M. Fenton-Kerimian

Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial

BACKGROUND An abscopal response describes radiotherapy-induced immune-mediated tumour regression at sites distant to the irradiated field. Granulocyte-macrophage colony-stimulating factor is a potent stimulator of dendritic cell maturation. We postulated that the exploitation of the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor might result in abscopal responses among patients with metastatic cancer. METHODS Patients with stable or progressing metastatic solid tumours, on single-agent chemotherapy or hormonal therapy, with at least three distinct measurable sites of disease, were treated with concurrent radiotherapy (35 Gy in ten fractions, over 2 weeks) to one metastatic site and granulocyte-macrophage colony-stimulating factor (125 μg/m(2) subcutaneously injected daily for 2 weeks, starting during the second week of radiotherapy). This course was repeated, targeting a second metastatic site. A Simons optimal two-stage design was chosen for this trial: an additional 19 patients could be enrolled in stage 2 only if at least one patient among the first ten had an abscopal response. If no abscopal responses were seen among the first ten patients, the study would be deemed futile and terminated. The primary endpoint was the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion). Secondary endpoints were safety and survival. Analyses were done based on intention to treat. The trial has concluded accrual, and is registered with ClinicalTrials.gov, number NCT02474186. FINDINGS From April 7, 2003, to April 3, 2012, 41 patients with metastatic cancer were enrolled. In stage 1 of the Simons two-stage design, ten patients were enrolled: four of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled. Due to protocol amendments 12 further patients were enrolled. Abscopal responses occurred in eight (27·6%, 95% CI 12·7-47·2) of the first 29 patients, and 11 (26·8%, 95% CI 14·2-42·9) of 41 accrued patients (specifically in four patients with non-small-cell lung cancer, five with breast cancer, and two with thymic cancer). The most common grade 3-4 adverse events were fatigue (six patients) and haematological (ten patients). Additionally, a serious adverse event of grade 4 pulmonary embolism occurred in one patient. INTERPRETATION The combination of radiotherapy with granulocyte-macrophage colony-stimulating factor produced objective abscopal responses in some patients with metastatic solid tumours. This finding represents a promising approach to establish an in-situ anti-tumour vaccine. Further research is warranted in this area. FUNDING New York University School of Medicines Department of Radiation Oncology and Cancer Institute.

PRONE ACCELERATED PARTIAL BREAST IRRADIATION AFTER BREAST-CONSERVING SURGERY: FIVE YEAR RESULTS OF 100 PATIENTS

PURPOSE To report the 5-year results of a prospective trial of three-dimensional conformal external beam radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation in the prone position. METHODS AND MATERIALS Postmenopausal patients with Stage I breast cancer with nonpalpable tumors <2 cm, negative margins and negative nodes, positive hormone receptors, and no extensive intraductal component were eligible. The trial was offered only after eligible patients had refused to undergo standard whole-breast radiotherapy. Patients were simulated and treated on a dedicated table for prone setup. 3D-CRT was delivered at a dose of 30 Gy in five 6-Gy/day fractions over 10 days with port film verification at each treatment. Rates of ipsilateral breast failure, ipsilateral nodal failure, contralateral breast failure, and distant failure were estimated using the cumulative incidence method. Rates of disease-free, overall, and cancer-specific survival were recorded. RESULTS One hundred patients were enrolled in this institutional review board-approved prospective trial, one with bilateral breast cancer. One patient withdrew consent after simulation, and another patient elected to interrupt radiotherapy after receiving two treatments. Ninety-eight patients were evaluable for toxicity, and, in 1 case, both breasts were treated with partial breast irradiation. Median patient age was 68 years (range, 53-88 years); in 55% of patients the tumor size was <1 cm. All patients had hormone receptor-positive cancers: 87% of patients underwent adjuvant antihormone therapy. At a median follow-up of 64 months (range, 2-125 months), there was one local recurrence (1% ipsilateral breast failure) and one contralateral breast cancer (1% contralateral breast failure). There were no deaths due to breast cancer by 5 years. Grade 3 late toxicities occurred in 2 patients (one breast edema, one transient breast pain). Cosmesis was rated good/excellent in 89% of patients with at least 36 months follow-up. CONCLUSIONS Five-year efficacy and toxicity of 3D-CRT delivered in prone partial breast irradiation are comparable to other experiences with similar follow-up.

Feasibility of Accelerated Whole-Breast Radiation in the Treatment of Patients with Ductal Carcinoma In Situ of the Breast

BACKGROUND We report the results of a prospective trial investigating the use of accelerated, hypofractionated whole-breast radiation therapy after breast-conservation surgery for ductal carcinoma in situ (DCIS). PATIENTS AND METHODS A total of 59 patients with a median age of 54 years (range, 36-78 years) completed a phase I/II study of hypofractionated radiation therapy for treatment of DCIS. Eligibility criteria included patients with mammographically detected DCIS, status after segmental mastectomy with negative margins, and no residual calcifications. All patients were treated with external-beam radiation therapy without a boost, over 3 weeks, to a total dose of 42 Gy to the entire breast (2.8 Gy per fraction in 15 fractions). To optimally spare heart and lung, 34 of the 59 patients (57%) were treated in the prone position. Twenty-nine of 59 patients (49%) received adjuvant hormonal therapy. RESULTS Overall, radiation therapy was well tolerated, with modest acute toxicity limited to grade 1 radiation dermatitis (76%), breast edema (17%), and fatigue (12%). With a median follow-up of 36 months, late toxicities included grade 1 hyperpigmentation changes (85%), induration (66%), asymmetry (64%), and breast fibrosis (17%), with 3 cases of grade 2 fibrosis and 1 case of grade 2 hyperpigmentation. Among the patients with >or= 3 years of follow-up, cosmesis was scored as good to excellent in 21 patients (91%) and fair in 2 patients (9%). At the time of this report, no ipsilateral or contralateral breast recurrences have occurred. CONCLUSION These data demonstrate the feasibility of treating the whole breast for DCIS with a hypofractionated regimen, with modest acute and late toxicity.

Comparison of Acute and Late Toxicity of Two Regimens of 3- and 5-Week Concomitant Boost Prone IMRT to Standard 6-Week Breast Radiotherapy

Purpose: Limited information is available comparing toxicity of accelerated radiotherapy (RT) to that of standard fractionation RT for early stage breast cancer. We report early and late toxicities of two prone regimens of accelerated intensity-modulated radiation therapy (IMRT) with a concomitant boost (CB) to the tumor bed delivered over 3 or 5 weeks as compared to standard 6 week RT with a sequential electron boost. Methods: From 2/2003 to 12/2007, 169 consecutive patients with Stage I–II breast cancer were offered the choice to undergo prone RT with either: a 6-week standard RT regimen of 46 Gy/23 fractions (fx) to the whole breast (WB), followed by a14 Gy sequential boost (SB) to the tumor bed (6wSB), a 5-week regimen of 50 Gy to WB with an IMRT CB of 6.25 Gy in 25 fx (5wCB); or a 3-week protocol of 40.5 Gy to WB with an IMRT CB of 7.5 Gy in 15 fx (3wCB). These regimens were estimated as biologically equivalent, based on alpha/beta = 4 for tumor control. Toxicities were reported using RTOG and LENT/SOMA scoring. Results: 51/169 patients chose standard 6wSB, 28 selected 5wCB, and 90 enrolled in 3wCB protocol. Maximum acute toxicity was Grade 3 dermatitis in 4% of the patients in the 6wSB compared 1% in 3wCB. In general, acute complications (breast pain, fatigue, and dermatitis) were significantly less in the 3wCB than in the other schedules (P < 0.05). With a median follow-up of 61 months, the only Grade 3 late toxicity was telangiectasia in two patients: one in 3wCB and one in 5wCB group. Notably, fibrosis was comparable among the three groups (P = NS). Conclusion: These preliminary data suggest that accelerated regimens of breast RT over 3 or 5 weeks in the prone position, with an IMRT tumor bed CB, result in comparable late toxicity to standard fractionation with a sequential tumor boost delivered over 6 weeks. As predicted by radiobiological modeling the shorter regimen was associated with less acute effects.

Breast, chest wall, and nodal irradiation with prone set-up: Results of a hypofractionated trial with a median follow-up of 35 months

PURPOSE To test clinical feasibility, safety, and toxicity of prone hypofractionated breast, chest wall, and nodal radiation therapy. METHODS AND MATERIALS Following either segmental or total mastectomy with axillary node dissection, patients were treated in an institutional review board-approved prospective trial of prone radiation therapy to the breast, chest wall, and supraclavicular and level III axillary lymph nodes. A dose of 40.5 Gy/15 fractions with a concomitant daily boost to the tumor bed of 0.5 Gy (total dose, 48 Gy) was prescribed. In postmastectomy patients, the same treatment was prescribed, but without a tumor bed boost. The primary endpoint was incidence of >grade 2 acute skin toxicity. The secondary endpoints were feasibility of treatment using prone set-up, compliance with protocol-defined dosimetric constraints, and incidence of late toxicity. A dosimetric comparison was performed between protocol plans (prone) and nonprotocol plans (supine), targeting the same treatment volumes. RESULTS Sixty-nine patients with stage IB-IIIA breast cancer enrolled in this trial. Surgery was segmental mastectomy (n = 45), mastectomy (n = 23), and bilateral mastectomy (n = 1), resulting in 70 cases. None experienced >grade 2 acute skin toxicity according to the Common Terminology Criteria for Adverse Events, v 3.0, meeting our primary endpoint. Ninety-six percent of patients could be treated with this technique prone. However, 17 plans (24%) exceeded protocol constraints to the brachial plexus. Maximum long-term toxicity was 1 grade 2 arm lymphedema, 1 grade 3 breast retraction, and no occurrence of brachial plexopathy. Dosimetric comparison of protocol with nonprotocol plans demonstrated significantly decreased lung and heart doses in prone plans. CONCLUSIONS Prone hypofractionated breast, chest wall, and nodal radiation therapy is safe and well tolerated in this study. Although the initial pattern of local and regional control is encouraging, longer follow-up is warranted for efficacy and late toxicity assessment, particularly to the brachial plexus.

Results of a phase I–II study of adjuvant concurrent carboplatin and accelerated radiotherapy for triple negative breast cancer

ABSTRACT Purpose: To determine feasibility and explore the clinical efficacy of concurrent radiotherapy and carboplatin as adjuvant treatment of triple negative breast cancer (TNBC). Patients and Methods: Women with Stage I-II TNBC were treated after surgery in a phase I–II prospective trial [NCT01289353]. Weekly carboplatin (AUC = 2.0) was delivered for 6 weeks. Concurrent radiotherapy was delivered in the prone position during weeks 2–4, for a total dose of 40.5 Gy in 15 fractions to the breast, and 46.5 Gy in 17 fractions to the tumor bed. Adverse events (AE) were assessed weekly during treatment, once at 45–60 d, and every 6 mo thereafter, using the Common Terminology Criteria for AE (CTCAE) v3.0. Results: A total of 39 patients accrued and 36 received treatment. Eight patients (22%, exact 95% CI: 10%, 39%) developed grade 2 or greater acute radiation dermatitis. Overall, grade 2 AE were seen in nine and grade 3 in two patients. Twenty-three patients (64%) received additional adjuvant chemotherapy. With a median follow-up of 48 mo, 34/36 (94%) are alive and disease free. One patient died of pulmonary failure with possible but unproven breast cancer recurrence, and one patient died of pelvic malignancy. One patient recurred locally and is alive and disease free after surgical management. Brisk lymphocytic infiltrate was present pre-treatment in 39% of 18 patients with evaluable tumor. Conclusions: Adjuvant concurrent carboplatin and prone accelerated radiotherapy is a well-tolerated and promising treatment of early stage TNBC. The observed 3% compares favorably with the expected 30% recurrence rate within 1–4 y from treatment, warranting further studies.

Optimal Topical Agent for Radiation Dermatitis During Breast Radiotherapy: A Pilot Study.

BACKGROUND Women receiving radiation to the breast will likely be recommended to use a topical cream to minimize and delay the development of radiation dermatitis. Although many topical products are commercially available and have been tested for safety and efficacy, few studies have compared various products to one another for superiority and cost effectiveness. OBJECTIVES The purpose of this pilot study was to compare three commonly used skin care products prospectively to one other in a homogenously controlled group of women undergoing whole breast irradiation to assess superiority in minimizing the common toxicity criteria grade of radiation dermatitis, effect on quality of life, and cost. METHODS The authors conducted a systematic review to determine the three types of skin care products with the strongest evidence of minimizing radiation dermatitis. Patients were voluntarily enrolled and randomized to one of three possible skin care topical regimens. Patients completed a quality-of-life survey to assess their preference in topical skin care regimen. The cost of each arms topical product was assessed at the completion of patient participation. FINDINGS No statistical difference was noted in the severity or occurrence of radiation dermatitis among the groups. In addition, no statistical difference was found among the three treatment arms in quality-of-life score changes, and no patients required a treatment interruption in their radiation or in the skin care product during treatment. A cost difference among the treatment arms was noted.

Changes in breast radiotherapy: prone positioning and hypofractionation.

Breast cancer management has drastically changed since the 1990s. Many patients with breast cancer now can opt to conserve their breast through a lumpectomy and radiation (breast conservation therapy), rather than a full mastectomy. Advances in the techniques of delivery and length of breast radiotherapy have been rapidly evolving. This article attempts to summarize some of those changes for nurses caring for patients with breast cancer during radiation therapy.

Abstract 244: Abscopal responses in patients with refractory metastatic NSCLC treated with concurrent radiotherapy and CTLA-4 immune checkpoint blockade: evidence for the in situ vaccination hypothesis of radiotherapy

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: The current median survival for patients with metastatic NSCLC is ∼7 mos. Novel approaches, such as immunotherapy, are warranted. Recent success with immune checkpoint blockade in metastatic NSCLC has been reported for blocking antibodies to PD-L1 and PD-1, but not to CTLA-4. We demonstrated pre-clinically that radiotherapy (RT) incites immunogenic cell death and enables cross-priming of tumor specific effector T-cells by DCs to eliminate in field and abscopal (ab-scopus, away from the target) metastases. We reported the 1st complete abscopal response in a patient with metastatic NSCLC, treated with RT and ipilimumab, who remains disease free >2.5 yrs. Thus, we initiated a prospective clinical trial (NYU S14-00208) to test this regimen in similar patients. We report the preliminary results on eight evaluable patients, who completed treatment. Methods: Eligible patients had chemo-resistant metastatic NSCLC, progressed on at least 1 chemotherapy regimen, ≥2 measurable lesions, ECOG PS ≤1, life expectancy >3 mos, non-steroid dependent, and no active intracranial disease. The first cohort consisted of patients treated with 6Gy x5 plus ipilimumab (3mg/kg x4 cycles). Patients were evaluated with pre and post-treatment (day 81 from treatment inception) PET/CTs. Results: Eight patients treated are currently evaluable (Table). The median prior chemotherapy regimens was 2, prior RT courses was 1.5, and time from diagnosis of metastatic disease was 6.75 mos. Conclusion: Metastatic NSCLC is only marginally responsive to CTLA-4 blockade alone; yet, our preliminary data suggest that with the addition of RT, objective responses are more common. This novel approach to treating metastatic NSCLC holds tremendous promise. The trial continues the planned accrual of 29 patients. | # | Time from Metastatic Disease (Mos) | # of Prior Treatments | Irradiated Site | irRECIST PET/CT | Best Abscopal Response | Maximum Toxicity | |:-- | ---------------------------------- | --------------------- | ---------------------------------------- | --------------- | -------------------------- | ---------------- | | 1 | 4.3 | 3 chemo | L para-spinal mass | SD (-37.5%) | L hilar lymph node | G2 fatige | | | | 2 RT | | | PR (-68%) | | | 2 | 38.5 | 4 chemo | L fissural nodule | SD (+7.2%) | L diaphragmatic lymph node | G2 rash | | | | 3 RT | | | SD (-16.7%) | | | 3 | 0.9 | 2 chemo | R anterior pleural nodule | CR (-100%) | R pleural nodule | G2 rash | | | | 2 RT | | | CR (-100%) | | | 4 | 3.5 | 1 chemo | R hilum | CR (-100%) | L Sclav lymph node | G3 (ALT) | | | | 1 RT | | | CR (-100%) | | | 5 | 7 | 1 chemo | R upper lobe nodule | POD (+57%) | R Sclav lymph node | G1 pruritis | | | | | | | SD (+10%) | | | 9 | 18.4 | 2 chemo | Porta hepatis lymph nodes | SD (+15%) | Peripancreatic lymph node | G1 fatigue | | | | 2 RT | | | PR (-65%) | | | 10 | 16 | 2 chemo | R lower lobe, posterior to the hilum | POD (+47.9%) | R peri-hilar lymph node | G2 pruritis | | | | | | | SD (+10%) | | | 11 | 6.5 | 1 chemo | Posterior L lower lobe subpleural nodule | POD (+479%) | Medial L lung base | G2 dyspnea | | | | | | | SD (-6.25%) | | Table: CR = complete response, PR = partial response, SD = stable disease, POD = progression of disease Citation Format: Encouse B. Golden, Abraham Chachoua, Maria Fenton-Kerimian, Sandra Demaria, Silvia C. Formenti. Abscopal responses in patients with refractory metastatic NSCLC treated with concurrent radiotherapy and CTLA-4 immune checkpoint blockade: evidence for the in situ vaccination hypothesis of radiotherapy . [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 244. doi:10.1158/1538-7445.AM2015-244

Abstract OT2-1-02: Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiotherapy in the treatment of breast cancer chest wall recurrences or skin metastases

Background/Rationale: To assess the immune and systemic anti-tumor effects of the novel combination of local radiotherapy combined with imiquimod applied topically to breast cancer metastatic to skin. Breast cancer is the most common tumor, excluding melanoma, to metastasize to the skin in women. Chest wall recurrence is debilitating for patients, substantially affecting quality of life. Current treatment modalities for unresectable lesions are rarely curative and patients ultimately die of visceral metastases, indicating the need for more effective therapies. Imiquimod (IMQ), a synthetic TLR-7 agonist has immunomodulatory activity with profound effects on the tumor environment and can lead to tumor regression of cutaneous breast cancer metastases (Adams et al, Clin Ca Res, Dec 15, 2012). Accumulating evidence indicates that the potential of local radiotherapy to convert the tumor into an in-situ vaccine can be enhanced by combination with immunotherapy to achieve a therapeutic synergy. We have previously shown in a mouse model of cutaneous breast cancer that topical IMQ synergizes with local RT to induce complete tumor regression (REF). Importantly, this approach used a local treatment to generate anti-tumor immune responses with ability to control the tumor systemically (Dewan et al, Clin Ca Res Dec 15, 2012). This trial was designed to test the feasibility of translating this therapeutic synergy in the clinic (clinicaltrials.gov [NCT01421017][1]). Methods: Eligibility includes patients with biopsy-confirmed breast cancer, measurable disease and skin metastases, ECOG PS 0-2 and adequate organ/marrow function. Radiation therapy is delivered to one area of skin metastases in five fractions of 6 Gy (days 1,3,5,8,10). IMQ 5% cream is applied topically to skin metastases overnight for 5 days/week for 8 weeks, beginning the evening of the first radiotherapy. Continuous imiquimod to all skin metastases even after completion of RT is based on our preclinical evidence of an improved effector phase of the immune response. Additional treatment cycles with IMQ/RT are permitted. Following a brief phase I portion to allow dose optimization in the event of unanticipated adverse events (3-3 design), the phase II study evaluates efficacy with a planned additional 25 patients. Primary endpoint is the response rate in untreated metastases, assessed by immune-related response criteria. Furthermore, the local tumor responses and safety of the combination will be determined; tumor FNA biopsies will be obtained to investigate signatures of immune-mediated rejection as recently described with IMQ mediated rejection of basal cell carcinomas; and peripheral lymphocytes will be examined for the induction/boosting of selected tumor antigen-specific T and B cell responses. The phase I portion has been successfully completed with 6 patients without DLT. Enrollment into the phase II portion has begun. At present, a total of 11 patients have been enrolled. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-1-02. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01421017&atom=%2Fcanres%2F73%2F24_Supplement%2FOT2-1-02.atom