Afatinib in EGFR TKI-naïve patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer: Interim analysis of a Phase 3b study.

OBJECTIVES: Randomized controlled trials have demonstrated that afatinib is a suitable treatment option for patients with epidermal growth factor receptor mutation-positive (EGFRm +) non-small cell lung cancer (NSCLC). However, such studies often exclude patients treated in routine clinical practice. We report interim results from a Phase 3b, open-label, multicenter, single-arm, exploratory trial, in which afatinib was investigated in a real-world setting. MATERIALS AND METHODS: Patients with EGFRm + tyrosine kinase inhibitor (TKI)-naïve NSCLC received afatinib 40 mg orally, once-daily, until disease progression, or voluntary withdrawal. Primary objective was safety. RESULTS: Overall, 479 patients received afatinib: median age 65 years, 8 % of patients had an ECOG performance status ≥ 2, 17 % had brain metastases, and 13 % had tumors containing uncommon mutations only. All but one patient (99.8 %) had an adverse event (AE). Treatment-related AEs (TRAEs; any/grade ≥ 3) occurred in 97 %/44 % of patients; most common were diarrhea (87 %/16 %) and rash (51 %/11 %). AEs leading to afatinib dose-reduction were reported in 258 patients (54 %), and 37 patients (8 %) discontinued treatment due to a TRAE. Objective response rate was 45.5 %, median duration of response was 14.1 months (95 % CI: 12.2-16.4). Overall median time to symptomatic progression and progression-free survival were 14.9 months (95 % CI: 13.8-17.6) and 13.4 months (95 % CI: 11.8-14.5), respectively, in the overall population and 19.3 months (95 % CI: 15.6-21.8) and 15.9 months (95 % CI: 13.9-19.1) in patients with EGFR exon 19 deletions. CONCLUSIONS: Afatinib administration in routine clinical practice was well tolerated with no new safety signals and demonstrated promising efficacy in patients with EGFRm + NSCLC. TRAEs were generally manageable with tolerability-guided dose reductions. Overall, these data independently support findings from randomized controlled trials of afatinib in EGFRm + NSCLC.

Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-022 with reference trastuzumab.

BACKGROUND: BCD-022 is a trastuzumab biosimilar which was shown to be equivalent to reference trastuzumab in a wide panel of physicochemical studies as well as preclinical studies in vitro and in vivo. International multicenter phase III clinical trial was conducted to comparatively assess efficacy and safety of BCD-022 and reference trastuzumab in combination with paclitaxel used as the therapy of metastatic HER2(+) breast cancer. Pharmacokinetics and immunogenicity were also studied. METHODS: Patients with no previous treatment for metastatic HER2(+) breast cancer were randomly assigned 1:1 to BCD-022 or reference trastuzumab and were treated with trastuzumab + paclitaxel. Therapy continued for 6 cycles of therapy (every 3 weeks), until progression of the disease or unbearable toxicity. Primary study endpoint was overall response rate. Study goal was to prove equivalent efficacy of BCD-022 and reference trastuzumab. Equivalence margins for 95% CI for difference in overall response rates were set at [- 20%; 20%]. RESULTS: In total 225 patients were enrolled into the study, 115 in BCD-022 arm and 110 in reference trastuzumab arm. Overall response rate was 49.6% in BCD-022 arm and 43.6% in reference trastuzumab arm. Limits of 95% CI for difference of overall response rates between arms were [(- 8.05)-19.89%], thus, they lied within predetermined equivalence margins [- 20%; 20%]. Profile of adverse events was similar between groups (any AEs were reported in 93.81% of patients in BCD-022 arm and 94.55% of patients in reference arm). No unexpected adverse reactions were reported throughout the study. No statistically significant differences regarding antibody occurrence rate (either BAb or NAb) was found between BCD-022 (n = 3; 2.65%) and comparator (n = 4; 3.64%). Both drug products are characterized with low occurrence rate and short life of anti-trastuzumab antibodies. Pharmacokinetics assessment after 1st and 6th study drug injection also demonstrated equivalent PK parameters by all outcome measures: AUC0-504, Сmах, Тmax, T1/2. Analysis of Ctrough did not reveal any significant inter-group differences as well. CONCLUSIONS: Thus, results of this study have demonstrated therapeutic equivalence of trastuzumab biosimilar BCD-022 and referent trastuzumab drug. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov (Study Number NCT01764022 ). The date of registration was January 9, 2013.

A quantitative treatment planning study evaluating the potential of dose escalation in conformal radiotherapy of the oesophagus.

BACKGROUND AND PURPOSE: This study aims to evaluate the reduction in radiation dose to normal thoracic structures through the use of conformal radiotherapy techniques in the treatment of oesophageal cancer, and to quantify the resultant potential for dose escalation. MATERIALS AND METHODS: Three different CT-derived treatment plans were created and compared for each of ten patients. A two-phase treatment with conventional straight-edged fields and standard blocks (CV2), a two-phase conformal plan (CF2), and a three-phase conformal plan where the third phase was delivered to the gross tumour only (CF3), were considered for each patient. Escalated dose levels were determined for techniques CF2 and CF3, which by virtue of the conformal field shaping, did not increase the mean lung dose. The resulting increase in tumour control probability (TCP) was estimated. RESULTS: A two-phase conformal technique (CF2) reduced the volume of lung irradiated to 18 Gy from 19.7+/-11.8 (1 SD) to 17.1+/-12.3% (P=0.004), and reduced the normal tissue complication probability (NTCP) from 2.4+/-4.0 to 0.7+/-1.6% (P=0.02) for a standard prescribed dose of 55 Gy. Consequently, technique CF2 permitted a target dose of 59.1+/-3.2 Gy without increasing the mean lung dose. Technique CF3 facilitated a prescribed dose of 60.7+/-4.3 Gy to the target, the additional 5 Gy increasing the TCP from 53. 1+/-5.5 to 68.9+/-4.1%. When the spinal cord tolerance was raised from 45 to 48 Gy, technique CF3 allowed 63.6+/-4.l Gy to be delivered to the target, thereby increasing the TCP to 78.1+/-3.2%. CONCLUSIONS: Conformal radiotherapy techniques offer the potential for a 5-10 Gy escalation in dose delivered to the oesophagus, without increasing the mean lung dose. This is expected to increase local tumour control by 15-25%.

Soft-tissue reconstruction of sole and heel defects with free tissue transfers.

Reconstruction of the weight-bearing surface of the foot is a challenging problem for the reconstructive surgeon. Because local tissues are not usually available for reconstruction, distant tissue transfers are often necessary. The authors report 20 patients with sole and heel defects that were reconstructed with free flaps. Two patients had bilateral reconstruction. Three patients were younger than 10 years. Etiological causes were burn scar (N = 7), trauma (N = 7), chronic wound (N = 3), and tumor resection (N = 5). All defects were located at a weight-bearing area. Gracilis muscle (N = 11), neurosensorial radial forearm (N = 7), latissimus dorsi muscle (N = 2), rectus abdominis muscle (N = 1), and posterolateral thigh flaps (N = 1) were used for reconstruction. Muscle flaps were preferred for the deep and irregular defects or chronic, open infected wounds. All flaps survived except for one total and two partial complications of necrosis. Recurrence of ulceration was observed in 1 patient with spinal cord trauma. The mean follow-up period was 33.7 months (range, 1-84 months). Patients were evaluated by direct gait observation, footprints, pedograms, and the Semmes-Weinstein monofilament test. All patients returned to normal daily activity with individual gait patterns. Functional outcomes of both muscle and fasciocutaneous flaps were satisfactory. Presence of deep sensation, preservation of musculoskeletal integrity, and patient compliance are the main factors for durability of reconstruction.

Malignant tumors requiring maxillectomy.

Seventy cases with malignant tumors requiring maxillary resection in the past 10 years were reviewed, retrospectively. The primary site of tumor was adjacent skin in 53%, maxillary sinus or maxilla in 20%, palate and alveolar arch in 13%, lip and buccal mucosa in 13%, and mandible in 1% of the cases. The most common histopathological diagnoses was squamous cell carcinoma (54%), followed by basal cell carcinoma (20%). Most of the patients had advanced tumors, either neglected or recurred. Orbital exenteration was performed in 28 cases, mandibulectomy in six cases, combined craniofacial resection in seven cases, and radical neck dissection in 18 cases. Major skin loss was present in majority of the patients. Postsurgical defects were reconstructed with pedicled flaps in 37 cases and free flaps in 12 cases. Lining of the maxillary sinus defects was provided with split-thickness skin grafts. Patients with palatal defects were encouraged to use prosthetic obturators. Postoperative radiotherapy was performed in 32 patients and combined radiotherapy and chemotherapy in 12 patients. Communication could be established with only 52 patients. Sixty-three percent of them have survived without recurrence and distant metastasis. Resection of the tumor with free surgical margins and appropriate evaluation of the surgical defect for the most suitable reconstruction are the mainstays of treatment of the midfacial tumors.

A comparison of conventional and conformal radiotherapy of the oesophagus: work in progress.

A retrospective treatment planning study was carried out in five patients to assess the effectiveness of conformal radiotherapy of the oesophagus. A two-phase conventional treatment plan was created for each patient, with a prescribed dose of 55 Gy. This plan was compared with a single-phase conformal plan consisting of the same field arrangement as the second phase of the conventional treatment, but with conformal blocks shaped to the beam's eye view of the planning target volume. A further comparison was made between the conventional plan and a two-phase plan using the same beam angles and weights as the conventional plan, but with conformal field shapes. The effectiveness of each treatment plan was assessed using dose--volume histograms and normal tissue complication probabilities for the lungs. On average, the single-phase conformal technique increased the mean lung dose from 22.5% (+/- 6.2 SD) of the prescribed dose to 29.5% (+/- 5.2 SD) compared with the conventional technique (p = 0.0001). This indicates that this technique did not offer any benefit in terms of reducing the risk of pneumonitis. However, the two-phase conformal technique reduced the mean lung dose from 22.5% (+/- 6.2 SD) of the prescribed dose to 19.8% (+/- 4.6 SD)(p = 0.03), showing that this technique should reduce the risk of pneumonitis. Further work is underway to study more patients and to investigate tumour control probability and dose escalation.

Extracorporeal septoplasty combined with open rhinoplasty.

Extracorporeal septoplasty is a radical solution for the severely deviated nose. The major problems associated with this procedure are fixation of the septal cartilage graft and dorsal irregularities. Extracorporeal septoplasty was performed in combination with open rhinoplasty in 17 patients with severe nasal deformities. In this technique septum was totally removed through the columellar incision of open rhinoplasty, corrected outside, and replaced as a free "L" shaped cartilage graft. The cartilage graft was fixated to the upper lateral cartilages to restore the natural relations of the anatomical structures. Additional rhinoplastic manipulations were also performed. The follow-up period was up to 18 months. The overall result was successful in all patients. Nasal deviation did not recur and secondary revisions were not needed for any patient during follow-up.

Coverage of knee-tumor-resection prostheses with free flaps.

Free latissimus dorsi free flaps were used for the treatment of three patients with malignant tumors localized at the distal end of the femur. In all cases, a knee prosthesis was used after tumor resection. In two patients, the prosthesis was covered with a free latissimus dorsi flap immediately after insertion. In one patient, the exposed prosthesis that was inserted 9 months previously was also covered with a free latissimus dorsi flap. Histopathologic diagnosis of the tumors was osteosarcoma in two cases and fusiform cell sarcoma in one case. Free-tissue transfers were successful in spite of preoperative chemotherapy and/or radiotherapy. Chemotherapy was started 3 weeks postoperatively in all cases. Patients ambulated 6 weeks after surgery and knee functions were satisfactory during a 1 year follow-up.

Postoperative radiotherapy in gastric cancer.

Surgeons in Poland are very skeptical about the positive role of adjuvant irradiation in patients with gastric cancer. A retrospective study of 21 patients with operable gastric cancer referred for irradiation to Cancer Centre in Warsaw between December 1984 and December 1991 was performed. Patients were qualified to receive adjuvant treatment because of bad prognostic factors--nonradical surgery (10 patients), infiltration of entire thickness of gastric wall (13 patients), and metastases in regional lymph nodes (9 patients). All patients were in good condition. They were treated by either telecobalt 60 unit or linear accelerator using 9-15 MeV photons. The total dose to the gastric bed and lymphatic was 46-50 Gy in 25 to 28 fractions, 5 days a week. The tolerance of treatment was good. None of these patients received 5-FU either during irradiation or as maintenance therapy. We have obtained more than 50% overall survival rate at 3 years. Median survival was 27 months and median recurrent-free interval 27 months. Local recurrence was found in four patients, distant metastases in five patients. In the group of 10 patients with nonradical surgery, 5 are alive without evidence of disease from 2 up to 7 years after treatment. Our preliminary results and good tolerance of treatment seem to support the beneficial role of adjuvant radiotherapy after gastrectomy in patients with risk factors of locoregional cancer recurrence.

[Survival of patients with anaplastic cerebral gliomas treated with a combination of surgery and radiotherapy]. / Przezycie chorych na anaplastyczne glejaki mózgu leczonych metoda skojarzona--operacja i napromienianiem.

The survival time was analysed in 42 patients with anaplastic cerebral gliomas after treatment by surgery and radiotherapy. The obtained therapeutic results were comparable with those reported in world literature: the 6-month survival rate was 60%, the 1-year survival rate was 31%, and at 2 years 19% of the patients were alive. A group of patients poorly tolerating radiotherapy was isolated, these patients required administration of brain-oedema-reducing drugs. The survival time after treatment in patients with well-controlled oedema was similar to that obtained in the whole group.