Tenesmo rettale e radioterapia - nicsonet.it · during and 2 weeks after RT. The grade of proctitis was registered in a daily diary. The grade of proctitis was registered in a daily

Marco Lupattelli - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016

Tenesmo rettale e radioterapia

Marco Lupattelli, Perugia

Proctite acuta: dati generali

Processo infiammatorio insorge durante RT o entro 3 mesi dal termine

Sintomi: tenesmo, diarrea, urgenza evacuativa, mucorrea, sanguinamento (ematochezia)

“Self-limiting” al termine RT

Terapia: antidiarroici, FANS, steroidi, 5-ASA e raramente oppiacei

Raramente sospensione RT


Proctite acuta: dati generali

Processo infiammatorio insorge durante RT o entro 3 mesi dal termine

Sintomi: tenesmo, diarrea, urgenza evacuativa, mucorrea, sanguinamento (ematochezia)

“Self-limiting” al termine RT

Terapia: antidiarroici, FANS, steroidi, 5-ASA e raramente oppiacei

Raramente sospensione RT

In genere proctite acuta non rappresenta

problematica clinica

ma può essere

fattore predittivo di tossicità cronica


Proctiti attiniche croniche: dati generali

Incidenza: 5-20% (Garg IJROBP 2006; Kuku Br J Cancer 2013; Krol IJCD 2014)

Neoplasie prostata e sfera ginecologica

Quadro clinico: sanguinamento, tenesmo, urgenza a defecare

Intervallo RT-inizio sintomi: > 6 mesi (in genere 12-24 mesi)

Possono essere autolimitanti (Mendenhall AJCO 2014)

Ruolo scale tossicità (EORTC-RTOG; CTCAE)

Scala endoscopica valutazione (VRS: Vienna Rectoscopy Score)






Componente infiammatoria: farmaci (sucralfato, 5-ASA, sulfasalazina, steroidi, metronidazolo, acidi grassi a catena corta, vit. A-E-C, pentossifillina)

Componente emorragica o mista: trattamenti locali endoscopici (APC, formalina) o ossigenoterapia iperbarica

Forme resistenti sanguinamento, necrosi, fistole, stenosi: chirurgia (colostomia, proctectomia, RAR o AAP)

Proctiti attiniche croniche: trattamento


Componente infiammatoria: farmaci (sucralfato, 5-ASA, sulfasalazina, steroidi, metronidazolo, acidi grassi a catena corta, vit. A-E-C, pentossifillina)

Componente emorragica o mista: trattamenti locali endoscopici (APC, formalina) o ossigenoterapia iperbarica

Forme resistenti sanguinamento, necrosi, fistole, stenosi: chirurgia (colostomia, proctectomia, RAR o AAP)

Proctiti attiniche croniche: trattamento

Assenza di linee-guida condivise


Trattamento CRP: possibile algoritmo


Correlate al trattamento RT:

Volume di retto irradiato

Dose totale (> 45-50Gy) e tipo frazionamento

Tecnica 3D vs IMRT

Associazione con chemioterapia

Correlate al paziente (comorbidità) (Shadad 2013; Theis 2010):

Fumo, diabete mellito, malattie vascolari

Connettivopatie, malattie infiammatorie intestinali

Nomogrammi (fattori predittivi) (Valdagni 2008-2012)

Anticoagulanti, antipertensivi

Terapia ormonale

Pregressa chirurgia

Emorroidi

Proctiti attiniche croniche: variabili


Tecnica RT (3DC vs IMRT)

IGRT (radioterapia guidata dalle immagini)

“Organ spacer”

Farmaci

Farmaci

Trattamenti locali

Prevenzione Trattamento

Proctiti attiniche croniche: up-date letteratura


Prevenzione: tecnica RT

IJROBP 2013

For G2+ acute GI/GU toxicity, both univariate and multivariate analyses show a

statistically significant decrease in G2+ acute collective GI/GU toxicity for IMRT.

On multivariate analysis, IMRT shows a 26% reduction in G2+ late GI toxicity

(p=0.099). Acute G3+ toxicity was associated with late G3+ toxicity (p=0.005).

White race (p=0.001) and rectal V70 ≥15% are associated with G2+ rectal toxicity

(p=0.034).

Up-date 2015 (Cancer e IJROBP)

No difference in patient-reported bowel, bladder, or sexual functions for

similar doses delivered.

Plan IMRT quality deficiencies in RTOG 0126 trial.



IJROBP 2013

For G2+ acute GI/GU toxicity, both univariate and multivariate analyses show a

statistically significant decrease in G2+ acute collective GI/GU toxicity for IMRT.

On multivariate analysis, IMRT shows a 26% reduction in G2+ late GI toxicity

(p=0.099). Acute G3+ toxicity was associated with late G3+ toxicity (p=0.005).

White race (p=0.001) and rectal V70 ≥15% are associated with G2+ rectal toxicity

(p=0.034).

Up-date 2015 (Cancer e IJROBP)

No difference in patient-reported bowel, bladder, or sexual functions for

similar doses delivered.

Plan IMRT quality deficiencies in RTOG 0126 trial.

CTV 3D group: prostate-SV followed by prostate boost

CTV IMRT group: prostate-SV Marco Lupattelli - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016


Cancer 2016

7 vs 24%; p = 0.001

CONCLUSIONS: IMRT reduced the delivery of significant radiation doses to the

bladder and rectum using a similar target volume. This dosimetric advantage resulted

in a lower rate of acute/late grade 2 GI and GU toxicity for IMRT compared with

3DCRT.

QOL significantly improves in IMRT arm. No difference in 5y-BC was observed.


Prevenzione: RT con protoni

IJROBP 2015

Methods and Materials: A total of 1285 consecutive patients were treated. CTCAE

3.0 was used to score toxicity.

Results: GR1 RB occurred in 217 patients (16.9%), GR2 RB in 187 patients

(14.5%) and GR3 in 11 (0.9%) patients. On multivariate analysis, anticoagulation

therapy (p=0.0034), relative volume of rectum receiving 75 Gy (V75; p=0.0102)

were significant predictors for G2+ RB.


Prevenzione: RT con protoni

IJROBP 2015

Methods and Materials: A total of 1285 consecutive patients were treated. CTCAE

3.0 was used to score toxicity.

Results: GR1 RB occurred in 217 patients (16.9%), GR2 RB in 187 patients

(14.5%) and GR3 in 11 (0.9%) patients. On multivariate analysis, anticoagulation

therapy (p=0.0034), relative volume of rectum receiving 75 Gy (V75; p=0.0102)

were significant predictors for G2+ RB.

Studi Tipo RT Scala tossicità

Tossicità G2

Colaco et al protoni CTCAE 3.0 14.5%

De Meerleer et al fotoni IMRT RTOG 18%

Vora et al fotoni IMRT RTOG 24%

Viani et al fotoni IMRT CTCAE 4.0 6.4%

Wortel et al fotoni IMRT RTOG 24.9% Marco Lupattelli - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016

Prevenzione: IGRT e “fiducial markers”







IJROBP 2016

Patients treated with 3D-CRT (n=189) or IG-IMRT (n=242) to 78 Gy in 39 fr

recruited from 2 Dutch randomized trials with identical toxicity scoring

protocols. Late toxicity (>90 days after treatment): self-assessment

questionnaires and case report forms, according to RTOG-EORTC scoring

criteria.

The 5-year cumulative incidence of grade 2 GI toxicity: 24.9% vs 37.6% in

favour of IG-IMRT (p=0.005), with significant reductions in proctitis

(p=0.047) and increased stool frequency (p<0.001).

Other predictors (p<0.01) of grade 2 late toxicity: baseline complaints, acute

toxicity, and age.



IJROBP 2016

Patients treated with 3D-CRT (n=189) or IG-IMRT (n=242) to 78 Gy in 39 fr

recruited from 2 Dutch randomized trials with identical toxicity scoring

protocols. Late toxicity (>90 days after treatment): self-assessment

questionnaires and case report forms, according to RTOG-EORTC scoring

criteria.

The 5-year cumulative incidence of grade 2 GI toxicity: 24.9% vs 37.6% in

favour of IG-IMRT (p=0.005), with significant reductions in proctitis

(p=0.047) and increased stool frequency (p<0.001).

Other predictors (p<0.01) of grade 2 late toxicity: baseline complaints, acute

toxicity, and age. Marco Lupattelli - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016

Both cohorts treated in different eras

Slight different policies in treating side effects

IG-IMRT included more advanced disease

Umbalance in ADT prescription (incresing GU toxicity?)

Reported toxicity rates higher than other studies, but toxicity scores based on both case-repot forms and self-assessment questionnaires.


IG-IMRT was associated with significant and clinically relevant reductions in

late GI toxicity. This resulted from IMRT planning, image-guidance, and

margin reduction. These data provide evidence that IG-IMRT is indeed

beneficial for the patient, suggesting that IMRT and image guidance should

be the preferred technique.


Prevenzione: “organ spacer”

Studi No pz Tipo RT Tox ≥ 2 (cronica)

Uhl 2014

52 IMRT 78Gy/39fr

2.1%

Chapet 2015

36 IMRT 62Gy/20fr

NO

Rucinski 2015

19 Ioni carbonio

Studio dosimetrico



IJROBP 2015

- 222 patients with cT1-T2

- fiducial marker placement,

- Spacer injection or no (control).

- IG-IMRT 79.2 Gy in 1.8-Gy fractions

- Impact on rectal irradiation, toxicity,

and QOL throughout 15 months.



IJROBP 2015

- 222 patients with cT1-T2

- fiducial marker placement,

- Spacer injection or no (control).

- IG-IMRT 79.2 Gy in 1.8-Gy fractions

- Impact on rectal irradiation, toxicity,

and QOL throughout 15 months.



2015


Prevenzione: farmaci

IJROBP 2014

Methods and Materials: 166 patients, randomly allocated to 1 of 4 groups (rectal

sodium butyrate 1 g, 2 g, or 4 g daily or placebo), were treated with NABUREN

during and 2 weeks after RT. The grade of proctitis was registered in a daily diary.

Results: No favorable trend in reduction of incidence, severity, and duration of ≥G1

and ≥G2 proctitis was observed with NABUREN use.

In univariate analysis, ≥G1+3d toxicity was found to be related to hemorrhoids

(p=0.008), and a slight correlation was found between G2 proctitis and hormonal

therapy (p=0.06). The RT effects on rectal mucosa as based on endoscopic

assessment were mainly related to diabetes (p<0.01).



IJROBP 2016

Methods and Materials: A propensity score analysis of 817 patients who underwent radical

radiation therapy with neoadjuvant or adjuvant hormone therapy as primary line management

in a cohort study during 2009 to 2013 was conducted.

ACEi

Time (years)

Cum

ula

tive Incid

ence

Time to resolution of proctitis

ACEi

Incidence of proctitis grade

p<0.001

p<0.001



IJROBP 2015


Trattamento: farmaci

2016

Colonoscopy to confirm the diagnosis of CRP and symptoms were graded (CTCAE 4.0–VRS).

A total of 59 patients enrolled

Gynecological cancer in 93.1%; mean RT dose 82.5 (40-120Gy)

Complete or reduction of bleeding observed in 90% (53/59)

Mean response time 12 days. No adverse effects.

Long-term successful rate in controlling bleeding 69% and quality of life (EORTC-QLQC30) improved (p=0.001).


Trattamento: farmaci

Sucralfate: short-term response 94%; long-term 70%. Response after 4-8 weeks

Almagate: more acid neutralizing properties than mucosa protecting.

Almagate acts more rapidly for antiacid property

Retrospective study


Trattamento locale con APC


Trattamento locale con APC

2014

Retrospectively, data from 30 pts due to refractory CRP

Grade 3 (CTCAE 3.0)

Prostate cancer treated with RT (mean dose 74Gy)

Median time RT-APC: 13 months

Performed 94 APC (median 3 each pt) every 3-4 w

After median F-U of 14-5 months, complete or reduction of bleeding observed in 94% (28/30)

In 2 pts, grade 2 rectal ulceration and incontinence.


Trattamento: HBOT

Eleven trials contributed to this review

(669 participants).

For pooled analyses, investigation of

heterogeneity suggested important variability between trials but……

2015


Trattamento: HBOT

Eleven trials contributed to this review

(669 participants).

For pooled analyses, investigation of

heterogeneity suggested important variability between trials but……

2015

Limiti HBOT:

- Esiguità numero centri

- Tempo trattamento (60-120min)

- Durata trattamenti (30-70 sedute)

- Costi


Linee-guida mucositi iatrogene

Cancer 2014


Radiogenomica

2014

Performed a genome-wide association study on a cohort of individuals

with prostate cancer.

….. suggest that the TANC1 locus influences the development of late

radiation-induced damage


Radiogenomica

2014


Ruolo definito IMRT e IGRT

Ruolo definito “organ spacer”

Ruolo protoni ????

Scale tossicità: linguaggio comune

Non evidenza attuale ruolo preventivo farmaci sulla tossicità tardiva

Considerazioni: prevenzione


Definizione pazienti ad alto rischio di tossicità tardiva

Pazienti portatori di markers molecolari???? (Fachal 2014, Barnett 2014)

Pazienti con proctite acuta attinica

Dorr and Hendry; Radiother Oncol 2001

Campostrini et al IJROBP 2013 (rischio di tox nel 77% pz con segni endoscopici di mucosite acuta attinica)

Woertel et al IJROBP 2015-2016

Studi prospettici di prevenzione farmacologica in questo sottogruppo di pazienti


Showalter et al 2014


Definizione pazienti ad alto rischio di tossicità tardiva

Pazienti portatori di markers molecolari???? (Fachal 2014, Barnett 2014)

Pazienti con proctite acuta attinica

Dorr and Hendry; Radiother Oncol 2001

Campostrini et al IJROBP 2013 (rischio di tox nel 77% pz con segni endoscopici di mucosite acuta attinica)

Woertel et al IJROBP 2015-2016

Studi prospettici di prevenzione farmacologica in questo sottogruppo di pazienti


Showalter et al 2014


Assenza studi randomizzati

Evidenza scientifica efficacia farmacologica derivante da piccoli studi (no EBM I Livello)

Non evidenza scientifica di superiorità di un trattamento locale endoscopico/HBOT per mancanza studi randomizzati (no EBM I Livello)

Considerazioni: trattamento


Documents

Tenesmo rettale e radioterapia - nicsonet.it · during and 2 weeks after RT. The grade of proctitis was registered in a daily diary. The grade of proctitis was registered in a daily