panel of the duct. Investigations had shown that tracers liberated outside the safety cabinet in the smallpox room reached the main corridor outside the pox-virus laboratory suite, so if the patient had visited the inquiry office or the dark21. Phillips, E. A., Kempin, S., Passe, S., Hemat. 1977, 6, 203. 22. Case, D. C., Lee, B. J., Clarkson, B. D.Am.
Mike, V., Clarkson,
B. D. Clins
J.Med 1977, 63, 897.