Miren Gaztañaga

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.

Patterns of Response After Preoperative Treatment in Gastric Cancer

PURPOSE To analyze the rate of pathologic response in patients with locally advanced gastric cancer treated with preoperative chemotherapy with and without chemoradiation at our institution. METHODS AND MATERIALS From 2000 to 2007 patients were retrospectively identified who received preoperative treatment for gastric cancer (cT3-4/ N+) with induction chemotherapy (Ch) or with Ch followed by concurrent chemoradiotherapy (45 Gy in 5 weeks) (ChRT). Surgery was planned 4-6 weeks after the completion of neoadjuvant treatment. Pathologic assessment was used to investigate the patterns of pathologic response after neoadjuvant treatment. RESULTS Sixty-one patients were analyzed. Of 61 patients, 58 (95%) underwent surgery. The R0 resection rate was 87%. Pathologic complete response was achieved in 12% of the patients. A major pathologic response (<10% of residual tumor) was observed in 53% of patients, and T downstaging was observed in 75%. Median follow-up was 38.7 months. Median disease-free survival (DFS) was 36.5 months. The only patient-, tumor-, and treatment-related factor associated with pathologic response was the use of preoperative ChRT. Patients achieving major pathologic response had a 3-year actuarial DFS rate of 63%. CONCLUSIONS The patterns of pathologic response after preoperative ChRT suggest encouraging intervals of DFS. Such a strategy may be of interest to be explored in gastric cancer.

Toxic epidermal necrolysis related to pemetrexed and carboplatin with vitamin B12 and folic acid supplementation for advanced non-small cell lung cancer.

Background: Pemetrexed is a multitargeted antifolate initially approved as a single agent for the second-line treatment of locally advanced or metastatic non-small cell lung cancer and more recently in the first-line setting combined with cisplatin. The combination of pemetrexed with carboplatin has been tested in several phase II clinical trials showing interesting antitumour activity with mild toxicity. Supplementation with folic acid and vitamin B12 during treatment with pemetrexed is recommended to reduce potential haematological and gastrointestinal adverse events. Case Report: A patient experienced cutaneous lesions including widespread erythema, epidermal detachment, and skin denudation, associated with deterioration of his general condition after the second cycle of this chemotherapy combination, which was clinically and histologically compatible with toxic epidermal necrolysis (Lyell’s syndrome). Treatment with systemic steroids, antihistamines, and antibiotics led to resolution of the skin lesions and improvement of his general condition. Conclusion: To our knowledge, this is the second case reported in the literature of this type of suspected adverse drug reaction associated with a pemetrexed-based chemotherapy combination.

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.

Interpreting a rising prostate-specific antigen after brachytherapy for prostate cancer

The aim of the present study was to review the English language literature on the topic of prostate‐specific antigen bounce after brachytherapy and present a summary of the current knowledge. Although ultimately prostate‐specific antigen is a reliable measure of success after prostate brachytherapy, it can be very misleading in the first 3 years because of the frequency with which temporary benign rises in prostate‐specific antigen occur. We have reviewed the English language literature on the topic of prostate‐specific antigen bounce under the following headings: prostate neoplasms, brachytherapy, biochemical definition of prostate‐specific antigen failure, “benign prostate‐specific antigen bounce” and “prostate‐specific antigen spike”. We included brachytherapy delivered as either low dose rate or high dose rate, and either as monotherapy or as a boost combined with external beam radiotherapy. A benign self‐limited rise in prostate‐specific antigen after prostate brachytherapy is seen in an average of 35% of patients, but increases in frequency with younger age. In patients aged less than 55 years, it is observed in up to 68%. Other factors, such as sexual activity, dose, prostate volume and the use of high dose rate versus low dose rate have been implicated in affecting the frequency of the benign bounce. Benign increases in prostate‐specific antigen are frequent after prostate brachytherapy. It is important to recognize and correctly diagnose this phenomenon in order to avoid unnecessary salvage treatment.

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.

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.

Long-term results of 1-week intravaginal high-dose-rate brachytherapy alone for endometrial cancer

OBJECTIVE To compare the biologic equivalence in terms of local control and toxicity of a short course of high-dose-rate intravaginal brachytherapy alone (IVBa) delivered over five consecutive days (25 Gy/5 Rx/5 days) to other more protracted classical schemes 21 Gy/3 Rx/14-28 days (Postoperative Radiation Therapy in Endometrial Carcinoma [PORTEC]-2/Memorial Sloan-Kettering Cancer Center). METHODS AND MATERIALS From February 2001 to May 2008, 122 patients with International Federation of Gynecology and Obstetrics Stage IaG3-IIIaG2 endometrial adenocarcinoma were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by postoperative IVBa. Seventy-seven patients (63.1%) underwent surgical staging. Total IVBa dose was 25Gy in five consecutive daily fractions prescribed at 0.5-cm depth. RESULTS After a median followup of 4.1 years, the rates of Radiation Therapy Oncology Group Grades 1, 2, and ≥3 complications were 12.9%, 3.4%, and 0.8%, respectively. Five patients (4.1%) presented locoregional failures: two isolated nodal pelvic failures, one vaginal pelvic relapse (intra-abdominal lymph node metastases), one vaginal distant failure, and one combined locoregional and distant failure. The 8.5-year actuarial vaginal control rate was 97.5%, and the pelvic control rate was 94.3%. Six other patients developed distant metastases alone. The 8.5-year actuarial overall and disease-free survival rates were 90.3% and 87.2%, respectively. Univariate analysis revealed that histologic grade, deep myometrial invasion, advanced age, and categorization as high intermediate-risk patient according to the PORTEC-2 and the Gynecologic Oncology Group (GOG)-99 stratifications were statistically significant prognostic factors. After multivariate analysis, histologic grade (p=0.001) and high intermediate risk according to GOG-99 (p=0.004) and PORTEC-2 (p=0.001) remained significant. CONCLUSIONS The proposed scheme reproduces the excellent results obtained with more protracted schemes and has the added advantage of shortened overall treatment time.

A phase II trial of less than 7 weeks of concomitant cisplatin-paclitaxel chemoradiation in locally advanced cervical cancer.

Objectives: This study was undertaken to determine the tolerability of a 7-week schedule of external beam radiation therapy, high-dose-rate brachytherapy, and weekly cisplatin and paclitaxel in patients with locally advanced carcinoma of the cervix. Methods: Twenty-nine patients with International Federation of Gynecology and Obstetrics stages IB2 to IVa cervical cancer were treated with 40 mg/m2 per week of intravenous (i.v.) cisplatin and 50 mg/m2 per week of i.v. paclitaxel combined with 45 Gy of pelvic external beam radiation therapy and 30 Gy of high-dose-rate brachytherapy. Results: Eleven patients (37.9%) were able to complete the 6 scheduled cycles of chemotherapy. The median number of weekly chemotherapy cycles administered was 5 (range, 2-7). Thirty-five (20.1%) of 174 cycles of chemotherapy were not given because of toxicity. The median dose intensity of cisplatin was 31 mg/m2 per week (95% confidence interval [CI], 25.2-36.8); that of paclitaxel was 44 mg/m2 per week (95% CI, 39.9-48.3). Twenty-two patients (78.6%) were able to complete the planned radiation course in less than 7 weeks. Median radiation treatment length was 45 days (95% CI, 43.4-46.6). After a median follow-up of 48 months, 7 patients (24.1%) experienced severe (Radiation Therapy Oncology Group grade 3 or higher) late toxicity. No fatal events were observed. Seven patients have failed, 1 locally and 6 at distant sites. The 8-year local/pelvic control rate was 95.7%, and the 8-year freedom from systemic failure rate was 76.1%. Eight-year actuarial disease-free survival and overall survival were 63.1% and 75.9%, respectively. Conclusions: This study demonstrated unacceptable toxicity of combining the stated doses of concurrent cisplatin and paclitaxel chemotherapy with definitive radiotherapy for patients with advanced cervical cancer. Additional phase I/II trials are recommended to clearly establish the recommended phase II dose for these drugs.