Файловый архив студентов. Файловый архив студентов.
1330 вузов, 5508 предметов.
/ Регистрация
FAQ Обратная связь Вопросы и предложения
Добавил:
kiopkiopkiop18@yandex.ru t.me/Prokururor I Вовсе не секретарь, но почту проверяю Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Ростовский Государственный Медицинский Университет
Предмет:
Медицина общая
Файл:

Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1185_Библиотеки_им_академика_М_И_Перельмана

.pdf
Скачиваний:
0
Добавлен:
15.09.2026
Размер:
17 Мб
Скачать
☆
440 J.L. Trudel and L.A. Påhlman
Many prospective trials have demonstrated the beneficial effect of preoperative and postoperative radiation therapy in patients with rectal cancer who had surgery with curative intent.
The clinical benefits of radiotherapy in the treatment of rec­tal cancer can be broadly divided under four categories: first, radiotherapy lowers local failure rates and improves survival in resectable rectal cancer; second, radiotherapy allows sur­gery in nonresectable rectal cancer; third, it facilitates sphinc­ter-preserving procedures in low-lying rectal cancer; and finally, it may offer a totally curative approach without major surgery.
Radiotherapy can either be used alone or in combination with chemotherapy. The numerous combinations and varia­tions in radiotherapy and chemotherapy regimens make the evaluation and comparison of different multimodal therapy pathways difficult. In this section, we will review the results of various adjuvant treatment modalities in rectal cancer focusing on areas of clinical benefit. We will not discuss the role of curative radiation alone.
Benefit No. 1: Radiotherapy Lowers the Local Failure Rates and Improves Survival in Resectable Rectal Cancer
According to three recently published metaanalyses, there is no doubt that neoadjuvant treatment is superior to adjuvant treatment with regard to reduction in local failure rates and cancer-specific survival. trials that specifically studied preoperative versus postopera­tive radiotherapy support the conclusions from the meta­analyses. The first report was the Uppsala trial in which short-course preoperative radiotherapy in all patients was compared with postoperative prolonged course only in patients with advanced cancers (Stages II and III). two trials compared neoadjuvant chemoradiotherapy with adjuvant chemoradiotherapy with the same schedules and doses. The results from the NSABP R-03 trial, which closed prematurely because of poor accrual, showed that 44% of patients having undergone preoperative chemoradiation were disease free at 1 year, compared with 34% of patients who had received postoperative chemoradiation. CAO/ARO/AIO trial has randomized patients with T3-4, N0, or any T,N1 rectal cancer to neoadjuvant chemoradiation fol­lowed by surgery and additional postoperative chemotherapy or postoperative chemoradiation. performed according to the principles of sharp mesorectal excision. The rates of complete resection (R0) and sphincter­saving surgery were similar in both groups, but the 5-year cumulative rate of local relapse was 6% for patients assigned to preoperative chemoradiation and 13% for the postoperative chemoradiation group. Survival was similar in both treatment arms. Grade 3 or 4 toxicity occurred in 27% of patients in the preoperative chemoradiation group and 40% of patients in
32–34
The results of two of three other
35
36
The German
37
In this study, surgery was
The other
the postoperative chemoradiation group. The results of this last study suggest that preoperative chemoradiation is the pre­ferred adjuvant treatment in patients with locally advanced rectal cancer.
Neoadjuvant Therapy: Radiation Alone Versus Chemoradiation
The potential advantages of neoadjuvant therapy include increased tumor radiosensitivity with decreased small bowel toxicity, decreased overall radiation-associated complica­tions, and decreased risk of tumor seeding during surgery. The primary disadvantage of neoadjuvant therapy is the risk for overtreatment in patients with early-stage disease. New imag­ing modalities such as endorectal ultrasound resonance imaging
39
now allow for increasingly precise pre­operative identification of patients with T2 and T3 tumors, thus minimizing the number of patients who would be overtreated by neoadjuvant therapy. Our ability to identify lymph node metastases preoperatively with any of these imaging modalities remains more limited.
A short course of preoperative radiation, 20–25 Gy given over 1 week is biologically equivalent to the traditional post­operative course of 45–55 Gy given over 5–6 weeks. It was long held that neoadjuvant radiation alone only improved local control but did not improve survival. In 1993, the ran­domized Swedish Rectal Cancer Trial (SRCT) demonstrated that a short course (25 Gy) of preoperative radiotherapy with surgery within the following week significantly reduced local recurrence from 27% to 12%, and improved 5-year survival rates from 48% to 58% when compared with surgery alone. The main objection to all trials showing improvement in local recurrence and survival rates with radiotherapy, including the SRCT, was the high rate of local recurrence in the control arm that has been attributed to nonstandardized surgical tech-
32–34
nique.
Case series from specialized centers have reported lower local recurrence rates with surgery alone using meticu­lous surgical technique compared with patients treated with radiation and surgery in prospective trials when surgery was not standardized.
41–43
Several reports from different countries have confirmed that surgical skill is of utmost importance, thus opening for discussion the real role of radiotherapy when surgical technique is optimized.
44–47
The role of preoperative radiation in patients with rectal cancer treated with optimal surgery was addressed in the Dutch Rectal Cancer Trial. All participating surgeons had adopted the technical “gold standard” of total mesorectal excision (TME) before entering patients. In this randomized, multicenter study of 1861 patients with rectal cancer, 2-year local recurrence rates were significantly improved from 8.2% to 2.4% when preoperative radiation was given before TME. Five-year figures confirm a reduction in local recurrence rates from 11.4% after TME alone versus 5.6% for preoperative radiotherapy followed by TME but this does not translate into an improvement in 5-year survival rates (van de Velde,
38
and magnetic
40
48
31. Adjuvant Therapy for Colorectal Cancer 441
personal communication). Thus, it seems that neoadjuvant radiotherapy still has a place in the treatment of rectal cancer, even when surgical technique is optimized.
The advisability of adding chemotherapy to preoperative radiation (and therefore to use neoadjuvant combined chemo­radiotherapy) is undergoing intense scrutiny. Additional 5-FU-based chemotherapy may theoretically act as a radiosensitizer at the high cost of increased hematologic and gastrointestinal toxicity. Neoadjuvant chemoradiotherapy is recommended for advanced disease (T4, N0-2), but there is no randomized phase III study comparing neoadjuvant radio­therapy versus neoadjuvant chemoradiotherapy in resectable rectal cancer (T2-3, N0-2). Only one study is currently under­way to examine this issue. In the EORTC 22921 trial, patients with T3, T4 NX rectal cancer are randomized to one of four treatment arms: preoperative radiotherapy followed by sur­gery only; preoperative radiotherapy followed by surgery and postoperative adjuvant chemotherapy; neoadjuvant chemoradia­tion followed by surgery only; and neoadjuvant chemoradiation followed by surgery and additional adjuvant chemotherapy.
49
The trial was closed in 2003 after enrolling 1100 patients. A preliminary analysis of acute toxicity has demonstrated that at the dose recommended in the trial, the addition of chemother­apy during the radiation increased the proportion of patients developing grade 2 diarrhea from 17% to 34%. However, compliance with the adjuvant therapy and the proportion of patients undergoing surgery did not change. The oncologic results of this trial have not yet been published.
Postoperative Adjuvant Therapy: Radiation Alone Versus Chemoradiation
The advantage of reserving adjuvant treatment for the postop­erative setting is the ability to restrict its use to patients who are at identified risk for failure, based on their histopathologic staging. In the German CAO/ARO/AIO trial, 18% of patients diagnosed with Stage II or III rectal cancer based on endorec­tal ultrasound had pathologic Stage I disease and were proba­bly overtreated. The disadvantages include the higher incidence of radiation-related complications, particularly small bowel radiation injury and a higher number of patients unable to complete the entire course of therapy because of treatment side effects. Other reasons are the relative radiore­sistance of the hypoxic surgical bed and the risk for repopu­lation of tumor cells from surgery to the start of radiotherapy.
Postoperative adjuvant radiation therapy alone decreases local recurrence, although not to the same extent as neoadju­vant treatment, and does not improve survival. early studies revealed that the addition of 5-FU-based chemotherapy to postoperative radiotherapy increased local control (Mayo Clinic/NCCTG 79-47-51
53
improved survival by 10%–15% (Gastrointestinal Tumor Study Group
54
and Mayo/NCCTG53). Despite the fact that all those trials were heavily underpowered, these findings prompted the National Cancer Institute Consensus
50–52
Several
) and significantly
Conference of 1990 to recommend combined modality chemoradiotherapy as the standard postoperative adjuvant treatment for patients with Stage II and Stage III rectal can-
55
Although a recently published Norwegian trial con-
cer.
56
firmed
these findings, many countries, especially in Europe, did not follow those recommendations mainly because by then neoadjuvant radiotherapy had been proven to be more efficacious.
Benefit No. 2: Radiotherapy Allows Surgery in Nonresectable Rectal Cancer
The definition of a nonresectable rectal cancer is controver­sial. These tumors are clinically tethered or fixed but it is often difficult to predict whether fixation is the result of fibrotic adhesions or tumor infiltration of the pelvic sidewalls or adjacent organs. propria of the rectum, and a standard surgical resection fol­lowing the principles of sharp mesorectal excision often results in tumor involvement of the circumferential resection margin. For the purpose of this section, we will define a non­resectable rectal cancer as a tumor that cannot be resected without a very high risk of local recurrence. Magnetic reso­nance imaging is particularly useful to determine the relation­ship of the tumor with the fascia propria of the rectum, and it may be the best imaging modality for the preoperative staging of patients with fixed tumors. Based on available data, patients with such locally advanced rectal cancer tumors ben­efit from preoperative radiotherapy with the aim of downsiz­ing the tumor. Approximately 10%–15% of all patients with rectal cancer fall into this category; half of those patients have no metastases, indicating that there is potential for a curative procedure.
26
unlikely to be curative and it is indicated to offer radiotherapy to those patients.
It must be emphasized that short-course radiotherapy is not an option in unresectable rectal cancer; a standard dose of 45–55 Gy over 5–6 weeks must always be given.
Radiotherapy is used to downsize tumors in this group of patients. After completion of standard-dose radiotherapy, a 6- to 8-week waiting period allows the tumor to shrink, increasing the possibility for a curative procedure.
The role of additional chemotherapy remains unclear in this context. There is very little solid evidence from randomized trials using chemoradiotherapy. One old trial (1969) reported positive results from chemoradiotherapy in locally unre­sectable rectal cancer. the late 1980s, reported increased toxicity. ered Swedish trial (2001) showed improved local recurrence rate and overall survival in patients randomized to chemora­diotherapy versus radiotherapy alone followed by surgery. Several phase II trials have reported a reduction in local recur­rence rates and impressive data regarding survival lems with interpretation of case-mix and definition of “nonresectability” make the results of those trials difficult to
57
Such tumors probably involve the fascia
Based on tumor characteristics, surgery alone is
58
Two other negative trials, published in
59,60
One underpow-
62,63
; prob-
61
442 J.L. Trudel and L.A. Påhlman
interpret. The LARCS Nordic trial, which randomized patients with unresectable rectal cancer to receiving either 50 Gy pre­operatively or 50 Gy and chemotherapy preoperatively just closed and will help to shed some light on this question.
At this time, there is no good evidence supporting the use of chemotherapy in addition to radiotherapy for unresectable rectal cancer. Despite the lack of data and scientific evidence, most radiotherapists and medical oncologists have more or less accepted the concept of using chemoradiotherapy for nonresectable rectal cancer patients. It is likely that the trend will continue, until ongoing trials answer that question. The newer chemotherapeutic agents currently in use or under study for treatment of locally advanced and metastatic colon cancer (e.g., irinotecan, capecitabine, and oxaliplatin) will doubtless be evaluated for their usefulness in neoadjuvant and adjuvant treatment of rectal cancer in the near future. Their efficacy and usefulness is unknown at this time.
64
Benefit No. 3: Radiotherapy Facilitates Sphincter-preserving Procedures in Low-lying Rectal Cancer
Several series claim that preoperative radiotherapy (and preferably chemoradiotherapy) downsizes tumors to the extent that it is possible to increase the number of patients in whom the sphincters can be preserved. report showing complete response to chemoradiotherapy in some patients with T4 tumors; some of these patients were not operated on and reportedly remain alive and well. Caution must be exercised when reading these studies. First, rates of sphincter preservation do not tell the entire story; sec­ond, the main criticism of these studies is that modern thera­pies are compared with historical controls. The dramatic recent changes in surgical technique (TME, staplers) and the modern approach to rectal cancer treatment may partially explain the increased rate of sphincter preservation. We now accept a 5- to 10-mm distal margin as curative procedure if a stapled anastomosis is done.
71,72
must be done to verify the sturdiness of the conclusions. In the French R9001 trial, patients with T2 and T3 tumors received preoperative 39 Gy (13 × 3 Gy) and were random­ized to immediate surgery or surgery 5 weeks after irradia­tion. Surgeons were asked before any treatment to evaluate the possibility to preserve the sphincters. Delaying surgery for 5 weeks after the end of radiation only slightly increased the rate of sphincter preservation.
73
This small trial indicates that there might be a downstaging and downsizing effect, which in turn might increase the rate of sphincter preservation. Of note, the overall recurrence rate in the trial was 9%, which is con­sidered a high figure; more crucially, the local recurrence rate was 12% among the patients in whom the surgeon had origi­nally planned an abdominoperineal excision but changed intraoperatively to a sphincter-preserving procedure because of the downsizing effect of radiotherapy.
65–69
There is even a
Modern randomized trials
73
The German trial (CAO/ARO/AIO trial), in which patients were randomized to pre- or postoperative chemoradiotherapy, has shown a clear tendency to more favorable stage in patients having had preoperative treatment compared with postopera­tive chemoradiotherapy. In a subgroup analysis of patients determined by the surgeon before randomization to require an abdominoperineal resection, the proportion of sphincter preservation rate was 39% in the preoperative chemoradiation group and 18% in the postoperative chemoradiotherapy group.
In a recent Polish study, more than 300 patients were ran­domized to either short-course radiotherapy (25 Gy) with immediate surgery or long-course chemoradiotherapy and delayed surgery. T3 or resectable T4 tumors located within the reach of the examining finger, without evidence of sphincter involvement, and resectable with a 1-cm macro­scopic distal margin were included in the study. Sphincter preservation and local recurrence rates were analyzed. Sphincter preservation rates were identical in both groups (61% in the short-course radiotherapy with immediate surgery versus 59% in the prolonged chemoradiotherapy course and delayed surgery).
74
This trial was conducted to determine whether chemoradiotherapy and delayed surgery had an impact on sphincter preservation. Accordingly, this is not a subset analysis of the data from the trial, indicat­ing the strength of the results. At this time, there is no evidence that prolonged-course radiotherapy combined with chemotherapy with delayed surgery impacts sphincter preservation. It is possible that increasing the waiting
70
time from end of radiotherapy to surgery will achieve further downsizing, which might improve sphincter preservation.
An important consequence of increased sphincter preserva­tion is poor function. Poor quality of life may be the price to pay for intact sphincters: up to 20% of all patients who undergo a low anterior resection are incontinent of solid
68
stool.
This contrasts with reports that patients with a stoma had a better quality of life compared with those with an ante­rior resection.
75
This must be considered when selecting sur-
gical options for individual patients.
Adjuvant Chemotherapy Alone in Rectal Cancer
In contrast to colon cancer, chemotherapy alone as adjuvant treatment in rectal cancer remains questionable. In the early 1980s, underpowered United States radiotherapy trials con­cluded that chemotherapy improved survival compared with surgery alone. Two large randomized trials comprising more than 4000 patients have studied the value of chemotherapy versus surgery alone in colon and rectal cancer patients. Combination 5-FU/levamisole and 5-FU/LV were found to improve survival in patients with colon cancer, but showed no benefit in patients with rectal cancer. score the difference in chemotherapy effectiveness for rectal cancer and colon cancer. The reasons for this are unclear:
76,77
These results under-
31. Adjuvant Therapy for Colorectal Cancer 443
different tumor profiles or lack of proper surgical technique at the time of these trials may partly explain the results. At this time, adjuvant chemotherapy alone is not acceptable in rectal cancer. However, postoperative chemotherapy is currently used to reduce the risk of distant relapse in patients with rec­tal cancer treated with pre- or postoperative chemoradiation and radical surgery.
References
1. Jemal A, Thomas A, Murray T, et al. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23–47.
2. National Comprehensive Cancer Network. Clinical practice guidelines in oncology. JNCCN 2003;1:40–53.
3. Wolmark N, Fisher B, Rockette H, et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from the NSABP protocol C-01. J Natl Cancer Inst 1988;80:30–36.
4. Laurie JA, Moertel CG, Fleming TR, et al. Surgical adjuvant therapy of large bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 1989;7:1447–1456.
5. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and 5-fluorouracil for adjuvant therapy of resected colon cancer. N Engl J Med 1990;322:352–358.
6. NIH Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:1444–1450.
7. Taal BG, Van Tinteren H, Zoetmulder FA, et al. Adjuvant 5-FU plus levamisole in colonic or rectal cancer: improved survival in stage II or III. Br J Cancer 2001;85:1437–1443.
8. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators: efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 1995;345:939–944.
9. Wolmark N, Rockette H, Fisher B, et al. The benefit of leucov­orin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer. Results form National Surgical Adjuvant Breast and Bowel Project protocol CO-3. J Clin Oncol 1993;11:1879–1887.
10. O’Connell MJ, Laurie JA, Kahn M, et al. Prospectively random­ized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998;16:295–300.
11. Haller DG, Catalano PJ, MacDonald JS, et al. Fluorouracil (FU), leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon cancer: five-year final report of INT-0089 [abstract]. Proc Am Soc Clin Oncol 1998;17:256.
12. Wolmark N, Rockette H, Mamounas E, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluo­rouracil and levamisole, and fluorouracil, leucovorin and lev­amisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project CO-4. J Clin Oncol 1999;17:3553–3559.
13. QUASAR Collaborative Group: comparison of fluorouracil with additional levamisole, higher dose leucovorin or both as adjuvant chemotherapy for colorectal cancer—a randomized trial. Lancet 2000;355:1588–1596.
14. Topham C, Boni C, Navarro M, et al. Multicenter international randomized study of oxaliplatin/5FU/LV (FOLFOX) in stage II and III colon cancer (MOSAIC trial): final results. Eur J Cancer 2003;1(suppl 5):S324–325. Abstr 1085.
15. Fallik D, Borrini F, Boige V, et al. Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res 2003;15: 5738–5744.
16. Barratt PL, Seymour MT, Stenning SP, et al. DNA markers pre­dicting benefit from adjuvant fluorouracil in patients with col­orectal cancer: a molecular study. Lancet 2002;360:1381–1391.
17. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) investigators: efficacy of adjuvant fluo­rouracil and folinic acid in B2 colon cancer. J Clin Oncol 1999;17:1356–1363.
18. Schrag D, Gelfand S, Bach P, et al Adjuvant chemotherapy for stage II colon cancer: insight from a SEER-Medicare cohort [abstract]. Proc Am Soc Clin Oncol 2001;20:488.
19. Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Projects adjuvant studies (CO-1, CO-2, CO-3 and CO-4). J Clin Oncol 1999;17:1349–1355.
20. Buyse M, Piedbois P. Should Dukes’ B patients receive adjuvant therapy? A statistical perspective. Semin Oncol 2001;28 (suppl 1):20–24.
21. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709–715.
22. Willett CG, Tepper JE, Cohen A, et al. Local failure following curative resection of colonic adenocarcinoma. Int J Radiat Oncol Biol Phys 1984;10:645–651.
23. Gunderson LL, Sosin H, Levitt S. Extrapelvic colon-areas of failure in a reoperation series: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 1985;11:731–741.
24. Willett CG, Fung CY, Kaufman DS, et al. Postoperative radiation therapy for high-risk colon carcinoma. J Clin Oncol 1993;11: 1112–1117.
25. Schild SE, Gunderson LL, Haddock MG, et al. The treatment of locally advanced colon cancer. Int J Radiat Oncol Biol Phys 1997;37:51–58.
26. Amos EH, Mendenhall WM, McCarty PJ, et al. Postoperative radiotherapy for locally advanced colon cancer. Ann Surg Oncol 1996;3:431–436.
27. Martenson J, Willett CG, Sargent D, et al. A phase III study of adjuvant radiation therapy (RT), 5-fluorouracil (5-FU), and lev­amisole (LEV) vs. 5-FU and LEV in selected patients with resected, high-risk colon cancer: initial results of INT 0130 [abstract]. Proc Am Soc Clin Oncol 1999;18:235.
28. Hanna MG Jr, Hoover HC Jr, Vermoken JB, et al. Adjuvant active specific immunotherapy of stage II and stage III colon cancer with autologous tumor cell vaccine: First randomized phase III trials show promise. Vaccine 2001;19:2576–2582.
29. Hoover HC Jr, Brandhorst JS, Peters LC, et al. Adjuvant active specific immunotherapy for human colorectal cancer: 6.5 year median follow-up of a phase III prospectively randomized trial. J Clin Oncol 1993;11:390–399.
30. Harris JE, Ryan L, Hoover HC Jr, et al. Adjuvant active specific immunotherapy for stage II and II colon cancer autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5238. J Clin Oncol 2000;18:148–157.
31. Vermoken JB, Claessen AM, Van Tinteren H, et al. Active spe­cific immunotherapy for stage II and stage III human colon can­cer: a randomized trial. Lancet 1999;353:345–350.
444 J.L. Trudel and L.A. Påhlman
32. Camma C, Giunta M, Fiorica F, et al. Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA 2000;284: 1008–1015.
33. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet 2001;358:1291–304.
34. Glimelius B, Grönberg H, Järhult J, Wallgren A, Cavallin-Ståhl E. A systematic overview of radiation therapy in rectal cancer. Acta Oncol 2003;42:476–492.
35. Påhlman L, Glimelius B. Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized multicentre trial. Ann Surg 1990;211:187–195.
36. Roh MS, Petrilli N, Wieand H, et al. Phase III randomized trial of preoperative versus postoperative multimodality therapy in patients with carcinoma of the rectum (NSABP R-03) [abstract]. Proc Am Soc Clin Oncol 2001;20:123a.
37. Sauer R, Fietkau R, Wittekind C, et al. Adjuvant versus neoad­juvant radiochemotherapy for locally advanced rectal cancer. Strahlenther Onkol 2001;177:173–181.
38. Garcia-Aguilar J, Pollack J, Lee SH, et al. Accuracy of endorec­tal ultrasonography in preoperative staging of rectal tumors. Dis Colon Rectum 2002;45:10–15.
39. Beets-Tan RGH, Beets GL, Vliegen RFA, et al. Accuracy of magnetic resonance imaging in prediction of tumour-free resec­tion margin in rectal cancer surgery. Lancet 2001;357:497–504.
40. Swedish Rectal Cancer Trial: initial report from a Swedish mul­ticentre study examining the role of preoperative irradiation in the treatment of patients with resectable rectal carcinoma. Br J Surg 1993;80:1333–1336.
41. Heald RJ, Karanjia ND. Results of radical surgery for rectal can­cer. World J Surg 1992;16:848–857.
42. Enker WE. Potency, cure, and local control in the operative treat­ment of rectal cancer. Arch Surg 1992;127:1396–1401.
43. Moriya Y, Hojo K, Sawada T, Koyama Y. Significance of lateral node dissection for advanced rectal carcinoma at or below the peritoneal reflection. Dis Colon Rectum 1989;32:307–315.
44. Wibe A, Rendedal PR, Svensson E, et al. Prognostic significance of the circumferential resection margin following total mesorec­tal excision for rectal cancer. Br J Surg 2002;89:327.
45. Dahlberg M, Glimelius B, Påhlman L. Changing strategy for rec­tal cancer is associated with improved outcome. Br J Surg 1999;86:379–84.
46. Martling AL, Holm T, et al. Effect of a surgical training programme on the outcome of rectal cancer in the County of Stockholm. Lancet 2000;356:93–96.
47. Swedish Rectal Cancer Register. Available at: http://www.SOS. se/mars/kvaflik.htm (Swe).
48. Kapiteijn E, Matijnen CA, Naggtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638–646.
49. Bosset JF, Pierat M, Van Glabbeke M. Preoperative radiochemo­therapy versus preoperative radiotherapy with or without postop­erative chemotherapy: progress report of the EORTC 22921 trial [abstract]. Radiother Oncol 2000;56:S52.
50. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer. Results from NSABP protocol R-01. J Natl Cancer Inst 1988;80:21–29.
51. Wolmark N, Weiand HS, Hyams DM, et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiother­apy for carcinoma of the rectum: National Surgical Adjuvant
Breast and Bowel Project protocol R-02. J Natl Cancer Inst 2000;92:388–396.
52. Willett CG, Tepper JE, Kaufman DS, et al. Adjuvant postopera­tive radiation therapy for rectal adenocarcinoma. Am J Clin Oncol 1992;15:371–375.
53. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709–715.
54. Gastrointestinal Tumor Study Group. Adjuvant therapy of colon cancer: results of a prospective randomized trial. N Engl J Med 1984;310:737–743.
55. National Institutes of Health Consensus Conference: adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:1444–1450.
56. Tveit KM, Guldvog I, Hagen S, et al. Randomised controlled trial of postoperative radiotherapy and short-term time-sched­uled 5-fluorouracil against surgery alone in the treatment of Dukes B and C rectal cancer. Br J Surg 1997;84:1130–1135.
57. Påhlman L, Enblad P, Glimelius B. Clinical characteristics and their relation to surgical curability in adenocarcinoma of the rectum and recto-sigmoid: a population-based study in 279 consecutive patients. Acta Chir Scand 1985;151:685–693.
58. Moertel CG, Childs DS, Reitemeier RJ, et al. Combined 5-fluo­rouracil and supervoltage radiation therapy of locally unre­sectable gastrointestinal carcinoma. Lancet 1969;2:865–867.
59. Overgaard M, Berthelsen K, Dahlmark M, et al. A randomized trial of radiotherapy alone or combined with 5-FU in the treatment of locally advanced colorectal carcinoma. ECCO 5, meeting abstract 1989:0-0626.
60. Wassif-Boulis S. The role of preoperative adjuvant therapy in management of borderline operability of rectal cancer. Clin Radiol 1982;33:353–358.
61. Frykholm GJ, Pahlman L, Glimelius B. Combined chemo and radiotherapy versus radiotherapy alone in the treatment of pri­mary, non-resectable adenocarcinoma of the rectum. Int J Radiat Oncol Biol Phys 2001;50:433–440.
62. Janjan NA, Abbruzzese J, Pazdur R, et al. Prognostic implica­tions of response to preoperative infusional chemoradiation in locally advanced rectal cancer. Radiother Oncol 1999;51: 153–160.
63. Bouzourene H, Bosman FT, Seelentag W, Matter M, Coucke P. Importance of tumor regression assessment in predicting the out­come in patients with locally advanced rectal carcinoma who are treated with preoperative radiotherapy. Cancer 2002;94: 1121–1130.
64. Glynne-Jones R, Sebag-Montefiore D. Chemoradiation sched­ules—what radiotherapy? Eur J Cancer 2002;38:258–269.
65. Valentini V, Coco C, Cellini N, et al. Preoperative chemoradia­tion with cisplatin and 5-fluorouracil for extraperitoneal T3 rec­tal cancer: acute toxicity tumor response, sphincter preservation. Int J Radiat Oncol Biol Phys 1999;45:1175–1184.
66. Grann A, Minsky BD, Cohen AM, et al. Preliminary results of preoperative 5-fluorouracil, low-dose leucovorin and concurrent radiation therapy for clinically respectable T3 rectal cancer. Dis Colon Rectum 1997;40:515–522.
67. Hyams DM, Mamounas EP, Petrelli N, et al. A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03. Dis Colon Rectum 1997;40:131–139.
31. Adjuvant Therapy for Colorectal Cancer 445
68. Rouanet P, Saint-Aubert B, Lemanski C, et al. Restorative and nonrestorative surgery for low rectal cancer after high-dose radi­ation. Dis Colon Rectum 2002;45:305–315.
69. Mohiuddin M, Regine WF, Marks GJ, Marks JW. High dose pre­operative radiation and the challenge of sphincter-preservation surgery for rectal cancer of the distal 2 cm of the rectum. Int J Radiat Oncol Biol Phys 1998;40:569–574.
70. Habr-Gama A, de Souza PM, Ribeiro U, et al. Low rectal cancer: impact of radiation and chemotherapy on surgical treatment. Dis Colon Rectum 1998;41:1087–1096.
71. Moore HG, Riedel E, Minsky BD, et al. Adequacy of 1 cm dis­tal margin after restorative rectal cancer resection with sharp mesorectal excision and preoperative combined-modality ther­apy. Ann Surg Oncol 2003;1:80–85.
72. Karnjia ND, Schache DJ, Nort WR, Heald RJ. ‘Close shave’ in anterior resection. Br J Surg 1990;63:673–677.
73. Francois Y, Nemoz CJ, Baulieux J, et al. Influence of the inter­val between preoperative radiation therapy and surgery on down­staging and on the rate of sphincter-sparing surgery for rectal
cancer: the Lyon R90-01 randomized trial. J Clin Oncol 1999; 17:2396–2402.
74. Bujko K, Nowacki MP, Bebenek M, et al. Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy versus con­ventionally fractionated radiochemotherapy. Radiother Oncol 2004;72(1):15–24.
75. Frigell A, Ottander M, Stenbeck H, Påhlman L. Quality of life of patients treated with abdominoperineal resection or anterior resection for rectal carcinoma. Ann Chir Gynaecol 1990;79: 26–30.
76. Taal BG, Van Tinteren H, Zoetmulder FA, et al. Adjuvant 5-FU plus levamisole in colonic or rectal cancer: improved survival in stage II or III. Br J Cancer 2001;85:1437–1443.
77. Glimelius B, Cedermark B, Dahl O, et al. Adjuvant chemother­apy in colorectal cancer: joint analyses of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Eur J Cancer, ECCO 12, abstract-book 2003;39(suppl 1):S318. Abstr 1066.
32
Colorectal Cancer Surveillance
Brett T. Gemlo and David A. Rothenberger
The majority of colorectal cancers are resected for cure, leav­ing many patients eligible for ongoing surveillance. The best schema for clinically useful and cost-effective follow-up is still controversial, but the goals are clear. Rational follow-up should detect treatable recurrent cancers, identify and remove metachronous polyps, and identify possible heredi­tary influences in development of a colorectal cancer. In the­ory, such follow-up will increase the survival of patients with cancer and improve their quality of life by successfully treat­ing recurrences, preventing metachronous cancers of the colon or rectum, as well as preventing subsequent hereditary cancers from developing in the patient and/or their family members. How to accomplish this is still controversial, but it is clear that accurate risk stratification and patient selection are central to any program of surveillance. The intensity of surveillance should be proportional to the patient’s risk of recurrence, and those patients unfit for further surgery because of age or comorbidity may be best served by colono­scopic follow-up only.
Types of Surveillance
Metachronous Colorectal Neoplasms
Those patients who have undergone successful treatment of a colorectal malignancy have an increased risk of developing subsequent polyps or cancers compared with the rate at which an age-matched control population would develop their first colorectal neoplasm. The period of risk for the development of metachronous disease seems to be lifelong and cumulative. The risk of developing metachronous polyps ranges between 30% and 56%, and the risk of a second cancer is 2%–8%. Because these cancers arise from adenomatous polyps, peri­odic colonoscopy with polypectomy should prevent the deve­lopment of subsequent cancers. The starting point and appropriate interval for surveillance colonoscopy in the pop­ulation of patients undergoing follow-up for colorectal cancer
1–3
are controversial and poorly studied. In the past, most clini­cians advocated colonoscopic follow-up 1 year after surgery to visualize the anastomosis and look for missed synchronous lesions. Recently, the utility of early follow-up colonoscopy 1 year after surgery compared with delaying colonoscopy until 3 years after surgery has been questioned. The Standards Task Force of the American Society of Colon and Rectal Surgeons (ASCRS) has recommended colonoscopy surveillance to begin 3 years after surgery assuming preoperative or intraop­erative clearance was done and was negative. or intraoperative clearance examination could not be done, postoperative colonoscopy within 6 months of surgery is rec­ommended. If multiple synchronous polyps are identified, dur­ing the clearance examination, it may be reasonable to do the first surveillance examination at 1 year. Otherwise, posttreat­ment colonoscopy should be performed at 3-year intervals. Follow-up surveillance colonoscopy every 3 years can be con­tinued for the duration of an individual’s active life. It is also acceptable to extend follow-up colonoscopy to every 5 years after a negative colonoscopy at 3 years. Once the patient is older than age 80, further examinations may be of limited use­fulness although exceptions can be made for individuals who are healthy and active despite their advanced age.
4
If preoperative
Recurrent Cancer
The term “recurrent cancer” is a misnomer because the can­cer does not disappear and then return. It simply progresses in sites not clinically detectable at the time of the original sur­gery. Locoregional recurrences are more common in cases of rectal cancer, and may represent inadequate tumor clearance at the time of surgery. Distant disease, typically in the liver or lungs, usually does not cause symptoms until the situation is quite advanced. Options for the detection of asymptomatic recurrences include physical examination, carcinoembryonic antigen (CEA) monitoring, colonoscopy, chest X-ray, (CXR), and various scans. In this high technology era, careful atten­tion to new symptoms such as abdominal pain, change in
446
32. Colorectal Cancer Surveillance 447
bowel habits, weight loss, or anorexia is often lacking, but such symptoms are the first sign of recurrence in many cases. When present, a meticulous physical examination is conducted. This should include a digital rectal and vaginal examination for patients with rectal cancer. CEA testing is most useful in cases in which the level was increased preop­eratively but decreased to normal levels after resection. Even in cases in which the preoperative CEA level is normal, serial CEA testing is often the first indication a patient has recurrent disease. Although CEA testing is controversial, the Standards Practice Task Force of the ASCRS recently recommended that CEA testing should be used as a part of follow-up for patients with colorectal cancer. This may be justified if its use is restricted to those who would tolerate reoperation if a recurrence were identified. Endoscopic follow-up is of lim­ited usefulness in looking for recurrences because only 2% of recurrences are visible at colonoscopy. This is especially true for colonic anastomoses where recurrence is rare as compared with rectal anastomoses where mucosal recurrences are more likely to develop. Rigid proctoscopy is an alternative and, some suggest, superior way to assess a rectal anastomosis for recurrence. Patients with rectal cancer, especially those treated with transanal excision, should undergo endorectal ultrasound surveillance (usually every 3 months for the first year). There are currently insufficient data to recommend for or against routine use of CXR to identify an asymptomatic pulmonary metastasis. Its use should be restricted to patients who would tolerate a pulmonary resection. Computerized tomography (CT) and magnetic resonance imaging (MRI) scanning are very sensitive ways to detect liver and lung metastases, but are not recommended as a routine screening procedure. Positron emission tomography (PET) scanning may become the most sensitive way to detect recurrences, but although it is becoming more widely available, data support­ing its use are still lacking. Although PET scanning is limited in its usefulness in detecting recurrence, it has been helpful in identifying patients with recurrence who have too many areas of distant recurrence to warrant operative therapy to remove the local, liver, or lung recurrence detected initially. Patients with isolated metastatic disease (fewer than eight liver metas­tases or 1 or 2 lobe lung involvement) may be candidates for operative treatment (see Chapter 34). As chemotherapy improves, operative therapy to resect residual disease may be more important to extract a cure.
Hereditary Cancer
Heredity is thought to be a major factor in 10%–25% of col­orectal cancers. Patients who developed their cancer before age 50 years or who have first-degree relatives who developed colorectal or associated cancers such as endometrial, ovarian, ureteral, or bladder cancer or who have multiple family mem­bers with varying cancers especially if diagnosed before 50 years of age may have a hereditary cancer. Some inherited syndromes predispose the individual not only to development
of young-age-of-onset colorectal cancer but also other organ cancers. Thus, in addition to informing family members of their risks and need for intensive surveillance, the patient’s follow-up plan may need to incorporate surveillance of other potential sites of cancer. Sometimes, genetic counseling and testing is useful and prophylactic surgery may be considered as in the case of hereditary nonpolyposis colon cancer syndrome.
Risk of Recurrence/Pattern of Recurrence
The risk of recurrence is proportional to the stage of the orig­inal disease. Most Stage IV patients have undergone palliative treatment and are not candidates for surveillance unless they were treated by operative removal of metastatic disease. Patients with Stage I colon cancer treated by radical surgery have such a low chance of recurrent disease that routine sur­veillance may not be justified. However, Stage I rectal cancer patients treated by local therapy are at significant risk of local recurrence and may deserve close follow-up. Patients with Stage II or III disease would seem to benefit most from close surveillance. Other tumor or surgery related factors such as degree of differentiation, presence of lymph node metastases, iatrogenic perforation, and poor primary tumor clearance, influence the risk of recurrence, and could be used to more accurately predict an individual patient’s risk of recurrence, and guide the development of a specific follow-up program. To date, there is no standardized formula for doing this but an experienced clinician can individualize follow-up based on the risk of recurrence, the patient’s overall health status, the patient’s willingness to undergo serial testing and the ability for the patient to undergo aggressive retreatment if recurrence is identified.
The patterns of recurrence reflect the location of the pri­mary tumor. but this tendency has diminished recently with improved mesorectal clearance techniques and the use of neoadjuvant chemoradiation. All colorectal cancers metastasize hematoge­nously to the liver and lungs as well as to regional lymphat­ics, and these areas need to be evaluated when looking for recurrent disease.
It is well established that 60%–80% of recurrences occur within 2 years of surgery, and more than 90% of recurrences are found within 5 years. Therefore, follow-up protocols should be most intensive for the first 2 years, and then taper off in frequency of evaluations over the next 3 years. The exception to this timing of recurrence is the patient who has had pelvic radiation. In such cases, recurrence tends to occur later so intensive surveillance may need to extend to 5 or 6 years. Subsequent to that, the risk of recurrence is so low that colonoscopic surveillance for metachronous cancers is all that is warranted. The development of symptoms at any time dur­ing follow-up should prompt a thorough diagnostic work-up and specific treatment.
5
Rectal cancers tend to recur locally in the pelvis,
448 B.T. Gemlo and D.A. Rothenberger
Surveillance Effectiveness
The utility of a surveillance program should be manifest in an improvement in survival or quality of life when compared with patients who have received little or no follow-up. Several variables confound our ability to evaluate the advantages derived from intensive efforts to detect recurrent cancer before it becomes evident clinically. The first is the lead time bias that results from detecting asymptomatic recurrences. Early detection of such a recurrence for which no effective treatment can be offered will still result in a measured pro­longation of survival from the time of diagnosis of the recur­rence when compared with those patients treated for symptomatic recurrences because they were identified earlier. Even if the treatment provided does impart some benefit, the bias between groups persists.
The identification of recurrent disease does not necessarily result in improved outcomes. Only about 10% of recurrences are resectable with curative intent and chemotherapy offers little chance of cure. Those patients who are fortunate to have a lesion amenable to surgery are often not suitable surgical candidates as a result of age or comorbidity, and should not be subjected to intense follow-up because any information obtained cannot be acted upon. There is a subset of patients with resectable disease, who may benefit from radical re­resection, with 5-year survivals of 25%–30% in most series. PET scanning can assist in identifying this small group of individuals.
6
The results of intensive follow-up programs reported in the literature have been disappointing. A recent review summa­rized the results of the six randomized, prospective trials of high-intensity versus low-intensity follow-up after surgical resection with curative intent for colorectal cancer.
7–13
Recurrences were not more common in the closely monitored group, but they were found earlier and were more likely to result in reoperation with curative intent. Despite this, only two of the six studies demonstrated a statistically significant improvement in overall survival as a result of intensive surveillance.
Because of the concern that inadequate sample size was in part responsible for the negative results encountered in the above studies, three separate metaanalyses have been con­ducted on these data.
6,14,15
Although this resulted in a more clearly discerned reduction in death from recurrent cancer, the reduction in absolute risk was only 7%.
Cost of Surveillance
Offsetting the survival benefits of an intensive surveillance program are the costs associated with such testing. Given the large number of patients involved, cost implications for Medicare and private insurers are significant. The hetero­geneity of follow-up regimens results in 5-year Medicare­allowed charges of $910 to $26,717 per patient.
16
One of the
above metaanalyses evaluated the cost-associated intensive follow-up in terms of cost per year of life gained and found it
17
to be $6096.
Beart’s hypothetical cost analysis of a program to closely follow Stage II and III patients resulted in a cost of $6558 per patient salvaged by resection.
18
Although these costs are significant, they seem to be below the accepted threshold of $30,000 per year of life gained.
Quality of Life
Intensive surveillance may have a negative impact on quality of life secondary to the anxiety, inconvenience, and cost asso­ciated with the testing. Conversely, intensive testing may be reassuring to patients and improve their quality of life. Investigators in Denmark found that although patients sub­jected to closer follow-up expressed greater confidence in their examinations, the increment in quality of life was mar­ginal and did not justify the expense of follow-up. Stiggelbout et al.20also showed no differences in health­related quality of life when different intervals of follow-up were studied but they did show patients had a strong prefer­ence for follow-up. Additional data are needed to determine methods and settings for follow-up that maximize both sur­vival and the quality of life.
Recommendations
Recommendations for surveillance of patients who have under­gone curative resection of colorectal cancer are as follows.
Virtually all patients can undergo follow-up studies that are focused on excluding hereditary cancer and on prevention of synchronous cancer by every 3- to 5-year surveillance colono­scopies to remove metachronous polyps. If hereditary cancer is likely, work-up appropriately and/or consider referral to experts in hereditary cancers. In addition to counseling the patient about their own risks for other sites of cancer devel­opment, the clinician must attempt to educate the patient’s family members about their risks and surveillance or treat­ment options.
The search for treatable recurrent disease is more selective. It is helpful to first determine whether the patient has a sig­nificant risk of recurrence. If so, determine whether the patient prefers an aggressive approach to follow-up testing and whether the patient could tolerate retreatment if recur­rence is identified. If there is a minimal risk of recurrence and/or the patient refuses or is not a candidate for aggressive follow-up, no additional testing is done. It is comforting for patients to know that should recurrence develop, you are available and palliative treatment can be instituted. Patients should still undergo routine colonoscopic surveillance every 5 years to detect metachronous polyps or cancer.
If there is a significant risk of recurrence and the patient wants aggressive follow-up and would tolerate retreatment,
19
32. Colorectal Cancer Surveillance 449
follow-up will include the search for recurrent disease. Typically this includes: history, physical examination, and serial testing as noted below every 3–6 months for the first 3 years, and then every 6–12 months for an additional 2 years. If pelvic radiation was used for rectal cancer, the closer inter­val of follow-up may need to be extended to 5 or 6 years. Careful attention to new symptoms and physical finding should be made.
Complete colonoscopy before resection, followed by an examination 1–3 years after surgery and every 3–5 years thereafter for the duration of the patient’s productive life.
Serial CEA testing every 3 months for the first postopera­tive year or two and every 6–12 months thereafter for patients who desire an aggressive follow-up protocol and would toler­ate aggressive retreatment for locoregional disease or hepatic or pulmonary metastasis.
Serial CXR every 6–12 months for patients who desire an aggressive follow-up protocol and would tolerate pulmonary resection.
Serial proctoscopy and selective endorectal ultrasound for rectal cancer patients who desire an aggressive follow-up pro­tocol and would tolerate aggressive radical pelvic surgery with or without additional radiation and chemotherapy.
Based on the available evidence, there is no role for the routine use of liver function tests, hemoglobin, CT scanning, MRI, or PET scanning in asymptomatic patients.
4,7
Future studies may more clearly define the role of these and other surveillance modalities.
References
1. Chen F, Stuart M. Colonoscopic follow-up of colorectal carci­noma. Dis Colon Rectum 1994;37(6):568–572.
2. Evers BM, et al. Multiple adenocarcinomas of the colon and rec­tum. An analysis of incidences and current trends. Dis Colon Rectum, 1988;31(7):518–522.
3. Reilly JC, Rusin LC, Theuerkauf FJ Jr. Colonoscopy: its role in cancer of the colon and rectum. Dis Colon Rectum 1982;25(6): 532–538.
4. Anthony T, et al. Practice parameters for the surveillance and fol­low-up of patients with colon and rectal cancer. Dis Colon Rectum 2004;47(6):807–817.
5. Kjeldsen BJ, et al. The pattern of recurrent colorectal cancer in a prospective randomised study and the characteristics of diagnos­tic tests. Int J Colorectal Dis 1997;12(6):329–334.
6. Jeffery GM, Hickey BE, Hider P. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 2002(1):CD002200.
7. Pfister DG, Benson AB 3rd, Somerfield MR. Clinical practice. Surveillance strategies after curative treatment of colorectal can­cer. N Engl J Med 2004;350(23):2375–2382.
8. Pietra N, et al. Role of follow-up in management of local recur­rences of colorectal cancer: a prospective, randomized study. Dis Colon Rectum 1998;41(9):1127–1133.
9. Schoemaker D, et al. Yearly colonoscopy, liver CT, and chest radiography do not influence 5-year survival of colorectal cancer patients. Gastroenterology 1998;114(1):7–14.
10. Ohlsson B, et al. Follow-up after curative surgery for colorectal carcinoma. Randomized comparison with no follow-up. Dis Colon Rectum 1995;38(6):619–626.
11. Secco GB, et al. Efficacy and cost of risk-adapted follow-up in patients after colorectal cancer surgery: a prospective, random­ized and controlled trial. Eur J Surg Oncol 2002;28(4):418–423.
12. Kjeldsen BJ, et al. A prospective randomized study of follow-up after radical surgery for colorectal cancer. Br J Surg 1997;84(5):666–669.
13. Makela JT, Laitinen SO, Kairaluoma MI. Five-year follow-up after radical surgery for colorectal cancer. Results of a prospec­tive randomized trial. Arch Surg 1995;130(10):1062–1067.
14. Figueredo A, et al. Follow-up of patients with curatively resected colorectal cancer: a practice guideline. BMC Cancer 2003;3(1):26.
15. Renehan AG, et al. Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials. BMJ 2002;324(7341):813.
16. Virgo KS, et al. Cost of patient follow-up after potentially curative colorectal cancer treatment. JAMA 1995;273(23):1837–1841.
17. Renehan AG, O’Dwyer ST, Whynes DK. Cost effectiveness analysis of intensive versus conventional follow up after curative resection for colorectal cancer. BMJ 2004;328(7431):81.
18. Beart RW Jr. Follow-up: does it work? Can we afford it? Surg Oncol Clin North Am 2000;9(4):827–834; discussion 835–837.
19. Kjeldsen BJ, et al. Influence of follow-up on health-related qual­ity of life after radical surgery for colorectal cancer. Scand J Gastroenterol 1999;34(5):509–515.
20. Stiggelbout AM, et al. Follow-up of colorectal cancer patients: quality of life and attitudes towards follow-up. Br J Cancer 1997;75(6):914–920.
Соседние файлы в папке Библиотека им академика М.И. Перельмана
Помощь Обратная связь Вопросы и предложения Пользовательское соглашение Политика конфиденциальности