RADIOTHERAPY IN CARCINOMA OVARY DR. DEBASHIS PANDA SENIOR RESIDENT DEPARTMENT OF RADIOTHERAPY LOK NAYAK HOSPITAL PRECEPTORS- DR. K. SINGH DR. A. SRIVASTAVA

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INTRODUCTION

Contemporary strategies

Surgical exploration

Staging, and cytoreduction

Chemotherappy- most often platinum and paclitaxel based adjuvant chemotherapy

Radiation therapy, known since 1912 to induce long term remission in certain patients with ovarian cancer.

RT has largely been excluded from routine use now.

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What NCCN says…

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RADIATION IN PRIMARY OVARIAN CANCER

Methods-

Localized pelvic radiation

Abdominopelvic radiation

Intraperitoneal radiocolloids

In reviewing the utility of primary irradiation as a sole treatment modality in ovarian cancer, it is useful to discuss its role, separately in,

Early stage

Advanced stage

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SIGNIFICANCE OF RT

Is there conclusive evidence that radiation therapy induces tumor cell kill in patients with ovarian cancer?

Residuum

Study End Point <2 cm >2 cm

Dembo % 10 yr relapse free 38% 6%

Martinez % 15 yr freedom from relapse 50% 14%

Fuller % 10 yr relapse free 62% 0%

Weiser % 10 yr survival 42% 10%

Goldberg 6 yr survival fraction 0.41 —

Thomas G. Dembo A: Integrating radiation therapy into the management of ovarian cancer.

Cancer 71:1710–8, 1993

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CT Vs RT

How do the results of APRT compare with those achieved with conventional chemotherapy?

No head to head trials between

APRT Vs Paclitaxel based chemotherapy.

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CT Vs RT

How do the results of APRT compare with those achieved with conventional chemotherapy?

No head to head trials between

APRT Vs Paclitaxel based chemotherapy.

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Someone had thought for

Prospective evaluation of APRT versus cisplatin chemotherapy

Stage IA/B grade 2 or 3; stage IC through FIGO

Stage IIA/B through EORTC

END POINTS= SURVIVAL and QOL.

However, because the survival rate in this subgroup of patients is 80% or better at 5 years, conclusions regarding these endpoints are years off.

A. Files et al, European Journal of Cancer Part A. 1997;33(1):12-19.

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CT+RT

4 X Cyclophosphamide and Hexamethylmeamine A/W 4 X concurrent cisplatin, whole abdominal radiotherapy, and intraperitoneal Misonidazole.

The entire treatment program lasted 6 months.

This outcome was no different than the previous experience with combination chemotherapy(NONCISPLATIN) performed by the same group.

N= 28

Stage III or IV

epithelial ovarian

carcinoma.

CR 50%

RESPONSE RATE 61%

pCR 18%

MEDIAN SURVIVAL 15.2 MONTHS

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WART AS CONSOLIDATION THERAPY

Rationale- 40% to 60% of patients achieving a pCR after chemotherapy ultimately recur and succumb.

Consolidation Regimens Additional intravenous chemotherapy

Intraperitoneal chemotherapy

Intraperitoneal radiocolloids

Intraperitoneal immunoconjugates (Cederkrantz E et al, Int J Radiat Oncol Biol Phys. 2015 Nov 1;93(3):569-76.)

Hormones

High dose chemotherapy

Abdominopelvic RT would be a reasonable choice to affect this recurrence rate, if given after primary induction chemotherapy. (Fuks Z et al.Int J Radiat Oncol Biol Phys 8: 903, 1982. & Mychalaczak B. Hematol Oncol Clin North Am 6: 895, 1992. Thomas G. Gynecol Oncol 51: 97, 1993)

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Game changer

Introduction of Cisplatin almost closed the trials of radiotherapy in Ovarian carcinoma.

In this Platinum era, very few prospective trials are there for RT as consolidation therapy.

Benefit from consolidation depends on residual tumor size.

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Swedish Norwegian Ovarian Cancer Study

In this latter stratification, no difference in survival was demonstrated. In the former, however, a significant improvement in disease free survival was noted for abdominal pelvic radiation therapy, although follow up is premature.

N=

172

4

X

CDDP

&

DOXO

SECOND

LOOK

LAPARO-

TOMY

RE

SID

UA

L NON or

MICRO

MACRO

(74)

CHEMO

APRT

OBSER

APRT

CHEMO

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BenBaruch and colleagues

In this trial, no significant difference was observed between the treatment arms initially;

however, in this updated report with now 5years of minimum followup, a nonsignificant trend to poorer survival was seen in the APRT arm

In addition, these authors report that survival after secondary recurrence was reduced significantly in those patients receiving APRT as their initial salvage regimen.

BenBaruch et al. Eur J Gynecol Oncol 15: 272, 1994

N= 37

SECOND

LOOK

LAPARO-

TOMY

INTRAPERITONEAL CDDP , THIOSULPHATE

APRT (N= 19)

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Pickel et al (Gynecol Oncol 68:119 (abstract 192), 1998)

Of the 64 patients randomized, 58 had stage III or IV disease at presentation.

PFS at 10 years was significantly higher in APRT arm (50% vs. 30%, p = 0.012).

OS at 10 years was significantly higher (62% vs. 38%, p = 0.029) in the APRT arm.

Subset analysis of the stage III/IV patients was comparable.

N= 64

FIGO- ICIV

MAXIMAL

CYTOREDUCTIO

N

6

X

CARBO

EPIRUBICIN

PREDNIMUSTINE

NO

RE

SID

UA

L

APRT

OBSER

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Recently

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A retrospective analysis

n= 27 for IFRT, n= 14 for NIFRT (control cohort)

Tumour volume-directed IFRT for localized extraperitoneal recurrences (either as consolidation after cytoreductive surgery (CRS) or as attempted salvage if unresectable)

All patients were heavily pretreated with multiple chemotherapy

Involved field radiation therapy was primarily with external beam (median dose, 50.4 Gy).

Technique- 3-dimensional conformal techniques in over half the patients with the remaining receiving 2-dimensional RT.

Local recurrence-free survival (LRFS) was defined as freedom from in-field recurrences and was considered as a measure of effectiveness of radiotherapy

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Of 27 patients, 17 had optimal CRS before RT.

None of the NIFRT patients survived beyond 5 years from initiation of salvage chemotherapy.

Yahara et al, maximal benefit in tumour size less than 3 cm. (J Radiat Res. 2013;54:322–329)

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5 years 10 years

LRFS 70% 60%

OS 30% 19%

DFS 33% 20%

Conclusion on WPRT as Consolidation therapy

Toxicity in this setting is significant.

Patients without any residual disease will have more benefit.

It will be very premature to comment on survival data from these trials.

Presented data are still inconclusive, in spite that we can try IFRT in highly selected patients.

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Salvage WPRT in Epithelial Ovarian Cancer

Reddy et al. IntJ Radiat Oncol Biol Phys 27: 879, 1993

Cases who have failed to one or more chemotherapeutic regimens. (N= 30)

2 groups- with microscopic(n=16) and with macroscopic(n=14) residual disease.

Subjected to WART (2500 cGy) f/b pelvic and paraaortic boost (2500 cGy)

Only 2 patients were unable to complete the planned therapy.

Another 26% of the patients required interruption of the therapy secondary to hematologic toxicity but eventually completed the treatment.

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With an overall median follow-up of 14 months 56% of the patients remain alive.

Two-year actuarial survival and recurrence-free survival rates are 47 and 32%, respectively.

The survival and recurrence-free survival rates for the group with microscopic residual disease--61 and 33%, respectively--are better than those for the patients with macroscopic residual disease--36 and 18%.

The abdominopelvic cavity was the first site of failure.

In spite of the higher doses, pelvic failure alone or as a component occurred in 54% of the patients.

Small bowel obstruction necessitating surgical intervention as a complication of therapy was seen in 13% of the patients.

Conclusion Whole abdominal radiation is unlikely to benefit those patients with macroscopic

disease, and only those patients with localized microscopic pelvic disease stand to gain from this treatment.

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Indications of RT

In good risk patients with stage I, grade I disease, adjuvant RT not required.

For patients with macroscopic disease in the abdomen and bulky disease in the pelvis (gross stage III and IV), RT is not a curative form of treatment.

Maximum benefit of post op RT is in patients with small volume (< 2 cm) residuum in the pelvis and without macroscopic disease in abdomen in salvage.

As a consolidative treatment in bulky post op residuum cases.

In palliative intent in cases of refractory or recurrent cases and also in cases of metastases.

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Radiotherapy

Now it is a history for routine use, unless otherwise specified.

Target - Whole abdominal cavity and pelvis.

Patient position- Supine/ Prone

Portals- AP/PA

Field borders for WART Superior- 1.5 to 2 cm (above diaphragm)

Inferior- inferior border of obturator foramen

Lateral- whole peritoneum with a margin of subcutaneous tissue

Techniques Moving strip technique (MST) (Delclos, 1963)

Martinez technique/ Open field technique (Martinez et al. J Clin Oncol 3:901-902, 1985)

Modified Martinez technique.

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Techniques

MST Dose Small fraction size 100- 125 cGy

daily is ideal for whole abdominal field. (Princess Margaret Hospital, Toronto, Canada, 1976)

At PMH- 2500- 2750 cGy WART f/b 2000- 2250 cGy boost to Pelvis.

25-30 Gy in 20# over 4 weeks + Pelvic Boost 20 Gy/ 10# over 2 weeks.

Both kidneys are shielded from posteriorly with 2 HVL and right half of liver is shielded with 1 HVL from both AP/PA.

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Techniques

MARTINEZ Doses WART- 30 Gy in 20 # over 4

weeks the Pelvic boost in phase I, 9 Gy in 5#, in Phase II (T- Field) 12 Gy in 8#

Full thickness kidney shield applied posteriorly after 10 Gy and a 50% transmission block for liver after 15 Gy in both AP/PA.

Total liver dose 22.5 Gy in 23 #, total kidney dose 20 Gy in 20 #.

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Techniques

Modified Martinez

Field and borders remain the same.

Except that the para-aortic boost field is omitted.

Used in cases with suspected bowel compromise

WART- 22 Gy/17#

Diaphragmatic boost- 15 Gy

Pelvic Boost- 24 Gy by 4 field or box technique

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Radiotherapy

Pelvic field borders-

Superior- L5- S1 junction

Inferior- lower border of obturator foramen

Laterally- 1.5 cm beyond the true boney pelvis.

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Complications of RT

Acute-

Small bowel symptoms

Nausea & vomiting

Bone marrow suppression

Late-

Adhesions

Perforation

Peritonitis

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RADIOACTIVE CHROMIC PHOSPHATE (P-32)

Pure beta emitter.

Improved tumour penetration.

Less hazard to treating personnel.

Has been used since early 1950s.

Intraperitoneally at a dose of 10 to 20 mCi mixed in 1 to 2L of saline.

Before instillation of the active P-32, a technetium scan usually is performed to determine whether distribution of the colloid in the abdominal cavity is satisfactory.

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Radioactive Chromic Phosphate in Primary Therapy

Several investigators have studied this therapy in combination with other modalities, such as chemotherapy (nonplatinum) or pelvic radiation.

because of significant complications, they have concluded that this agent is best considered singly.

Soper J, Wilkinson R, Bandy L et al: Intraperitoneal chromic phosphate P32 as salvage therapy for persistent carcinoma of the ovary after surgical restaging. Am J Obstet Gynecol 156: 1153, 1987

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As consolidation therapy

It is clear that volume of residual disease is an important predictor of response.

No much improvement in survival.

Toxicity is high, some require surgical intervention.

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Palliative therapy

For stage IV patients, and in metastatic cases

Dose and field depends on the site of the disease.

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Reference

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1.

2.

3. NCCN version 2.2015

4.

5.

Devita Clinical Oncology 10th edition

Text book of Radiation Oncology, principles and practice-

Rath & Mohanty

T H A N K U

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