Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1370_Библиотеки_им_академика_М_И_Перельмана
.pdf
improved outcomes in colon and rectal surgery
96. Schlag P, Hohenberger P, Herfarth C. Resection of liver
metastases in colorectal cancer–competitive analysis of
treatment results in synchronous versus metachronous
metastases. Eur J Surg Oncol 1990; 16(4): 360–5.
97. Jovine E, Biolchini F, Talarico F, et al. Major hepatectomy
in patients with synchronous colorectal liver metastases:
whether or not a contraindication to simultaneous colorectal and liver resection? Colorectal Dis 2007; 9(3): 245–52.
98. Adam R, Aloia T, Levi F, et al. Hepatic resection after rescue
cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin
Oncol 2007; 25(29): 4593–602.
99. Adam R, Miller R, Pitombo M, et al. Two-stage hepatectomy
approach for initially unresectable colorectal hepatic metastases. Surg Oncol Clin N Am 2007; 16(3): 525–36, viii.
100. Adam R, wicherts da, de Haas RJ, et al. Complete pathologic
response after preoperative chemotherapy for colorectal liver
metastases: myth or reality? J Clin Oncol 2008; 26(10): 1635–41.
101. Topham C, Adam R. Oncosurgery: a new reality in metastatic
colorectal carcinoma. Semin Oncol 2002; 29(5 Suppl 15): 3–10.
102. Wicherts DA, de Haas RJ, Adam R. Bringing unresectable
liver disease to resection with curative intent. Eur J Surg
Oncol 2007; 33(Suppl 2): S42–51.
103. Shimizu Y, Yasui K, Sano T, et al. Validity of observation
interval for synchronous hepatic metastases of colorectal
cancer: changes in hepatic and extrahepatic metastatic foci.
Langenbecks Arch Surg 2008; 393(2): 181–4.
104. Yoshidome H, Kimura F, Shimizu H, et al. Interval period
tumor progression: does delayed hepatectomy detect occult
metastases in synchronous colorectal liver metastases?
J Gastrointest Surg 2008; 12(8): 1391–8.
105. Mitry E, Mitry E, Fields A, et al. Adjuvant chemotherapy
after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials.
J Clin Oncol 2008; 26(30): 4906–11.
106. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative
chemotherapy with FOLFOX4 and surgery versus surgery
alone for resectable liver metastases from colorectal cancer
(EORTC Intergroup trial 40983): a randomised controlled
trial. Lancet 2008; 371(9617): 1007–16.
107. Ishibashi K, Yoshimatsu K, Yokomizo H, et al. Hepatic arterial infusion (HAI) chemotherapy achieved a complete
response (CR) for multiple liver metastases of colorectal cancer–two case reports. Gan To Kagaku Ryoho 2005;
32(11): 1832–4.
108. Kelly RJ, Kemeny NE, Leonard GD. Current strategies using
hepatic arterial infusion chemotherapy for the treatment
of colorectal cancer. Clin Colorectal Cancer 2005; 5(3):
166–74.
109. Sadahiro S, Suzuki T, Ishikawa K, et al. Prophylactic hepatic
arterial infusion chemotherapy for the prevention of liver
metastasis in patients with colon carcinoma: a randomized
control trial. Cancer 2004; 100(3): 590–7.
110. Allen PJ, Nissan A, Picon A, et al. Technical complications
and durability of hepatic artery infusion pumps for unresectable colorectal liver metastases: an institutional experience of 544 consecutive cases. J Am Coll Surg 2005; 201(1):
57–65.
111. Bilchik AJ, Poston G, Curley S, et al. Neoadjuvant chemotherapy for metastatic colon cancer: a cautionary note.
J Clin Oncol 2005; 23(36): 9073–8.
112. Pawlik TM, Choti M. Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and
postoperative outcome. J Gastrointest Surg 2007; 11(7):
860–8.
113. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol
2006; 24(13): 2065–72.
114. Kesmodel SB, Ellis LM, Lin E, et al. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery
for colorectal cancer liver metastases. J Clin Oncol 2008
26:5245-60. Epub Oct 14, 2008.
115. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapyassociated hepatotoxicity and surgery for colorectal liver
metastases. Br J Surg 2007; 94(3): 274–86.
116. Abulkhir A, Limongelli P, Healey A, et al. Preoperative portal
vein embolization for major liver resection: a meta-analysis.
Ann Surg 2008; 247(1): 49–57.
117. Covey AM, Brown K, Jarnagin W, et al. Combined portal vein
embolization and neoadjuvant chemotherapy as a treatment
strategy for resectable hepatic colorectal metastases. Ann Surg
2008; 247(3): 451–5.
118. Jaeck D, Oussoultzoglou E, Rosso E, et al. A two-stage hepatectomy procedure combined with portal vein embolization
to achieve curative resection for initially unresectable multiple and bilobar colorectal liver metastases. Ann Surg 2004;
240(6): 1037–51.
119. Madoff DC , Hicks ME, Abdalla EK, et al. Portal vein embolization with polyvinyl alcohol particles and coils in preparation for major liver resection for hepatobiliary malignancy:
safety and effectiveness–study in 26 patients. Radiology 2003;
227(1): 251–60.
120. Ravikumar TS, Kane R, Cady B, et al. A 5-year study of cryosurgery in the treatment of liver tumors. Arch Surg 1991;
126(12): 1520–3.
121. Ravikumar TS, Kan R, Cady B, et al. Hepatic cryosurgery
with intraoperative ultrasound monitoring for metastatic
colon carcinoma. Arch Surg 1987; 122(4): 403–9.
122. Ravikumar TS, Steele G, Kane R, et al. Experimental and
clinical observations on hepatic cryosurgery for colorectal
metastases. Cancer Res 1991; 51(23 Pt 1): 6323–7.
123. Yan TD, Padang R, Morris DL. Longterm results and prognostic indicators after cryotherapy and hepatic arterial
chemotherapy with or without resection for colorectal
liver metastases in 224 patients: longterm survival can be
achieved in patients with multiple bilateral liver metastases.
J Am Coll Surg 2006; 202(1): 100–11.
124. Yan TD, Padang R Xia H, et al. Management of involved
or close resection margins in 120 patients with colorectal
liver metastases: edge cryotherapy can achieve long-term
survival. Am J Surg 2006; 191(6): 735–42.
125. Rossi S, Stasi M, Buscarini E, et al. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR
Am J Roentgenol 1996; 167(3): 759–68.
indications and outcomes for treatment of recurrent rectal cancer
126. Park IJ, Kim HC, Yu CS, et al. Radiofrequency ablation for
metachronous liver metastasis from colorectal cancer after
curative surgery. Ann Surg Oncol 2008; 15(1): 227–32.
127. White RR, Avital I, Sofocleous CT, et al. Rates and patterns
of recurrence for percutaneous radiofrequency ablation and
open wedge resection for solitary colorectal liver metastasis.
J Gastrointest Surg 2007; 11(3): 256–63.
128. Kaneko H, Otsuka Y, Tsuchiay M, et al. Application of
devices for safe laparoscopic hepatectomy. HPB (Oxford)
2008; 10(4): 219–24.
129. Pai M, Jiao LR, Khorsani S, et al. Liver resection with bipolar
radiofrequency device: Habibtrade mark 4X. HPB (Oxford)
2008; 10(4): 256–60.
130. Pai M, Navarra G, Ayav A, et al. Laparoscopic Habibtrade
mark 4X: a bipolar radiofrequency device for bloodless
laparoscopic liver resection. HPB (Oxford) 2008; 10(4):
261–4.
131. Are C, Gonen M, Zazzali K, et al. The impact of margins
on outcome after hepatic resection for colorectal metastasis.
Ann Surg 2007; 246(2): 295–300.
132. de Haas RJ, Wicherts DA, Flores E, et al. R1 resection by
necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg 2008; 248(4): 626–37.
133. Cho JY, Han HS, Yoon YS, et al. Feasibility of laparoscopic
liver resection for tumors located in the posterosuperior
segments of the liver, with a special reference to overcoming current limitations on tumor location. Surgery 2008;
144(1): 32–8.
134. Cho JY, Han HS, Yoon YS, et al. Experiences of laparoscopic
liver resection including lesions in the posterosuperior segments of the liver. Surg Endosc 2008; 22(11): 2344–9.
135. Lesurtel M, Belghiti J. Open hepatic parenchymal transection using ultrasonic dissection and bipolar coagulation.
HPB (Oxford) 2008; 10(4): 265–70.
136. Rau HG, Duessel AP, Wurzbacher S. The use of water-jet
dissection in open and laparoscopic liver resection. HPB
(Oxford) 2008; 10(4): 275–80.
137. Belli G, Limongelli P, Belli A, et al. Ultrasonically activated
device for parenchymal division during open hepatectomy.
HPB (Oxford) 2008; 10(4): 234–8.
138. Gold JS, Are C, Kornprat P, et al. Increased use of parenchymal-sparing surgery for bilateral liver metastases from
colorectal cancer is associated with improved mortality
without change in oncologic outcome: trends in treatment
over time in 440 patients. Ann Surg 2008; 247(1): 109–17.
139. Fong Y. Hepatic colorectal metastasis: current surgical therapy, selection criteria for hepatectomy, and role for adjuvant
therapy. Adv Surg 2000; 34: 351–81.
140. Fong Y, Salo J. Surgical therapy of hepatic colorectal metastasis. Semin Oncol 1999; 26(5): 514–23.
141. Ahmad A, Chen SL, Bilchik AJ. Role of repeated hepatectomy in the multimodal treatment of hepatic colorectal
metastases. Arch Surg 2007; 142(6): 526–31.
142. Antoniou A, Lovegrove RE, Tilney HS, et al. Meta-analysis
of clinical outcome after first and second liver resection for
colorectal metastases. Surgery 2007; 141(1): 9–18.
143. Takahashi S, Nagai K, Saito N, et al. Multiple resections for
hepatic and pulmonary metastases of colorectal carcinoma.
Jpn J Clin Oncol 2007; 37(3): 186–92.
144. Adam R, Pascal G, Castaing D, et al. Tumor progression
while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg 2004;
240(6): 1052–61.
145. Bismuth H, Adam R, Levi F, et al. Resection of nonresectable
liver metastases from colorectal cancer after neoadjuvant
chemotherapy. Ann Surg 1996; 224(4): 509–20.
146. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin Oncol 1997; 15(3): 938–46.
147. Kattan MW, Gonen M, Jarnagin WR, et al. A nomogram for
predicting disease-specific survival after hepatic resection for
metastatic colorectal cancer. Ann Surg 2008; 247(2): 282–7.
148. Zakaria S, Donohue JH, Que FG, et al. Hepatic resection for
colorectal metastases: value for risk scoring systems? Ann
Surg 2007; 246(2): 183–91.
149. Poston GJ, Figueras J, Giuliante F, et al. Urgent need for a
new staging system in advanced colorectal cancer. J Clin
Oncol 2008; 26(29): 4828–33.
150. Blalock A. Recent Advances in Surgery. N Engl J Med 1944;
231: 261–7.
151. Girard P, Ducreux M, Baldeyrou P, et al. Surgery for lung
metastases from colorectal cancer: analysis of prognostic
factors. J Clin Oncol 1996; 14(7): 2047–53.
152. Headrick JR, Miller DL, Nagorney DM, et al. Surgical treatment of hepatic and pulmonary metastases from colon cancer. Ann Thorac Surg 2001; 71(3): 975–9.
153. Labow DM, Buell JE, Yoshida A, et al. Isolated pulmonary
recurrence after resection of colorectal hepatic metastases–
is resection indicated? Cancer J 2002; 8(4): 342–7.
154. McAfee MK, Allen MS, Trastek VF, et al. Colorectal lung
metastases: results of surgical excision. Ann Thorac Surg
1992; 53(5): 780–5.
155. Colice GL, Shafazand S, Griffin JP, et al. Physiologic evaluation of the patient with lung cancer being considered for
resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007; 132(3 Suppl):
161S–77S.
156. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung
cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;
60(3): 615–22.
157. Saito Y, Omiya H, Kohno K, et al. Pulmonary metastasectomy
for 165 patients with colorectal carcinoma: A prognostic assessment. J Thorac Cardiovasc Surg 2002; 124(5): 1007–13.
158. Irshad K, Ahmad F, Morin JE, et al. Pulmonary metastases
from colorectal cancer: 25 years of experience. Can J Surg
2001; 44(3): 217–21.
159. Hendriks JM, van Putte B, Romjin S, et al. Pneumonectomy for
lung metastases: report of ten cases. Thorac Cardiovasc Surg
2003; 51(1): 38–41.
160. Koong HN, Pastorino U, Ginsberg RJ. Is there a role for pneumonectomy in pulmonary metastases? International Registry
of Lung Metastases. Ann Thorac Surg 1999; 68(6): 2039–43.
29
Chemotherapy for colon and rectal cancer
Liliana Bordeianou and Judith L Trudel
CHALLENGING CASE
A 56-year-old man presented with a 5 cm rectal cancer. It was
located posteriorally at 8 cm from the anal verge. The preop
ultrasound suggested a T3N1 tumor. The patient received preoperative chemoradiotherapy. He had a superb clinical response
with tumor shrinkage. Six weeks after completing the therapy,
the patient underwent a low anterior resection with a diverting
loop ileostomy. The final pathology was a T1N0 with five negative
lymph nodes identified. All margins were negative. Should the
patient receive postoperative chemotherapy?
CASE MANAGEMENT
There is little data on which to base this clinical decision. Most
practioneers lean toward recommendations for postoptherapy
based on the pretreatment clinical stage if the patient receives
neoadjuvant therapy. In a good risk patient, most would recommend 6 months of postoperative adjuvant chemotherapy.
INTRODUCTION
Colorectal cancer (CRC) is the third most common cancer diagnosed in men and women in the United States. Approximately
148,810 new cases of colon and rectal cancer were reported in
2007, with an estimated 49,960 deaths attributed to it.(1) This is
higher than the number of deaths attributed to pancreatic cancer,
liver and intrahepatic bile duct cancer or esophageal cancer.
While surgery remains the mainstay of treatment for this common disease, it is the recent noteworthy changes in the indications
for chemotherapy, the timing strategy as far as chemotherapy
administration and the actual therapeutic regimens used to treat
advanced colon and rectum cancers that may provide the next step
toward the improvement in the survival rates of these patients.
CHEMOTHERAPY AGENTS OR COMBINATIONS MOST
COMMONLY USED AGAINST COLORECTAL CANCER
5-FU with Either Leucovorin or Levamisole
Since its original use in the 1950s, 5-FU remains one the oldest
chemotherapeutic agents used today to target colorectal cancer.
5-FU inhibits DNA synthesis via blockage of thymidylate synthase. At first used alone, and then in combination with levamisole, 5-FU/levamisole combination was noted to significantly
decrease recurrence rates and improve overall survival, particularly in Dukes’C patients.(2) This observation was subsequently
confirmed in a large study of 971 patients with stage III and IV
disease (intergroup 0035) which in 1990 showed that this drug
combination reduced the risk of cancer recurrence by 41% and
the overall death by 33 % in this group of patients.(3) Given
these results, this drug combination was regarded as gold standard therapy for CRC till 1996, when an even more effective regimen using 5-FU in combination with leucovorin (folinic acid)
was described.
Leucovorin is a 5-FU biomodulator. Leucovorin and 5-FU
form a stable ternary complex with thymydylate synthetase, permitting prolonged inhibition of the enzyme by 5-FU. Its applicability to stage II and stage II disease was confirmed by the
IMPACT (International Multicenter Pooled Analyses of Colon
Cancer Trials) study of 1,526 patients in 1995, which showed
that 5-FU/leucovorin increased the 3-year disease free survival
from 62% to 71% while overall survival increased from 78%
to 83%.(4) The NSAPB C-03 randomized trial of 1,081 stage
II and stage III patients comparing MOF (semustine, vincristine and 5-FU) to 5-FU/leucovorin had documented a similar
advantage of 5-FU/leucovorin, with a 3 year disease-free survival increase from 64% to 73% and an overall survival increase
from 77% to 84%.(5)
The relative merits of levamisole and leucovorin as modulators
of 5-FU-based adjuvant chemotherapy, and the optimal duration of
treatment were documented in several studies between 1998 and 2000.
The NCCTG/NCIC (National Cancer Institute of Canada) study of
915 patients compared 6 months 5-FU/leucovorin; 6 months 5-FU/
leucovorin/levamisole; 1 year 5-FU/levamisole; and 1 year 5-FU/leucovorin/levamisole.(6) Triple therapy for 6 months was as effective
as 12 months; and 6-month triple therapy provided superior 5-year
overall survival and disease-free survival compared to 5-FU/levamisole.(6) The Intergroup trial 0089 of 3,759 patients compared 1 year
5-FU/levamisole; 5-FU/high-dose leucovorin for 32 weeks; 5-FU/
low-dose leucovorin for 6 cycles; and 5-FU/low-dose leucovorin/
levamisole for 6 cycles.(7) There were no differences between the
four treatment arms with regards to 5-year disease-free and overall
survival. The NSABP CO-4 study essentially confirmed these results.
(8) The QUASAR Collaborative Group study confirmed the survival
advantage provided by leucovorin modulation over levamisole.(9)
Based on the results of these studies, the new standard for treatment
was changed to 6 months of adjuvant chemotherapy with 5-FU/
leucovorin for stage III, node-positive disease.
Until recently, this course of therapy was the standard of care for
patients with advanced colorectal cancer. However, with increasing understanding of the molecular basis of cancer and the development of biologic-based therapy, chemotherapy for CRC has
evolved once more and a variety of new agents are now available
to treat this disease.
Oxaliplatin-Containing Regimens (FOLFOX, XELOX)
Oxaliplatin inhibits DNA replication through creation of bulky DNA
adducts. It was first introduced to treat patients with recurrent or metastatic colorectal cancer that was otherwise unresectable. A study of 795
patients enrolled by Intergroup N9741 compared FOLFOX (oxaliplatin and infused fluorouracil plus leucovorin) to either IFL (irinotecan
and bolus fluorouracil plus leucovorin) or IROX (irinotecan and oxaliplatin) to show that patients treated with FOLFOX had an increased
median survival of 19.5 months (compared to 15 and 17.4 months in
chemotherapy for colon and rectal cancer
the control arms) and an increased time to progression: 8.7 months as
compared to 6.9 and 6.5 months in the two control arms.(10) Given
the improved response rates with FOLFOX in metastatic disease, the
MOSAIC trial of 2,246 patients compared this regimen to the standard 5-FU leucovorin regimen in the adjuvant setting of resected colon
cancer. After a median follow-up of 56.2 months, the 3 year diseasefree survival in the FOLFOX group was 76.4% (compared to 69.8%
observed in 5-FU/leucovorin group).(11)
On the strength of these results, FOLFOX is now the most
popular first-line therapy for the adjuvant treatment of resected
CRC and for metastatic CRC. In patients interested in avoiding
IV infusions, the combination of capecitabine and oxaliplatin
(XELOX) may be used. Capecitabine is the prodrug to 5-FU, and
is administered orally.
Irinotecan-Containing Regimens (FOLFIRI, IFL, IROX)
Irinotecan inhibits DNA replication and transcription via topoisomeraze blockade. Irinotecan has been shown to have activity
against CRC, though its effects are less pronounced than those
of oxaliplatin. IFL therapy (5-FU, leucovorin and irinotecan) has
been shown to be superior to 5FU/leucovorin therapy alone in
patients with metastatic colorectal cancer.(12) However, the N9741
Intergroup trial described above showed that patients treated with
FOLFOX had superior results to those treated with FOLFIRI (5-FU
and irinotecan), or IROX(irinotecan and oxaliplatin).(10) Based
on the results of this and other studies irinotecan containing combinations are now mostly used as second line therapy.(13)
Bevacizumab (AVASTIN®)
Bevacizumab (a monoclonal antibody that binds to the vascular
endothelial growth factor (VEGF) ligand) is one of the first biologic
therapy agents shown to be effective against CRC. Bevacizumab,
which blocks angiogenesis, was first found to improve efficacy of
FOLFOX alone in patients with metastatic disease: the median duration of survival for the group treated with FOLFOX and bevacizumab was 12.9 months compared with 10.8 months for the group
treated with FOLFOX alone.(14, 15) Additional information on the
feasibility and efficacy of bevacizumab in combination with FOLFOX
or other oxaliplatin combinations was gleaned in the TREE-2 trial,
where the percentages of patients with progressive disease decreased
substantially in all arms when bevacizumab was added.(16)
Cetuximab (ERBITUX®)
Cetuximab (a monoclonal antibody blocking epidermal growth
factor (EGFR) is currently approved only as therapy as a single
agent or in combination with irinotecan for patients with previously treated advanced colorectal cancer. A number of recently
published trials suggested that patients treated with cetuximab
have a longer time to disease progression, and this effect is augmented with addition of bevacizumab.(17)
INDICATIONS AND TIMING OF CHEMOTHERAPY FOR
COLORECTAL CANCER
Adjuvant Chemotherapy for Stage III
and Stage IV Colon Cancer
While surgical resection is the only curative treatment for localized colon cancer, the 5-year survival rates vary from 93% in
the patients with Stage I disease to 44% in patients with Stage
III disease (Table 29.1). For the patients who have undergone
potentially curative resection, disease recurrence is thought
to derive from clinically occult micrometastases. The goal of
Table 29.1 American Joint Committee on Cancer (AJCC) colon cancer staging versus survival (37).
Stage T Stage N Stage M Stage 5-year Survival
I T1
(tumor invades submucosa)
T2
(tumor invades muscularis propria)
IIA T3
(tumor invades through muscularis propria into
subserosa or nonperitonealized pericolic tissues)
IIB T4
(tumor directly invades into other organs and/or
perforates visceral peritoneum)
IIIA T1
T2
IIIB T3
T4
IIIC Any T N2
IV Any T Any N M1
N0
(no regional lymph nodes
metastasis)
N0 M0 85%
N0 M0 72%
N1
(metastasis to 1–3 regional
lymph nodes)
N1 M0 64%
(metastasis to four or more
regional lymph nodes)
M0
(no evidence of distant
metastasis)
M0 83%
M0 44%
(distant metastasis)
93%
8%
improved outcomes in colon and rectal surgery
postoperative (adjuvant) chemotherapy is to eradicate these
micrometastases.
Adjuvant chemotherapy for colon cancer has been studied for
at least 40 years. Interestingly, 5-FU monotherapy did not improve
5-year survival following curative resection.(18) However, the
discovery of modulators of 5-FU activity and of the effects of
combination regimens on survival reignited the interest in adjuvant chemotherapy. The first large-scale trial to demonstrate a survival benefit for adjuvant chemotherapy in colon cancer, National
Surgical Adjuvant Breast and Bowel project (NSABP) C-01 included
1,166 patients with Dukes’ B or C colon cancer.(19) The patients
randomized to adjuvant MOF chemotherapy instead of surgery
alone had significant improvement in their 5-year overall survival.
These improvements became even more pronounced as advances
in chemotherapy described earlier and postoperative (adjuvant)
systemic therapy has become routine and standard for node positive or metastatic disease. Clinical data indicates that access to a
multidrug regimen consisting of two or more of the agents discussed earlier (in addition to 5-FU therapy) has almost doubled
median survival in the patients with advanced colorectal cancer
from 10–12 months to more than 20 months.
Adjuvant Chemotherapy for Stage II Colon Cancer
In contrast to the clear benefit of adjuvant chemotherapy for patients
with node-positive disease, its role in resected stage II colon cancer
remains controversial. While a number of clinical trials have included
stage II patients and have suggested a benefit from adjuvant therapy,
none of these have reached statistical significance. Several metaanalyses have been performed to evaluate this question further. An
NSABP analysis of the data pooled from the adjuvant C-01, C-02,
C-03 and C-04 trials of 3,820 patients (1,556 with T3N0 disease)
suggested that the relative reduction in recurrence and mortality
from adjuvant therapy for patients with resected T3N0 colon cancer
was comparable to that seen in patients with node-positive disease.
(20) In contrast, a 2004 systematic review by the Ontario Cancer
Care Program did not find a statistically significant improvement in
survival in the T3N0 patients treated with at least one 5-FU chemotherapy regimen after surgery.(21) In hopes of settling this debate, a
panel of the American Society of Clinical Oncology reviewed all the
pertinent information in regards to this issue.(22) This panel concluded that routine use of adjuvant chemotherapy for medically fit
patients with stage II colon cancer is not recommended.
Parenthetically, the panel also felt that selected patients with
stage II disease—such as patients with inadequately sampled
nodes, T4 lesions, perforation, or poorly differentiated histology—could still be considered for adjuvant therapy.(22, 23) The
identification of patients with stage II colon cancer who might
benefit from adjuvant chemotherapy is an area of ongoing
research. The prognostic value of additional molecular markers,
such as microsatellite instability and loss of 18Q allele is being
investigated. (http://cancer.gov).
Neoadjuvant Chemoradiotherapy for T3
or Node-Positive Rectal Cancer
The management of rectal cancer is radically different from the
management of colon cancer. While recommendations for adjuvant postoperative therapy for advanced colon cancer are based
on the pathological stage revealed by the surgical specimen, rectal
cancer staging determines initial management. This, after much
debate, is based on conclusive evidence that has clearly shown neoadjuvant preoperative therapy to improve local control, diseasefree survival, and overall survival compared to surgery alone or
to postoperative adjuvant therapy.
The Swedish Rectal Cancer Trial examined whether neoadjuvant preoperative radiation therapy was of benefit to patients
with advanced rectal cancer. The study randomly assigned 1,168
patients to receive or not receive radiation therapy prior to surgery. After 5 years, preoperative radiation therapy was associated
with significant improvements in both local control (89% vs.
73%) and overall survival (58% vs. 48%).(24)
The German Rectal Cancer Trial examined whether radiation
is more beneficial before or after surgery. The study randomly
assigned 823 patients with clinically staged T3/T4 or node-positive
rectal cancer to either neoadjuvant or adjuvant chemoradiotherapy.
With a 46 month median follow-up, preoperative chemoradiotherapy was associated with a significantly lower local recurrence rate
(6% vs. 13%), though the 5-year disease-free and overall survival
rates were similar.(25) These two studies made preoperative radiotherapy for advanced rectal cancer the standard of care.
At least two randomized trials have directly assessed the potential benefits of concurrent chemotherapy with neoadjuvant radiotherapy. A European trial randomly assigned 762 patients with
T3/4 rectal cancer within reach of the digital rectal exam to either
preoperative radiotherapy alone or preoperative chemoradiotherapy. At a median 69 month follow-up, the combined modality
group had lower local recurrence rates (8.1% vs. 16.5 %), but the
rate of sphincter preservation surgery and 5-year overall survival
rates were similar.(26) Another study, EORTC 22921 showed a
similar benefit with chemoradiotherapy enhancing local control
in comparison to radiotherapy alone.(27)
Based on these studies, neoadjuvant chemoradiotherapy is
generally considered in all patients with T3 N0 and node positive
tumors of any T stage. Stage of the disease determines the need
for neoadjuvant therapy. Because of this, the importance of pretreatment staging of rectal tumors becomes paramount and cannot be overemphasized. The standard of care now dictates that
all patients with rectal cancer should undergo a staging endorectal ultrasound or pelvic MRI to determine initial management.
Tumors penetrating into perirectal fat and/or lymph nodes should
undergo neoadjuvant chemoradiotherapy. Tumors that do not
penetrate through muscularis propria (T1-2, N0) are candidates
for initial surgical resection. If the final pathological stage confirms the stage suspected on imaging, no further chemotherapy
(and/or radiation) is indicated. However, if the final pathology
reveals penetration into perirectal fat or into the lymph nodes,
postoperative chemoradiotherapy is indicated.
Adjuvant Chemotherapy Alone for T3
or Node-Positive Rectal Cancer
The benefit of 5-FU based postoperative chemotherapy in patients
undergoing chemoradiotherapy has not been studied in prospective randomized trials. However, in EORTC trial 22921, patients
who had received preoperative radiotherapy with or without
chemotherapy were then further randomized to postoperative
2
chemotherapy for colon and rectal cancer
chemotherapy versus no further therapy.(27) In the entire group,
there were trends favoring adjuvant chemotherapy in both 5-year
progression free survival (58% vs. 52%), and overall survival
(67% vs. 63%), but the trends were not statistically significant,
Nevertheless, these results are frequently quoted as justification of
adjuvant chemotherapy for patients treated with or without preoperative chemoradiotherapy. Further information of the benefits of
postoperative chemotherapy are expected from the multicentre
British CHRONICLE trial.(28)
SIDE EFFECTS OF CHEMOTHERAPY
The benefits of modern chemotherapy with regards to its ability to delay disease progression and improve survival in patients
with advanced colon and rectal cancer are unquestionable.
Nonetheless, these benefits should be balanced against individual
patient tolerance to the side effects of chemotherapy (Table 29.2),
as this may impact therapeutic effectiveness. The elderly and the
medically compromised patients represent a group at particular
risk. Very few elderly patients or patients with renal/hepatic failure or other major comorbidities have been enrolled in clinical
trials; the choices of therapeutic regimens in these subgroups
should be tailored to individual patients.
5-FU/leucovorin alone is fairly well tolerated, and the
most commonly described side effects are those of diarrhea,
Table 29.2 Side Effects and Mechanism of Action of Commonly
Used Chemotherapeutic Agents
Chemotherapy
Agent
5-FU Inhibits DNA synthesis via
Oxaliplatin Inhibits DNA replication
Irinotecan Inhibits DNA replication
Bevacizumab
(Avastin®)
Cetuximab
(Erbitux®)
Mechanism of Action
blockage of thymidylate
synthase
through creation of
bulky DNA adducts
and transcription via
topoisomeraze blockade
A monoclonal antibody
that binds to the vascular
endothelial growth factor
(VEGF) ligand and
inhibits tumor blood
supply growth
A monoclonal antibody
that blocks epidermal
growth factor (EGFR)
and decreases tumor
growth
Common Side-Effects
Heartburn, nausea, vomiting,
anorexia, stomatitis,
esophagitis, diarrhea,
myelosuppression, cardiac
toxicity
Peripheral neuropathy,
anemia,
thrombocytopenia,
neutropenia, nausea,
diarrhea, vomiting,
abdominal pain, fatigue
Alopecia, diarrhea,
nausea, emesis, severe
myelosupression, colitis,
gastrointestinal ulceration,
gastrointestinal bleeding,
ileus
Alopecia, thrombosis,
bleeding, hyperkalemia,
hypertension, abdominal
pain, anorexia, vomiting,
diarrhea, neutropenia,
delayed wound healing
and wound dehiscence,
bowel perforation
Fatigue, confusion, pruritis,
insomnia, abdominal
pain, nausea, vomiting,
diarrhea,weakness, lung
disease, dyspepsia
stomatitis, vomiting and nasea. These side effects become much
more pronounced when mutidrug chemotherapy regimens are
used. For example, addition of oxaliplatin to 5-FU, which is the
most common first line chemotherapy regimen currently used in
the US to treat colorectal cancer (FOLFOX), leads to an increased
rate of diarrhea, nausea and vomiting, as well as alopecia. In
addition, the rates of significant neutropenia become relatively
high. One of the clinically relevant side effect of oxaliplatin-based
chemotherapy is a late-onset predominantly sensory neuropathy
with may require drug discontinuation despite ongoing tumor
response. Ultimately, more than 50 percent of patients receiving
FOLFOX discontinue treatment for reasons other than disease
progression.(29)
Multidrug combinations adding irinotecan, or bevacizumab to
the standard 5-FU can cause serious toxic events, mainly severe
hematological toxicity, diarrhea, thrombotic events, and neurosensory disorders.(30) The 5-FU, leucovorin, irinotecan, plus
bevacuzimab regimen especially, while having the highest probability of improving survival, might also lead to significant adverse
effects to as many as 84.9% of patients, including a 1.5% chance
of gastrointestinal perforation.(30)
While these side effects are temporary in patients undergoing adjuvant treatment for nonmetastatic disease, their effect on
quality of life becomes quite important when the treatments are
continuous and indefinite, as is the current practice in the patients
with metastatic disease. One potential way of reducing treatmentrelated side effects in this cohort is via a “chemotherapy holiday”,
but the impact of a completely chemo-free interval on long term
survival is of significant concern. Two European phase II trials,
OPTIMOX1 (which compared continuous FOLFOX versus maintenance chemotherapy with 5-FU/leucovorin) and OPTIMOX2
(which compared maintenance chemotherapy using a nonoxaliplatin regimen versus a totally chemotherapy free interval) were
designed to address some of these concerns.(31, 32) Their results
unfortunately suggested that a full break in therapy resulted in a
decrease in overall survival and that some form of maintenance
treatment is preferable to chemotherapy-free intervals.
FUTURE DIRECTIONS
One of the major drawbacks of the current chemotherapy regimens
for colorectal cancer is our inability to identify before treatment
which patient will respond to a particular combination of
chemotherapy drugs. Knowledge of tumor gene expression and
other biomarkers will hopefully provide clues and inroads in this
direction. Microarray profiling of gene expression in colorectal
cancer patients has already been shown to stratify risk and predict
lymph node involvement.(33) Just like in patients with breast
cancer, patients with CRC might soon be screened in a prospective
fashion to determine those with stage III disease that are unlikely to
recur or those who may be resistant to a particular drug regimen.
A promising area for colorectal cancer treatment is immunotherapy. The goal of cancer immmunotherapy is to stimulate the
body’s immune system in order to improve host defense mechanisms against growing tumors, through either cell mediated or
humoral immunity pathways. Over 25 different vaccines, virusmodified tumor cells, gene-modified tumor cells, tumor-antigen
derived peptides, tumor lysates, proteins or carbohydrates have
improved outcomes in colon and rectal surgery
been studied in Phase I and II studies. Three large studies looking at the immune stimulation with autologous irradiated tumor
vaccine plus BCG in colorectal cancer patients suggest that this
approach may have merits. For example, one study randomized 98
patients with colon or rectal cancer treated surgically to vaccination
with autologous irradiated tumor plus BCG versus placebo. While
the study did not find a significant difference in the outcomes
between the two arms, a subset analysis of the colon cancer patients
did show an improvement in disease-free survival.(34) Similarly,
Eastern Cooperative Oncology Group (ECOG) randomized stage
II and II colon cancer patients to surgery alone versus surgery and
vaccine and found that patients with a marked delayed cutaneous
hypersensitivity response had a trend toward better disease-free
and overall survival.(35) Finally a study of 244 patients with colon
cancer randomized to receive a postoperative vaccine showed that
the overall risk for recurrence was decreased by 44% in all vaccinated patients, with a 61% reduction in stage II patients.(36)
CONCLUSION
In the past 20 years, advances in the adjuvant treatment of colon
and rectal cancer have significantly increased the rates of diseasefree and overall survival, increased survival rates in metastatic
disease, and decreased the rates of recurrence. Ongoing research
focuses on developing more potent chemotherapeutic agents and
on identifying patients who may best benefit from those advances.
REFERENCES
1. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA
Cancer J Clin 2008; 58(2): 71–96.
2. 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(10): 1447–56.
3. Moertel CG, Fleming TR, Macdonald JS et al. Levamisole
and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322(6): 352–8.
4. Efficacy of adjuvant fluorouracil and folinic acid in colon
cancer. International Multicentre Pooled Analysis of
Colon Cancer Trials (IMPACT) investigators. Lancet 1995;
345(8955): 939–44.
5. Wolmark N, Rockette H, Fisher B et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant
therapy for primary colon cancer: results from National
Surgical Adjuvant Breast and Bowel Project protocol C-03.
J Clin Oncol 1993; 11(10): 1879–87.
6. 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(1): 295–300.
7. Haller DG, Catalano PJ, Macdonald JS et al. Phase III study
of fluorouracil, leucovorin, and levamisole in high-risk stage
II and III colon cancer: final report of Intergroup 0089. J Clin
Oncol 2005; 23(34): 8671–8.
8. 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 C-04. J Clin Oncol 1999; 17(11): 3553–9.
9. Comparison of flourouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for
colorectal cancer: a randomised trial. QUASAR Collaborative
Group. Lancet 2000; 355(9215): 1588–96.
10. Goldberg RM, Sargent DJ, Morton RF et al. A randomized
controlled trial of fluorouracil plus leucovorin, irinotecan, and
oxaliplatin combinations in patients with previously untreated
metastatic colorectal cancer. J Clin Oncol 2004; 22(1): 23–30.
11. Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin,
fluorouracil, and leucovorin as adjuvant treatment for colon
cancer. N Engl J Med 2004; 350(23): 2343–51.
12. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil
and leucovorin for metastatic colorectal cancer. Irinotecan
Study Group. N Engl J Med. 2000; 343(13): 905–14.
13. Hriesik C, Ramanathan RK, Hughes SJ. Update for surgeons:
recent and noteworthy changes in therapeutic regimens for
cancer of the colon and rectum. J Am Coll Surg 2007; 205(3):
468–478.
14. Giantonio BJ, Levy DE, O’Dwyer PJ et al. A phase II study
of high-dose bevacizumab in combination with irinotecan,
5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology
Group study E2200. Ann Oncol 2006; 17(9): 1399–403.
15. Giantonio BJ, Catalano PJ, Meropol NJ et al. Bevacizumab in
combination with oxaliplatin, fluorouracil, and leucovorin
(FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group
Study E3200. J Clin Oncol 2007; 25(12): 1539–44.
16. Hochster HS. Bevacizumab in combination with chemotherapy: first-line treatment of patients with metastatic colorectal cancer. Semin Oncol 2006; 33(5 Suppl 10): S8–14.
17. Saltz LB, Lenz HJ, Kindler HL et al. Randomized phase II
trial of cetuximab, bevacizumab, and irinotecan compared
with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 2007;
25(29): 4557–61.
18. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC. Adjuvant
therapy of colorectal cancer. Why we still don’t know. JAMA
1988; 259(24): 3571–78.
19. Smith RE, Colangelo L, Wieand HS, Begovic M, Wolmark N.
Randomized trial of adjuvant therapy in colon carcinoma:
10-year results of NSABP protocol C-01. J Natl Cancer Inst
2004; 96(15): 1128–32.
20. 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 Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 1999; 17(5):
1349–55.
21. Figueredo A, Charette ML, Maroun J, Brouwers MC, Zuraw
L. Adjuvant therapy for stage II colon cancer: a systematic
review from the Cancer Care Ontario Program in evidencebased care’s gastrointestinal cancer disease site group. J Clin
Oncol 2004; 22(16): 3395–407.
chemotherapy for colon and rectal cancer
22. Benson AB 3rd, Schrag D, Somerfield MR et al. American
Society of clinical oncology recommendations on adjuvant
chemotherapy for stage II colon cancer. J Clin Oncol 2004;
22(16): 3408–19.
23. Andre T, Sargent D, Tabernero J et al. Current issues in adju-Current issues in adjuvant treatment of stage II colon cancer. Ann Surg Oncol
2006; 13(6): 887–98.
24. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med
1997; 336(14): 980–7.
25. Sauer R, Becker H, Hohenberger W et al. Preoperative versus
postoperative chemoradiotherapy for rectal cancer. N Engl J
Med 2004; 351(17): 1731–40.
26. Gerard JP, Conroy T, Bonnetain F et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin
Oncol 2006; 24(28): 4620–5.
27. Bosset JF, Calais G, Mineur L et al. Enhanced tumorocidal
effect of chemotherapy with preoperative radiotherapy for
rectal cancer: preliminary results–EORTC 22921. J Clin Oncol
2005; 23(24): 5620–7.
28. Glynne-Jones R, Meadows H, Wood W. Chemotherapy or
no chemotherapy in clear margins after neoadjuvant chemoradiation in locally advanced rectal cancer: CHRONICLE.
A randomised phase III trial of control vs. capecitabine
plus oxaliplatin. Clin Oncol (R Coll Radiol) 2007; 19(5):
327–9.
29. Seymour MT, Maughan TS, Ledermann JA et al. Different
strategies of sequential and combination chemotherapy for
patients with poor prognosis advanced colorectal cancer
(MRC FOCUS): a randomised controlled trial. Lancet 2007;
370(9582): 143–52.
30. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab
plus irinotecan, fluorouracil, and leucovorin for metastatic
colorectal cancer. N Engl J Med 2004; 350(23): 2335–42.
31. Tournigand C, Cervantes A, Figer A et al. OPTIMOX1: a ran-OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin
in a stop-and-Go fashion in advanced colorectal cancer–a
GERCOR study. J Clin Oncol 2006; 24(3): 394–400.
32. Andre T, Tournigand C, Mineur L et al. Phase II study of an
optimized 5-fluorouracil-oxaliplatin strategy (OPTIMOX2)
with celecoxib in metastatic colorectal cancer: a GERCOR
study. Ann Oncol 2007; 18(1): 77–81.
33. Croner RS, Peters A, Brueckl WM et al. Microarray versus
conventional prediction of lymph node metastasis in colorectal carcinoma. Cancer 2005; 104(2): 395–404.
34. Hoover HC Jr, Brandhorst JS, Peters LC et al. Adjuvant active
specific immunotherapy for human colorectal cancer: 6.5year median follow-up of a phase III prospectively randomized trial. J Clin Oncol 1993; 11(3): 390–9.
35. Harris JE, Ryan L, Hoover HC Jr. et al. Adjuvant active spe-Adjuvant active specific immunotherapy for stage II and III colon cancer with an
autologous tumor cell vaccine: Eastern Cooperative Oncology
Group Study E5283. J Clin Oncol 2000; 18(1): 148–57.
36. Vermorken JB, Claessen AM, van Tinteren H et al. Active spe-Active specific immunotherapy for stage II and stage III human colon
cancer: a randomised trial. Lancet 1999; 353(9150): 345–50.
37. O’Connell JB, Maggard MA, Ko CY. Colon cancer survival
rates with the new American Joint Committee on Cancer sixth
edition staging. J Natl Cancer Inst 2004; 96(19): 1420–5.
Radiation therapy: Acute and late toxicity
Roland Hawkins
CHALLENGING CASE
A 62-year-old man presents with blood per rectum. He has mild
rectal discomfort with bowel movements and a feeling of incomplete evacuation. Two years previously he received external beam
radiotherapy for prostate cancer. His rectal examination is normal
except for some blood on the gloved finger. A flexible sigmoidoscopy demonstrates friable mucosa with neovascularity of the
distal 4 cm of rectum. The mucosa is friable with telangectasia.
CHALLENGING CASE MANAGEMENT
The history and endoscopic exam is suggestive of radiation proctitis.
Management includes fiber and topical therapy. The friable areas of
the rectum can be treated with topical application of a large swab
soaked with 10% formalin passed through an anoscope or proctoscope. Argon plasma coagulation is also effective treatment.
INTRODUCTION
Apart from a few exceptional circumstances, radiation treatment
is used as an adjunct to surgical resection in the potentially curative treatment of adenocarcinoma of the rectum. As such, it is
employed to reduce the tumor burden and eradicate deposits of
cancer in pelvic lymph nodes and soft tissue not removed, or not
expected to be removed, by the surgeon. In this setting, radiation
treatment is administered either before or following en bloc resection of the involved length of large bowel by low anterior (LAR) or
abdominal perineal resection (APR) that is intended to remove all
evident disease, i.e., to be an R0 resection. Preoperative treatment
is referred to as neoadjuvant or adjuvant, and postoperative treatment as adjuvant. These are usually administered to patients with
locally advanced but resectable stage II or III disease (Table 30.1).
Less often adjuvant radiation treatment is administered following
local excision of less advanced disease. Local excision is elected in
patients with small distal rectal tumors to avoid APR or LAR.
Recurrence after apparently curative surgery for rectal cancer
may develop in structures adjacent to the margin of resection or
regional nodes in the pelvis (local recurrence), or as metastasis
to the peritoneal surface or distant organs (distant recurrence).
Treatment with radiation and/or chemotherapy added to surgery is judged as beneficial in so far as it increases overall patient
survival and reduces the incidence of local and distant recurrence. Overall survival is the most important outcome in judging
benefit. It is unambiguously evaluable and reflects the balance of
benefit and potentially lethal adverse effects of treatment. Local
recurrence is not often salvagable. Its prevention is important, if
not a requirement, for achieving cure of the disease. It may itself
be life threatening and may act as a source of distant metastasis.
Further, uncontrolled recurrence in the pelvis is particularly detrimental to the quality of life of patients who are not cured by
the treatment by causing pain, bleeding, infection, obstruction
and incontinence affecting bowel and urogenital organs. Distant
recurrence is important because it is the most unsalvageable life
threatening form of treatment failure.
Evolution of the method of radiation treatment over the past
30 years has produced what are now two more or less standard
regimens, referred to here as the short and long treatment courses.
The short course has been used only for preoperative treatment.
It typically consists of a dose of 25 Gy in fractions of 5 Gy each
over a period of 5 to 7 days with surgery following within a week.
The long course has been used for both pre and postoperative
treatment. It typically consists of 45 to 54 Gy in fractions of 1.8
to 2 Gy over a period of 5 to 6 weeks. When used preoperatively
the long course is usually followed by about 6 weeks rest before
surgery and may include concurrent chemotherapy.
There are several ways to compare the intensity of radiation
treatment courses that differ in fractionation of dose and are
given over different time intervals. One in current use consists of
calculating a biologically equivalent dose (BED) for each treatment course using the relation: (1)
d
g
BED = nd 1 +
a/b
-
(T - Tk)
a
Table 30.1 Staging of rectal carcinoma.
Dukes TNM Group
A I T1N0M0
B II T3N0M0
C III N1 or N2, any T N1 (1 to 3 nodes +), N2 (>3
D IV M1, any T or N Distant metastasis
TNM (AJCC
and UICC)
T2N0M0
T4N0M0
Description
Tumor limited to submucosa,
Tumor into, not through,
muscularis propria
Tumor through muscularis
propria
Tumor invades other organs or
through peritoneal serosa.
nodes +)
Wherein n is the number of fractions, d is the dose per fraction,
a/b
is a ratio characteristic of cell type or tissue and ranging
from about 2 to 20 or more. For meta-analysis overview of the
effect of radiation in the treatment of rectal cancer
assumed to be about 10.(2, 3) The value of the
a/b
has been
g/a
ratio corrects
for the repopulation of cells during the length of the treatment
course and has been assumed to be 0.6 Gy per day. The value of
T is the time from first to last radiation fraction in days and Tk is
a lag time taken to be 7 days. With these parameters the BED of
the short course of 5 fractions of 5 Gy each is 37.5 Gy and that of
a long course consisting of 50.4 Gy in 28 fractions of 1.8 Gy each
is 40.9 Gy, implying they are roughly equivalent. The validity of
equation 1 in establishing equivalency with respect to the chance
radiation therapy: acute and late toxicity
of eliminating pelvic cancer or causing any specific organ injury
is dependent on the appropriateness to the specific endpoint in
question and of the values chosen for
a/b, g/a
and Tk.
The physiologic death, disintegration, and disappearance of
nearly all cells lethally injured by radiation takes place only after
they and/or their descendents go through one or more, often
aberrant, mitotic cell divisions. An exception to this is some lymphocyte subsets that die within hours of irradiation. As a result
there is a time lag between irradiation and response of a cancer
that is variable and dependent on the mitotic activity of the cancer cells. This lag ranges from a few days up to a year or more
for the various carcinomas. A typical time to manifest the maximal response of a carcinoma to radiation is the order of a month
or two. The same phenomenon is in part responsible for delay
of up to a year or more in the development of some forms of
radiation injury. With short course preoperative radiation there
is little time for tumor response before surgery. There is evidence
that at surgery after short course irradiation the average tumor
size and average number of nodes with metastatic carcinoma has
decreased slightly but this is not sufficient to produce a change in
the distribution of tumor or nodal stage in a study population.(4)
With long course preoperative irradiation more time is allowed
for response of the disease and down staging to occur. This is
evident in some of the trials listed in tables 30.3 and 30.4 and was
demonstrated in a trial in which all patients were treated with 13
daily fractions of 3 Gy each and randomly assigned to surgery
within 2 weeks after the end of radiation or surgery 6 to 8 weeks
after radiation.(5)
With both the long and short course, radiation treatment is
directed at the pelvis with the superior border placed at about
the L5S1 interspace. The inferior border is placed at least 3 to 5
cm below the most distal extent of tumor or below the obdurator foramen. For distal tumors it may include all or part of the
anal canal. In earlier studies treatment was restricted to anteriorposterior directed beams.(6) More recently, laterally directed
beams that exclude bowel in the anterior part of the pelvis are a
standard part of treatment plans. Only the volume in which the
beams overlap is exposed to the full prescribed dose. This usually
includes, in addition to the rectum, small and large bowel in the
posterior pelvis, the posterior part of bladder and prostate, the
soft tissue in the ischiorectal fossa and presacral areas, the sacrum and the lymph nodes of the internal iliac and most distal
part of the common iliac chains. If there is extension of tumor to
invade urogenital organs the external iliac nodes are sometimes
included. After APR, the perineal incision, which tends to be a site
of recurrence, is included in the treatment volume.(7, 8)
Tables 30.2, 30.3 and 30.4 summarize several trials in which randomization was between arms composed of various combinations
of pre and postoperative radiation and chemotherapy.(9–26) The
radiation treatment plans in each are similar to either the short or
long course described above and can be gleaned from the table by
noting the dose shown. When the dose is about 25 Gy it is a short
course and when 40 to 60 Gy it is similar to the long course. The
benefits and adverse effects of preoperative and postoperative radiation treatment reported in these studies will be examined and compared. Adjuvant treatment after local excision is also discussed.
BENEFIT OF ADJUVANT AND NEOADJUVANT
RADIATION TREATMENT
Several randomized trials of postoperative adjuvant therapy in
the late 1970s and 1980s listed in Table 30.2 indicate that postoperative radiation and chemotherapy can lead to statistically
Table 30.2 Postoperative adjuvant radiation studies.
Study Open/Closed
GITSG (9) 202 S
NCCTG (10)
794751
NSABP (11)
R-01
11/77 to 10/86
Norway (12, 13) 144 S
NSABP (14)
R-02
Retrospective
Study of Trans
anal excision (15)
MGH/Emory
RTOG 8902 (16) 65
S indicates LAR or APR, LE is local excision, C is chemotherapy. A dose in Gy indicates irradiation. The dash line shows time sequence.
Number
of Pts. Therapy Arms
S–C
S–44Gy
S–44Gy-C
204 S–50.4Gy
S–50.4Gy+C
555 S
S–46Gy
S–C
S–46Gy+C
694 S–C
S–50.4Gy+C
99 LE (T1)
LE–xrt (T1)
LE–(T2)
LE–xrt (T2)
LE (T1, fav)
LE-xrt (T1,2,3)
Local (Pelvic)
Recurrence % at 5 years
24
27
20
11
25
13 (p = 0.036)
25
16 (p = 0.06)
21.4
30
12 (p = 0.01)
14
8 (p = 0.02)
11
0.0
67
15 (p = 0.004)
14.3
17.6
Overall Survival
% at 5 years
46
56
52
59 (p = 0.07)
47
57 (p = 0.02)
43
41
53 (p = 0.01)
50
64 (p = 0.05)
58
58
86
72
Comments
T3,T4 or N+
Semustine and 5Fu
Semustine and 5Fu.
Semustine, 5Fu, vincristine
Bolus 5Fu on 6 days during
radiation
Semustine, 5Fu, vincristine
in 10 week cycles or 5Fu
and leukovorin in 8 week
cycles.
Concurrent chemotherapy
for some patients
fav = favorable features, see
text.
Соседние файлы в папке Библиотека им академика М.И. Перельмана