The next ASTRO 2021 Congress was held in Chicago in a mixed format. It seems that the second year of the pandemic has shown us all that it is not necessary to go a long way to actively participate in an event and even give lectures, almost without interrupting current affairs. Of course, live communication can not be replaced – but there is a risk of succumbing to a sedentary lifestyle.
Some news from ASTRO 2021
Neoadjuvant chemotherapy has become an integral part of the treatment plan for most breast cancerpatients. In many patients, it is possible to achieve a pronounced – up to complete – regression of the tumor. But at the same time, such a scenario raises many questions for radiotherapists, one of them: is it necessary to irradiate patients with previously clinically positive lymph nodes, who subsequently have a full pathomorphological response to NACHT? Extrapolating from earlier studies demonstrating the benefits of adding LT to regional areas, many radiotherapists prefer to irradiate them for any lesion, regardless of the response to chemotherapy. However, a number of retrospective studies also show that the risk of relapse with a full response even without radiation is low. Irradiation, as you know, increases the frequency of local complications – lymphostasis, fibrosis, pneumonitis. The eagerly anticipated prospective study of NSABP B-51 (RTOG 1304), designed to evaluate the effect of LT in patients with complete pathomorphological regression after NACHT, will be completed tentatively in July 2023. In the meantime, preliminary results for the average follow-up period of 24 months were presented at the congress . 231 patients with clinically positive lymph nodes were recruited, all of them were diagnosed with a complete response to the lymph nodes after NAHT and surgery. One group of patients underwent LT for regional zones (112 patients), the other – no (119).
Relapses in the lymph nodes in both groups were noted. Survival without local progression was comparable: 98.2% in the LT group and 100% in the follow-up group (p = 0.28); survival without distant metastases – 93.6% against 97.4% (p = 0.93), respectively. Overall survival also did not differ between the groups: 96.3% versus 99.1% (p= 0.75), with only age younger than 35 years being the factor associated with worse survival (p= 0.03). The data demonstrate that avoiding irradiation of regional areas in patients with cN+ and ypN0 after NAHT does not impair long-term treatment outcomes. We are waiting for the final long-term data.
In the treatment of patients with recurrent breast cancer – after resection or mastectomy – a strictly individual approach is extremely necessary. In addition to systemic treatment, in most cases it comes to radiation, but many patients have previously received radiation therapy during primary treatment, and the possibilities of repeated irradiation, alas, are already limited. At the same time, a number of studies demonstrate that repeated salvaic radiation therapy is possible both after organ-preserving treatment (partial irradiation option) and after mastectomy. In such situations, protons are the best choice. AT ASTRO 2021, the results for salvagic proton LT in the recurrence of breast breast grac are presented, and so far this is the largest series of data on this problem. Researchers from Memorial Sloan Kettering Cancer Center, New York Proton Center (MSKCC/NYPC) and ProCure Proton Therapy Center, New Jersey, performed proton LT on 46 patients with breast recurrence, with 17.4% irradiated breast, 28.3% breast wall without reconstruction, and 43.5% chest wall after reconstruction; 11% had only relapses in the region of regional lymph nodes. The average dose of LT with repeated irradiation was 50.4 Gy, and the cumulative dose reached 109 Gy (in recalculation by 2 Gy). For the average follow-up period of 21 months after salvagnaya LT, neither local nor regional relapses were recorded. Not without complications: early toxicity of the 3rd degree was represented only by dermatitis in 30% of patients. Of the late complications of the 3rd degree, capsular contracture was noted in 3 patients and pain in one. These preliminary data demonstrate the logic of the use of proton irradiation in patients with relapses with good tolerance and excellent local effect .
Determining the optimal sequence for immunotherapy for locally advanced non-small cell lung cancer (NSCLC) remains an open question. Updated data from the PACIFIC study reported an unprecedented five-year overall survival rate of 33.1% in stage 3 NSCLCS with durvalumab consolidation after chemoradiation therapy. However, in real-world settings, the discontinuation rate of durvalumab due to side effects is 16.7% . In addition, a recent multicenter Dutch real-world analysis showed that only 57% of patients received the adjuvant durvalumab in stage 3 NSCLS . The task of increasing the proportion of patients receiving immunotherapy continues to be relevant.
It was in this context that researchers at H. Lee Moffitt Cancer Center studied the combination of ipilimumab (anti-CTLA-4) in combination with chemoradiotherapy followed by consolidation with nivolumab (anti-PD-1) . According to data obtained in a preclinical model in mice, the combination was acceptable, with 3% of mice dying from simultaneous chest LT and anti-PD-1 therapy. In this study, presented at ASTRO 2021, patients with stage 3 NSCLC received a platinum-based chemotherapy doublet with simultaneous radiation therapy of up to 60 Gy for 30 fractions for six weeks and two doses of IPI (1 mg/kg) at 1 and 4 weeks, followed by maintenance treatment of 12 cycles of nivolumab every four weeks (480 mg). The main endpoints were security and portability of the mode (phase I) and 12 months (phase II) BBS.
The study was terminated early, as 19 of the planned 55 patients exceeded the toxicity limit. The incidence of grade 2+ pneumonis at 6 and 12 months was 57% (CI 30-84) and 74% (CI 49-99), respectively. Five patients (26%, CI 6-46) had grade 5 toxicity most likely associated with treatment, including three patients with grade 5 pulmonary toxicity (16%, CI 0-32). There was no association of moderate lung dose or V20 with increased toxicity, suggesting that such negative events were caused primarily by immunotherapy.
Previously, the ETOP-NICOLAS study reported nine patients (11.7%) with grade 3+ pneumonitis and seven (6%) cases of grade 5 toxicity associated with treatment with chemoradiation therapy with simultaneous and adjuvant nivolumab in patients with stage 3 NSCLCS . Thus, the use of a combination of ipilimumab and nivolumab may be too dangerous in combination with chemoradiotherapy. The main conclusion of the study: alternative strategies or sequences for integrating immunotherapy with cytotoxic chemotherapy and radiation therapy for patients with stage 3 inoperable NSCLC should be carefully examined. And it looks like a lot of work will have to be done to optimize the outcomes in these patients in the era of immunotherapy.
But there is good news regarding radiation therapy for oligometastatic NSCLC. Previously, the SABR-COMET study demonstrated the advantage of overall survival with consolidated stereotactic ablative radiation therapy of the body compared to standard palliative radiation therapy in patients with oligometastatic disease and controlled primary process. In SABR-COMET, 3 of the 66 participants (4.5%) in the SABR group died due to treatment (grade 5 toxicity), which many believed was unexpectedly high toxicity to ablative radiation therapy. Thus, the SABR-5 study was designed with the main goal of establishing more precise toxicity criteria in preparation for a possible Phase III randomized trial.
SABR-5 is a population-based single-arm Phase II study of stereotactic ablative radiation therapy for all lesions in patients with five oligometastatic or oligoprogressive lesions and a controlled primary tumor . 399 patients were included (which exceeds the original goal of 200 participants). The primary endpoint was toxicity with the a priori determination that SABR is clinically safe if the risk of Grade 3 toxicity does not exceed 25%, the risk of Grade 4 toxicity is up to 10%, and the risk of Grade 5 toxicity is up to 5%. The main inclusion criteria were a controlled primary tumor, ECOG 0-2 with a life expectancy of more than six months, and the presence of distant metastases (including the brain) of 5 or less, which were considered safe for radiation. Depending on the anatomical location, standard ablative dose regimens were used. Dose restrictions for risk organs (OAR) took precedence over PTV coverage. The average follow-up period was 28 months. Nineteen patients did not receive SABR after enrollment in the study (the final number of patients included for analysis is 380). The most common tumor localizations were prostate cancer (32%), colorectal cancer (14%), breast cancer (11%), lung cancer (9%), and kidney cancer (9%). The number of foci exposed to SABR was one (69%), two (22%) and three or more (9%). The most common targets for SABR were foci in the lungs (33%), bones outside the spine (28%), spine (14%), lymph nodes (13%), liver (5%), and adrenal glands (3%).
Updated toxicity data were presented at ASTRO 2021. The frequency of complications was: 2 degrees – 14.2% (n = 54), 3 degrees – 4.2% (n = 16), 4 degrees were not recorded and 1 patient died (0.3%) for reasons related to treatment. Grade 3 toxicity or more most often included: 1.3% pain, 1.1% spinal fractures, 0.3% diarrhea and other manifestations including nausea/vomiting, bile duct stenosis, jaundice, fatigue, ascites and hydronephrosis. There were no rib fractures of grade 3+ degree, neuropathy, gastrointestinal fistulas, perforations, hemorrhages or pneumonitis.
The only complication of grade 5 among 380 patients arose in a patient irradiated with two metastases of colorectal cancer to the liver, who received 54 Gy for 3 fractions. One of the foci was in the gate of the liver. Fifteen months after SABR, the patient required an intervention for bile duct stenosis, which could be due to disease progression or SABR toxicity. The patient’s death occurred directly due to recurrent infections caused by cholangitis and was assessed by the toxicity committee as “possibly related” to SABR. An independent external examination conducted by infectious disease specialists testifies in favor of death associated with infections associated with the outflow of the external biliary tract.
Overall, SABR-5 demonstrates excellent results for patients with oligometastatic disease, confirming the changing landscape of cancer treatment thanks to advances in all areas of radiation oncology. OV after SABR for oligometastases was 93% for 1 year, for 2 years – 84%, for 3 years – 76% and 70% of the total survival for 4 years. The authors conclude that carefully planned SABR for oligometastases is relatively safe, with very moderate toxicity. This supports the continued conduct of phase III randomized trials such as SABR-COMET-3 and SABR-COMET-10. However, the toxicity of SABR to liver and adrenal metastases requires caution and further study. Future studies should continue to study toxicity, given the relatively long overall survival of this patient population. SABR-5 is a truly landmark study that highlights the primary role of radiation therapy in the treatment of patients with metastatic disease and adds to the list of literature that favors the use of SABR over traditional purely palliative approaches.
The ASTRO 2021 Congress is also notable for what it demonstrated: the joint session of the two professional communities – ASTRO and RUSSCO – is becoming regular and traditional. In 2019, even before the pandemic, the first such session was held at the largest congress on radiation oncology in the world, it was devoted to various aspects of palliative radiation therapy. In 2020, the congress was held in an online format, and our second joint session was devoted to the treatment of patients with head and neck tumors in countries with reduced resources. Finally, the third session was held on 25 October in a mixed format. Some of the speakers, including the current president of ASCO Lorie Pierce, Professor Alphonse Taghian of Harvard Medical School and the chairman of the session Timur Mitin, were in the hall of the McCormick center in Chicago, the rest were present online – William Pirl, an oncopsychologist from the Dana Farber Cancer Center, Dan Spratt from the Seidman Cancer Center Case Western Reserve University, on the part of RUSSCO – Natalia Dengina as a speaker and Marina Chernykh as a moderator. At first glance, the topic of the session was not directly related to radiation therapy, since it was devoted to the issues of emotional and mental disorders in cancer patients during treatment. But the lecturers have demonstrated that considerable attention is paid to this problem in the world, numerous large population studies demonstrate: patients with a violation of the psycho-emotional state without the necessary correction have worse treatment results, a higher risk of progression. This is especially true of patients with prostate and breast tumors. Oncopsychologists should be on the staff of each cancer center, and, alas, in Russia this problem remains unheeded and, accordingly, without a solution. The help of oncopsychologists (or ordinary psychologists) is sporadic, limited and geographically uneven. If St. Petersburg has its own school, then in many other, even large cities, oncopsychologists are absent at all. This topic is worth returning separately.
In any case, it is safe to say: by the anniversary of RUSSCO and the Russian Cancer Congress, the ties between the two professional communities have strengthened, and cooperation looks promising. At the anniversary XXV Congress, the fourth joint session of ASTRO-RUSSCO will be held, dedicated to the problem of the use of radiation therapy in patients with NSCLC with brain metastases in the era of targeted and immunotherapy.
- Diaa M, et al. The Impact of Regional Nodal Irradiation on the Outcomes After Neoadjuvant Chemotherapy in Node Positive Breast Cancer Patients With ypN0: Interim Analysis of a Prospective Randomized Trial. IJROBP. 2021; 111(3): S109-S110.
- Choi IJ, et al. Proton Reirradiation for Recurrent or New Primary Breast Cancer in the Setting of Prior Breast Irradiation. IJROBP. 2021; 111(3): S110.
- Girard N, Smit H, Sibille A, McDonald F, Mornex F, Garassino M, et al. 1171MO PACIFIC-R real-world study: Treatment duration and interim analysis of progression-free survival in unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy. Annals of Oncology. 2021; 32: S939-S40.
- Ronden MI, Bahce I, Claessens NJM, Barlo N, Dahele MR, Daniels JMA, et al. The Impact of the Availability of Immunotherapy on Patterns of Care in Stage III NSCLC: A Dutch Multicenter Analysis. JTO Clinical and Research Reports. 2021; 2.
- Liveringhouse C, et al. Prospective Phase I/II Study of Radiation and Chemotherapy With Ipilimumab Followed by Nivolumab for Patients With Stage III Unresectable NSCLC. IJROBP. 2021; 111(3): S3-S4.
- Peters S, et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial. Lung Cancer. 2019 Jul; 133: 83-87. doi: 10.1016/j.lungcan.2019.05.001. Epub 2019 May 3. PMID: 31200833.
- Olson RA, et al. Population Based Phase II Trial of Stereotactic Ablative Radiotherapy (SABR) for up to 5 Oligometastases: Preliminary Results of the SABR-5 Trial. IJROBP. 2021; 111(3): S4.