[STEREOTACTIC BODY RADIATION THERAPY IN MALIGNANT TUMORS].

INTRODUCTION: Ionizing radiation plays an important role in the treatment of patients with malignancy for cure and palliation. In the last decade there have been significant technological advances in radiation equipment, imaging and software. Owing to these developments, modern radiation is being shaped according to the size and form of the target organ and is accurate in locating the target location and can even take into account respiratory motion. Thanks to these developments, radiobiological concepts in radiation therapy have been tested and applied. Radiation doses have been increased to 5-20Gy/fraction and the number of treatments has been reduced to an average of five. This type of treatment is called Stereotactic Body Radiation Therapy (SBRT). The application of this treatment to various tumors may improve the effectiveness of radiation therapy, increasing local tumor control and reducing side effects. Another benefit is cutting the overall treatment time. The present article presents a review of literature on stereotactic radiation in lung tumors, prostate cancer, primary liver tumors and in oligo-metastases.

Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations.

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812-21. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.

Stereotactic radiosurgery (SRS) in high-grade glioma: judicious selection of small target volumes improves results.

We present a retrospective review of 55 Stereotactic Radiosurgery (SRS) procedures performed in 47 consecutive patients with high-grade glioma (HGG). Thirty-three (70.2%) patients were diagnosed with glioblastoma and 14 (29.8%) with grade III glioma. The indications for SRS were small (up to 30 mm in diameter) locally progressing lesions in 32/47 (68%) or new distant lesions in 15/47 (32%) patients. The median target volume was 2.2 cc (0.2-9.5 cc) and the median prescription dose was 18 Gy (14-24 Gy). Three patients (5.5% incidence in 55 treatments) developed radiation necrosis. In eight cases (17%) patients received a second salvage SRS treatment to nine new lesions detected during follow-up. In 22/55 SRS treatments (40.0%) patients received concurrent chemo- or biological therapy, including temozolamide (TMZ) (15 patients), bevacizumab (BVZ) (6 patients) and carboplatin in one patient. Median time to progression after SRS was 5.0 months (1.0-96.4). Median survival time after SRS was 15.9 months (2.3-109.3) overall median survival (since diagnosis) was 37.4 months (9.6-193.6 months). Long-lasting responses (>12 months) after SRS were observed in 25/46 (54.3%) patients. We compared a matched (histology, age, KPS) cohort of patients with recurrent HGG treated with BVZ alone with the current study group. Median survival was significantly longer for SRS treated patients compared to the BVZ only cohort (12.6 vs. 7.3 months, p = 0.0102). SRS may be considered an effective salvage procedure for selected patients with small volume, recurrent high-grade gliomas. Long-term radiological control was observed in more than 50% of the patients.

Molecular Profiling-Selected Therapy for Treatment of Advanced Pancreaticobiliary Cancer: A Retrospective Multicenter Study.

This multicenter cohort study assessed the impact of molecular profiling (MP) on advanced pancreaticobiliary cancer (PBC). The study included 30 patients treated with MP-guided therapy after failing ≥ 1 therapy for advanced PBC. Treatment was considered as having benefit for the patient if the ratio between the longest progression-free survival (PFS) on MP-guided therapy and the PFS on the last therapy before MP was ≥ 1.3. The null hypothesis was that ≤ 15% of patients gain such benefit. Overall, ≥ 1 actionable (i.e., predictive of response to specific therapies) biomarker was identified/patient. Immunohistochemistry (the most commonly used method for guiding treatment decisions) identified 1-6 (median: 4) actionable biomarkers per patient. After MP, patients received 1-4 (median: 1) regimens/patient (most commonly, FOLFIRI/XELIRI). In a decision-impact analysis, of the 27 patients for whom treatment decisions before MP were available, 74.1% experienced a treatment decision change in the first line after MP. Twenty-four patients were evaluable for clinical outcome analysis; in 37.5%, the PFS ratio was ≥ 1.3. In one-sided exact binomial test versus the null hypothesis, P = 0.0015; therefore, the null hypothesis was rejected. In conclusion, our analysis demonstrated the feasibility, clinical decision impact, and potential clinical benefits of MP-guided therapy in advanced PBC.

Application of an interstitial and biodegradable balloon system for prostate-rectum separation during prostate cancer radiotherapy: a prospective multi-center study.

BACKGROUND AND PURPOSE: Rectal toxicity presents a significant limiting factor in prostate radiotherapy regimens. This study evaluated the safety and efficacy of an implantable and biodegradable balloon specifically designed to protect rectal tissue during radiotherapy by increasing the prostate-rectum interspace. PATIENTS AND METHODS: Balloons were transperineally implanted, under transrectal ultrasound guidance, into the prostate-rectum interspace in 27 patients with localized prostate cancer scheduled to undergo radiotherapy. Patients underwent two simulations for radiotherapy planning--the first simulation before implant, and the second simulation seven days post implant. The balloon position, the dimensions of the prostate, and the distance between the prostate and rectum were evaluated by CT/US examinations 1 week after the implant, weekly during the radiotherapy period, and at 3 and 6 months post implant. Dose-volume histograms of pre and post implantation were compared. Adverse events were recorded throughout the study period. RESULTS: Four of 27 patients were excluded from the evaluation. One was excluded due to a technical failure during implant, and three patients were excluded because the balloon prematurely deflated. The balloon status was evaluated for the duration of the radiotherapy period in 23 patients. With the balloon implant, the distance between the prostate and rectum increased 10-fold, from a mean 0.22 ± 0.2 cm to 2.47 ± 0.47 cm. During the radiotherapy period the balloon length changed from 4.25 ± 0.49 cm to 3.81 ± 0.84 cm and the balloon height from 1.86 ± 0.24 cm to 1.67 ± 0.22 cm. But the prostate-rectum interspace distance remained constant from beginning to end of radiotherapy: 2.47 ± 0.47 cm and 2.41 ± 0.43 cm, respectively. A significant mean reduction in calculated rectal radiation exposure was achieved. The implant procedure was well tolerated. The adverse events included mild pain at the perineal skin and in the anus. Three patients experienced acute urinary retention which resolved in a few hours following conservative treatment. No infections or thromboembolic events occurred during the implant procedure or during the radiotherapy period. CONCLUSION: The transperineal implantation of the biodegradable balloon in patients scheduled to receive radiotherapy was safe and achieved a significant and constant gap between the prostate and rectum. This separation resulted in an important reduction in the rectal radiation dose. A prospective study to evaluate the acute and late rectal toxicity is needed.

Interstitial biodegradable balloon for reduced rectal dose during prostate radiotherapy: results of a virtual planning investigation based on the pre- and post-implant imaging data of an international multicenter study.

PURPOSE: To evaluate dose reduction caused by the implantation of an interstitial inflatable and biodegradable balloon device aiming to achieve lower rectal doses with virtual 3D conformal external beam radiation treatment. MATERIALS AND METHODS: An inflatable balloon device was placed, interstitially and under transrectal ultrasound guidance, into the rectal-prostate interspace prior treatment initiation of 26 patients with localized prostate cancer, who elected to be treated with radiotherapy (3D CRT or IMRT). The pre- and post-implant CT imaging data of twenty two patients were collected (44 images) for the purpose of the 3D conformal virtual planning presented herein. RESULTS: The dorsal prostate-ventral rectal wall separation resulted in an average reduction of the rectal V70% by 55.3% (± 16.8%), V80% by 64.0% (± 17.7%), V90% by 72.0% (± 17.1%), and V100% by 82.3% (± 24.1%). In parallel, rectal D2 ml and D0.1 ml were reduced by 15.8% (± 11.4%) and 3.9% (± 6.4%), respectively. CONCLUSIONS: Insertion of the biodegradable balloon into the prostate-rectum interspace is similar to other published invasive procedures. In this virtual dose distribution analysis, the balloon insertion resulted in a remarkable reduction of rectal volume exposed to high radiation doses. This effect has the potential to keep the rectal dose lower especially when higher than usual prostate dose escalation protocols or hypo-fractionated regimes are used. Further prospective clinical investigations on larger cohorts and more conformal radiation techniques will be necessary to define the clinical advantage of the biodegradable interstitial tissue separation device.

Hyperbaric oxygen therapy for hemorrhagic radiation cystitis.

BACKGROUND: Hemorrhagic radiation cystitis (HRC) is a significant clinical problem that occurs after pelvic radiation therapy and is often refractory. OBJECTIVES: To evaluate the efficacy and safety of hyperbaric oxygen therapy (HBO) for HRC. METHODS: Daily 90 minute sessions of HBO at 2 ATM 100% oxygen were given to 32 HRC patients with ASTRO grades 3-4 hematuria. RESULTS: The median age was 72.5 (48-88 years). The median time interval between radiation therapy and HBO was 4 years (1-26 years). The patients received a median of 30 HBO sessions (3-53). Hematuria resolved in 27 patients (84%) and persisted in 5. Cystectomy was required in two, and ileal-conduit and bilateral percutaneous nephrostomies were performed in one and two patients, respectively. With a median follow-up of 12 months (5-74 months), the hematuria cleared completely in 16 patients (59%) and mild hematuria requiring no further treatment recurred in 10 others. Another patient with ASTRO grade 4 hematuria needed bladder irrigation and blood transfusions. Complications included eardrum perforation in four patients and transient vertigo and mild hemoptysis in one case each. None of them required HBO discontinuation. CONCLUSIONS: HBO controlled bleeding in 84% of the patients. A durable freedom from significant hematuria was achieved in 96% of the patients. HBO seems to be an effective and safe modality in patients with HRC.

Breast-conserving surgery and intraoperative electron radiotherapy in early breast cancer: experience at the Rambam Health Care Campus.

BACKGROUND: Local recurrences after breast-conserving surgery occur mostly at the site of the primary carcinoma. The main objective of postoperative radiotherapy is sterilization of residual cancer cells. Whole-breast radiotherapy is the standard of care, but its utility has recently been challenged in favor of radiotherapy limited to the area at highest risk of recurrence. Intraoperative electron radiotherapy (IOeRT) is an innovative technique for accelerated partial breast irradiation (APBI) that is applied to selected patients affected by early breast cancer. OBJECTIVES: To describe our experience with IOeRT at the Rambam Health Care Campus in Haifa since we began utilizing this modality in 2006. METHODS: From April 2006 to September 2010, 31 patients affected by unifocal invasive duct breast carcinoma < or = 2 cm diameter received wide local resection followed by intraoperative radiotherapy with electrons. Patients were evaluated for early and late complications, and other events, 1 month after surgery and every 3 months thereafter for the duration of the first 2 years. RESULTS: After a mean follow-up of 36 months, seven patients developed mild breast fibrosis and three suffered from mild postoperative infection. Rib fractures were observed in four patients before routine lead shielding was initiated. Additional whole-breast irradiation was given to four patients. None of the patients developed local recurrences or other ipsilateral cancers. Similarly, no contralateral cancers or distant metastases were observed. CONCLUSIONS: Intraoperative electron radiotherapy may be an alternative to external beam radiation therapy in an appropriate selected group of early-stage breast cancer patients. However, long-term results of clinical trials are required to better evaluate the indications and utility of this technique in the management of breast cancer.

AP-PA field orientation followed by IMRT reduces lung exposure in comparison to conventional 3D conformal and sole IMRT in centrally located lung tumors.

Little attention has been paid to the fact that intensity modulated radiation therapy (IMRT) techniques do not easily enable treatment with opposed beams. Three treatment plans (3 D conformal, IMRT, and combined (anterior-posterior-posterio-anterior (AP-PA) + IMRT) of 7 patients with centrally-located lung cancer were compared for exposure of lung, spinal cord and esophagus. Combined IMRT and AP-PA techniques offer better lung tissue sparing compared to plans predicated solely on IMRT for centrally-located lung tumors.

Duration of androgen suppression in the treatment of prostate cancer.

BACKGROUND: The combination of radiotherapy plus long-term medical suppression of androgens (> or = 2 years) improves overall survival in patients with locally advanced prostate cancer. We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus long-term androgen suppression in the treatment of locally advanced prostate cancer. METHODS: We randomly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further treatment (short-term suppression) and the other to receive 2.5 years of further treatment with a luteinizing hormone-releasing hormone agonist (long-term suppression). An outcome of noninferiority of short-term androgen suppression as compared with long-term suppression required a hazard ratio of more than 1.35 for overall survival, with a one-sided alpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjusted one-sided alpha level of 0.0429. RESULTS: A total of 1113 men were registered, of whom 970 were randomly assigned, 483 to short-term suppression and 487 to long-term suppression. After a median follow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P=0.65 for noninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hot flushes. CONCLUSIONS: The combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment of locally advanced prostate cancer. (ClinicalTrials.gov number, NCT00003026.)

The curative role of radiotherapy in adenocarcinoma of the prostate in patients under 55 years of age: a rare cancer network retrospective study.

To determine whether radiation therapy could be an acceptable alternative to surgery in young patients with adenocarcinoma of the prostate, we analysed the outcome of 39 patients aged under 55 with organ confined tumours who received external radiation therapy in a curative intent. Our results suggest that similar local control in younger and older patients can be expected from either external beam radiotherapy or radical prostatectomy.

Nasopharyngeal carcinoma in the pediatric age group: the northern Israel (Rambam) medical center experience, 1989-2004.

Nasopharyngeal carcinoma (NPC) is rare in children, accounting for less than 1% of all malignancies. Radiation therapy has been the mainstay of treatment of many years, but to improve survival, the use of chemotherapy has been advocated. This is a retrospective analysis of 13 patients less than 20 years of age treated for NPC the Rambam Medical Center during 1989 to 2004. Eight boys and five girls with a median age of 14.5 years (range 10-19) were included. Median follow up (including patients who died) was 6.15 years (range 1-15 years). Duration of symptoms was 1 to 24 months (median 5 months). Of the 13 patients, one patient had stage I, 6 had stage III, 5 had stage IV-A, and 1 had stage IV-B disease. Ten patients (77%) had undifferentiated carcinoma (WHO type III) and three patients (23%) had nonkeratinizing carcinoma (WHO type II). Most of the children received two or three courses of neoadjuvant multiagent chemotherapy consisting of cisplatin and 5-FU, followed by radiotherapy with doses in excess of 60 Gy. One child received concomitant chemoradiation. Ten of the 13 patients (77%) are alive without disease 6 years after diagnosis (range 1-15 years). One patient developed local and distant metastases 1 year after diagnosis and is currently receiving combined radiochemotherapy. Two patients died. Overall survival was 84%; event-free survival was 77%. Nine patients (69%) developed moderate to severe long-term complications. Pediatric NPC is curable by combined radiation and chemotherapy, with doses of radiation in excess of 60 Gy. Long-term follow-up is important for early detection of second malignancies as well as for radiation-induced endocrinologic deficiencies and other normal tissue complications.

Postmastectomy radiotherapy in breast cancer with high risk of relapse: current and future approaches.

Postmastectomy radiotherapy in patients with breast cancer remains controversial in oncology . The major risk factor for local-regional recurrence is the tumor size and the number of lymph node metastases. The common sites of postmastectomy recurrence are the chest wall and the supraclavicle fossa. Postmastectomy radiotherapy decreases local-regional recurrence and improves survival in selected patients . This article presents a short overview of this issue based on the author's professional medical experience and reviews the literature.

Postmastectomy electron-beam chest-wall irradiation in women with breast cancer.

PURPOSE: This retrospective study evaluates the results of postmastectomy electron-beam chest-wall irradiation in patients with breast cancer. METHODS AND MATERIALS: From 1980 to 1994, 144 women with localized breast cancer received postmastectomy radiotherapy. The chest wall was irradiated by electron beam, 6 to 12 MeV energy, depending on wall thickness, 2.0 Gy daily, 5 times/week for total dose of 50 Gy. Forty-one patients received 16-Gy boosts to the mastectomy scar. In addition, the supraclavicular and axilla areas were irradiated by anterior field with 6-MV photon beam. RESULTS: Median follow-up was 84 months. Fifteen patients (10%) had local-regional recurrence (LRR) and 57 patients (40%) had systemic relapse (SR). Median time from mastectomy to LRR was 20 months and median time to SR was 33 months. Axillary lymph nodes status influenced both LRR and SR. LRR rate was 0% in N0 and 12% in N1 disease; SR rate was 14% in N0 and 45% in N1 disease. Disease-free and overall survival was 58% and 67% in 10 years and 50% and 55% in 20 years, respectively. No cardiac toxicity was related to left chest-wall irradiation. CONCLUSION: Postmastectomy electron-beam chest-wall irradiation is as effective as photon-beam irradiation in breast cancer.

[Prostate cancer diagnosed before 55: a retrospective study from the Rare Cancer Network]. / Cancers de la prostate diagnostiqués avant 55 ans: une étude rétrospective du groupe des cancers rares.

This retrospective study on a large number of cases offers a vision of the modalities of care in prostate cancer diagnosed before the age of 55, according to different policies, aiming to propose other directions for 2005. Between January 1974 and December 2001, 365 patients had a pathological diagnosis of prostate cancer occurring before the age of 55. These patients were referred to the departments of radiation therapy affiliated to the Rare Cancer Network. A questionnaire was filled in retrospectively to allow further analysis of medical and surgical data. The treatments were those recommended at the time of analysis and progressed according to new accepted standards. Clinical and pathological features of the patients were as follows: 36% of the tumours were Gleason > 7 scored, 56% of the patients had a T3-T4 and 31 had metastases at the time of diagnosis. As far as treatment was concerned, 4 groups were considered: 83 patients had a radical prostatectomy, 155 received radiation therapy with a curative intent, 87 were treated by hormonal manipulation, and the remaining 40 patients received palliative care. The free of disease survival rate at 10 years was 38% for patients without immediate metastases, only 1% of patients with metastases were alive. The multivariate analysis demonstrated the significant impact of radiotherapy on both local and distant failure rates and of T stage on distant failure rate. Survival was affected by nodal involvement and local failure. A separate analysis of two periods of time (1974-1989 and 1990-2001) did not show any differences in terms of treatment results. This retrospective study suggests that age is not a negative prognostic factor as far as adequate curative treatments are carried out. Therapeutic modalities having considerably evolved in prostate cancer, a further analysis with a longer follow up may allow the evaluation of these treatments on rates of failures and survival. Screening for prostate cancer in family histories is likely to increase the number of cases diagnosed before 55. Therefore, a complete information on morbidity associated to the different means of treatment would lead to a better acceptance of late side effects.

Interleukin-2, interferon-alpha, 5-fluorouracil, and vinblastine in the treatment of metastatic renal cell carcinoma: a prospective phase II study: the experience of Rambam and Lin Medical Centers 1996-2000.

BACKGROUND: The current study evaluated the efficacy and toxicity of interleukin-2 (IL-2), interferon-alpha (IFN-alpha), 5-fluorouracil (5-FU), and vinblastine (VBL) in the treatment of metastatic renal cell carcinoma (MRCC). METHODS: Sixty-two MRCC patients, median age 63 years, received immunochemotherapy. Eastern Cooperative Oncology Group performance status was 1 for 45 patients and 2 for 17 patients. Fifty-four patients underwent nephrectomy prior to treatment. Sites of disease were lungs, lymph nodes, bone, kidney, and liver. Treatment consisted of IL-2 10 MIU/m(2) subcutaneous (SC), three times per week, Weeks 1-4; IFN-alpha 6 MIU/m(2) SC, once per week, Weeks 1-4 and 9 MIU/m(2), three times per week, Weeks 5-7; 5-FU 600 mg/m(2) and VBL 6 mg/m(2), intravenous bolus, Day 1 of Weeks 5 and 7. RESULTS: In a median followup of 34 months, 62 patients were evaluated for tumor response. Four patients achieved complete response for 26+, 34+, 51+, and 56+ months, respectively; 14 patients achieved partial response for a median of 14 months; and 20 patients achieved stable disease for a median of 9 months. Seven patients (5 partial response, 2 stable disease) underwent complete resection of residual tumor. Five patients remained alive with no evidence of disease for 27, 32, 36, 42, and 48 months, respectively. Nine patients achieved long-term complete response for a median of 36 months. Three-year survival rate for the entire group and for 11 complete responders was 88%. Common side effects were flu-like symptoms, nausea, headache, and depression. Four patients were excluded because of treatment intolerance, and one patient died after nephrectomy. CONCLUSIONS: Immunochemotherapy is effective and well-tolerated by patients with MRCC. Surgical intervention for resection of residual disease is justified.

Postoperative irradiation in localized renal cell carcinoma: the Rambam Medical Center experience.

OBJECTIVE: This study evaluated the results of postoperative adjuvant radiotherapy in patients with localized renal cell carcinoma (RCC). PATIENTS: Eighty-six patients (median age, 60 years) with RCC treated by radical nephrectomy were evaluated for the efficacy of postoperative radiotherapy. Twenty-four percent of patients had stage T2, 35% T3a, 36% T3b and 5% T4 disease. Seventy-seven percent had clear cell carcinomas and 23% granular cell or spindle and mixed cell carcinomas. Radiotherapy was given to the renal bed and adjacent lymphatic basin at a median dose of 46 Gy. RESULTS: Thirty-two (37%) patients relapsed: 27 (84%) had systemic relapse only and five (16%) had local and systemic relapse; all patients of the latter group had stage T3b disease. The 10-year disease-free and overall survival was 40% and 42%, respectively. Tumor invasion of the renal vessels and stage of disease were correlated with survival. Side effects of radiotherapy were mainly gastrointestinal, but one patient who received right abdominal irradiation died because of liver failure. CONCLUSION: The results of our study are comparable with those reported in the literature. Since postoperative irradiation did not improve the survival of patients with RCC and showed toxicity, it is not recommended.