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The management of colorectal cancer
Critical Reviews in Oncology/Hematology 30 (1999) 181 – 182
Editorial
The management of colorectal cancer
Colorectal cancer is the second most common cause of cancer death in the European Union and the United States, accounting for 165 000 deaths per annum [1]. Outcome from the disease varies with stage and site of the primary tumour [1]. Overall however, the prognosis from colorectal cancer is relatively poor with only one third of patients alive five years from diagnosis [2]. Age standardised mortality rates fell from the 1920s to 1950s in the UK, with similar trends observed in other developed nations. Over the last 40 years there has been a minimal decline in the rates of rectal cancer in both men and women, but colon cancer has declined only in women. However, the last decade has seen developments, which will reduce mortality from colorectal cancer. Colorectal cancer may occur in patients with a genetic/familial predisposition or more commonly without such a predisposition (sporadic colorectal cancer). The familial syndromes can be divided into those with a predisposition to polyp formation, familial adenomatous polyposis (FAP), and hereditary non-polyposis colorectal cancer (HNPCC). FAP is due to abnormalities in the adenomatous polyposis coli gene on chromosome 5. More recently, the association between DNA mismatch repair genes (hMLH1, hMSH2, hPMSH1, hPMSH2) and HNPCC has been identified. Targeting screening to families with these syndromes has been demonstrated to be effective and of cost-benefit. More recently, it has become possible to identify gene carriers pre-symptomatically. Carriers will then be offered screening and/or prophylactic surgery, whilst other family members who do not possess mutations need not undergo endoscopic screening. However, over 90% of colorectal cancers are sporadic developing from adenomas accumulating genetic abnormalities as they progress through the ‘adenoma-carcinoma’ sequence. A seminal paper by Vogelstein et al. (1988) identified mutations in the Kirsten ras gene in 50% of adenomas larger than 1 cm and of 50% of colorectal cancers, and allelic deletions of chromosome 5q in 29% of adenomas and 35% of colorectal cancers
[3]. In contrast, allelic deletions of chromosome 17p usually only occurred in carcinomas. Allelic deletions of 18q occurred in many carcinomas, less frequently in advanced adenomas and only occasionally in earlier staged adenomas. Since the publication of this paper in 1988 there has been a rapid increase in the knowledge of the molecular genetics of colorectal cancers. Recently, Andreyev et al. (1998) demonstrated that patients whose primary tumour demonstrates a mutation in Kirsten ras carry a worse prognosis [4]. The possibility of community screening programmes for sporadic colorectal cancers is the subject of much debate. Whilst it is generally accepted that colonoscopy is inappropriate for population screening, trials have evaluated both faecal occult blood testing and flexible sigmoidoscopy. The problems of population screening are discussed in this issue by Houlston [5]. Compliance will ultimately be a major factor in the success of any screening programme and this will depend on public health education. In this regard, the recent interest demonstrated by the UK Government in establishing a pilot screening programme is to be welcomed. Surgery continues to be the mainstay of treatment and complete resection is required for curative therapy. However, 10–50% of patients with rectal cancer develop local recurrence following ‘curative resection’. The use of staple guns has enabled the development of the technique of total mesorectal excision. This has been proposed as the new ‘gold standard’ for preventing local recurrence. Adjuvant chemotherapy for colorectal cancer was demonstrated to reduce the risk of recurrence and death by an Intergroup study published in 1990 [6]. Three further large randomised studies have been published demonstrating a survival benefit for patients with Dukes’ C colon cancers. The role of adjuvant therapy in Dukes’ B cancers remains controversial but evidence demonstrating a survival advantage is accumulating. Outcomes following complete resection of rectal cancers are less favourable due to the higher local recurrence rate. Post-operative radiotherapy reduces the
1040-8428/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 9 8 ) 0 0 0 4 6 - 8
182
Editorial
incidence of local recurrence without improving survival. Trials have indicated a role for post-operative radiotherapy to be combined with adjuvant chemotherapy in rectal cancer. The optimal timing of radiotherapy is currently the subject of considerable research. A Swedish study has suggested a survival advantage from the use of pre-operative radiotherapy [7]. However, there is an imbalance in tumour stage in this trial with more early stage cancers in the radiotherapy arm than in the surgery alone arm; the differences in stage would explain the differences in outcome for the two groups. The differences in stage may be due to a down-staging effect of radiotherapy but previous trials using similar radiotherapy schedules have not observed this effect. Combined chemo-radiotherapy may downstage locally advanced rectal cancers rendering them operable. The benefits of palliative chemotherapy in advanced colorectal cancer were established by randomised trials demonstrating improved survival and quality of life with chemotherapy compared to best supportive care. 5-Fluorouracil (5-FU) has been the mainstay of chemotherapy since its introduction 40 years ago. Whilst the Mayo schedule of 5-FU and folinic acid remains the most widely used regimen, increasingly regimens employing continuous infusions of 5-FU are being used in Europe. These schedules have a favourable therapeutic index with greater efficacy and less toxicity, particularly myelosuppression, than the Mayo schedule. Several new agents are currently being evaluated for the treatment of colorectal cancer, including oral 5-FU analogues which offer an attractive alternative to intravenous 5-FU schedules. In addition, two new agents, irinotecan and oxaliplatin, have demonstrated activity in 5-FU resistant colorectal cancer. A recently reported randomised trial demonstrated a significant improvement in survival with 1-year survival of 36% with irinotecan after failure of 5-FU compared to 14% with supportive care alone [8]. Furthermore, symptom-free
.
survival and time to deterioration in quality of life were significantly longer in patients treated with irinotecan. As a consequence of recent developments in the management of colorectal cancer the prognosis is beginning to improve both for patients with operable primary tumours and those with advanced disease. The expansion of molecular genetics is providing new hope for early detection and identifying patients at greatest risk of recurrence for adjuvant therapy. Additionally, the molecular abnormalities are being evaluated as targets for novel therapeutics strategies including antisense therapy, ribozymes, gene therapy and immune therapy.
References [1] American Joint Commission on Cancer: Manual for staging cancer. Philadelphia: JB Lippencott. [2] Cancer of the large bowel-UK. Cancer Research Factsheet 1993 (18.1). [3] Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal tumour development. New Engl J Med 1988;319:525 – 32. [4] Andreyev HJN, Norman AR, Cunningham D, Oates J, Clarke PA. Kirsten ras mutations in 2721 patients with colorectal cancer: the RASCAL study. J Natl Cancer Inst 1998;19:24. [5] Houlston RS. Colorectal Cancer Screening. Crit. Rev. Haem. Onc. 1998. [6] Moertel CG, Fleming TR, MacDonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New Engl J Med 1990;322:352 – 8. [7] Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. New Engl J Med 1997;336:980 – 7. [8] Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1413– 8.
P.J. Ross, D. Cunningham Department of Medicine and the Gastrointestinal Unit, Royal Marsden Hospital, London and Sutton, Surrey, SM2 5PT, UK
Editorial
The management of colorectal cancer
Colorectal cancer is the second most common cause of cancer death in the European Union and the United States, accounting for 165 000 deaths per annum [1]. Outcome from the disease varies with stage and site of the primary tumour [1]. Overall however, the prognosis from colorectal cancer is relatively poor with only one third of patients alive five years from diagnosis [2]. Age standardised mortality rates fell from the 1920s to 1950s in the UK, with similar trends observed in other developed nations. Over the last 40 years there has been a minimal decline in the rates of rectal cancer in both men and women, but colon cancer has declined only in women. However, the last decade has seen developments, which will reduce mortality from colorectal cancer. Colorectal cancer may occur in patients with a genetic/familial predisposition or more commonly without such a predisposition (sporadic colorectal cancer). The familial syndromes can be divided into those with a predisposition to polyp formation, familial adenomatous polyposis (FAP), and hereditary non-polyposis colorectal cancer (HNPCC). FAP is due to abnormalities in the adenomatous polyposis coli gene on chromosome 5. More recently, the association between DNA mismatch repair genes (hMLH1, hMSH2, hPMSH1, hPMSH2) and HNPCC has been identified. Targeting screening to families with these syndromes has been demonstrated to be effective and of cost-benefit. More recently, it has become possible to identify gene carriers pre-symptomatically. Carriers will then be offered screening and/or prophylactic surgery, whilst other family members who do not possess mutations need not undergo endoscopic screening. However, over 90% of colorectal cancers are sporadic developing from adenomas accumulating genetic abnormalities as they progress through the ‘adenoma-carcinoma’ sequence. A seminal paper by Vogelstein et al. (1988) identified mutations in the Kirsten ras gene in 50% of adenomas larger than 1 cm and of 50% of colorectal cancers, and allelic deletions of chromosome 5q in 29% of adenomas and 35% of colorectal cancers
[3]. In contrast, allelic deletions of chromosome 17p usually only occurred in carcinomas. Allelic deletions of 18q occurred in many carcinomas, less frequently in advanced adenomas and only occasionally in earlier staged adenomas. Since the publication of this paper in 1988 there has been a rapid increase in the knowledge of the molecular genetics of colorectal cancers. Recently, Andreyev et al. (1998) demonstrated that patients whose primary tumour demonstrates a mutation in Kirsten ras carry a worse prognosis [4]. The possibility of community screening programmes for sporadic colorectal cancers is the subject of much debate. Whilst it is generally accepted that colonoscopy is inappropriate for population screening, trials have evaluated both faecal occult blood testing and flexible sigmoidoscopy. The problems of population screening are discussed in this issue by Houlston [5]. Compliance will ultimately be a major factor in the success of any screening programme and this will depend on public health education. In this regard, the recent interest demonstrated by the UK Government in establishing a pilot screening programme is to be welcomed. Surgery continues to be the mainstay of treatment and complete resection is required for curative therapy. However, 10–50% of patients with rectal cancer develop local recurrence following ‘curative resection’. The use of staple guns has enabled the development of the technique of total mesorectal excision. This has been proposed as the new ‘gold standard’ for preventing local recurrence. Adjuvant chemotherapy for colorectal cancer was demonstrated to reduce the risk of recurrence and death by an Intergroup study published in 1990 [6]. Three further large randomised studies have been published demonstrating a survival benefit for patients with Dukes’ C colon cancers. The role of adjuvant therapy in Dukes’ B cancers remains controversial but evidence demonstrating a survival advantage is accumulating. Outcomes following complete resection of rectal cancers are less favourable due to the higher local recurrence rate. Post-operative radiotherapy reduces the
1040-8428/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 9 8 ) 0 0 0 4 6 - 8
182
Editorial
incidence of local recurrence without improving survival. Trials have indicated a role for post-operative radiotherapy to be combined with adjuvant chemotherapy in rectal cancer. The optimal timing of radiotherapy is currently the subject of considerable research. A Swedish study has suggested a survival advantage from the use of pre-operative radiotherapy [7]. However, there is an imbalance in tumour stage in this trial with more early stage cancers in the radiotherapy arm than in the surgery alone arm; the differences in stage would explain the differences in outcome for the two groups. The differences in stage may be due to a down-staging effect of radiotherapy but previous trials using similar radiotherapy schedules have not observed this effect. Combined chemo-radiotherapy may downstage locally advanced rectal cancers rendering them operable. The benefits of palliative chemotherapy in advanced colorectal cancer were established by randomised trials demonstrating improved survival and quality of life with chemotherapy compared to best supportive care. 5-Fluorouracil (5-FU) has been the mainstay of chemotherapy since its introduction 40 years ago. Whilst the Mayo schedule of 5-FU and folinic acid remains the most widely used regimen, increasingly regimens employing continuous infusions of 5-FU are being used in Europe. These schedules have a favourable therapeutic index with greater efficacy and less toxicity, particularly myelosuppression, than the Mayo schedule. Several new agents are currently being evaluated for the treatment of colorectal cancer, including oral 5-FU analogues which offer an attractive alternative to intravenous 5-FU schedules. In addition, two new agents, irinotecan and oxaliplatin, have demonstrated activity in 5-FU resistant colorectal cancer. A recently reported randomised trial demonstrated a significant improvement in survival with 1-year survival of 36% with irinotecan after failure of 5-FU compared to 14% with supportive care alone [8]. Furthermore, symptom-free
.
survival and time to deterioration in quality of life were significantly longer in patients treated with irinotecan. As a consequence of recent developments in the management of colorectal cancer the prognosis is beginning to improve both for patients with operable primary tumours and those with advanced disease. The expansion of molecular genetics is providing new hope for early detection and identifying patients at greatest risk of recurrence for adjuvant therapy. Additionally, the molecular abnormalities are being evaluated as targets for novel therapeutics strategies including antisense therapy, ribozymes, gene therapy and immune therapy.
References [1] American Joint Commission on Cancer: Manual for staging cancer. Philadelphia: JB Lippencott. [2] Cancer of the large bowel-UK. Cancer Research Factsheet 1993 (18.1). [3] Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal tumour development. New Engl J Med 1988;319:525 – 32. [4] Andreyev HJN, Norman AR, Cunningham D, Oates J, Clarke PA. Kirsten ras mutations in 2721 patients with colorectal cancer: the RASCAL study. J Natl Cancer Inst 1998;19:24. [5] Houlston RS. Colorectal Cancer Screening. Crit. Rev. Haem. Onc. 1998. [6] Moertel CG, Fleming TR, MacDonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New Engl J Med 1990;322:352 – 8. [7] Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. New Engl J Med 1997;336:980 – 7. [8] Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1413– 8.
P.J. Ross, D. Cunningham Department of Medicine and the Gastrointestinal Unit, Royal Marsden Hospital, London and Sutton, Surrey, SM2 5PT, UK