CHEMORADIOTHERAPY AFTER SURGERY COMPARED WITH SURGERY ALONEFOR ADENOCARCINOMA OF THE STOMACH OR GASTROESOPHAGEAL JUNCTIONJOHN S. MACDONALD, M.D., STEPHEN R. SMALLEY, M.D.,JACQUELINE BENEDETTI, PHD et.al.N Engl J Med, Vol. 345, No. 10 · September 6, 2001 Presenter: Adhikari Abish. (firstname.lastname@example.org) Resident, Radiation Oncology Moderator: Karn A, MD
Cancer. 1978 Mar;41(3):941-7.Adenocarcinoma of the stomach: review of 1,497 cases. Dupont JB Jr, Lee JR, Burton GR, Cohn I Jr.“The five-year survival rate was 7.4% overall, and 5.4% survived ten years or more after the diagnosis of gastric cancer.”
Cancer. 1987 Jun 15;59(12):2006-10. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Gastrointestinal Tumor Study Group. "Median survival in the group randomized to control was 10.9months, compared with 21.0 months for those randomized to treatment."
J Clin Oncol. 1993 Aug;11(8):1441-7.Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. Hermans J, Bonenkamp JJ, Boon MC, Bunt AM, Ohyama S, Sasako M, Van de Velde CJ “11 trials were included with 2,096 patients. They indicate that postoperativechemotherapy in general offers no additional survival benefit for patients with curatively resected gastric cancer.”
~In the Gastrointestinal Tumor Study Group (GITSG)study, 142 patients were randomized to receive adjuvantchemotherapy of semustine (methyl CCNU) and5-fluorouracil (5-FU) or to be followed with no further treatment aftercurative-intent resection.~Mitomycin was used in some European/Japanese trials.~ The International Collaborative Cancer Group conducted arandomized study in 315 gastric cancer patients after curativeresection. Patients were randomized to receive either a combinationof 5-FU, doxorubicin, and mitomycin (FAM) or no treatment.~ A different study of doxorubicin randomized 125 patients who hadundergone potential curative resection to treatment with 5-FUplus doxorubicin or to observation alone.
Int J Radiat Oncol Biol Phys. 1998 Dec 1;42(5):929-34. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia- a report on 370 patients. Zhang ZX, Gu XZ, Yin WB, Huang GJ, Zhang DW, Zhang RG.“The 5- and 10-year survival rates of the R+S Group and the S Alone Group were 30.10% and 19.75%, 20.26% and 13.30%,respectively. Preoperative radiation therapy is able to improve the results of surgery for adenocarcinoma of the gastric cardia.”
Lancet. 1969 Oct 25;2(7626):865-7 "Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer." Moertel CG, et alMedian OS RT alone 6.3 months vs. chemo-RT 10.4 months; 1-year OS 6% vs. 22% Concurrent chemo-RT significantly better.
Background• The curative treatment of stomach cancer requires gastric resection.• However, most patients are not cured by this surgery.• The high rate of relapse after resection makes it important to consider adjuvant treatment for patients with stomach cancer.• However, adjuvant chemotherapy has not resulted in higher survival rates than surgery alone.
Background• Local or regional recurrence in the tumor bed, the anastomosis, or regional lymph nodes occurs in 40 to 65 percent of patients after gastric resection with curative intent.• A phase 3 trial found clinically limited but statistically significant improvement in survival after preoperative regional radiotherapy in patients with cancer of the gastric cardia.
Methods• The trial was initiated in 1991 to compare surgery followed by fluorouracil plus irradiation of the gastric bed and regional lymph nodes with surgery alone.
Eligibility• Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction• Complete resection of the neoplasm (free margins)• A performance status of 2 or lower according to the criteria of the Southwest Oncology Group• Adequate function of major organs.• A caloric intake greater than 1500 kcal per day• Written Consent taken
Treatment Plan• After undergoing gastrectomy, patients were randomly assigned to surgery alone or to the postoperative combination of fluorouracil plus leucovorin and local–regional radiation.• Randomization was performed 20 to 40 days after surgery by means of a dynamic balancing procedure that included stratification according to the tumor stage and the nodal status.
Chemotherapy: – 5-FU 425mg/m2/day & Leucovorin 20mg/m2/day for 5 days28 days later 1.Radiotherapy 45Gy/25# at 1.8Gy/day, 5days/wk for five weeks with: – 5-FU 400mg/m2/day & Leucovorin 20mg/m2/day for first 4 days and last 3 days of RTOne month after the completion of radiotherapy5. 5-FU 425mg/m2/day & Leucovorin, 20mg/m2/day for5 days.(2 cycles are given one month apart)
Radiotherapy4500cGy/25 fractions, to the tumor bed, to theregional nodes, and 2 cm beyond the proximal anddistal margins of resection.The tumor bed was defined by preoperative CT,Barium study.Perigastric, celiac, local paraaortic, splenic,hepatoduodenal or hepatic-portal, andpancreaticoduodenal lymph nodes were includedin the radiation fields.
~ the residual stomach is also a radiation-sensitive organ; thus,adjuvant radiation may result in significant ulceration and bleeding.Acute side effects including nausea, fatigue, and weight loss mayoccur when the upper abdomen is irradiated, which may makepostoperative treatment difficult in a recovering patient.~A survival advantage of a single dose of intraoperative radiation (20to 25 Gy) after resection for patients with stages II, III, and IVdisease (gross residual disease without metastases) was reported byJapanese researchers. But done without proper randomization.
Follow-upFollow-up of both groups occurred at three-monthintervals for two years, then at six-month intervalsfor three years, and yearly thereafter.Follow-up consisted of physical examination, CBC,LFT, CXR and CT scanning as clinically indicated.The site and date of the first relapse and the dateof death, if the patient died, were recorded.
603 Registered 47 556 Randomized ineligible275 Surgery only 281 Surgery+ ChemoRadiotherapy Cessation of Treatment 181 Complete Rx
Results: Surgery• Registered between 1st Aug 91 to 15th July 98• The only surgery-related eligibility were resection with curative intent and en bloc and with negative margins.• Extensive (D2) lymph-node dissection was recommended. ( All perigastric lymph nodes and some celiac, splenic or splenic-hilar, hepatic artery, and cardial lymph nodes, depending on the location of the tumor in the stomach.)
Results: Surgery• Only 54 (10%) had acutally undergone a formal D2 dissection.• A D1 dissection (removal of all invaded [N1] lymph nodes) had been performed in 199 patients (36 percent)• Most patients (54%) had undergone a D0 dissection, which is less than a complete dissection of the N1 nodes• 94 percent of the patients were ambulatory or asymptomatic after surgery.
In D1 dissections, only the perigastric nodes directlyattached along the lesser curvature and greatercurvatures of the stomach are removed (stations 1-6,N1 level).An incomplete N1 dissection is labelled a D0lymphadenectomy.D2 dissections (N2 level) add the removal of nodesalong the left gastric artery (station 7), common hepaticartery (station 8), celiac trunk (station 9), splenic hilus,and splenic artery (station 10 and 11).D3 dissections include the dissection of lymph nodesat stations 12 through 14, along the hepatoduodenalligament and the root of the mesentery (N3 level).D4 resections add the stations 15 and 16 in theparaaortic and the paracolic region (N4 level).
Results: Toxicity CTC: Common Toxicity Criteria / ECOGCriteria 0 1 2 3 4Leukopenia >4000 >3000 >2000 >1000 <1000Granulocytes >2000 >1500 >1000 >500 <500Diarrhoea As PreRx Increase by Increase by Increase by >7/day Intensive Care <4/day 4-6/day or Incontinence or needed/ or Night Stools needs parentral Haemodynamic support CollapseNausea None Able to eat Oral Intake No Significant Oral - significantly Intake, IV needed decreasedVomiting None 1/day 2-5/day >6/day or requiring Requiring IV fluids Parentral nutrition/ Intensive care
Results: Toxicity • The most common hematologic toxic effect was leukopenia. • GI toxic effects included nausea, vomiting & diarrhea. • Deaths were due to: o Pulmonary fibrosis o Cardiac event o Sepsis (myelosupression)
Survival• The median duration of survival was 36 months in the chemoradiotherapy group and 27 months in the surgery only group. (p=0.005)• The three-year survival rates were 50% in the chemoradiotherapy group and 41% in the surgery-only group.• The median duration of relapse-free survival was 30 months in the chemoradiotherapy group and 19 months in the surgery-only group. (P<0.001)• The hazard ratio for relapse:1.52 (64% vs 43%)
Hazard Ratio“In survival analysis, the hazard ratio (HR) is theratio of the hazard rates corresponding to theconditions described by two sets of explanatoryvariables. For example, in a drug study, the treatedpopulation may die at twice the rate per unit timeas the control population. The hazard ratio wouldbe 2, indicating higher hazard of death from thetreatment. Or in another study, men receiving thesame treatment may suffer a certain complicationten times more frequently per unit time thanwomen, a hazard ratio of 10”
Discussion“In patients with rectal carcinoma, adenocarcinomaof the pancreas and incompletely resectedstomach cancer, postoperative regional radiationplus chemotherapy reduces the risk of relapse andprolongs survival.”“The frequent occurrence of local and regionalrelapses after resection for gastric cancer providedthe rationale for our evaluation.”
Discussion“Results demonstrate that chemo-radiotherapyafter resection for gastric cancer significantlyimproves relapse-free and overall survival amongsuch patients.”“An extensive (D2) lymph-node dissection wasrecommended, but only 10% had undergoneproper D2 dissection.”“ ..no phase 3 trial to date has demonstrated asurvival benefit resulting from D2 nodal resection.”