Charles A. Kunos

Radiation therapy compared with pelvic node resection for node-positive vulvar cancer: a randomized controlled trial.

OBJECTIVES: To report long-term survival and toxicity of radiation compared with pelvic node resection for patients with groin node–positive vulvar cancer. METHODS: A Gynecologic Oncology Group protocol enrolled 114 patients randomly allocated to postoperative pelvic and groin radiation (45–50 Gy, n=59) or to ipsilateral pelvic node resection (n=55) after radical vulvectomy and inguinal lymphadenectomy. Retrospective analyses for 114 enrolled patients included both risk of progression and death after treatment and assessment of toxicity. RESULTS: Median age was 70 years. Median survivor follow-up was 74 months. The relative risk of progression was 39% in radiation patients (95% confidence interval [CI] 0.17–0.88, P=.02). Fourteen intercurrent deaths occurred after radiation as compared with only two after pelvic node resection, narrowing 6-year overall survival (51% compared with 41%, hazard ratio 0.61 [95% CI 0.30–1.3], P=.18). However, the cancer-related death rate was significantly higher for pelvic node resection compared with radiation (51% compared with 29% at 6 years, hazard ratio 0.49 [95% CI 0.28–0.87], P=.015). Six-year overall survival benefit for radiation in patients with clinically suspected or fixed ulcerated groin nodes (P=.004) and two or more positive groin nodes (P<.001) persisted. A ratio of more than 20% positive ipsilateral groin nodes (number positive/number resected) was significantly associated with contralateral lymph node metastasis, relapse, and cancer-related death. Late chronic lymphedema (16% compared with 22%) and cutaneous desquamation (19% compared with 15%) were balanced after radiation and pelvic node resection. CONCLUSION: Radiation after radical vulvectomy and inguinal lymphadenectomy significantly reduces local relapses and decreases cancer-related deaths. Late toxicities remained similar after radiation or pelvic node resection. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00898352. LEVEL OF EVIDENCE: I

Phase I Trial of Pelvic Radiation, Weekly Cisplatin, and 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, NSC #663249) for Locally Advanced Cervical Cancer

Purpose: This study assessed the safety/tolerability, pharmacokinetics, and clinical activity of three times weekly i.v. 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in combination with once-weekly i.v. cisplatin and daily pelvic radiation in patients with gynecologic malignancies. 3-AP is a novel small-molecule inhibitor of ribonucleotide reductase (RNR) and is being tested as a potential radiosensitizer and chemosensitizer. Experimental Design: Patients with stage IB2 to IVB cervical cancer (n = 10) or recurrent uterine sarcoma (n = 1) were assigned to dose-finding cohorts of 2-hour 3-AP infusions during 5 weeks of cisplatin chemoradiation. Pharmacokinetic and methemoglobin samples and tumor biopsy for RNR activity were obtained on day 1 and day 10. Clinical response was assessed. Results: The maximum tolerated 3-AP dose was 25 mg/m2 given three times weekly during cisplatin and pelvic radiation. Two patients experienced manageable 3-AP–related grade 3 or 4 electrolyte abnormalities. 3-AP pharmacokinetics showed a 2-hour half-life, with median peak plasma concentrations of 277 ng/mL (25 mg/m2) and 467 ng/mL (50 mg/m2). Median methemoglobin levels peaked at 1% (25 mg/m2) and 6% (50 mg/m2) at 4 hours after initiating 3-AP infusions. No change in RNR activity was found on day 1 versus day 10 in six early complete responders, whereas elevated RNR activity was seen on day 10 as compared with day 1 in four late complete responders (P = 0.02). Ten (100%) patients with stage IB2 to IVB cervical cancer achieved complete clinical response and remained without disease relapse with a median 18 months of follow-up (6-32 months). Conclusions: 3-AP was well tolerated at a three times weekly i.v. 25 mg/m2 dose during cisplatin and pelvic radiation. Clin Cancer Res; 16(4); 1298–306

Breast Conservation Surgery Achieving ≥ 2 mm Tumor-Free Margins Results in Decreased Local-Regional Recurrence Rates

Abstract:  Whether cosmetically acceptable tumor‐free (≥2 mm) surgical margins reduce the local‐regional recurrence risk for patients treated with fractionated radiation therapy, chemotherapy, and hormonal therapy is unknown. The benefit of a minimum cosmetically acceptable tumor‐free margin remains speculative because no contemporary studies have investigated the extent of invasive disease infiltration within the breast beyond the primary tumor. To address these clinical issues, we conducted a retrospective study of 341 women diagnosed with stage I or II invasive breast cancer to determine the rate of local in‐breast, elsewhere in‐breast, and ipsilateral regional lymph node recurrences of breast cancer after conservation surgery achieving either tumor‐free (≥2 mm) or close (>0 mm to <2 mm) surgical margins followed by whole breast radiation therapy over a 6‐year period from January 1996 to December 2002. Women may have received adjuvant chemotherapy or hormonal therapy as clinically indicated. After a median follow‐up of 56 months from the completion of breast conservation surgery, 14 of the 341 women (4.1%) developed breast cancer recurrences. Crude ipsilateral recurrence rates were 1.8% (4 of 222) for tumor‐free (≥2 mm) versus 8.4% (10 of 119) for close (>0 mm to <2 mm) surgical margins (p = 0.007). The estimated 5‐year cumulative local recurrence rate was significantly less for women with tumor‐free margins (2.1%) as compared to close surgical margins (8.9%) (p = 0.004). Multivariate analyses identified negative estrogen receptor expression (p = 0.004), close surgical margins (p = 0.012), and the presence of angiolymphatic invasion (p = 0.040) as prognostic factors for local‐regional recurrences. Microscopically the extent of invasive disease infiltration beyond the primary tumor was on average 1 mm, with all measured invasive disease less than 1 cm. Based on our findings, cosmetically acceptable tumor‐free (≥2 mm) surgical margins significantly reduce local in‐breast and regional lymph node recurrences with fractionated radiation therapy, chemotherapy, and hormonal therapy.

First rib metamorphosis : Its possible utility for Human age-at-death estimation

Human first ribs demonstrate predictable, sequential changes in shape, size, and texture with increasing age, and thus, can be used as an indicator of age at death. Metamorphosis of the first ribs head, tubercle, and costal face was documented in a cross-sectional sample of preadult and adult first ribs of known age at death from the Hamann-Todd skeletal collection (Cleveland Museum of Natural History, Cleveland, Ohio). Blind tests of the usefulness of the first rib as an age indicator were conducted, including tabulation of intraobserver and interobserver inaccuracies and biases. First rib age estimates show inaccuracies and biases by decade comparable to those generated by other aging techniques. Indeed, the first rib method is useful as an isolated age indicator. When used in conjunction with other age indicators, the first rib improves the quality of summary age assessments.

Comparison and consensus guidelines for delineation of clinical target volume for CT- and MR-based brachytherapy in locally advanced cervical cancer

OBJECTIVE To create and compare consensus clinical target volume (CTV) contours for computed tomography (CT) and 3-Tesla (3-T) magnetic resonance (MR) image-based cervical-cancer brachytherapy. METHODS AND MATERIALS Twenty-three experts in gynecologic radiation oncology contoured the same 3 cervical cancer brachytherapy cases: 1 stage IIB near-complete response (CR) case with a tandem and ovoid, 1 stage IIB partial response (PR) case with tandem and ovoid with needles, and 1 stage IB2 CR case with a tandem and ring applicator. The CT contours were completed before the MRI contours. These were analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE), with κ statistics as a measure of agreement between participants. The conformity index was calculated for each of the 6 data sets. Dice coefficients were generated to compare the CT and MR contours of the same case. RESULTS For all 3 cases, the mean tumor volume was smaller on MR than on CT (P<.001). The κ and conformity index estimates were slightly higher for CT, indicating a higher level of agreement on CT. The Dice coefficients were 89% for the stage IB2 case with a CR, 74% for the stage IIB case with a PR, and 57% for the stage IIB case with a CR. CONCLUSION In a comparison of MR-contoured with CT-contoured CTV volumes, the higher level of agreement on CT may be due to the more distinct contrast medium visible on the images at the time of brachytherapy. MR at the time of brachytherapy may be of greatest benefit in patients with large tumors with parametrial extension that have a partial or complete response to external beam. On the basis of these results, a 95% consensus volume was generated for CT and for MR. Online contouring atlases are available for instruction at http://www.nrgoncology.org/Resources/ContouringAtlases/GYNCervicalBrachytherapy.aspx.

Stereotactic Body Radiation Therapy for Nonresectable Tumors of the Pancreas

BACKGROUND Stereotactic body radiation therapy (SBRT) has emerged as a potential treatment option for local tumor control of primary malignancies of the pancreas. We report on our experience with SBRT in patients with pancreatic adenocarcinoma who were found not to be candidates for surgical resection. METHODS The prospective database of the first 20 consecutive patients receiving SBRT for unresectable pancreatic adenocarcinomas and a neuroendocrine tumor under an IRB approved protocol was reviewed. Prior to SBRT, cylindrical solid gold fiducial markers were placed within or around the tumor endoscopically (n = 13), surgically (n = 4), or percutaneously under computerized tomography (CT)-guidance (n = 3) to allow for tracking of tumor during therapy. Mean radiation dose was 25 Gray (Gy) (range 22-30 Gy) delivered over 1-3 fractions. Chemotherapy was given to 68% of patients in various schedules/timing. RESULTS Patients had a mean gross tumor volume of 57.2 cm(3) (range 10.1-118 cm(3)) before SBRT. The mean total gross tumor volume reduction at 3 and 6 mo after SBRT were 21% and 38%, respectively (P < 0.05). Median follow-up was 14.57 mo (range 5-23 mo). The overall rate of freedom from local progression at 6 and 12 mo were 88% and 65%. The probability of overall survival at 6 and 12 mo were 89% and 56%. No patient had a complication related to fiducial markers placement regardless of modality. The rate of radiation-induced adverse events was: grade 1-2 (11%) and grade 3 (16%). There were no grade 4/5 adverse events seen. CONCLUSION Our preliminary results showed SBRT as a safe and likely effective local treatment modality for pancreatic primary malignancy with acceptable rate of adverse events.

Radiochemotherapy plus 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage cervical and vaginal cancers ☆ ☆☆

OBJECTIVE Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. METHODS We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m(2)) co-administered with 1× weekly intravenous cisplatin (40 mg/m(2)) and daily pelvic radiation (45 Gy) in women with stage I(B2)-IV(B) cervical (n=22) or stage II-IV vaginal (n=3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[(18)F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. RESULTS 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80-99%]) of 25 patients (median follow-up 20 months, range 2-35 months). 23 (96% [95% confidence interval: 80-99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. CONCLUSIONS The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted.

Ribonucleotide Reductase Inhibition Enhances Chemoradiosensitivity of Human Cervical Cancers

Abstract For repair of damaged DNA, cells increase de novo synthesis of deoxyribonucleotide triphosphates through the rate-limiting, p53-regulated ribonucleotide reductase (RNR) enzyme. In this study we investigated whether pharmacological inhibition of RNR by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) enhanced chemoradiation sensitivity through a mechanism involving sustained DNA damage. RNR inactivation by 3-AP and resulting chemoradiosensitization were evaluated in human cervical (CaSki, C33-a) cancer cells through study of DNA damage (&ggr;-H2AX signal) by flow cytometry, RNR subunit p53R2 and p21 protein steady-state levels by Western blot analysis and laser scanning imaging cytometry, and cell survival by colony formation assays. 3-AP treatment led to sustained radiation- and cisplatin-induced DNA damage (i.e. increased &ggr;-H2AX signal) in both cell lines through a mechanism of inhibited RNR activity. Radiation, cisplatin and 3-AP exposure resulted in significantly elevated numbers and persistence of &ggr;-H2AX foci that were associated with reduced clonogenic survival. DNA damage was associated with a rise in p53R2 but not p21 protein levels 6 h after treatment with radiation and/or cisplatin plus 3-AP. We conclude that blockage of RNR activity by 3-AP impairs DNA damage responses that rely on deoxyribonucleotide production and thereby may substantially increase chemoradiosensitivity of human cervical cancers.

Cyberknife stereotactic body radiation therapy for nonresectable tumors of the liver: preliminary results.

Purpose. Stereotactic body radiation therapy (SBRT) has emerged as a treatment option for local tumor control of primary and secondary malignancies of the liver. We report on our updated experience with SBRT in patients with non-resectable tumors of the liver. Methods. Our first 17 consecutive patients (mean age 58.1 years) receiving SBRT for HCC (n = 6), IHC (n = 3), and LM (n = 8) are presented. Mean radiation dose was 34Gy delivered over 1–3 fractions. Results. Treated patients had a mean decrease in maximum pretreatment tumor diameter from 6.9 ± 4.6 cm to 5.0 ± 2.1 cm at three months after treatment (P < .05). The mean total tumor volume reduction was 44% at six months (P < .05). 82% of all patients (14/17) achieved local control with a median follow-up of 8 months. 100% of patients with HCC (n = 6) achieved local control. Patients with surgically placed fiducial markers had no complications related to marker placement. Conclusion. Our preliminary results showed that SBRT is a safe and effective local treatment modality in selected patients with liver malignancies with minimal adverse events. Further studies are needed to define its role in the management of these malignancies.

Modulating Radiation Resistance by Inhibiting Ribonucleotide Reductase in Cancers with Virally or Mutationally Silenced p53 Protein

Abstract Kunos, C. A., Chiu, S., Pink, J. and Kinsella, T. J. Modulating Radiation Resistance by Inhibiting Ribonucleotide Reductase in Cancers with Virally or Mutationally Silenced p53 Protein. Therapeutic ionizing radiation damages DNA, increasing p53-regulated ribonucleotide reductase (RNR) activity required for de novo synthesis of the deoxyribonucleotide triphosphates used during DNA repair. This study investigated the pharmacological inhibition of RNR in cells of virally or mutationally silenced p53 cancer cell lines using 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®, NSC #663249), a chemotherapeutic radiosensitizer that equally inhibits RNR M2 and p53R2 small subunits. The effects of 3-AP on RNR inhibition and resulting radiosensitization were evaluated in cervical (CaSki, HeLa and C33-a) and colon (RKO, RKO-E6) cancer cells. 3-AP treatment significantly enhanced radiation-related cytotoxicity in cervical and colon cancer cells. 3-AP treatment significantly decreased RNR activity, caused prolonged radiation-induced DNA damage, and resulted in an extended G1/S-phase cell cycle arrest in all cell lines. Similar effects were observed in both RKO and RKO-E6 cells, suggesting a p53-independent mechanism of radiosensitization. We conclude that inhibition of ribonucleotide reductase by 3-AP enhances radiation-mediated cytotoxicity independent of p53 regulation by impairing repair processes that rely on deoxyribonucleotide production, thereby substantially increasing the radiation sensitivity of human cancers.