Mauricio Cambeiro

Perioperative high dose rate brachytherapy (PHDRB) in previously irradiated head and neck cancer: Results of a phase I/II reirradiation study

BACKGROUND AND PURPOSE This study was undertaken to determine the feasibility of salvage surgery and PHDRB in patients with previously irradiated, recurrent head and neck cancer or second primary tumors arising in a previously irradiated field. METHODS AND MATERIALS Sixty-three patients were treated with surgical resection and PHDRB. The PHDRB dose was 4Gy b.i.d.×8 (32Gy) for R0 resections and 4Gy b.i.d.×10 (40Gy) for R1 resections, respectively. Further external beam radiotherapy or chemotherapy was not given. RESULTS Resections were categorized as R0 in 7 patients (11.1%) and R1 in 56 (88.9%). Thirty-four patients with R1 resections (54.0%) had microscopically positive margins, and 22 patients (34.9%) had close margins. Thirty-two patients (50.8%) developed RTOG grade 3 or greater adverse events including 3 fatal events. After a median follow-up of 6.8years, the 5-year locoregional control rate and 5-year overall survival rates were 55.0% and 35.6%, respectively. CONCLUSIONS Surgical resection and PHDRB is a successful treatment strategy in selected patients with previously irradiated head and neck cancer. Long-term locoregional control can be achieved in a substantial number of cases despite a high rate of inadequate surgical resections although at the expense of substantial toxicity.

External-beam radiation therapy and high-dose rate brachytherapy combined with long-term androgen deprivation therapy in high and very high prostate cancer: preliminary data on clinical outcome.

PURPOSE To determine the feasibility of combined long-term androgen deprivation therapy (ADT) and dose escalation with high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS Between 2001 and 2007, 200 patients with high-risk prostate cancer (32.5%) or very high-risk prostate cancer (67.5%) were prospectively enrolled in this Phase II trial. Tumor characteristics included a median pretreatment prostate-specific antigen of 15.2 ng/mL, a clinical stage of T2c, and a Gleason score of 7. Treatment consisted of 54 Gy of external irradiation (three-dimensional conformal radiotherapy [3DCRT]) followed by 19 Gy of HDR brachytherapy in four twice-daily treatments. ADT started 0-3 months before 3DCRT and continued for 2 years. RESULTS One hundred and ninety patients (95%) received 2 years of ADT. After a median follow-up of 3.7 years (range, 2-9), late Grade ≥2 urinary toxicity was observed in 18% of the patients and Grade ≥3 was observed in 5%. Prior transurethral resection of the prostate (p = 0.013) and bladder D(50) ≥1.19 Gy (p = 0.014) were associated with increased Grade ≥2 urinary complications; age ≥70 (p = 0.05) was associated with Grade ≥3 urinary complications. Late Grade ≥2 gastrointestinal toxicity was observed in 9% of the patients and Grade ≥3 in 1.5%. CTV size ≥35.8 cc (p = 0.007) and D(100) ≥3.05 Gy (p = 0.01) were significant for increased Grade ≥2 complications. The 5-year and 9-year biochemical relapse-free survival (nadir + 2) rates were 85.1% and 75.7%, respectively. Patients with Gleason score of 7-10 had a decreased biochemical relapse-free survival (p = 0.007). CONCLUSIONS Intermediate-term results at the 5-year time point indicate a favorable outcome without an increase in the rate of late complications.

Four-Week Neoadjuvant Intensity-Modulated Radiation Therapy With Concurrent Capecitabine and Oxaliplatin in Locally Advanced Rectal Cancer Patients: A Validation Phase II Trial

PURPOSE To validate tolerance and pathological complete response rate (pCR) of a 4-week preoperative course of intensity-modulated radiation therapy (IMRT) with concurrent capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer. METHODS AND MATERIALS Patients with T3 to T4 and/or N+ rectal cancer received preoperative IMRT (47.5 Gy in 19 fractions) with concurrent capecitabine (825 mg/m(2) b.i.d., Monday to Friday) and oxaliplatin (60 mg/m(2) on Days 1, 8, and 15). Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation. Primary end points were toxicity and pathological response rate. Local control (LC), disease-free survival (DFS), and overall survival (OS) were also analyzed. RESULTS A total of 100 patients were evaluated. Grade 1 to 2 proctitis was observed in 73 patients (73%). Grade 3 diarrhea occurred in 9% of the patients. Grade 3 proctitis in 18% of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments. The rate of Grade 3 proctitis decreased to 4% thereafter (odds ratio, 0.27). A total of 99 patients underwent surgery. A pCR was observed in 13% of the patients, major response (96-100% of histological response) in 48%, and pN downstaging in 78%. An R0 resection was performed in 97% of the patients. After a median follow-up of 55 months, the LC, DFS, and OS rates were 100%, 84%, and 87%, respectively. CONCLUSIONS Preoperative CAPOX-IMRT therapy (47.5 Gy in 20 fractions) is feasible and safe, and produces major pathological responses in approximately 50% of patients.

Phase I-II trial of perioperative high-dose-rate brachytherapy in oral cavity and oropharyngeal cancer.

BACKGROUND To determine the feasibility of combined perioperative high-dose-rate brachytherapy (PHDRB) and intermediate-dose external beam radiation therapy (EBRT) as an alternative to full-dose adjuvant EBRT in patients with unirradiated squamous cell cancer (SCC) of the oral cavity and oropharynx. METHODS AND MATERIALS Forty patients were treated with surgical resection and PHDRB. PHDRB dose was 4Gy b.i.d.x4 (16Gy) for R0 resections and 4Gy b.i.d.x6 (24Gy) for R1 resections, respectively. External beam radiotherapy (45Gy in 25 fractions) was added postoperatively. Patients with Stage III, IVa tumors, and some recurrent cases received concomitant cisplatin-paclitaxel chemotherapy during EBRT. RESULTS The rate of protocol compliance was 97.5%. Eleven patients (27.5%) developed RTOG Grade 3 or greater toxicity. Four patients (10%) presented complications requiring a major surgical procedure (RTOG 4), and one patient died of bleeding (RTOG 5). Three complications (7.5%) occurred in the perioperative period, and 8 (20.0%) occurred more than 3 months after the completion of the treatment program. Severe complications were more frequent in posteriorly located implants than in anterior implants (p=0.035). After a median follow-up of 50 months for living patients (range, 2.5-86.1+), the 7-year actuarial rates of local and locoregional control were 86% and 82%, respectively; and the 7-year disease-free survival and overall survival rates were 50.4% and 52.3%, respectively. CONCLUSIONS PHDRB can be integrated into the management of patients with resected cancer of the oral cavity who are candidates to receive postoperative radiation or chemoradiation. The local control and toxicity rates were similar to those expected after standard chemoradiation. PHDRB was associated with high toxicity in posterior locations, and the scheduled PHDRB dose was shifted to the closest lower level.

Prognostic Value of External Beam Radiation Therapy in Patients Treated With Surgical Resection and Intraoperative Electron Beam Radiation Therapy for Locally Recurrent Soft Tissue Sarcoma: A Multicentric Long-Term Outcome Analysis

BACKGROUND A joint analysis of data from centers involved in the Spanish Cooperative Initiative for Intraoperative Electron Radiotherapy was performed to investigate long-term outcomes of locally recurrent soft tissue sarcoma (LR-STS) patients treated with a multidisciplinary approach. METHODS AND MATERIALS Patients with a histologic diagnosis of LR-STS (extremity, 43%; trunk wall, 24%; retroperitoneum, 33%) and no distant metastases who underwent radical surgery and intraoperative electron radiation therapy (IOERT; median dose, 12.5 Gy) were considered eligible for participation in this study. In addition, 62% received external beam radiation therapy (EBRT; median dose, 50 Gy). RESULTS From 1986 to 2012, a total of 103 patients from 3 Spanish expert IOERT institutions were analyzed. With a median follow-up of 57 months (range, 2-311 months), 5-year local control (LC) was 60%. The 5-year IORT in-field control, disease-free survival (DFS), and overall survival were 73%, 43%, and 52%, respectively. In the multivariate analysis, no EBRT to treat the LR-STS (P=.02) and microscopically involved margin resection status (P=.04) retained significance in relation to LC. With regard to IORT in-field control, only not delivering EBRT to the LR-STS retained significance in the multivariate analysis (P=.03). CONCLUSION This joint analysis revealed that surgical margin and EBRT affect LC but that, given the high risk of distant metastases, DFS remains modest. Intensified local treatment needs to be further tested in the context of more efficient concurrent, neoadjuvant, and adjuvant systemic therapy.

Determinants of Toxicity, Patterns of Failure, and Outcome Among Adult Patients With Soft Tissue Sarcomas of the Extremity and Superficial Trunk Treated With Greater Than Conventional Doses of Perioperative High-Dose-Rate Brachytherapy and External Beam Radiotherapy

PURPOSE The present study was undertaken to determine factors predictive of toxicity, patterns of failure, and survival in 60 adult patients with soft tissue sarcomas of the extremity and superficial trunk treated with combined perioperative high-dose-rate brachytherapy and external beam radiotherapy. METHODS AND MATERIALS The patients were treated with surgical resection and perioperative high-dose-rate brachytherapy (16 or 24 Gy) for negative and close/microscopically positive resection margins, respectively. External beam radiotherapy (45 Gy) was added postoperatively to reach a 2-Gy equivalent dose of 62.9 and 72.3 Gy, respectively. Adjuvant chemotherapy with ifosfamide and doxorubicin was given to patients with advanced high-grade tumors. RESULTS Grade 3 toxic events were observed in 18 patients (30%) and Grade 4 events in 6 patients (10%). No Grade 5 events were observed. A location in the lower limb was significant for Grade 3 or greater toxic events on multivariate analysis (p = .013), and the tissue volume encompassed by the 150% isodose line showed a trend toward statistical significance (p = .086). The local control, locoregional control, and distant control rate at 9 years was 77.4%, 69.5%, and 63.8%, respectively. On multivariate analysis, microscopically involved margins correlated with local control (p = .036) and locoregional control (p = .007) and tumor size correlated with distant metastases (p = .004). The 9-year disease-free survival and overall survival rate was 47.0% and 61.5%, respectively. Multivariate analysis showed poorer disease-free survival rates for patients with tumors >6 cm (p = .005) and microscopically involved margins (p = .043), and overall survival rates decreased with increasing tumor size (p = .011). CONCLUSIONS Grade 3 or greater wound complications can probably be decreased using meticulous treatment planning to decrease the tissue volume encompassed by the 150% isodose line, especially in lower limb locations. Microscopically involved margins remain a predictor of local and locoregional failure, despite radiation doses >70 Gy. Patients with tumors ≥6 cm and microscopically involved margins are at high risk of treatment failure and death from the development of distant metastases.

Determinants of Complications and Outcome in High-Risk Squamous Cell Head-and-Neck Cancer Treated With Perioperative High–Dose Rate Brachytherapy (PHDRB)

PURPOSE To determine the impact of a set of patient, tumor, and treatment factors on toxicity and outcome in patients with head-and-neck squamous cell cancer treated with surgical resection and perioperative high-dose rate brachytherapy (PHDRB) alone (single-modality [SM] group) (n = 46) or PHDRB combined with postoperative radiation or chemoradiation (combined-modality [CM] group) (n = 57). METHODS AND MATERIALS From 2000 to 2008, 103 patients received PHDRB after complete macroscopic resection. SM patients received 32 or 40 Gy of PHDRB in 8 or 10 twice-daily treatments for R0 and R1 resections. CM patients received 16 or 24 Gy of PHDRB in 4 or 6 twice-daily treatments for R0 and R1 resections, followed by external radiation of 45 Gy in 25 fractions with or without concomitant chemotherapy. RESULTS Grade ≥4 complications according to the Radiation Therapy Oncology Group were more frequent in the SM group than in the CM group (p = 0.024). Grade ≥3 and ≥4 complications increased with the antecedent of prior irradiation (p = 0.032 and p = 0.006, respectively) and with TV(150) values of 13 mL or greater (p = 0.032 and p = 0.032, respectively). After a median follow-up of 34.8 and 60.8 months for SM and CM patients, respectively, patients with high-risk margins had a 9-year local control rate of 68.0% whereas patients with wider margins had a 9-year local control of 93.7% (p = 0.045). Patients with primary and recurrent tumors had 9-year actuarial locoregional control rates of 81.8% and 54.2%, respectively (p = 0.003). Patients with lymph-vascular space invasion (LVSI)-positive and LVSI-negative tumors had 9-year distant control rates of 62.8% and 81.6%, respectively (p = 0.034). Disease-free survival rates decreased in recurrent cases (p = 0.006) as well as in LVSI-positive patients (p = 0.035). CONCLUSIONS The complications observed are largely attributable to the antecedent of prior irradiation but can possibly be minimized by meticulous mapping and exhaustive planning to reduce TV(150) values. Patients with high-risk margins, LVSI-positive status, and recurrent disease have a higher risk of treatment failure, and therefore risk-directed treatment strategies are required.

Concomitant cisplatin, paclitaxel, and hyperfractionated radiotherapy in locally advanced head and neck cancer: comparison of two different schedules.

Purpose:To determine feasibility and efficacy of concurrent paclitaxel and cisplatin with definitive hyperfractionated radiotherapy (HFRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). Patients and Methods:Forty-two patients stages III to IV head-and-neck squamous cell carcinoma were enrolled in 2 consecutive prospective trials from August 1998 to January 2006. In study 1, 16 patients received HFRT in 2 courses of 39.6 Gy each with a split of 2 weeks with concurrent paclitaxel (175 mg/m2) and cisplatin (100 mg/m2) on days 1, 21, 36, and 57. In study 2, 26 patients received a continuous course of 74.4 Gy of HFRT with concurrent weekly paclitaxel (50 mg/m2) and cisplatin (30 mg/m2). Results:Tumor locations included oropharynx 48%, hypopharynx 24%, larynx 12%, paranasal sinuses 7%, salivary gland 2%, oral cavity 2% and unknown primary 5%. In study 1, all patients received 3 to 4 cycles of chemotherapy and completed the programmed radiotherapy course. In study 2, 69% received 5 to 6 cycles of chemotherapy and 92% completed the irradiation. Overall, 93% of objective responses were observed (complete 76%, partial 17%). Median follow-up was 50 months (range: 12–97). Pattern of recurrence was local 8%, distant 13%, and combined 3%. Acute toxicity grades 3 to 4 in studies 1 and 2 was 75% and 88%, respectively (P = ns). Globally, 5-year overall survival were 68%, with a median of 71 months (range: 50–91). On multivariate analysis, male gender (P = 0.04) and complete response (P = 0.01) were predictive of improved survival. Conclusion:HFRT combined with cisplatin and paclitaxel is very active but at the expense of severe toxicity. Efficacy and toxicity in studies·1 and 2 were not different despite completely different treatment strategies (chemotherapy dose intensity vs. radiotherapy dose intensity).

Early breast cancer treated with conservative surgery, adjuvant chemotherapy, and delayed accelerated partial breast irradiation with high-dose-rate brachytherapy

PURPOSE To evaluate the feasibility and intermediate-term results of conservative surgery, adjuvant chemotherapy, and delayed accelerated partial breast irradiation (APBI) with high-dose-rate brachytherapy. METHODS AND MATERIALS Between 2000 and 2007, a total of 26 patients with a median age of 54 years were treated with conservative surgery followed by adjuvant chemotherapy and exclusive high-dose-rate brachytherapy. Inclusion criteria followed the Radiation Therapy Oncology Group 95-17 trial guidelines. The tumor bed was marked at the time of surgery (n = 2) or before brachytherapy (n = 24). The brachytherapy procedure was performed at a median of 22 weeks after surgery. A median of 14 brachytherapy catheters were placed in three to four parallel planes. A dose of 34.0 Gy in 10 b.i.d. fractions given over 5 consecutive days was prescribed to the clinical target volume (CTV90). RESULTS After a median followup of 53 months (range, 6.8-81), Radiation Therapy Oncology Group Grade 1-2 events and Grade 3 events were observed in 10 (38.4%) patients and 3 (11.5%) patients, respectively. No Grade 4-5 events were observed. Patients rated their cosmetic result as excellent (37.5%), good (50.0%), fair (8%), or poor (4%) based on the Wazers Criteria. The 6-year actuarial local, elsewhere in the breast, and distant control rates were 100%, 96.2%, and 96.2%, respectively. Six-year disease-free survival and overall survival were 92.3% and 96.2%, respectively. CONCLUSIONS Patients undergoing surgery and adjuvant chemotherapy can still be candidates for APBI. Optimal visualization of the internal lumpectomy scar before implantation is mandatory. Cosmetic results may be slightly worse due to the interaction between chemotherapy and APBI, and technical refinements may be needed in this group of patients.

INTERACTION OF 2-Gy EQUIVALENT DOSE AND MARGIN STATUS IN PERIOPERATIVE HIGH-DOSE-RATE BRACHYTHERAPY

PURPOSE To determine patient, tumor, and treatment factors predictive of local control (LC) in a series of patients treated with either perioperative high-dose-rate brachytherapy (PHDRB) alone (Group 1) or with PHDRB combined with external-beam radiotherapy (EBRT) (Group 2). PATIENT AND METHODS Patients (n = 312) enrolled in several PHDRB prospective Phase I-II studies conducted at the Clínica Universidad de Navarra were analyzed. Treatment with PHDRB alone, mainly because of prior irradiation, was used in 126 patients to total doses of 32 Gy/8 b.i.d. or 40 Gy/10 b.i.d. treatments after R0 or R1 resections. Treatment with PHDRB plus EBRT was used in 186 patients to total doses of 16 Gy/4 b.i.d. or 24 Gy/6 b.i.d. treatments after R0 or R1 resections along with 45 Gy of EBRT with or without concomitant chemotherapy. RESULTS No dose-margin interaction was observed in Group 1 patients. In Group 2 patients there was a significant interaction between margin status and 2-Gy equivalent (Eq2Gy) dose (p = 0.002): (1) patients with negative margins had 9-year LC of 95.7% at Eq2Gy = 62.9Gy; (2) patients with close margins of >1 mm had 9-year LC of 92.4% at Eq2Gy = 72.2Gy, and (3) patients with positive/close <1-mm margins had 9-year LC of 68.0% at Eq2Gy = 72.2Gy. CONCLUSIONS Two-gray equivalent doses ≥70 Gy may compensate the effect of close margins ≥1 mm but do not counterbalance the detrimental effect of unfavorable (positive/close <1 mm) resection margins. No dose-margin interaction is observed in patients treated at lower Eq2Gy doses ≤50 Gy with PHDRB alone.