Education and debate

Controversies in Management: Important progress in treatment

^a Cancer Research Campaign, Section of Medicine, Institute of Cancer Research, Royal Marsden Hospital, Sutton, Surrey SM2 5PT

Sometimes I think that the treatment of cancer in the United Kingdom has lost its way; there are just over 400 clinical and medical oncologists in Britain. Some may consider this an advantage. The proportion of patients receiving cytotoxic drugs for cancer is probably less here than any other Western country. Is this approach justified? Recently, the trial of global utilisation of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO) showed that tissue plasminogen activator reduced the absolute death rate after myocardial infarction by 1% compared with streptokinase.¹ The authors described it as "a major stepwise increment in survival beyond that of the established standard."² When the difference between the two treatments was analysed it was calculated to cost $220000 to save a single life.³ Although real progress in medicine is relatively slow, a reassessment of the role of cytotoxic drugs in the management of common solid tumours is long overdue. Where better to start than colonic cancer, a tumour in which chemotherapy is widely regarded as ineffective.

Evidence of benefit

In 1990 a study of over 900 patients in the United States showed that systemic chemotherapy with fluorouracil and levamisole given for 12 months after surgery produced an absolute reduction in cancer deaths of 12% in patients with Dukes's C carcinoma of the colon.^{4 5} The National Cancer Institute of the United States issued an alert stating that this treatment should now be part of the standard management of Dukes's C colonic cancer. The response in Britain was more conservative. The study was criticised for not having included treatment with fluorouracil alone, and the debate became side tracked into the role (if any) of levamisole, why the treatment had been ineffective in patients with Dukes's B2 tumours, and the need for further comparative studies.

Subsequent clinical trials of fluorouracil and folinic acid (started before the results of the first trial were available) have shown a benefit in Dukes's B and C tumours of the colon.⁶ Despite these results, many patients in Britain still do not receive adjuvant chemotherapy. Clinicians seem concerned with money to pay for treatment and whether giving this chemotherapy to a group of patients with a median age of 70 years is justified. The resources should be simple to obtain. The NHS Executive's research and development committee facilitates the application of new techniques and treatment based on well designed clinical trials. Whether the treatment is justified depends on the decision made by individual patients and their doctors after an informed discussion about the risk-benefit ratio of adjuvant chemotherapy. It should also be borne in mind that the average life expectancy of a healthy 75 year old is 10 years.⁷ The debate about the potential benefit of adjuvant chemotherapy in Dukes's B and C tumours should be dead.

At the Royal Marsden we are now investigating shortening the duration of treatment and increasing the dose intensity of fluorouracil by using ambulatory chemotherapy, which keeps patients in the community rather than in hospital. This approach may also reduce costs.

Other tumours

In other tumours of the gastrointestinal tract--the role of adjuvant chemotherapy is much less convincing. A meta-analysis of adjuvant chemotherapy in gastric cancer showed no benefit on survival,⁸ although a recent small randomised trial from Japan reported improved survival by putting carbon adsorbed mitomycin into the peritoneum at the time of surgery.⁹ In pancreatic cancer two trials have shown improvement in median survival (23 months v 11 months) with adjuvant chemotherapy with or without radiotherapy.^{10 11} The total number of patients randomised in these trials was small (102 patients), and the rate of cure was not increased. Neither regimen has been adopted as standard practice in Europe. A European trial of adjuvant chemoradiotherapy in pancreatic cancer was launched this year and plans to recruit sufficient numbers of patients to provide more definitive results. Participation in this trial should be widely encouraged; nevertheless, provided with current data many patients might choose to have 18 weeks of chemotherapy to prolong life by one year.

In locally advanced oesophageal cancer, the addition of chemotherapy to radiotherapy increases the survival rate at two years from 10% to 38%.¹² Inoperable gastric cancers can be resected after successful chemotherapy.¹³ When compared with best supportive care, chemotherapy doubles median survival in colorectal cancer (table)^{14 15} and increases median survival in gastric cancer from 12 weeks to 12 months.¹⁶ More importantly, symptoms improve in over 80% of these patients,⁶ and quality of life is maintained.^{6 13}

Too often in evaluations of cost effectiveness of treatment emphasis is placed on the expense of the cytotoxic drugs. In fact they account for a relatively small proportion (5-10%) of overall treatment costs, and one study in lung cancer has shown that the cost of a policy of best supportive care may exceed that of a chemotherapy treatment programme.¹⁷ Within specialist units, adjuvant chemotherapy and chemotherapy for advanced disease can be delivered safely and with appropriate selection of patients can improve quality and quantity of life.

Chemotherapy versus best supportive care in metastatic colorectal cancer
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                                   No of         Median
                                  patients       survival     P value
-------------------------------------------------------------------------
Scheithauer et al14:
  Fluorouracil folinic acid, and
    cisplatin                       24             11
       v                                                      P=0.006
  Best supportive care              12              5
Allen-Mersh et al15:
  Intrahepatic floxuridine          51             14
       v                                                      P<0.05
Best supportive care                49              7

1. The GUSTO Investigators. An international randomised trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-82. [Abstract/Free Full Text]
2. Topol EJ, Califf RM, Van De Werf F for the GUSTO Steering Committee. Thrombolytic therapy for acute myocardial infarction: GUSTO criticized. N Engl J Med 1993;330:505-6.
3. Friedman HS. Thrombolytic therapy for acute myocardial infarction: GUSTO criticized. N Engl J Med 1993;330:504. [Free Full Text]
4. Moertel CG, Fleming TR, MacDonald JS, Haller DG, Laurie JA, Goodman PJ. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352-8. [Abstract]
5. Moertel C, Fleming T, MacDonald J, Haller D, Laurie J. The Intergroup study of fluorouracil (5FU) plus levamisole and levamisole alone as adjuvant therapy for stage C colon cancer. A final report. Proc Am Soc Clin Oncol 1992;11:161.
6. Cunningham D, Findlay M. The chemotherapy of colon cancer can no longer be ignored. Eur J Cancer. 1991;15:2077-9.
7. Katz S, Branch LG, Branson MH, Papsidero JA, Beck JC, Greer DS. Active life expectancy. N Engl J Med 1983;309:1218-24. [Abstract]
8. Hermans J, Bonenkamp JJ, Boon MC, Bunt AMG, Ohyama S, Sasako M, et al. Adjuvant therapy after curative resection for gastric cancer: metaanalysis of randomised trials. J Clin Oncol 1993;11:1441-7. [Abstract/Free Full Text]
9. Hagiwara A, Takahashi T, Kojima O, Sawai K, Yamaguchi T, Yamane T, et al. Prophylaxis with carbon-adsorbed mitomycin against peritoneal recurrence of gastric cancer. Lancet 1992;339:629-31. [Medline]
10. Gastrointestinal Tumour Study Group. Therapy of locally resectable pancreatic carcinoma: a randomised comparison of high dose (6000 rads) radiation alone, moderate dose (4000 rads) radiation and high dose radiation and 5-fluorouracil. Cancer 1981;48:1705-10. [Medline]
11. Bakkevold KE, Arnesjo B, Dahl O, Kambestad B, Adjuvant combination chemotherapy (DMF) following radical resection of carcinoma of the pancreas and papilla of vater. Results of a controlled, prospective, randomised multicentre study. Eur J Cancer 1993;29:698-703.
12. Herskovic A, Martz K, Al-Sarraf M, Leichman L, Brindle J, Vaitevicius V, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the oesophagus. N Engl J Med 1992;24:1593-8.
13. Findlay M, Cunningham D, Norman A, Mansi J, Nicolson M, Hickish T, et al. A phase II study in advanced gastro-oesphageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol (in press).
14. Scheithauer W, Rosen H, Kornek GV, Sebesta C, Depisch D. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 1993;306:752-5.
15. Allen-Mersh TG, Earlam S, Fordy C, Abrams K, Houghton J. Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet 1994;344:1255-60. [Medline]
16. Pyrhonen S, Knitarness T, Kouri M. A randomised phase II trial comparing fluorouracil, epidoxorubicin, and methotrexate (FEMTX) with best supportive care in non-resectable gastric cancer. Ann Oncol 1993;3(suppl 3):47.
17. Jaakkimainen L, Goodwin PJ, Pater J, Warde P, Murray N, Rapp E. Counting the costs of chemotherapy in a National Cancer Institute of Canada randomised trial in nonsmall-cell lung cancer. J Clin Oncology 1990;8: 1301-9.