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Arresting metastases during excisional cancer surgery
Reflection & Reaction p=0·08) and an overall survival (96% vs 92%, p=0·14) that favour BEP over EP when all eligible patients are included, although the advantage was not significant. Furthermore, when the authors excluded patients judged retrospectively to have a poor outlook because they had extrapulmonary metastases, event-free survival was 90% for those given BEP compared with 84% for those given EP—again favouring BEP, although not significantly (p=0·06). The question is, therefore, how to incorporate these new data, which are not significant, into treatment of patients with metastatic germ-cell tumours that have a good prognosis. Culine and co-workers believe that the trend is too strong to be ignored. They believe that their trial was underpowered to detect a small, but real, difference that would have been significant if they had included more
patients or had longer follow-up. Because treatment of this malignant diesease is curative, they argue that the data are convincing enough to suggest that we should now be treating all patients who have a good outlook with three cycles of BEP. In view of their data we agree that three cycles of BEP should now be regarded the treatment of choice. However, it is important not to forget the potential pulmonary toxic effects of bleomycin or that some patients are more susceptible to this side-effect than others. Thus, we also believe that EP chemotherapy should still be considered for patients older than 40 years or for those with respiratory impairment. Robert H Jones* and Paul A Vasey† *Cancer Research UK Molecular Oncology Group, School of Medical Sciences, Bristol, UK. †Beatson Oncology Centre, Western Infirmary, Glasgow, UK.
References
1 Vasey P, Jones R. Testicular cancer— management of advanced disease. Lancet Oncol 2003; 4: 738–47. 2 Culine S, Kerbrat P, Bouzy J, et al. The optimal chemotherapy regimen for goodrisk metastatic non-seminomatous germcell tumors (MNSGCT) is 3 cycles of bleomycin, etoposide and cisplatin: mature results of a randomized trial. Proc Am Soc Clin Oncol 2003, 22: (abstr 1536). 3 Loehrer PJ, Johnson D, Elson P, et al. Importance of bleomycin in favorable prognosis disseminated germ cell tumors: An Eastern Cooperative Group trial. J Clin Oncol 1995; 13: 470–76. 4 de Wit R, Stoter G, Kaye SB, et al. Importance of Bleomycin in combination chemotherapy for good prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol 1997; 15: 1837–43. 5 Culine S, Kerbrat P, Bouzy J, et al. Are 3 cycles of bleomyicin, etoposide, and cisplatin (3BEP) or 4 cycles of Etoposide and Cisplatin (4EP) equivalent regimens for patients (pts) with good–risk metastatic non seminomatous germ cell tumors (NSGCT)? Proc Am Soc Clin Oncol 1999; 18: (abstr 1188).
Arresting metastases during excisional cancer surgery Coffey and colleagues1 in the December issue of The Lancet Oncology emphasise the neglected perioperative window of opportunity, during which surgical intervention might reduce the implantation and growth of metastases. Biopsies and surgical excision commonly disseminate tumour cells,2 and open surgery and laparoscopy have adverse immunological consequences.3 In many patients, tumour cells disseminated during surgery can spread systemically and contribute to future metastases.4,5 Indeed, the process of taking a biopsy sample has been associated with tumour progression and with the spread of tumour cells.6 Harvesting tumour cells from bone marrow or from circulating cells in the blood stream could provide an alternative source of neoplastic tissue and be a good substitute for conventional tumour biopsy, thus eliminating one way in which tumours cells are distributed beyond the primary site by therapeutic intervention.7 Diagnostic characterisation of circulating tumour cells8 could be done easily if patients were encouraged to donate a unit of blood 2 weeks before surgery. The patient’s red THE LANCET Oncology Vol 5 March 2004
blood cells, washed to remove any tumour cells, could then be made available for reinfusion at the time of the operation. Hoover and Ketcham have stated that to prevent haematogenous metastasis, at least one of the following stages of development needs to be inhibited: growth of the primary tumour; invasion of vessel walls; release of viable tumour cells; or entrapment and growth of tumour cells in distant organs. Judicious handling of the primary tumour can decrease metastasis by reducing the spread of tumour cells. Other important actions have also been identified to reduce neoplastic spread: manipulation of the primary tumour should be kept to a minimum; biopsies should be done sparingly and with sharp dissection; and full surgical interventions should be done as soon a possible, taking great care in handling the tumour and to excise wide margins around the neoplastic mass.3,4 The importance of these aspects was previously noted in the study of Liotta and colleagues: “Tumour massage results in at least a ten-fold rise over the initial concentration of tumour cells,
http://oncology.thelancet.com
as well as a higher proportion of large clumps. Furthermore, the centrally placed tumour cells in a clump may be protected from immunologically mediated destruction”.9 At present, there are no published intraoperative studies investigating the amount of tumour-cell shedding in patients treated surgically for cancer. The type of surgery used to excise breast cancer, melanoma, and colorectal cancer could potentially be guided by real-time measurement of tumour-cell dissemination during the patient’s operation. Real-time, sizebased, cell-sorting techniques are feasible and would enable separation of 7 m red blood cells from 15 m white cells and tumour-cell clumps larger than 30 m . Intraoperative measurement of both tumour cells and cell clumps shed into tumour-draining veins (such as the internal mammary vein and breast tributaries of the axillary vein in patients with breast cancer) could provide therapeutic benefit as well as crucial documentation about the biological consequences of the operation. Catheterisation of the internal mammary vein and the axillary vein, for
147
For personal use. Only reproduce with permission The Lancet Publishing Group.
Reflection & Reaction example, could be done from the contralateral brachial vein. Collection of blood from this portal during surgery could yield up to 750 mL, a quantity sufficient for cell analyses and for purification of red blood cells for future reinfusion. Use of blood from tumourdraining veins, rather than the more common reliance on peripheral blood, would also facilitate more realistic estimates of circulating tumour cells. Tumour cells and small cancer-cell clumps found in peripheral blood have already passed through the lungs and reticulothelial filters such as the liver, spleen, and bone marrow. Highly metastatic cancer-cell clumps are filtered during the first-pass through the lungs and consequently circulating tumour cells in peripheral blood are only a very small fraction of the potentially metastatic cells. Crucially, by using the intraoperative approach, disseminated tumour cells would not enter the patient’s lungs and increase the risk of distant metastases,5 rather
they could be quantified, characterised, genetically studied, and implanted into nude mice to measure metastatic potential to generate useful prognostic information. Intraoperative removal and measurement of tumour cells via catheterisation of a tumour-draining vein before the passage of blood through the lungs potentially has great clinical importance in reducing the risk of secondary cancers and providing useful information on the biological consequence of surgical practice and patient prognosis. Thus, the paper from Cork University Hospital1 documents a clear need to apply new interventions clinically to reduce tumour progression and metastases. Robert G Carroll Oncology Innovations, Largo, FL, USA. Conflict of interest
Oncology Innovations designs products that reduce operative tumour-cell spillage. These products are currently unavailable commercially.
References
1 Coffey JC, Wang JH, Cotter TG, Redmond HP. Excisional surgery for cancer cure— therapy at a cost. Lancet Oncol 2003; 4: 760–68. 2 Da Costa ML, Redmond HP, Finnegan N, et al. Laparotomy and laparoscopy differentially accelerate experimental flank tumour growth. Br J Surg 1998; 85: 1439–42. 3 Carter JJ, Whelan RL. The immunologic consequences of laparoscopy in oncology. Surg Oncol Clin N Am 2001; 10: 655–77. 4 Hoover HCJ, Ketcham AS. Techniques for inhibiting tumour metastases. Cancer 1975; 35: 5–14. 5 Wong CW, Song C, Grimes MM, et al. Intravascular location of breast cancer cells after spontaneous metastasis to the lung. Am J Pathol 2002; 161: 749–53. 6 Retsky M, Demicheli R, Hrushesky W. Wounding from biopsy and breast-cancer progression. Lancet 2001; 357: 1048. 7 Klein CA, Blankenstein TJ, Schmidt-Kittler O, et al. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 2002; 360: 683–89. 8 Ring A, Smith IE, Dowsett M. Circulating tumour cells in breast cancer. Lancet Oncol 2004; 5: 79–88. 9 Liotta L, Kleinerman J, Saidel G. Quantative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res 1974; 34: 997–1004.
If you would like to respond to an article in The Lancet Oncology, or share your views on a current topic of interest or concern in oncology, please email your submission to the Editor at: [email protected]
148
THE LANCET Oncology Vol 5 March 2004
http://oncology.thelancet.com
For personal use. Only reproduce with permission The Lancet Publishing Group.
patients or had longer follow-up. Because treatment of this malignant diesease is curative, they argue that the data are convincing enough to suggest that we should now be treating all patients who have a good outlook with three cycles of BEP. In view of their data we agree that three cycles of BEP should now be regarded the treatment of choice. However, it is important not to forget the potential pulmonary toxic effects of bleomycin or that some patients are more susceptible to this side-effect than others. Thus, we also believe that EP chemotherapy should still be considered for patients older than 40 years or for those with respiratory impairment. Robert H Jones* and Paul A Vasey† *Cancer Research UK Molecular Oncology Group, School of Medical Sciences, Bristol, UK. †Beatson Oncology Centre, Western Infirmary, Glasgow, UK.
References
1 Vasey P, Jones R. Testicular cancer— management of advanced disease. Lancet Oncol 2003; 4: 738–47. 2 Culine S, Kerbrat P, Bouzy J, et al. The optimal chemotherapy regimen for goodrisk metastatic non-seminomatous germcell tumors (MNSGCT) is 3 cycles of bleomycin, etoposide and cisplatin: mature results of a randomized trial. Proc Am Soc Clin Oncol 2003, 22: (abstr 1536). 3 Loehrer PJ, Johnson D, Elson P, et al. Importance of bleomycin in favorable prognosis disseminated germ cell tumors: An Eastern Cooperative Group trial. J Clin Oncol 1995; 13: 470–76. 4 de Wit R, Stoter G, Kaye SB, et al. Importance of Bleomycin in combination chemotherapy for good prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol 1997; 15: 1837–43. 5 Culine S, Kerbrat P, Bouzy J, et al. Are 3 cycles of bleomyicin, etoposide, and cisplatin (3BEP) or 4 cycles of Etoposide and Cisplatin (4EP) equivalent regimens for patients (pts) with good–risk metastatic non seminomatous germ cell tumors (NSGCT)? Proc Am Soc Clin Oncol 1999; 18: (abstr 1188).
Arresting metastases during excisional cancer surgery Coffey and colleagues1 in the December issue of The Lancet Oncology emphasise the neglected perioperative window of opportunity, during which surgical intervention might reduce the implantation and growth of metastases. Biopsies and surgical excision commonly disseminate tumour cells,2 and open surgery and laparoscopy have adverse immunological consequences.3 In many patients, tumour cells disseminated during surgery can spread systemically and contribute to future metastases.4,5 Indeed, the process of taking a biopsy sample has been associated with tumour progression and with the spread of tumour cells.6 Harvesting tumour cells from bone marrow or from circulating cells in the blood stream could provide an alternative source of neoplastic tissue and be a good substitute for conventional tumour biopsy, thus eliminating one way in which tumours cells are distributed beyond the primary site by therapeutic intervention.7 Diagnostic characterisation of circulating tumour cells8 could be done easily if patients were encouraged to donate a unit of blood 2 weeks before surgery. The patient’s red THE LANCET Oncology Vol 5 March 2004
blood cells, washed to remove any tumour cells, could then be made available for reinfusion at the time of the operation. Hoover and Ketcham have stated that to prevent haematogenous metastasis, at least one of the following stages of development needs to be inhibited: growth of the primary tumour; invasion of vessel walls; release of viable tumour cells; or entrapment and growth of tumour cells in distant organs. Judicious handling of the primary tumour can decrease metastasis by reducing the spread of tumour cells. Other important actions have also been identified to reduce neoplastic spread: manipulation of the primary tumour should be kept to a minimum; biopsies should be done sparingly and with sharp dissection; and full surgical interventions should be done as soon a possible, taking great care in handling the tumour and to excise wide margins around the neoplastic mass.3,4 The importance of these aspects was previously noted in the study of Liotta and colleagues: “Tumour massage results in at least a ten-fold rise over the initial concentration of tumour cells,
http://oncology.thelancet.com
as well as a higher proportion of large clumps. Furthermore, the centrally placed tumour cells in a clump may be protected from immunologically mediated destruction”.9 At present, there are no published intraoperative studies investigating the amount of tumour-cell shedding in patients treated surgically for cancer. The type of surgery used to excise breast cancer, melanoma, and colorectal cancer could potentially be guided by real-time measurement of tumour-cell dissemination during the patient’s operation. Real-time, sizebased, cell-sorting techniques are feasible and would enable separation of 7 m red blood cells from 15 m white cells and tumour-cell clumps larger than 30 m . Intraoperative measurement of both tumour cells and cell clumps shed into tumour-draining veins (such as the internal mammary vein and breast tributaries of the axillary vein in patients with breast cancer) could provide therapeutic benefit as well as crucial documentation about the biological consequences of the operation. Catheterisation of the internal mammary vein and the axillary vein, for
147
For personal use. Only reproduce with permission The Lancet Publishing Group.
Reflection & Reaction example, could be done from the contralateral brachial vein. Collection of blood from this portal during surgery could yield up to 750 mL, a quantity sufficient for cell analyses and for purification of red blood cells for future reinfusion. Use of blood from tumourdraining veins, rather than the more common reliance on peripheral blood, would also facilitate more realistic estimates of circulating tumour cells. Tumour cells and small cancer-cell clumps found in peripheral blood have already passed through the lungs and reticulothelial filters such as the liver, spleen, and bone marrow. Highly metastatic cancer-cell clumps are filtered during the first-pass through the lungs and consequently circulating tumour cells in peripheral blood are only a very small fraction of the potentially metastatic cells. Crucially, by using the intraoperative approach, disseminated tumour cells would not enter the patient’s lungs and increase the risk of distant metastases,5 rather
they could be quantified, characterised, genetically studied, and implanted into nude mice to measure metastatic potential to generate useful prognostic information. Intraoperative removal and measurement of tumour cells via catheterisation of a tumour-draining vein before the passage of blood through the lungs potentially has great clinical importance in reducing the risk of secondary cancers and providing useful information on the biological consequence of surgical practice and patient prognosis. Thus, the paper from Cork University Hospital1 documents a clear need to apply new interventions clinically to reduce tumour progression and metastases. Robert G Carroll Oncology Innovations, Largo, FL, USA. Conflict of interest
Oncology Innovations designs products that reduce operative tumour-cell spillage. These products are currently unavailable commercially.
References
1 Coffey JC, Wang JH, Cotter TG, Redmond HP. Excisional surgery for cancer cure— therapy at a cost. Lancet Oncol 2003; 4: 760–68. 2 Da Costa ML, Redmond HP, Finnegan N, et al. Laparotomy and laparoscopy differentially accelerate experimental flank tumour growth. Br J Surg 1998; 85: 1439–42. 3 Carter JJ, Whelan RL. The immunologic consequences of laparoscopy in oncology. Surg Oncol Clin N Am 2001; 10: 655–77. 4 Hoover HCJ, Ketcham AS. Techniques for inhibiting tumour metastases. Cancer 1975; 35: 5–14. 5 Wong CW, Song C, Grimes MM, et al. Intravascular location of breast cancer cells after spontaneous metastasis to the lung. Am J Pathol 2002; 161: 749–53. 6 Retsky M, Demicheli R, Hrushesky W. Wounding from biopsy and breast-cancer progression. Lancet 2001; 357: 1048. 7 Klein CA, Blankenstein TJ, Schmidt-Kittler O, et al. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 2002; 360: 683–89. 8 Ring A, Smith IE, Dowsett M. Circulating tumour cells in breast cancer. Lancet Oncol 2004; 5: 79–88. 9 Liotta L, Kleinerman J, Saidel G. Quantative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res 1974; 34: 997–1004.
If you would like to respond to an article in The Lancet Oncology, or share your views on a current topic of interest or concern in oncology, please email your submission to the Editor at: [email protected]
148
THE LANCET Oncology Vol 5 March 2004
http://oncology.thelancet.com
For personal use. Only reproduce with permission The Lancet Publishing Group.