Journal Club:

Comparison Of IMRT and 3DCRT

as Adjuvant Therapy for Gastric

Cancer

Yuriko Minn, Annie Hsu et al.

Cancer, 15Aug.2010. 116:3943-3952

Radiation Oncology

Dr BRAIRCH, AIIMS

Moderator : Prof. BK MohantiPresenter : Dr Akhilesh Mishra

Sites of Origin And Histologies

• Antrum and Distal Stomach: ~ 40%

• Body: ~ 25%

• Proximal Stomach and GE Jn. : ~ 35%

• Adenocarcinomas : 90-95%

• Lymphomas (Usually with Unfavourable Histologies) : 4-5%

• Leiomyosarcomas : ~2%

• Rest : Carcinoids, Adenocanthomas, SCCs.

General Anatomy

Japanese Surgical Staging for Ca. Stomach

• S0 No serosal invasion

• S1 Suspected serosal invasion

• S2 Defi nite serosal invasion

• S3 Adjacent organ involvement

• N1 Perigastric lymph nodes

• N2 Lymph nodes around the left gastric artery, common

• hepatic artery, splenic artery, and celiac axis

• N3 Lymph nodes in the hepatoduodenal ligament, posterior

• aspect of pancreas, and root of mesentery

• N4 Periaortic and middle colic lymph nodes

• P0 No peritoneal metastases

• P1 Adjacent peritoneal involvement

• P2 A few scattered metastases to distant peritoneum

• P3 Many distant peritoneal metastases

• H0 No liver metastases

• H1 Metastases limited to one lobe

• H2 A few bilateral metastases

• H3 Numerous bilateral metastases

• STAGE GROUPING

• Stage I S0, N0, P0, H0

• Stage II S1, N0-1, P0, H0

• Stage III S2, N0-2, P0, H0

• Stage IV S3, N3-4, P1-3, H1-3

Prognostic Factors

• Stage is the most important prognostic factor

• Regional nodal involvement adversely affects the prognosis. The number and locations of the affected lymph nodes are both significant.

• According to the Japanese Classification of gastric cancer, numbers of positive level II nodes have more influence on the prognosis.

• The prognosis of proximal cancers is less favorable.

• Diffuse type pathology cases are associated with worse treatment results compared with intestinal type

• No biologic markers routinely utilized.

Genetic Alterations Associated With

Worse Prognosis

• Aneuploidy

• Presence of viral genome (H. pylori)

• Telomerase Reactivation

• P53 gene Inactivation

• Dysfunction of repair genes Hmsh3 & Hmlh1

• Overexpression: Her2Neu, bcl2, c-met, k-sam

• Oestrogenic Receptor Expression

• CD44 Expression

Ca. Stomach: General Guidelines • Surgery – primary curative treatment modality

– Proximal stomach total gastrectomy– Distal stomach distal radical gastrectomy

• Nodal DissectionD2

• Avoid splenectomy if possible.

• Consider placing feeding jejunostomy-tube.

• Aim for 5 cm proximal and distal margins whenever possible.

• Remove minimum of 15 LNs.

Chemo & Radiotherapy used mainly in Adjuvant setting for stage II and onwards

• Indications of adjuvant therapy– Margin positive– Gross residual disease – Transmural infiltration – Serosal involvement– Regional node positivity

Surgery: Important Points

• D1 dissection: removes involved proximal or distal or entire stomach, including the greater and lesser omental LN.

• D2 dissection: Also removes the omentalbursa, the front leaf of the transverse mesocolon, and the corresponding arteries are completely cleared, including the portal, celiac, and splenic LN.

• Sites of LF after surgery: Gastric bed ~50%, LN ~40%, anastomosis or stumps ~25%,

ADJUVANT THERAPY

4 wks

Curative resection (R0)

C1 5FUFA

Inj LV-20 mg/m2 IV D1-D5

Inj FU-425 mg/m2 IV D1-D5

EBRT-45 Gy/25#/5 wks

C2-C3 5FUFA with RT (D1-D4; D23-D25)

Inj LV-20 mg/m2 IV bolus

Inj FU-400 mg/m2 IV bolus*

C4-C5 5FUFA q 4wk

Inj LV-20 mg/m2 IV D1-D5

Inj FU-425 mg/m2 IV D1-D5

4 wks

-Macdonald etal. NEJM 2001; 345: 725-30.

* IRCH modification:1)C2-3 5FUFA-

Inj FU-375mgm2 IV bolus2)EBRT by 3D-CRT instead of

conventional RT

INOPERABLE/METASTATIC GASTRIC

CANCER

• LAGC (inoperable)

– NACT 2-3 cycles (CDDP+ Capecitabine) f/b

assessment for surgery

• Palliative –

– Radiotherapy30Gy/10#/2wks (rarely used)

– Chemotherapy5FUFA / capecitabine+ CDDP

– Surgeryfeeding procedure/ gastric bypass surgery

• Best supportive care

Level and Extent of Surgery

• The Dutch and UK-MRC trials compared D1 versus D2 dissection: No signifi cant differences in 5-year survival but higher postoperative mortality and morbidity rates in the D2 dissection (Bonenkamp et al. 1999; Hartgrink et al. 2004; Cuschieri et al. 1999).

• Wu et al. 2006 ,Taipei: the overall 5-year survival significantly improved in patients receiving D3 surgery than D1.

• The Japanese Research Society for Gastric Cancer (JRSGC) considered surgery without D2 dissection inadequate (Kajitani 1981).

Level and Extent of Surgery

• Japan, which reported a hospital mortality rate of

in D2 suegery:0.8% :JCOG 95-01;Sasako et al.

2006; Sano et al. 2004.

• Italian study similar results on postoperative

mortality:Degiuli et al. 2004.

• Spleenectomy is not routinely recommended.

• Spleen and pancreas-preserving

lymphadenectomies are becoming more popular

(Fenoglio-Preiser et al. 1996).

Latest in Surgery

• Endoscopic mucosal dissection (EMR) has been

increasingly used in selected patients with early

stage gastric cancer. Indications for EMR include :

• Tumor size < 3 cm,

• Absence of ulceration,

• Well differentiated histology,

• Absence of lymph node metastasis,

• And no evidence of invasive findings

(Ono et al. 2001; Hiki et al. 1995; Noda et al.

1997).

Areas Included In Radiation Field

• Based On the likely sites of Locoregional Failure ,

the following are included in Radiation Field:

• Gastric / Tumour Bed

• Anastomosis and Gastric Remnant

• Nodal Chains at lesser and greater curvatures

• Celiac Axis, PancreatoDuodenal, Splenic nodes

• SupraPancreatic, Porta Hepatis

• GastroDuodenal & ParaAortic upto level of L3

Conventional Radiation Portal:IRCH

• Upper Border - The bottom of T8 or T9 to cover celiac axis ,GE Jn fundus and dome of Left hemidiaphragm.

• Lower Border - The Bottom of L3 vertebra for Gastro-Duodenal nodes.

• Left Border- 2/3 to 3/4 of Left Hemidiaphragm for Fundus with Supra-Pancreatic and Splenic nodes.

• Right Border – 3-4 cms lateral to vertebral bodies for Antrum with Porta-Hepatis & Gastro-Duodenal nodes.

• 3DCRT is the preferred modality currently.

3DCRT in Ca. Stomach

Radiation Oncology , IRCH

3DCRT in Ca. Stomach

Radiation Oncology , IRCH

Abstract

• The current study was performed to compare the clinical outcomes and toxicity in patients treated with post-operative chemo-radiotherapy for gastric cancer using intensity-modulated radiotherapy (IMRT) versus 3-dimensional conformal radiotherapy (3D CRT).

• From December 1998 to June 2008, 61 patients with non-metastatic gastric or gastroesophageal (GE) junction cancer were treated with postoperative radiotherapy at Stanford University. Two patients treated with IMRT and 2 patients treated with 3D CRT who did not complete their radiation course were excluded, leaving 57 patients for this analysis.

Methods

• Fifty-seven patients with gastric or gastroesophageal

junction cancer were treated postoperatively: 26 with

3D CRT and 31 with IMRT.

• Earlier patients were treated with 3D CRT; however,

there was a gradual shift of practice toward IMRT

beginning in 2002.

• Concurrent chemotherapy was capecitabine (n = 31),

5-fluorouracil (5-FU) (n = 25), or none (n = 1).

• The median radiation dose was 45 Gy. Dose volume

histogram parameters for kidney and liver were

compared between treatment groups

Methods• For the bowel, the intestinal loops outside the

planning treatment volume (PTV) were contoured, not the whole abdominal space. To account for daily setup error and organ motion, the CTV to PTV expansion was typically 5 to 10 mm. Normal structures were also contoured, including kidneys, liver, spinal cord, and bowel.

• Patients were treated with either a 3 or 4-field technique to 43.2 to 50.4 Gy (median, 45 Gy), 5 days a week.

• The PTV received a median dose of 45Gy(range, 41.4-54 Gy) with a median fraction size of 1.8 Gy(range, 1.8-2.08 Gy).

Methods• Although the median doses were similar between

the treatment groups, more patients received >45 Gy in the IMRT group than in the 3DCRT group (10 vs 2, respectively).

• For the 12 patients who received>45 Gy, the additional 5 to 9 Gy were given a sequential conedown or simultaneous integrated boost.

• Six patients with positive margins and 2 patients with close margins received >45 Gy.

• Twenty-three patients treated with IMRT were treated with respiratory gating while all other patients were treated with free breathing. Beam energies used included 6MV, 10 MV, 15 MV, or a mix of 6 and 15 MV.

Methods

• Dose constraint guidelines used for IMRT planning

included:

• 75% of the liver<15 Gy; mean liver dose<20Gy;

• 70% of each kidney<15 Gy or 2/3 of 1 kidney <18

Gy;

• 95% of the bowel <45Gy.Max dose to the

bowel<54Gy. The bowel space was contoured.

• The spinal cord dose was limited to 45 Gy.

• The IMRT plans were normalized to 95% volume to

get 100% of the dose.

Methods

• All patients underwent routine systemic workup and disease evaluation that included history and physical examination, routine laboratory studies,CT of the chest and abdomen, and esophagogastroduodenoscopywith biopsy.

• Fifty-three patients (93%) received chemotherapy that was FU-based (5-fluorouracil [5-FU] or capecitabine) with or without Carboplatin before the start of radiotherapy, the latter regimen being part of an institutional protocol.

Methods

• The majority of patients received 2 cycles

before radiation. Patients received concurrent

chemotherapy with capecitabine (n ¼ 31), 5-

FU (n ¼ 25), or none (n ¼ 1).

• After the completion of radiotherapy, 45

patients (79%) received 1 to 2 cycles of the

same chemotherapy that was given before

radiation, as directed by their medical

oncologists

RESULTS

RESULTS

RESULTS

RESULTS

Results• The 2-year overall survival rates for 3D CRT versus IMRT were

51% and 65%, respectively (P = .5)

• Four locoregional failures occurred each in the 3D CRT (15%) and

the IMRT (13%) patients

• Median OS & DFS from initiation of RT:5.4 & 4.7 Yrs

respectively

• The 2 Yrs DFS for 3DCRT & IMRT: 60% & 54% respectively

(P=0.8)

• The 2 Yrs Local Control Rates for 3DCRT & IMRT: 83% &

81%(P=0.9) respectively

• The median volume receiving 42.75 Gy (95% of 45Gy) for

3DCRT versus IMRT: 1606ml versus 1282.6ml

respectively(P=0.048)

Results• Grade ≥2 acute gastrointestinal toxicity was found to

be similar between the 3D CRT and IMRT patients (61.5% vs 61.2%, respectively) but more treatment breaks were needed (3 vs 0, respectively)

• Grade ≥2 acute haematological toxicity was found to be 35% in 3D CRT and 29% of IMRT patients respectively

• Grade 3 late toxicity in 3DCRT arm in 3 patients versus 1 in IMRT arm

• 49 Patients had > 6 months F/U.

• A total of 17 patients developed distant metastases,the median time to distant metastases:8.7 months(range 3.9-21.6 months)

Results• The median serum creatinine from before radiotherapy

to most recent creatinine was unchanged in the IMRT group (0.80 mg/dL) but increased in the 3D CRT group from 0.80 mg/dL to 1.0 mg/dL (P = .02)

• The median kidney mean dose was higher in the IMRT versus the 3D CRT group (13.9 Gy vs 11.1 Gy; P = .05). The median kidney V20 was lower for the IMRT versus the 3D CRT group (17.5% vs 22%; P = .17)

• The median liver mean dose for IMRT and 3D CRT was 13.6 Gy and 18.6 Gy, respectively (P = .19). The median liver V30 was 16.1% and 28%, respectively (P < .001)

Discussion

• Although the data are not consistent in

demonstrating an advantage of IMRT over 3D CRT,

there may be some gains in acute toxicities with the

use of IMRT because of generally decreased dose to

normal organs such as bowel, kidney, and liver.

• In addition, IMRT may allow for dose escalation in

the hopes to improve disease control, especially in

cases such as close/positive margins, extranodal

disease spread, or other situations believed to have a

high risk of residual microscopic disease, without

increasing the dose to critical structures.

Discussion

• Adjuvant chemoradiotherapy was well tolerated

with either 3D CRT or IMRT, with similar acute

and late toxicities reported.

• The incorporation of image guidance likely

confers additional improvements.

• Further investigation is required to determine the

true clinical benefit of IMRT for this disease, and

we believe it is highly warranted given the

generally poor outcomes of this disease and the

high rate of treatment morbidity.

Discussion• Despite higher doses used, IMRT provides

sparing to the liver and possibly the kidneys

• Although the dosimetric advantage of IMRT

for the kidneys was not consistent, renal

function appears to be preserved better

• These results need to be validated with longer

follow-up as well as in larger studies

Conclusion• LRC is good with adjuvant

chemoradiotherapy but overall outcomes

for Ca. Stomach remains poor.

Improvement in both systemic & local t/t

is required

• Adjuvant chemoradiotherapy was well

tolerated with either 3D CRT or IMRT,

with similar acute and late toxicities

reported

Conclusion

• The differences in clinical outcomes

were not statistically significant in

3DCRT versus IMRT

• IMRT was found to provide sparing

to the liver and possibly renal

function.

• (Cancer 2010;116:3943–52. VC

2010 American Cancer Society)

REFERENCES AND LANDMARK

TRIALS

• Moertel et al (1969) first time demonstrated

the clinical benefit of combining 5FU to

Radiation in locally advanced unresectable

Ca. Stomach.

• INT0116/-SWOG 9008 (Macdonald et al.

2001, 2004, 2009)

• UK-MRC MAGIC Trial 2006 NEJM.

• Japanese S-1 Trial 2007 NEJM.

• Boige et al. 2007 ASCO

Other Major References

• ECOG-CALGB 80101 Trial,2002-2009

• Ringash J, et al.2005. IJROBP

• Wieland P, et al.2004. IJROBP

• Smalley,Gunderson.2002.IJROBP

• Tepper & Gunderson.2002.SRO

• Boda-Heggemann, Hofheinz et al.

2009.IJROBP

• RTOG 9904 Trial

Other Major References

• Milano et al. 2006.BJR

• Chung et al. 2008.IJROBP

• Alani et al. 2009.IJROBP

• Leong T et al.Radiother Oncol 2005

• van der Geld YG et al.IJROBP 2007

• de la Torre et al. Med. Dosim. 2004

• ICRU-62(supplement to ICRU Report 50)1999

• ICRU-83,VOL-10,No.1,2010

THANKS