Ludzkie koronawirusy - autor: Krzysztof Pyrć z Zakładu Mikrobiologii, Wydział Biochemii, Biofizyki i Biotechnologii, Uniwersytet Jagielloński, Kraków

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© Borgis - Postępy Nauk Medycznych 2/2011, s. 131-136
*Krzysztof G. Jeziorski
Rak żołądka
Gastric cancer
Department of Digestive Tract Cancers, Centre of Oncology – M. Skłodowska-Curie Memorial Institute, Warsaw, Poland
Head of Department: prof. dr hab. med. Zbigniew Nowecki
Streszczenie
Wyniki leczenia raka żołądka są niezadowalające. Zwiększenie zakresu limfadenektomii nie prowadzi do poprawy wyników. Poprawy wyników leczenia poszukuje się w leczeniu okołooperacyjnym, tj. kojarzeniu leczenia chirurgicznego z radioterapią, chemioterapią lub chemioradioterapią. Ze względu na znaczną toksyczność leczenia, jak również brak dobrze przeprowadzonych badań III fazy, przedoperacyjna chemioradioterapia raka żołądka nadal pozostaje metodą eksperymentalną, natomiast przedoperacyjna chemioterapia na podstawie badań MAGIC i FFCD rekomendowana jest jako standard postępowania w Wielkiej Brytanii i większości pozostałych krajów europejskich. W odróżnieniu od przedoperacyjnej chemioradioterapii, uzupełniająca chemioradioterapia uznawana jest za standard postępowania w Stanach Zjednoczonych Ameryki i niektórych krajach europejskich. W leczeniu rozsianej choroby nowotworowej trastuzumab w skojarzeniu z chemioterapią stanowi nową opcję terapeutyczna u chorych, u których stwierdzono w komórkach guza nadekspresję HER2.
Summary
Gastric cancer stall remains a common and highly fatal disease. Despite potentially curative resection of stomach cancer, majority of patients die of disease relapse. Randomized study in the Western world failed to show improvement in survival with extended lymph node dissection (D2 lymphadenectomy). The high recuurence rate makes gastric cancer a disease difficult to cure by surgery alone. In order to improve the survival different perioperative modalities are assessed. Results from the randomized phase III MAGIC trial and French FFCD trial support the idea of preoperative chemotherapy. Neoadjuvant 5-fluorouracil/cisplatin based chemotherapy is now a standard of care in many European countries for locally advanced gastric cancer. Neoadjuvant chamoradiation still remains experimental. As against neoadjuvant chemoradiation, adjuvant chemoradiation is considered to be a standard therapy in the USA and some European countries. Trastuzumab is recommended in patients diagnosed with metastatic cancer of the stomach and of gastro-esophageal junction who did not earlier receive anti-cancer therapy due to disseminated disease and whose tumor cells show HER2 overexpression.
Although most countries around the world report decreased incidence of gastric cancer (i.e. tumors located distally to the gastroesophageal junction), the disease continues to pose a significant epidemiological problem in Poland. Gastric cancer incidence and mortality rates in Poland among both men and women remain at similar levels (in 2007, standardized incidence and mortality ratios in men were 12.8/100,000 and 13.11/100,000, respectively, and in women 4.87/100,000 and 4.87/100,000, respectively), which makes the incidence and mortality ratio oscillate around 1, and in the population of women it is exactly equal to 1(1). This indicates ineffectiveness of treatment and poor prognosis for patients with this disease. Five-year survival rates are highly unsatisfactory.
In Poland, the relative 5-year survival rates in male and female populations are 14.9% and 18.2%, respectively, and 16.1% for both populations combined (2). These results are worse than in other European countries. The mean 5-year survival in women and men estimated for patients diagnosed between 2000 and 2002 in Europe based on the EUROCARE-4 study is 23.4% (1).
The reasons behind poor treatment results include: a high postoperative local or nodal recurrence rate of 30-87%, a high postoperative metastasis rate of 20-66%, limited effectiveness of earlier treatments, limited knowledge of molecular biology of gastric cancer. The WHO classification distinguishes the following types of gastric cancer: a high-, moderate-, and low-grade adenocarcinoma with its two subtypes: tubular and papillary, mucinous carcinoma, squamous carcinoma; adenosquamous carcinoma, poorly differentiated carcinoma, mucocellular carcinoma and nondifferentiated carcinoma.
The most recent staging classification of gastric cancer (7th edition) published by the International Union Against Cancer has introduced changes to the T and N descriptors (3).
Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria
T1 Tumor invades lamina propria, muscularis mucosae or submucosa
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures
T4 Tumor invades serosa (visceral peritoneum) or adjacent structures
T4a Tumor invades serosa (visceral peritoneum)
T4b Tumor invades adjacent structures
Regional Lymph Nodes (N)
NX Regional lymph node(s) cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1-2 regional lymph nodes
N2 Metastasis in 3-6 regional lymph nodes
N3 Metastasis in seven or more regional lymph nodes
N3a Metastasis in 7-15 regional lymph nodes
N3b Metastasis in 16 or more regional lymph nodes
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Histologic Grade (G)
GX Grade cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated
G4 Undifferentiated
Anatomic stage/Prognostic groups
StagePrimary Tumor (T)Regional Lymph Nodes (N)Distant Metastasis (M)
0TisN0M0
IA
IB
T1
T2
T1
N0
N0
N1
M0
M0
M0
IIA


IIB


T3
T2
T1
T4a
T3
T2
T1
N0
N1
N2
N0
N1
N2
N3
M0
M0
M0
M0
M0
M0
M0
IIIA


IIIB


IIIC
T4a
T3
T2
T4b
T4a
T3
T4a
T4b
N1
N2
N3
N0, N1
N2
N3
N3
N2,N3
M0
M0
M0
M0
M0
M0
M0
M0
IVAnyAny NM1
The main treatment for gastric cancer patients remains to be surgery, the extent of which depends on the clinical stage and location of the disease. Depending on tumor location, total or subtotal gastrectomy is performed. D2 lymphadenectomy (removal of D1 lymph nodes: located along the lesser and greater gastric curvatures plus the celiac-axis, the common hepatic artery, the splenic artery, the splenic hilum, the left hepatic artery) and a minimum of 25 lymph nodes in the sample is the established standard of treatment.
Theoretically, improvement in gastric cancer treatment results should be sought via improving surgical treatment results or using adjuvant or neoadjuvant treatment. Unfortunately, increasing the extent of lymphadenectomy from D1 to D2 does not result in an increased 5-year survival rate in operated patients. Moreover, D2 lymphadenectomy is associated with a higher rate of complications and postoperative deaths. Therefore, seeking the options for improving treatment results in perioperative treatments seems to be rational.
Neoadjuvant treatment in gastric cancer
Studies on neoadjuvant treatment include both radiotherapy and chemotherapy, as well as both of these methods combined – chemoradiotherapy.
Neoadjuvant radiotherapy
A randomized study evaluating the effectiveness of neoadjuvant radiotherapy in comparison with surgical treatment alone by Zhang et al. showed a 10% increase in 5-year survival rate in the group receiving preoperative radiotherapy in comparison with the group who underwent surgical treatment only. The 5-year survival rates were 30 and 20%, respectively (4). Moreover, the group receiving radiotherapy showed a decrease in local recurrence rate.
In a randomized study by Skoropad et al., a group of 152 patients underwent surgical treatment preceded by 20 Gy radiotherapy or surgical treatment alone. After a 20-year follow-up the authors did not detect any difference in survival between the two study groups (5).
Neoadjuvant chemotherapy
The first results of randomized studies on the role of neoadjuvant chemotherapy have been discouraging. A Dutch study comparing survival rates between two groups of patients who either received 4 preoperative courses of FAMTX chemotherapy (5-fluorouracil, doxorubicin and methotrexate) or were treated with surgery alone found increased median survival (30 months) among patients who underwent only a surgical procedure, compared to the group of patients receiving combined therapy (18 months) (6). Moreover, the resectability rates were similar in both study groups. What is noteworthy is that the study was performed in a small patient population (59 patients). A Japanese study evaluating the effectiveness of neoadjuvant chemotherapy with the UFT (tegafur + uracil) regimen revealed a beneficial effect of chemotherapy on improving survival, but only in patients with stage II and stage III disease (7). Based on a result analysis of 4 studies, Wu et al. revealed a lack of effect of neoadjuvant chemotherapy on survival (8).
The first randomized clinical study that proved the effectiveness of preoperative chemotherapy in patients with gastric cancer was the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) study comparing perioperative treatment (3 courses of preoperative ECF (epirubicin, 5-FU, cisplatin) chemotherapy and 3 courses of postoperative chemotherapy with the same regimen) in combination with surgery with surgical treatment alone. The group of patients receiving preoperative chemotherapy showed a 13% increase in overall 5-year survival. The 5-year survival rates in the group receiving combination treatment and in the group treated only surgically were 36 and 23%, respectively (9). The MAGIC study has been criticized for inadequate patient qualification for neoadjuvant treatment. Neither the peritoneal fluid cytology nor the endoscopic ultrasound (EUS) was routinely performed.
Another randomized study on the role of preoperative chemotherapy, albeit published only in the form of a summary, is the Fédération Francophone de la Cancérologie Digestive (FFCD) study (10). This study randomized patients to receive either surgical treatment preceded by chemotherapy with cisplatin and 5-fluorouracil or surgical treatment as the sole treatment method. The group of patients receiving combination therapy was found to have a higher proportion of R0 resections than the group treated with surgery only. This proportion in the two groups was 84% and 73%, respectively. Also, the overall 5-year survival rate was higher in the group receiving combination treatment. The 5-year survival rates in the two groups were 38 and 24%, respectively.
Due to significant treatment toxicity, as well as a lack of well-conducted phase III studies, neoadjuvant chemoradiotherapy in gastric cancer patients remains an experimental method, however, based on the results of MAGIC and FFCD studies, preoperative chemotherapy is recommended as a standard procedure in the UK and in most of the other European countries (11).
Adjuvant radiotherapy
Adjuvant radiotherapy in gastric cancer patients includes the use of intraoperative radiotherapy (IORT) and teleradiotherapy.
IORT allows:
? improvement of the therapeutic index
? reduction of the irradiated area
? protection of normal radiation-sensitive structures
? an increase in therapeutic dose
As far as adjuvant therapy in gastric cancer is concerned, IORT causes a decrease in the risk of local recurrences by approximately 50%, however, there is no effect on patient survival. Moreover, IORT is associated with a high rate of vascular toxicity (3-12%).
A study by Hallisey et al. evaluating three treatment methods; surgery, surgery in combination with postoperative chemotherapy, and surgery in combination with postoperative radiotherapy did not show superiority of any of these methods in improving survival, nonetheless adjuvant radiotherapy showed an over two-fold decrease in the local recurrence rate in comparison with surgery alone (12).
Adjuvant chemotherapy

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Piśmiennictwo
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2. Wojciechowska U, Didkowska J, Zatoński W: Wskaźniki przeżyć chorych na nowotwory złośliwe w Polsce w latach 2000-2002. Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie. Warszawa 2009.
3. Sobin L, Gospodarowicz M, Wittekind C: UICC TNM Klasyfikacja nowotworów złośliwych. Wyd. 7. Via Medica 2010; 58-61.
4. Zhang ZX, Gu XZ, Yin WB et al.: Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC) – report on 370 patients. Int J Radiat Oncol Biol Phys 1998; 42: 929-934.
5. Skoropad V, Berdov B, Zagrebin V: Concentrated preoperative radiotherapy for resectable gastric cancer: 20-years follow-up of a randomized trial. J Surg Oncol 2002; 80: 72-78.
6. Hartgrink HH, van de Velde CJ, Putter H et al.: Neo-adjuvant chemotherapy for operable gastric cancer: long term results of the Dutch randomised FAMTX trial. Eur J Surg Oncol 2004; 30: 643-649.
7. Nio Y, Koike M, Omori H et al.: A randomized consent design trial of neoadjuvant chemotherapy with tegafur plus uracil (UFT) for gastric cancer – a single institute study. Anticancer Res 2004; 24: 1879-1887.
8. Wu AW, Xu GW, Wang HY et al.: Neoadjuvant chemotherapy versus none for respectable gastric cancer. Cochrane Database Syst Rev 2007; (4): CD005047.
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12. Hallisey MT, Dunn JA, Ward LC et al.: The second British Stomach Cancer Group Trial of adjuvant radiotherapy or chemotherapy in respectable gastric cancer: five-year follow-up. Lancet 1994; 343: 1309-1312.
13. Fujimoto S, Akao T, Itoh B et al.: Protracted oral chemotherapy with fluorinated pyrimidines as an adjuvant to surgical treatment for stomach cancer. Ann Surg 1977; 185: 462-466.
14. Nakajima T, Fukami A, Ohashi I et al.: Long-term follow-up study of gastric cancer patients treated with surgery and adjuvant chemotherapy with mitomycin C. Int J Clin Pharmacol Biopharm 1978; 16: 209-216.
15. Nakajima T, Kinoshita T, Nashimoto A et al.: Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer. Br J Surg 2007; 94: 1468-1476.
16. Sakuramoto S, Sasako M, Yamaguchi T et al.: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007; 357: 1810-1820.
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19. Van Cutsem E, Kang Y, Chung L et al.: Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. J Clin Oncol 2009;27 (June suppl.), No 18S, abstract LBA 4509.
20. Bang YJ, VanCutsem E, Feyereislova A et al.: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet 2010; 376 (9742): 687-697.
otrzymano: 2010-12-21
zaakceptowano do druku: 2011-01-10

Adres do korespondencji:
*Krzysztof G. Jeziorski
Klinika Nowotworów Układu Pokarmowego
Centrum Onkologii – Instytut im. M. Skłodowskiej-Curie w Warszawie
ul. Roentgena 5, 02-781 Warszawa
e-mail: krzysztof.jeziorski@wp.pl

Postępy Nauk Medycznych 2/2011
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