sbrt in head and neck cancer

SBRT in Head and Neck Cancer Workflow &

indication

Dr Rushi Panchal, MDConsultant Radiation OncologistM S Patel Cancer Centre,Shree Krishna Hospital,Karamsad-Anand, GujaratEmail id: [email protected] no: 09727757165

mailto:[email protected]

SBRT• Extra cranial Radiosurgery• Role in Primary case of Ca Lung/Prostate/Pancreas• Role in oligo-metastatic disease of spine/lung/liver/adrenal• Emerging data on head and neck cancer

SBRT in H&N Cancer • Indications• Efficacy• Toxicity profile• QoL• Fractionation • Target Definition• Constrains• Role of Cetuximab

Prospects in H & N Ca

• Salvage option for unresectable recurrent, previously irradiated SHNC.

• Definitive treatment of 2nd primary – unresectable & heavily irradiated earlier.

• Palliative radiotherapy metastasis to head and neck region from primary GI/Breast Cancer.

SBRT as re-irradiation• Rate of severe late toxicity of re-irradiation major concern because of poor tolerance of previous irradiated tissue.• SBRT has become an attractive alternative for the retreatment of patients with rSCCHN because of the highly conformal dose distribution(high precision of localization & delivery to target and small volume of normal tissue irradiated) as compared to 3D/IMRT intern causes less side effects, and delivered in the outpatient setting over 1 to 2 weeks as opposed to 3D/IMRT that last for 6-7week ( not be ethically compatible with expected survival for most patient).

PH-I Study

•All patients were treated to the 80% isodose line, whichwas intended to cover >90% of the target volume•Critical structure constraints were as follows:spinal cord maximum dose: <8 Gy; larynx: < 20 Gy; mandible: < 20 Gy; parotid: variable; brainstem: <8 Gy; oral cavity: variable

Heron et al. IJROBP 2009

In the present study, we found that in the short term SBRT was feasible and safe. The overall responserate in this group of heavily pre-treated patients was 28% (CR + PR). No Grade 3 or 4 toxicities were noted among our patients.

Metabolic response may precede anatomic response seen on CT good agreementbetween PET and CT for the assessment of CR and PD.


Vargo et al, IJROBP 2015

•This ph I study evaluated the feasibility of dose escalation in rSCCHN and met its accrual without dose-limiting toxicity at 8.8 Gy per fraction to 44 Gy in 5 fractions However, survival and durable control remained suboptimal.

•Therapy began with a loading dose of cetuximab, 400 mg/m2, intravenous (IV) infusion over 120 minutes on day - 7 and then 250 mg/m2 on days 0 and +8 during the SBRT course.

• Tumors <25 cc received 8.0 Gy per fraction for 5 fractions to 40 Gy; tumours >25 cc received 8.8 Gy per fractions for 5 fractions to 44 Gy

• Prescription IDL were chosen to at least encompass 95% of the PTV with no more than 20% of any PTV receiving doses >110% of the prescribed dose, no more than 2% of any PTV receiving <93% of the prescribed dose, and no more than 5% of any normal tissue receiving doses in excess of 110% of the primary PTV dose.

• cumulative spinal cord dose not exceed 50 Gy at the equivalent dose of 2 Gy per fraction, whereas the remaining normal tissues be constrained as much as possible without compromising the target volume on a case-by-case determination

Ph-II Study


• GTV-to-PTV expansion(3-5mm), PTV volumes were often reduced from the skin to account for the dose build-up region in plan optimization and, might elect to reduce the PTV expansion in proximity to surrounding serial critical organs to prevent circumferential treatment of adjacent critical organs.

• Daily image guidance is mandatory, with each fraction either by cone beam CT or the 6-dimensional skull-based or X-sight tracking system

Ph-II Study


1-year local PFS was 60% 1-year locoregional PFS was 37% 1-year distant PFS was 71%1- year PFS was 33% median overall survival was 10m 1-year overall survival of 40%Vargo et al, IJROBP 2015

No grade IV toxicity present studyNo carotid blow out syndrome

difference in oropharyngeal cancer patients( HPV +)between the French trial (80%) and the presented study

(42%) may explain the slight survival differencesVargo et al, IJROBP 2015

62% patients reporting improved or stabilized overall QoL at the time of the last survey compared to baseline, which suggests that SBRT plus Cetuximab did not negatively impact QoL and helped in most patients


Vargo et al. radiotherapy and oncology 2012

here-in demonstrate that QoL was preserved following SBRT re-irradiation, as evidenced by progressive improvements in PR-QoL noted throughout the duration of clinical follow-up across all domains in a validated PRQoL assessment tool independent of age, use of cetuximab, tumor volume, and interval since prior irradiation.

Vargo et al. radiotherapy and oncology 2012

• There were no significant differences in local control, distant control, or overall survival by reirradiation interval, treatment platform (cyberknife /Triology/ Truebeam), or second primary versus local recurrence.

• Recurrent GTV (<25 cm3) was associated with significantly improved locoregional PFS (1 year, 53%, and 22%, p 0.029%) and overall survival (1 year, 70%, and 22%,p <0.01).

• Compared to our prior phase 1 dose escalation study, the combination of 40 to 44 Gy over 5 fractions plus 3 doses of Cetuximab translated into a 67% relative increase in median OS (10 vs. 6 months ) with acceptable toxicity.

• Short overall treatment time and low rates of acute toxicity which allow patients with a generally poor prognosis to complete a potentially aggressive salvage therapy without compromising QoL

Ph-II Study


Ph-II Study• Compliance with the prescribed treatment course in this protocol

was 100% (with only 4% requiring treatment interruption both of equivocal treatment association), which compares favourably to the prior RTOG 9911 experience with conventional reirradiation plus chemotherapy where RT was administered according to protocol in only 46% with but 74% completing the prescribed 4 cycles of cisplatin-paclitaxel.

• SBRT is safe , improved patient compliance & fewer treatment related toxicity & 1 year PFS is similar to another retreatment regimen.


prospective randomized phase 2 protocol that combines fractionated SBRT (40-50 Gy) plus concurrent cetuximab with or without concurrent radiation sensitizing docetaxel and 3 months of adjuvant cetuximab with or without concurrent full-dose docetaxel in hopes of improving outcomes in this challenging patient population of unresectable locally recurrent previously irradiated SCCHN (NCT02057107).

first report in the literature describing the use of SBRT as a definitive therapy forselected patients with primary cancers of the head and neck who were not eligible for or declined other treatment options

Siddiqui et al. IJROBP 2009

These patients had primary cancers in the lung (non–small-cell and small-cell lung cancers), breast (invasive lobular and invasive ductal carcinomas),renal cell carcinoma, gastric adenocarcinoma, and brain (glioblastoma multiforme). Sites of metastatic disease in the head-and-neck region were mandible, gingival mucosa, periorbital, maxillary, neck nodes, and scalp (three lesions in the patient with glioblastoma).


Comet et al. IJROBP 2011

No grade 4 toxicities were observed Four patients (10.3%) presented with grade 3 toxicities: mucositis, dysphagia, induration, and fibrosis, 3 of whom had received cetuximab as the concomitant treatment. Eight patients (20.6%) experienced grade 2 10 (25.6%) grade 1 toxicities. Altogether, 17 (43.6%) patients presented no toxicityOnly 2 patients with concomitant cetuximab experienced a skin rash

Comet et al. IJROBP 2011

Median overall survival was 13.6 months.One- and 2-year overall survival rates were 58% & and 24%.

• Treatment-related carotid blow-out syndrome was observed in 8 patients (17.8%), 7 (15.2% of whom died of bleeding from carotid.

• Bleeding was not statistically significantly related to tumor volume (p =0.682), response to treatment (p = 1.00), sex (p = 0.698), or time elapsed between SBRT and previous radiotherapy (p = 0.113). However, when the dose received by the carotid artery was grouped as <100% of the prescribed dose, a significant relation was observed between the carotid artery dose and bleeding (p = 0.021). None of the patients with carotid artery dose <100% experienced carotid blow-out syndrome.

• Bleeding occurred only in patients whose carotid artery walls were circumscribed by the tumor with a degree of >180 (p = 0.073).

Cengiz et al. IJROBP 2011

Yamazaki et al. radiotherapy and oncology 2015

Carotid blow out syndrome index

summation of number of risk factors; carotid invasion >180 (yes = 1, no = 0)presence of ulceration ( yes = 1, no = 0)lymph node area irradiation (yes = 1, no = 0)

The Cox regression model revealed that the hazard ratios to the index 268 [95% confidence interval (CI) = 8.04–896, p = 0.002] for index (3)31.2 (95% CI = 1.13–859, p = 0.04) for index (2)4.68 (95% CI = 0.17– 129, p = 0.36) for index (1)


Although the absence of these three risk factorscould be indicative of safer reirradiation, it does not necessarilysuggest 100% prevention of CBOS

Alternated day treatment is better: Sequentially 16% developed CBOS, whereas only 12% patients who received treatment every alternate day (group II) developed CBOS. Only 14% patients with CBOS survived in group I, whereas 50% in group II who developed CBOS survived.

mortality rate from CBS was 5.8% (22/381), and of the total number of CBS patients, the mortality rate was 68.8% (22/32). The median survival time after CBS was 0.1 month and the 1-year survival rate was 37.5%


In multivariate analysis, only skin invasion is identified as statistically significant prognostic factor after CBS


-The 1-year survival rate for the skin invasion (-) group was 42%, whereas no patient with active skin invasion survived beyond4 months (0% at 1 year, p = 0.0049)- Patients with necrosis/infection formation at CBS onset showed17% of 1-year survival rate, whereas 67% of value was identified incounterpart (p = 0.003)


• patients treated 1.8–2-Gy daily fractions or 1.2-Gy twice daily fractions rate of CBS was 1.3%.

• Patients treated with 1.5-Gy twice daily fractions over alternating weeks or with delayed accelerated hyperfractionation received concurrent chemotherapy, and the rate of CBS was 4.5% (p = 0.002).

• Intensity-modulated radiation therapy (IMRT) series reported bleeding rates of 0–3%.

• 6.6% of CBS ratio in SBRT seems to be higher than conventional Fraction.

• In conclusion, careful attention should be paid to the occurrence of CBS if the tumor is located adjacent to the carotid artery. The presence of skin invasion at CBS onset is ominous sign of lethal consequences.


Assessment of the impact of retrospectively adding margins/automatedPET volumes to the gross tumor volume (GTV) in patients with post-SBRT recurrences.

Target Volume delineation• Sharp dose fall-off and high dose per fraction of SBRT, accurate

tumor delineation and treatment planning are essential to adequately cover tumors while avoiding excessive toxicity.

• Primary head and neck cancer, standard practice is to contour regions of lymphatic drainage and large margins around the gross tumor volume (GTV). For conventional hyperfractionated re-irradiation of rSCCHN, many institutions have used margins of 6–10 mm around the GTV. However, there is no standard regarding the use of such margins for hypofractionated techniques such as SBRT for rSCCHN. Furthermore, the addition of margins has differed greatly between institutions studying this technique: Roh – 2-3mm , Siddiqui – ‘‘slight’’ margin , Unger – 2-10mm , Cengiz – none.

Target Volume delineation• A detailed description of our assessment of patterns of failure

following SBRT for rSCCHN can be found ,Pre-treatment planning scans and GTVs were deformed to posttreatment follow-up scans with Velocity A I™ (Velocity Medical Systems, Atlanta, GA), which uses a modified B-spline deformable registration algorithm with a mean error of 1–2 mm for noise-free Images. Use of deformable registration to analyze patterns of failure.

• Recurrent tumors were categorized: In-field (>75% inside GTV), Overlap (20–75% inside GTV), Marginal (<20% inside GTV but closest edge within 1 cm of GTV), or Regional/Distant (more than 1 cm from GTV). In-field, Overlap, and Marginal failures were considered local failures

Target Volume delineation

If internal physiological variations such as respiration and swallowing movements were anticipated, the contour was slightly overdrawn especially in the superior–inferior direction and was defined as the internal target volume (ITV).

For unresectable patients, especially in the intensity-modulated radiation therapy (IMRT) era, conventional re-irradiation ± chemotherapy offers potential for long-term salvage with LC rates >50% at 5-years combined with 2- to 5-year OS >30%, but is often balanced with significant acute (grade >/=3: mucositis 5–79%, dermatitis 16–46%, and neutropenia 18–26%) as well as latetoxicity (grade >/= 3 fibrosis 31–48%, trismus 9–24%, osteonecrosis 5–16%, and carotid blowout 2–5%)


(rSCCHN) with shorter treatment times (1–2 weeks), decreased toxicity (toxicity grade > 3: 0–20%), and comparable LC/OS (2-year LC 31–41%,2-year OS 14–50%) compared to conventional re-irradiation ± chemotherapy

Salama JK, et al. Semin Oncol 2008

Take home message on SBRT • SBRT was selected as the choice for reirradiation when the treating radiation

oncologist deemed full-dose re-treatment (i.e., >60 Gy) with either three-dimensional or IMRT as challenging because of proximity to the spinal cord or other critical structures

• Even if there is no demonstrated biological advantage (overcome the radioresistance of recurrent tumor cells) using hypofractionation in recurrent HNC, there is a major clinical advantage in keeping the overall treatment time ) short, improved therapeutic ratio (local control/morbidity) in a population with a poor clinical prognosis.

• Combining with targeted therapies has the advantage of minimal acute toxicity, with the exception of an acceptable skin rash for patients with short life expectancy

• The lack of hematologic or systemic toxicity permits the inclusion of patients in poor general condition.

• Acute Mucositis was temporary and well managed with supportive care• 5 Fraction protocol alternative day is better for toxicity than delivered daily(<10% vs.

20%)

Take home message on SBRT • reirradiation with IMRT or conventionally fractionated SBRT is relatively safe with

regard to carotid blowout syndrome; however the risk of Grade 3 and 4 toxicities is high . So, in patients with carotid arteries entrapped by the tumor, SBRT with hypofractionation should be cautiously delivered. IMRT or conventionally fractionated SBRT may be a better treatment option in these cases. Another possible approach is to delineate the carotid artery and define it as an organ at risk to prevent hot spots of >100 Gy (EQD 2) on significant carotid sheath volumes . Similarly, in the Turkish study, all the patients who developed CBOS had received a maximal carotid artery dose of >34 Gy.

• CT and/or Doppler ultrasound surveillance might be helpful to detect carotid radionecrosis and indicate prophylactic intervention for preventing CBOS.

• At present, cases of recurrent head and neck cancers with carotid invasion of >180, the presence of ulceration, and irradiation to areas of lymph nodes are not good candidates for SBRT.

• SBRT for previously-irradiated, recurrent squamous cell carcinoma of the head and neck (rSCCHN) have demonstrated control rates comparable to Conventional radiotherapy with acceptable treatment- related toxicities.

Thank you

sbrt in head and neck cancer

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