Management of carcinoma esophagus DR BHARTI DEVNANI

MODERATOR:- DR ANJALI K. PAHUJA

Localised disease Metastasis

Definitive therapy Palliative therapy

Diagnostic workupo

rk

up

. At the time of diagnosis, approximately 80% patients have locally advanced or distant disease

EVOLUTION OF TREATMENT

Non surgical treatment Radiation therapy alone Combined modality therapy(CT+RT) Intensification of the radiation dose

Surgical treatmentSx aloneSx+adjuvantPreop CT + Sx

RT ALONE

6

RADIATION ALONE

AUTHOR NO OF PTS DOSE 2 YRS SURVIVAL

5 YRS SURVIVAL

Pearson 208 50Gy/4Wks NA 17%

Beatty et al 344 >40Gy to > 50Gy

21% 0%

Schuchmann et al

127 <45Gy>45 Gy

0%0%

Newaishy et al

444 50-55Gy/4 Wks

19% 9%

Okawa et al 96 NR 9%(I-20%,II-10%,III-3%,IV-0%)

Lederman et al

263 11%(yrs) 7%

COMBINED MODALITY TREATMENT (CT+RT V/S RT ALONE)

RTOG 85-01 TRIAL(RT ALONE V/S CMT)

RANDOMISE

Wk 1

50Gy/25 fractions

Wk 5 Wk 11

CDDP 75mg/m2 Day 1 and 5-FU 1gm/m2 C.I. day 1- 4

CT+RT

RT

Wk 8

64Gy/32 fractions

RESULTS OF RTOG 85-01 TRIALComp-liance

Gr III toxicity

Gr IV Gr V Localfailure

Distfailure

Median and 5yr survival

CT+RT (n=61)

54% 44% 20% 3% 43% 22% 12.5 mo, 27%

RT (n=60)

83% 25% 3% 0 64% 38% 8.9 mo, 0%

P-value

Sig Sig Sig Sig Sig Sigp<0.0001

All patients who received RT alone were dead of disease by 3 years. Established chemoradiation as the conventional nonsurgical treatment for esophageal cancer

Herskovic A et al. NEJM 1992;326:1593-1598

10

CONCURRENT CT+RT- META ANALYSIS OF 11RCT

Cochrane Database of Systematic Reviews

RESULTS OF METANALYSIS

Concomitant RTCT provided significant reduction in mortality with a HR of 0.73.

The absolute survival benefit for RTCT at 1yr and 2 yr was 9%and 4% respectively.

There was an absolute reduction of local recurrence rate of 12%

INTENSIFICATION OF RADIATION DOSE (BY BRACHYTHERAPY BOOST)

The cumulative incidence of fistula was 18%/year and the crude incidence was 14%.

Esophageal fistulas were treatment-related rather than tumor-related of the six treatment-related fistulas, three were fatal .

Occurred in the region of the brachytherapy.

Five of the six patients developing fistulas received 15 Gy brachytherapy dose. (median-3.9 months)

The other patient received just one fraction of 5 Gy and developed a fistula within 0.5 months.

HIGH DOSE V/S STANDARD RADIATION DOSE

17

RANDOMISE

Wk 1

50.4Gy/28 fractions

Wk 5 Wk 13

CDDP 75mg/m2 Day 1 and 5-FU 1gm/m2 C.I. day 1- 4

StandardCT+RT

CT + High dose RT

Wk 9

64.8Gy/36 fractions

Wk 1 Wk 5 Wk 11 Wk 15

Minsky BD et al. JCO 2002;20:1167-1174

No significant difference in survival(p=NS)

MS-18 v/s 13 months2 yr survival—40% v/s 31%

No significant difference in time to first failure(52% v/s 56%)

(local /regional failure or locoregional persistance of

cancer)

This trial demonstrated that for patients who receive concurrent chemotherapy with radiation, higher doses of radiation therapy do not offer a local/regional control or survival advantage.

PREOPERATIVE CHEMORADIATION THERAPY

20

PRE OP.CT+RT+S VS S

AUTHOR MEDIAN FOLLOW UP

REGIMEN NO OF PTS

Ro resection/Dist Met

PATH CR LOCOREG FAILURE

3-Yr Survival

SURVIVAL DIFF

Urba et al

8.2 5fu+cddp+Vbl+RT+SS

50

50

90 60%90 65%

28-

19%42%P=0.02

30

16

p=0.15

Boset et al

4.6 Cddp+RT+SS

143138

81 69

26---

3436

NS

Walsh et al

1.5 5fu+cddp+RT+SS

58

58

NR NR

25 32

6

P+0.01

Burmeister et al

5.4 5fu+cddp+RT+SS

128

128

80 59

16

---

35

30

NS

Tepper et al

6.0 5fu+cddp+RT+SS

30

26

NRNR

33 13

15

39

16

P=0.008

9 RCT 1116 patients

Three-year survival (odds ratio 0.66, 95% confidence interval 0.47to 0.92; P 0.016).

Rate of complete resection (odds ratio 0.53, 95% confidence interval0.33 to 0.84; P 0.007).

Compared with surgery alone, neoadjuvant chemoradiation and surgery

Improved 3-year survival

Reduced local-regional cancer recurrence.

Higher rate of complete (R0) resection.

Pathological complete response in 21% patients

Survival benefit was most pronounced when CT+RT were given concurrently instead of sequentially

Lancet Oncol 2011; 12: 681–92

Provides strong evidence for a survival benefit of neoadjuvantchemoradiotherapy or chemotherapy over surgery alone in patients with oesophageal carcinoma. clear advantage ofneoadjuvant chemoradiotherapy over neoadjuvant chemotherapy has not been established.

CAN SURGERY BE AVOIDED

46 Gy20 Gy

In patients with locally advanced thoracic esophageal cancers, especially epidermoid, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation.

chemoradiation alone entailed fewer early deaths and a shorter hospital stay

More locoregional relapses. Because clinical prognostic factors donot help in

choosing between both strategies, further studies comparing surgery and chemoradiation should search for newpredictive factors and evaluate new tools to detect early responders.

PET scan was reported to discriminate responders from nonresponders as early as 14 days after starting chemoradiation and should be re-evaluated in future studies.

The study suggests that there is no difference in clinical toxicity profiles or survival outcomes with either definitive chemoradiotherapy or chemoradiation followed by surgery in management of locally advanced esophageal cancer.

Future studies are necessary to investigate dose escalation of chemoradiotherapy, thereby reducing the risk of treatment failures in patients treated without surgery.

RADIATION

The design and delivery of radiation therapy for esophageal cancer requires a knowledge of the –

Natural history of the disease Patterns of failure Anatomy, Radiobiologic principles. Use of proper equipment Implementation of methods to decrease

treatment-related toxicity Close collaboration with the physics and

technology staff are essential. As radiation oncology is both an art and a

science.

RADIOTHERAPY

CurativeDose-50.4 Gy/28# Conventional Conformal 3 D CRT IMRT IGRT Arc Respiratory gating Proton

Palliative

EBRTDose-30 Gy/10#

Brachytherapy12 Gy/#18 Gy/3#

TECHNIQUES OF RADIATION THERAPY

External beam radiotherapy Important considerations for RT

Nearby vital structures: spinal cord. lungs, heart Movement in target tissue and vital structures: lungs,

heart Variable density of tissues: lungs

TECHNIQUES OF RADIATION THERAPY

SIMULATION

Extent of the disease should be known based on imaging Barium swallow, CT, PET Endoscopy. During simulation, the patient is positioned, straightened,

and immobilized on the simulation table. Arms are generally placed overhead. Palpable neck disease should be marked with a radio-

opaque wire Administration of oral contrast to delineate the esophagus is

used. Some authors recommend placing the patient in the prone

position for treatment to displace the esophagus away from the spinal cord

Conventional technique

TREATMENT PORTALS

Parallel opposed AP-PA fields

EBRT TECHNIQUES

Initial phase (39.6-41.4 Gy)

- 5cm prox and distal margins

- 2 cm lateral margins

Off cord Boost: After 40-44Gy

3 field technique -- one direct anterior and two lateral/ posterior oblique

Advantages - Homogeneous dose distribution- Tumor better covered - Critical organs are out of the field

‘T’ shaped AP-PA field:

Upper cervical esophagus lesion - Treated from laryngopharynx to carina - Supraclavicular and upper mediastinal LN s irradiated electively

AP-PA fields with lung shielding

BORDERS:

Superior: Thyroid notchLateral : Junction of medial 2/3rd and lateral 1/3rd clavicleLower: Adequate margins from lesion (include upper mediastinal LNs)

Shielding: 5 HVL lead shield from 1cm below the Clavicles Lung correction factor

-Co 60 - dose decreased by 4%/cm- For 4 MV - 3% /cm - 10 MV -2 %/cm of lung

NORMAL TISSUE TOLERANCE

Organ TD5/5 Gy TD50/5 Gy Field size

Spinal cord 4750

-70

20cm5-10cm

Heart 4060

5070

Whole1/3rd

Lung 17.545

24.565

Whole1/3rd

APPROPRIATE TARGET VOLUME AND NEED OF ELECTIVE NODAL IRRADIATION IN CONFORMAL THERAPIES

•In patients treated with 3D-CRT for esophageal SCC, the omission of elective nodal irradiation was not associated with a significant amount of failure in lymph node regions not included in the planning target volume.•Local failure and distant metastases remained the predominant problems.•A longitudinal margin of 3 cm from the GTV to the CTV1 is probably enough

BASIS OF OMITTING ENI

Recurrence was with in GTV

1. Recurrene pattern(in-field) Predominant failure pattern in with esophageal SCC was

local in-field or distant failures. Regional nodal recurrence (out-of-field) was infrequent (8%) in the absence of elective node irradiation.

2. Biological behavior of the disease Esophageal cancer is characterized by a high rate of

nodal involvement and its spread pattern is not always predictable. Also, skip node metastases are frequently observed. Thus the biological behavior of this disease makes it difficult to define in advance the extent of coverage of elective nodal irradiation.

3. Toxicities If distant lymph node areas were irradiated

prophylactically, patients would then experience more severe radiation complications and have a poorer treatment tolerance.

In CRT for esophageal SqCC, ENI was effective for preventing regional nodal failure. TheUPPER THORACIC esophageal carcinomas had significantly more local recurrences than the middle or lower thoracic sites.

No global consensus on whether or not ENI should be performed.

POST-OPERATIVE MANAGEMENT IN CASES OF UPFRONT SURGERY

WHEN NO PRE –OP RT+CCT RECIEVEED

RECEIVED PRE-OP RT+CCT

TARGATED THERAPIES

TRASTUZUMAB + CHEMOTHERAPY IN ADVANCED HER2+ GASTRIC CANCER: TOGA STUDY

Rationale: a subpopulation of gastric cancers overexpress HER2

*

(n = 584)

R

Patients with advanced

gastric adenocancer screened for HER2 status

(N = 3803)

Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ,

measurable disease, capecitabine vs 5-FU

Patients with HER2+

advanced gastric cancer(n = 810; 22% of successful screenings)

5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6 +

Trastuzumab 6 mg/kg q3w until PD

(8 mg/kg loading dose)(n = 294)

5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6

(n = 290)

Bang YJ, et al. Lancet. 2010;376:687-697.

Outcome Chemotherapy +

Trastuzumab(n = 294)

Chemotherapy Alone(n = 290)

HR (95% CI) P Value

Median OS, mos

13.8 11.1 0.74 (0.60-0.91)

.0046

Median PFS, mos

6.7 5.5 0.71 (0.59-0.85)

.0002

Established transtuzumab and chemotherapy is a new standard of care for Her-2 neu expressing advanced gastric

and EGJ adenocarcinoma.Significant OS benefit

Safety profile were similar

PALLIATIVE CARE

IMPORTANCE OF PALLIATIVE CARE IN CA ESOPHAGUS

Majority of the patients diagnosed with advanced disease(80%) therefore palliation is an important goal.

1.Dysphagia

2.ObstructionEBRTBTEBRT+CCTSurgeryEndoscopic lumen restorationStenting

3.Pain(WHO pain ladder)

4. Nausea and vomitting (Antiemetics)

5.BleedingAcute bleedingChronic bleeding

6.Tracheo-oesophageal fistula

Fractionated BT is the best modality of palliation in comparison to all other modalities.for advanced esophageal cancers. It offers best palliation both in terms of survival(6.2) as well as symptom

free duration40% pts were free of dysphagia for one yr.

16Gy/2# or 18 Gy/3#

Versus

Dysphagia improved more rapidly after stent placement than after brachytherapy, but longterm relief of dysphagia was better after brachytherapy.

Stent placement had more complications than brachytherapy which was mainly due to an increased incidence of late haemorrhage .

No difference for median survival (p=0·23).

Quality-of-life scores were in favour of brachytherapy compared with stent placement.

Total medical costs were also much the same for stent placement (€8215) and brachytherapy (€8135).

Due to better long-term relief of dysphagia with fewer complications brachytherapy is recommended as the primary treatment for palliation of dysphagia from oesophageal cancer.

BRACHYTHERAPY

Procedure• After placing the patient in left lateral position, a fibre-

optic endoscope is passed. • The esophagus will be evaluated for extent of residual

tumor, presence of ulcer and stricture. • If suitable for brachytherapy, a stainless steel guide wire

will be passed through the biopsy channel of the endoscope and passed beyond the tumor site

• Depending upon the site of lesion, the length of selectron boogie will be adjusted by altering position of the mouth piece, so that lower end of the boogie is 2cm beyond the lower limit of initial lesion.

• The boogie will be threaded over the guide wire, which is then withdrawn

BRACHYTHERAPY

Prescription

1 cm from the mid-source / mid-dwell position without optimization

BRACHYTHERAPY ON TREATMENT

SURGICAL APPROCHES FOR ESOPHAGOGASTRECTOMY

Transthoracic approach

Transhiatal approch

TRANSTHORACIC APPROACH

Right thoracotomy & laparotomy Ivor lewis Mckeown

(with cervical anastomosis)

APPROACHES TTE IVOR LEWIS

APPROACHES TTE MCKEOWN

•Transient myelosuppression (30%)

• Esophagitis

• Dysphagia

• Pneumonitis

• Perforation with fistula or

hemorrhage

• Skin changes: hair loss, redness

• Pericarditis

• Nausea/ vomiting

• LOW/LOA

• Stenosis/ strictureOccurs in 60 % of casesStricture requiring dilatation-15-20 %

• Pneumonitis/ pulmonary fibrosis

• Esophagotracheobronchial fistulae

• Aortic rupture and hemorrhage

• Pericarditis with pericardial

constriction

• Transverse myeiltis

• Myocardial damage

• Radionecrosis of bone

COMPLICATIONS OF CRT

PROBLEMS WITH TRIMODALITY

Haematological toxicity – 30 % Mucositis Gr 3,4 Oesophagitis Pulm complications (ARDS) 14 % Surgical complications - anastomotic leak 6 % Local recurrence 6 % Operative deaths 6 %

TOXICITY TUMOUR CONTROL

MANAGING COMPLICATIONS

Smoking cessation

Nutrition maintenance:

- Assess radiation tolerability before starting radiation

- Plenty of fluids, frequent sips of cool liquids

- Disprin and local anesthetic gargles

- Avoid hot spicy, dry food

- Ryles tube insertion: Grade 3-4 dysphagia/ <1500kcal/day

Respiratory physiotherapy: to improve pulmonary function

During radiation, check patient status at least once a week

Antiemetics, Antacids, soothening agents be prescribed when needed

Treatment interruptions or dose reductions for manageable acute

toxicities should be avoided.

THANK U

PHOTODYNAMIC THERAPY

PRINCIPLE:

- Uses photosensitiser (Hematoporphyrin) and red (WL=630nm) LASER

- Resultant free radicals destroy DNA of rapidly dividing cells.

INDICATIONS:

Barrets esophagus

Early esophageal cancer

Persistant or recurrent esophageal cancer post RT, CCT, Sx

ADVERSE EFFECTS:

Local swelling and inflammation

Photosensitivity: shield skin and eyes for 4 hours

SURGERY

Resection should include

Lower esophagus to a point above azygos vein

Celiac lymph nodes

Left gastric lymph nodes

Division of left gastric artery

Proximal part of stomach

Pyloroplasty