IMRT oggi: Luci ed ombre in un commento critico

IMRT oggi: Luci ed ombre in un commento critico

R. Calandrino, S. Broggi, G.M. Cattaneo, B. Longobardi, V. Fossati, A. Nahum

Med. Phys. Dep.IRCCS San Raffaele , MilanoRadioterapia Ist. Naz.Tum, MilanoRadioterapia oncologica, ASMN, Reggio Emilia

Reggio Emilia, Imaging Metabolico per una Moderna Radioterapia 14,15/ott/ 2003

Why IMRT?

The main question facing IMRT is whether the increase in the use of this expensive technology will improve cancer survival and reduce morbidity.

A second point is to demonstrate the uniqueness of this particular strategy for the achievement of the above goals.

Will the increase in high-cost technology improve cancer

survival and reduce morbidity ?

In order to answer this question it is necessary to analyzethe different types of cancer (i.e. different anatomical sites) and evaluate, case by case, the rationale for a local control strategy.

site

New

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es %

Dea

ths %

RT

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Add

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RT

(%)

Prostate 15,6 5,7 YES YES 5-8% Breast 15,3 7,3 NO YES 5-10

Lung & Bronchus

13,4 28,4 NO YES Early : 15

Colorectal 10,7 10,2 NO YES (rectum) 10 - 20 (Leukemia)

Hd and non-Hd Lymphomas

8,0 9,0 NO YES 15 -20

Digestive Tumours

6,3 12,4 NO YES YES

Bladder 4,3 2,3 NO YES 2 - 5 Head & Neck 4,6 4,5 YES

(larynx early +

nasopharynx)

YES (advanced)

YES

Gynecological 5,8 4,5 YES (cervix / endometrium)

YES (cervix /

endometrium)

6-7%

TOTAL 84,0 84,3

R .J. Shultz, et al : On the role of IMRT in radiation oncology, Med. Phys. 29, July 2002

V. Fossati; private communication, april 2003

Outline of the percentages, for all cancers, cured solely by Surgery - byExt. Beam RT (EBRT) - by Brachy RT

Site % allnew

cancers

Surgery%

EBRT%

Brachy%

Prostate 15.6 37 20 12,5Gynaecological 5.8 80 0 20Head andNeck

4.6 94 6 0

Total 26 14.9 3.4 3.11

Perspective 2005 by BBI Newsletter American Cancer Society

Site % newcases

Surgery EBRT%

Brachy

Prostate 15.6 23 23 25

Prostate cancer

USA (2001) Incidence: 198.100 cases Deaths: 31.500

Europe (1995) Incidence: 145.003 cases Deaths: 55.526

Prostatectomy is still considered the gold standard by many.

Prostate cancer

IMRT makes a dose-escalation strategy possible, keeping toxicity below or equal to 5% for grade-2 or -3 rectal side effects (4-year control) 1.

1) Leibel et al.; Treatment of prostate cancer: External Beam Radiotherapy; Progress in Oncology, 2001)

Prostate cancer: IMRT vs 3D-CRT

PTV

OAR

PTV

OAR

No concave target

No advantage from IMRT

Concave shaped PTV

IMRT is able to better conform dose distribution

PTV

OAR

For maximum gain with IMRT the degree of overlap between rectum and prostate should be as small as possible

Potential of IMRT in prostate

• IMRT as “concomitant boost” in portions of the prostate (functional-imaging guide IMRT)“DOSE PAINTING”

• IMRT for concomitant delivery of different total and daily doses to different CTVs (eg: pelvis, prostate, seminal vesicles)

• IMRT for pelvic node irradiation (concave-shaped distributions) – QUESTIONABLE CLINICAL VALUE

Prostate cancer with IMRT:limiting factors

• internal movements: in a period of 15-20 min(average total IMRT treatment time), the prostate might move several mm with respect to the assumed position

• lack of knowledge making it impossible to define a sharp border between neoplastic and healthy tissues (inter-observer variability)

Prostate cancer with IMRT

Without improvements in life expectancy equal to or better than those obtained by other methods of treatment, it is questionablewhether reduced rectal toxicity (and erectile dysfunction??) justifies this complex andcostly technology.R.J Shultz et al., IMRT in Radiation Oncology, Med. Phys, July2002.

Prostate cancer with IMRT

A comparison between standard conformal therapy and IMRT, considering organ motionand set up errors, demonstrates the following:•conformal therapy has a higher chance to cover the CTV homogeneously•no gains by IMRT in rectal and bladder NTCP

L.Happerset et. al.; RT&O 66 (march 2003)

Prostate cancer radiobiology

The (prostate PO2)/(muscle PO2) ratio proved to bethe most powerful predictor for biochemicalcontrol on a multivariate model. At a median follow-up of 19 weeks, patients with a ratio < 0.05 had 31% rate of biochemical controlvs a 92% rate for patients with a ratio > 0.05 (P < .001)

Movsas B, Chapman JD, Hanlon AL, et al. A hypoxic ratio of prostate pO2/muscle pO2 predicts for biochemical failure in prostate cancer patients. American Society for Therapeutic Radiology andOncology 43rd Annual Meeting; November 4-8, 2001; San Francisco, California.

Int J Radiat Oncol Biol Phys. 2001;51(suppl 1):111. Abstract 199

External-beam: Hanks' data vs TLC- model predictions

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 100 120 140 160TOTAL DOSE (Gy): in 2-Gy fractions

TLC

P

100% HYPOXIC

107 clonogens

100% AEROBIC

106 clonogens

PSA < 10 ng/ml

PSA > 20 ng/ml

PSA 10-20 ng/ml

Prostate cancer and hypoxia

Nahum A et al IN PRESS Int. J. Rad. Onc. Biol. Phys.

LDR Brachy: our parameters

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 100 120 140 160Dose (Gy)

TCU

P

Popn I

Popn II

Combined pop'n

Stock et alclinical

α =0.2603 σα= N =0.06 5.00E+06β = 0.000

I: (% pop'n) = 5050hypoxic frac'n (%) = 0

II: % pop'n =hypoxic frac'n (%) = 100

10.DEC.2002

Aerobic

Hypoxic

Nahum A et al IN PRESS Int. J. Rad. Onc. Biol. Phys.

LDR Brachytherapy (seeds) for prostate cancer

Head and Neck cancer

USA(2001) Incidence: 40.100 cases Deaths: 8.200

Europe(1995) Incidence: 52.659 cases Deaths: 19.729

Treatment modality 5-year survival Early localized lesions (35%) Surgery or EBRT 80% Regional disease Surgery/EBRT with or

without chemo 40%

Advanced/metastatic disease Surgery/EBRT with or without chemo

20%

IMRT and Head-Neck cancer

Increase of local-regional control (by dose-escalation)

Improvement of patient’s quality of life

No increase in survival

IMRT dose distributions are highly conformal w.r.t. the tumor volume;

Reduction of the dose to OARs such as salivary glands and spinal cord

IMRT in Head and Neck cancerIncrease of PTV minimum dose: 95% vs 91 % (Eisbruch, 1998)

Increase of PTV mean dose: 77.3 Gy vs 74.6 Gy , for a ICRU dose equal to 70 Gy (Hunt, 2001)

Reduced spinal cord maximum dose: 34.5 Gy vs44 Gy (Hunt , 2001)

Reduced parotid-gland mean dose, 32% vs 93%, with improved salivary function recovery (Eisbruch, 1998)

IMRT in Head-Neck cancer

Nasopharynx as site of primary choice for IMRT in Head and Neck. Improved GTV coverage and OAR sparing for all stages

M.K.M. Kam et al IMRT in Nasopharingeal Carcinoma ....; Int. J. Rad. Onc. Biol. Phys.; Vol 56 n.1, 2003

IMRT in Head-Neck cancer

NASOPHARYNGEAL CARCINOMA T1N0M0 M.K.M. Kam et al IMT in Nasopharingeal Carcinoma ....; Int. J. Rad. Onc. Biol.

Phys.; Vol 56 n.1, 2003

Lung & Bronchial tumours

USA(2001) Incidence:169.500 cases Deaths: 157.400

Europe(1995) Incidence:196.957 cases Deaths: 180.572

Lung & Bronchial tumours

When surgery is not possible for clinical reasons, radiation treatment is radical for all stages up to IIA.

( IIB T2 N0,IIIA T1,T2 without bulky nodes).

Lung & Bronchus tumoursSCLC (20-25%) Rapid growth and occult distant

metastases

More precise dose distributions and dose escalation are unlikely to affect level of survival

NSCLC (75-80%) RT as primary therapy for medically inoperable patients (3% ) with

localised or regional disease. 55--y survival is y survival is about one half of that obtained with surgeryabout one half of that obtained with surgery

More precise dose distributions and dose escalation through IMRT could benefit a small number of patients (800/y in USA)

R.J Shultz et al., IMRT in Radiation Oncology, Med. Phys, July2002.

Lung & Bronchial tumours

The introduction of screening programs in heavy smokers by means of spiral CT and selective use of PET will increase the number of early detected Lung tumors.

U.Pastorino et al; Early lung cancer detection with spiral CT and PET in heavy smokers; The Lancet vol 362 august 2003

Lung & Bronchial tumours

IMRT with a better dose distribution and higher doses could improve clinical outcome for early detected Lung Tumor

Radiobiological considerations which could justify IMRT derive from the parallel structure of the lung.

But respiratory movement makes gating obligatory.

Lung & Bronchial tumours α/β•Tumor = 10

•Normal tissues

Pneumonitis = 4

Oesophagitis = 10

Pulmonary fibrosis < 3.5

Oesophageal stricture = 1.7

(Chartwell, Bentzen clinical oncology 2002)

Lung & Bronchial tumours α/β•The evaluation of a clonogenic cells doubling time, for L.T., of (Tp=) 3 days invite serious consideration of how to escalate dose without escalating overall time, that means increasing the dose per fraction .

•Late effects increase recommend great care in clinical trials using fraction size larger than 2 Gy.

Lung & Bronchial tumours α/β

By a rabiobiological point of view,

hypofractionated regimens are not suitable to

cure Lung Cancer .

Comparison between conventionalRT and tomotherapy in lung cancer

5 pts with III NSCLC: 2 TP generating for each with:Similar EUD for the two treatmentsSimilar tumor dose

⇒ NTDmean (both lungs): reduced (mean 31%)⇒V20 (both lungs) : reduced (mean 22%)⇒ NTDOAR(esophagus, spinal cord) : reduced

chance for dose escalationR.A. Rufus et al:”Reduction in radiation dose to lung and other normal tissue using helical tomotherapy to treat

lung cancer, in comparison to conventional field arrangements”; Am J Clin Oncol (CCT):70-78, 2003

Comparison between conventionalRT and tomotherapy in lung cancer

R.A. Rufus et al:”Reduction in radiation dose to lung and other normal tissue using helical tomotherapy to treat lung cancer, in comparison to conventional field arrangements”; Am J Clin Oncol (CCT):70-78, 2003

Comparison between conventionalRT and tomotherapy in lung cancer

R.A. Rufus et al:”Reduction in radiation dose to lung and other normal tissue using helical tomotherapy to treat lung cancer, in comparison to conventional field arrangements”; Am J Clin Oncol (CCT):70-78, 2003

IMRT : opened remarks (I)Target volume specification

• Suspected microscopic and lymph-node spread• Inter-observer contouring variability• Set-up error • Inter/intra fraction organ motion

Radiobiological knowledge• Inhomogeneous dose distributions: the effect of

cold spots on the TCP and the effect of small hot spots on the NTCP

• Altered dose –time fractionation

IMRT : opened remarks (II)Dosimetric accuracy

Small fields, High dose gradients, Short beam pulse segment decrease the accuracy of the absolute dose evaluation

Increase of the time and scattered dose to the patient : 2nd tumor induction risk

Conclusions I

No clinical data at present demonstrate an improvement of survival due to IMRT dose-escalation compared to conventional EBRT.Meanwhile, the reduction of toxicity has been widely demonstrated by several authors

At present, concave PTV close to highlysensitive OAR in patients candidates to long survival are the most realistic targets for IMRT (Prostate, Nasopharinx early stages,......)

Conclusions II

The improvement of functional diagnostics(Hypoxia, Proliferation ..) and of radiobiological knowledge will indicate, for selected cases, where abetter outcome might be expected

Conclusions III

Keep in mind that :in many cases, e.g. brain tumors, prostate, and uterine cervix, we already have dedicated techniques capable of yielding similar dose distributions with much lower costs and less departmental stress.

In cases with high probability of distant microscopic spread (eg:lung advanced cancers, ...) the increase of local control by IMRT causes no improvements to clinical outcome

Conclusions IV

In the future, with the improvement of biochemical diagnostic tools, and selective screening programs, the target localization during the asymptomatic phase of the tumor will be possible.

Thus, IMRT will gain a more relevant function to eradicate the tumor with maximum sparing of healthy surrounding tissues