Daryl Lim Joon

Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation

PURPOSE Androgen ablation is often combined with radiation in the treatment of patients with prostate cancer, yet, the optimal sequencing and the mechanisms governing the interaction are not understood. The objectives were to determine if cell killing via apoptosis is enhanced when the combined treatment is administered and to define the relationship of changes in this form of cell killing to tumor volume growth delay. MATERIALS AND METHODS Dunning R3327-G rat prostate tumors, grown in the flanks of Copenhagen rats, were used at a volume of approximately 1 cc. Androgen ablation was initiated by castration, and androgen restoration was achieved with 0.5 cm silastic tube implants containing testosterone. 60Co was used for irradiation. The terminal deoxynucleotidyl transferase (TUNEL) histochemical assay was used to quantify apoptosis. RESULTS Tumors from intact and castrate unirradiated control rats had average apoptotic indices (percent of apoptotic cells) of 0.4 and 1.0%, respectively. The apoptotic index varied only slightly over time (3 h to 28 days) after castration (range 0.75-1.43%). Irradiation of intact rats to 7 Gy resulted in a peak apoptotic response at 6 h of 2.3%. A supraadditive apoptotic response was seen when castration was initiated 3 days prior to 7 Gy radiation, with peak levels of about 10.1%. When the radiation was administered at increasing times beyond 3 days after castration, the apoptotic response gradually diminished and was back to levels seen in intact rats by 28 days after castration. Tumor volume growth delay studies were consistent with, but not conclusive proof of, a supraadditive effect when the combination was used. DISCUSSION A supraadditive apoptotic response was seen when androgen ablation and radiation were used to treat androgen sensitive R3327-G rat prostate tumors. This supraadditive effect was dependent on the timing of the two treatments. Further studies are required to more fully define the optimal timing and administration of androgen ablation and radiation.

Assessing the impact of FDG-PET in the management of anal cancer

PURPOSE To assess the utility of FDG-PET in anal cancer for staging and impact on radiotherapy planning (RTP), response and detection of recurrent disease. METHODS AND MATERIALS Fifty histopathological anal cancer patients were reviewed between 1996 and 2006. The median age was 58 years (range 36-85) with 19 males:31females. Clinical assessment with CT was compared to PET. Impact on management, disease response, recurrence and metastases was evaluated. RESULTS The non-PET staging was Stage I(8), Stage II(18), Stage III(22), and Stage IV(2)s. The primary was strongly FDG avid in 98% with non-excised tumors compared to CT (58%). PET upstaged 17% with unsuspected pelvic/inguinal nodal disease. Pre-treatment PET identified 11 additional by involved nodal groups in 48 patients causing RTP amendments in 19%. Post-treatment PETs at median 17 weeks (range 9-28) showed complete responses in 20 (80%) and 5 (20%) partial responses (PR). PRs were biopsy positive in 2 and negative in 3. Fifteen had follow-up scans of which all nine PETs detected recurrences were pathologically confirmed. CONCLUSIONS Anal cancer is FDG-PET avid. PET upstages 17% and changes the RTP in 19%. PET can aid in anal cancer staging and identification of residual disease, recurrent/metastatic disease but warrants further prospective studies.

Effect of sequencing of androgen deprivation and radiotherapy on prostate cancer growth

PURPOSE Androgen deprivation (AD) is frequently combined with radiotherapy (RT); however, the optimal sequence in vivo is currently unknown. Previous published work from our laboratory demonstrated that AD with RT was consistent with at least an additive, and possibly supra-additive, effect with the combined approach. We, therefore, performed additional experiments to elucidate the optimal sequence. METHODS AND MATERIALS R3327-G Dunning rat prostate tumor cells were grown s.c. in the flanks of Copenhagen rats. Treatment was initiated when the tumor reached approximately 1 cm(3). Temporary AD was performed by a transscrotal orchiectomy followed 14 days later with androgen restoration using s.c. testosterone implants. RT was delivered using (60)Co to 7 Gy. Seven groups, including the controls, were analyzed: Group 1, sham control (Day 0: AD + testosterone); 2, AD control (Day 0: AD, Day 14: testosterone); 3, RT alone on Day 7 (Day 0: AD + testosterone, Day 7 RT); 4, RT alone on Day 3 (Day 0: AD + testosterone, Day 3: RT); 5, RT during AD (Day 0: AD, Day 7: RT, Day 14: testosterone); 6, RT before AD (Day 0: RT, Day 3: AD, Day 17: testosterone); and Group 7, RT after AD (Day 0: AD, Day 14: testosterone, Day 17: RT). The doubling times for tumor growth were calculated for the seven groups from the end of treatment plus 1 day. Differences in doubling time were assessed using analysis of variance, with pair-wise comparisons accomplished using post-hoc Bonferroni tests. RESULTS An analysis of the differences in the tumor volume doubling time as measured from the end of treatment suggests that Groups 1 and 7 were statistically different from the other groups (p = 0.02). As expected, the sham control group had the shortest doubling time at 5.4 days and Group 7 (14 days of AD administered before RT) had the longest doubling time at 32.6 days. The findings were similar even after excluding an outlying doubling time of 85 days from Group 7 (p < 0.0001). To assess the effect of sequencing further, only Groups 5 through 7 (excluding the outlier) were compared in an analysis of variance with post-hoc Bonferroni tests. Group 7 (RT after AD) demonstrated a significantly longer doubling time than Groups 5 and 6 (p = 0.0024). CONCLUSION The results suggest that neoadjuvant AD may result in prolonged suppression of tumor growth, even after testosterone replacement.

Hypoxia-targeted radiotherapy dose painting for head and neck cancer using (18)F-FMISO PET: a biological modeling study.

Abstract Background. This study investigates the use of 18F-fluoromisonidazole (FMISO) PET-guided radiotherapy dose painting for potentially overcoming the radioresistant effects of hypoxia in head and neck squamous cell carcinoma (HNSCC). Material and methods. The study cohort consisted of eight patients with HNSCC who were planned for definitive radiotherapy. Hypoxic subvolumes were automatically generated on pre-radiotherapy FMISO PET scans. Three radiotherapy plans were generated for each patient: a standard (STD) radiotherapy plan to a dose of 70 Gy, a uniform dose escalation (UDE) plan to the standard target volumes to a dose of 84 Gy, and a hypoxia dose-painted (HDP) plan with dose escalation only to the hypoxic subvolume to 84 Gy. Plans were compared based on tumor control probability (TCP), normal tissue complication probability (NTCP), and uncomplicated tumor control probability (UTCP). Results. The mean TCP increased from 73% with STD plans to 95% with the use of UDE plans (p < 0.001) and to 93% with HDP plans (p < 0.001). The mean parotid NTCP increased from 26% to 44% with the use of UDE plans (p = 0.003), and the mean mandible NTCP increased from 2% to 27% with the use of UDE plans (p = 0.001). There were no statistically significant differences between any of the NTCPs between the STD plans and HDP plans. The mean UTCP increased from 48% with STD plans to 66% with HDP plans (p = 0.016) and dropped to 37% with UDE plans (p = 0.138). Conclusion. Hypoxia-targeted radiotherapy dose painting for head and neck cancer using FMISO PET is technically feasible, increases the TCP without increasing the NTCP, and increases the UTCP. This approach is superior to uniform dose escalation.

Intensity Modulated Radiation Therapy Dose Painting for Localized Prostate Cancer Using 11C-choline Positron Emission Tomography Scans

PURPOSE To demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) dose painting using (11)C-choline positron emission tomography PET scans in patients with localized prostate cancer. METHODS AND MATERIALS This was an RT planning study of 8 patients with prostate cancer who had (11)C-choline PET scans prior to radical prostatectomy. Two contours were semiautomatically generated on the basis of the PET scans for each patient: 60% and 70% of the maximum standardized uptake values (SUV(60%) and SUV(70%)). Three IMRT plans were generated for each patient: PLAN(78), which consisted of whole-prostate radiation therapy to 78 Gy; PLAN(78-90), which consisted of whole-prostate RT to 78 Gy, a boost to the SUV(60%) to 84 Gy, and a further boost to the SUV(70%) to 90 Gy; and PLAN(72-90), which consisted of whole-prostate RT to 72 Gy, a boost to the SUV(60%) to 84 Gy, and a further boost to the SUV(70%) to 90 Gy. The feasibility of these plans was judged by their ability to reach prescription doses while adhering to published dose constraints. Tumor control probabilities based on PET scan-defined volumes (TCP(PET)) and on prostatectomy-defined volumes (TCP(path)), and rectal normal tissue complication probabilities (NTCP) were compared between the plans. RESULTS All plans for all patients reached prescription doses while adhering to dose constraints. TCP(PET) values for PLAN(78), PLAN(78-90), and PLAN(72-90) were 65%, 97%, and 96%, respectively. TCP(path) values were 71%, 97%, and 89%, respectively. Both PLAN(78-90) and PLAN(72-90) had significantly higher TCP(PET) (P=.002 and .001) and TCP(path) (P<.001 and .014) values than PLAN(78). PLAN(78-90) and PLAN(72-90) were not significantly different in terms of TCP(PET) or TCP(path). There were no significant differences in rectal NTCPs between the 3 plans. CONCLUSIONS IMRT dose painting for localized prostate cancer using (11)C-choline PET scans is technically feasible. Dose painting results in higher TCPs without higher NTCPs.

Relationship of Ki-67 labeling index to DNA-ploidy, S-phase fraction, and outcome in prostate cancer treated with radiotherapy

Our purpose was to evaluate the relationship of Ki‐67 labeling index (Ki67‐LI) to deoxyribonucleic acid (DNA) ploidy, S phase fraction (SPF), other clinical prognostic factors, and clinical outcome for patients with prostate cancer treated by external beam radiotherapy.

Histopathological correlation of 11C-choline PET scans for target volume definition in radical prostate radiotherapy

BACKGROUND AND PURPOSE To evaluate the accuracy of (11)C-choline PET scans in defining dominant intraprostatic lesions (DILs) for radiotherapy target volume definition. MATERIAL AND METHODS Eight men with prostate cancer who had (11)C-choline PET scans prior to radical prostatectomy were studied. Several methods were used to contour the DIL on the PET scans: visual, PET Edge, Region Grow, absolute standardised uptake value (SUV) thresholds and percentage of maximum SUV thresholds. Prostatectomy specimens were sliced in the transverse plane and DILs were delineated on these by a pathologist. These were then compared with the PET scans. The accuracy of correlation was assessed by the Dice similarity coefficient (DSC) and the Youden index. RESULTS The contouring method resulting in both the highest DSC and the highest Youden index was 60% of the maximum SUV (SUV(60%)), with values of 0.64 and 0.51, respectively. However SUV(60%) was not statistically significantly better than all of the other methods by either measure. CONCLUSIONS Although not statistically significant, SUV(60%) resulted in the best correlation between (11)C-choline PET and pathology amongst all the methods studied. The degree of correlation shown here is consistent with previous studies that have justified using imaging for DIL radiotherapy target volume definition.

The use of PET in assessing tumor response after neoadjuvant chemoradiation for rectal cancer

PURPOSE To assess the correlation of 18F-FDG-PET (PET) response to pathological response after neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer. METHODS AND MATERIALS Twenty patients with locally advanced rectal cancer were identified between 2001 and 2005. The median age was 57 years (range 37-72) with 14 males and 6 females. All patients were staged with endorectal ultrasound and/or MRI, CT, and PET. The clinical staging was T3N0M0 (16), T3N1M0 (2), and T3N0M1 (2). Restaging PET was performed after CRT, and prior to definitive surgery. The response on PET and pathology was assessed and correlated. Patient outcome according to PET response was also assessed. RESULTS Following CRT, a complete PET response occurred in 7 patients, incomplete response in 10, and no response in 3 patients. At surgery, complete pathological response was recorded in 7 patients, incomplete response in 10 and no response in 3. There was a good correlation of PET and pathological responses in complete responders (5/7 cases) and non-responders (3/3 cases). After a median follow-up of 62 months (range 7-73), twelve patients were alive with no evidence of disease. All patients achieving complete metabolic response were alive with no evidence of disease, while as those who had no metabolic response, all died as a result of metastatic disease. CONCLUSIONS PET is a promising complementary assessment tool for assessing tumor response after CRT if there is a complete or no response. PET response may also predict for outcome.

Adjuvant chemoradiation for gastric cancer using epirubicin, cisplatin, and 5-fluorouracil before and after three-dimensional conformal radiotherapy with concurrent infusional 5-fluorouracil: a multicenter study of the Trans-Tasman Radiation Oncology Group.

PURPOSE The INT0116 study has established postoperative chemoradiotherapy as the standard of care for completely resected gastric adenocarcinoma. However, the optimal chemoradiation regimen remains to be defined. We conducted a prospective, multicenter study to evaluate an alternative chemoradiation regimen that combines more current systemic treatment with modern techniques of radiotherapy delivery. METHODS AND MATERIALS Patients with adenocarcinoma of the stomach who had undergone an R0 resection were eligible. Adjuvant therapy consisted of one cycle of epirubicin, cisplatin, and 5-FU (ECF), followed by radiotherapy with concurrent infusional 5-FU, and then two additional cycles of ECF. Radiotherapy was delivered using precisely defined, multiple-field, three-dimensional conformal techniques. RESULTS A total of 54 assessable patients were enrolled from 19 institutions. The proportion of patients commencing Cycles 1, 2, and 3 of ECF chemotherapy were 100%, 81%, and 67% respectively. In all, 94% of patients who received radiotherapy completed treatment as planned. Grade 3/4 neutropenia occurred in 66% of patients with 7.4% developing febrile neutropenia. Most neutropenic episodes (83%) occurred in the post-radiotherapy period during cycles 2 and 3 of ECF. Grade 3/4 gastrointestinal toxicity occurred in 28% of patients. In all, 35% of radiotherapy treatment plans contained protocol deviations that were satisfactorily amended before commencement of treatment. At median follow-up of 36 months, the 3-year overall survival rate was estimated at 61.6%. CONCLUSIONS This adjuvant regimen using ECF before and after three-dimensional conformal chemoradiation is feasible and can be safely delivered in a cooperative group setting. A regimen similar to this is currently being compared with the INT0116 regimen in a National Cancer Institute-sponsored, randomized Phase III trial.

Primary adenocarcinoma of the anus: a retrospective analysis

PURPOSE To report the clinical features and outcome of patients with primary adenocarcinoma of the anus following radiotherapy with or without chemotherapy. METHODS AND MATERIALS A retrospective analysis was performed on 15 patients referred to Peter MacCallum Cancer Institute between 1981 to 1998 with primary adenocarcinoma of the anus. The median follow-up was 7.5 years. Six patients underwent treatment with curative intent-either chemoradiation or radiotherapy alone. Surgery was mainly limited to either incisional or excisional biopsy. The remaining nine patients were treated with palliative intent because of advanced age, advanced disease, or poor medical status. The biological equivalent doses were calculated for all patients and correlated with time to progression. RESULTS None of the curative group had relapsed after a median follow-up of 6.6 years. All except one were alive and well. No patient developed any serious long-term toxicity and all patients avoided colostomy. All patients managed with palliative intent died with persistent locoregional disease with a median survival of 0.8 year. CONCLUSION Primary adenocarcinoma of the anus is a very rare disease that precludes a rigorous analysis. This study demonstrates that radiation and in particular chemoradiation are effective therapies consistent with other recent series and analogous to squamous cell carcinomas of the anus. It also emphasizes the poor prognosis of patients treated with palliative intent.