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Radiation Oncology/Endometrium/Early Stage

Early Stage Endometrial Cancer (Stage I-II)

Preop BT vs EBRT

 * St. Louis/Peoria, Illinois (1968-1975) -- Intrauterine BT vs EBRT
 * Randomized. 105 patients, adenocarcinoma, FIGO clinical Stage I. Arm 1) Single implant Cs-137 with Heyman capsules and/or T&O 6000-6500 mg-hrs vs Arm 2) EBRT 40/20
 * 1984 PMID 6360334 -- "Preoperative radiation therapy in Stage I endometrial adenocarcinoma. II. Final report of a clinical trial." (Weigensberg IJ, Cancer. 1984 Jan 15;53(2):242-7.)
 * Outcome: pCR at surgery BT 49% vs 30%; pelvic failure 4% vs 13%; 5-year DFS BT 80% vs EBRT 70%; 10-year DFS 67% vs 59%. Half recurrences in pelvis
 * Toxicity: BT 46% vs EBRT 24%
 * Conclusion: Intracavitary radiation is superior to EBRT

Pre-op RT vs. Adjuvant RT

 * GOG 16
 * Randomized. Clinical Stage I, Grade 1-3. Closed early due to non-accrual.

Adjuvant RT

 * 4 randomized trials published thus far
 * The Norwegian trial randomized patients with surgical Stage I (but no lymph node dissection) and brachytherapy to +/- EBRT. There was local control overall, but survival benefit only for Stage IC G3
 * The PORTEC trial randomized patients with intermediate-risk Stage I (specifically no IC G3; no lymph node dissection) to +/- EBRT. There was local control benefit, but no survival benefit
 * The GOG 99 trial randomized patients with Stage IB-IC or occult IIA-IIB (selective LND) to +/- EBRT. There was local control benefit, but no survival benefit
 * Data from ASTEC/CTG EN.5 trials randomizing patients with IC-IIA or IA-IIAG3 or serous papillary/clear cell (PLND done per institution) to +/- EBRT. Approximately 50% of patients in observation arm received vaginal brachytherapy. There was no OS or DFS benefit, and higher toxicity
 * Due to low number of events, none of the trials were really powered to show overall survival benefit. Endpoint for GOG 99 was DFS
 * Cochrane meta-analysis didn't find benefit for EBRT in IA-ICG2, but found 10% survival benefit in ICG3
 * SEER Registry population-based analysis revealed statistically significant benefit for survival with adjuvant radiation in Stage IC patients, but not IA-B
 * A Japanese randomized trial comparing pelvic RT vs. chemotherapy in patients with >50% myometrial invasion (Stage IC-IV) found no overall difference in PFS or OS, and on subset found benefit in high risk patients in favor of chemotherapy
 * PORTEC 2 has been published (see below) comparing EBRT vs BT (but excluding ICG3). BT had slightly higher pelvic failure rate (NS), but no impact on OS, and was felt to be the standard of care for these patients

Randomized
Meta-analysis
 * Cochrane; 2007 PMID 17803718 -- "Survival and recurrent disease after postoperative radiotherapy for early endometrial cancer: systematic review and meta-analysis." (Johnson N, et al. BJOG. 2007 Nov;114(11):1313-20. Epub 2007 Sep 5.)
 * Cochrane methodology. 5 randomized trials.
 * Low-risk disease (IA, IBG1-2): EBRT worsens survival (OR for death without RT 0.71, SS)
 * Intermediate-risk disease (IBG3, ICG1-2): EBRT doesn't alter survival (OR 0.97, NS)
 * High-risk disease (ICG3): EBRT offers DFS benefit (OR 1.76, SS), and benefits 1/10 women
 * Conclusion: Adjuvant EBRT should not be used for IA, IB, or IC G1-2 disease. There is a 10% survival advantage for IC G3 patients

Randomized
 * PORTEC 2 (2002-2006) -- Pelvic EBRT 46/23 vs. vaginal BT
 * Randomized. 427 patients, intermediate-high risk endometrial CA. Eligible if: (1) age greater than 60 years and stage 1C grade 1 or 2 disease, or stage 1B grade 3 disease; and (2) stage 2A disease, any age (apart from grade 3 with greater than 50% myometrial invasion). TAH/BSO, PLND not allowed. Excluded papillary serous and clear cell. Arm 1) EBRT 46/23 vs. Arm 2) HDR 21/3 or LDR 30/1. Primary endpoint vaginal relapse.
 * 2008 ASCO Abstract -- "Vaginal brachytherapy versus external beam pelvic radiotherapy for high-intermediate risk endometrial cancer: Results of the randomized PORTEC-2 trial." (Nout RA, et al. J Clin Oncol. 2008 May 20;26(15_suppl):LBA5503.) Median F/U 2.8 years
 * Outcome: 3-year vaginal relapse EBRT 2.0% vs. VBT 0.9% (NS), pelvic relapse 0.7% vs. 3.6% (SS), OS 90% vs. 91% (NS)
 * Toxicity: Significantly higher rate of diarrhea, persisted >2 years in EBRT group
 * Conclusion: Vaginal BT effective in preventing vaginal recurrences, with slightly higher pelvic failure rate, but no impact on RFS or OS. Quality of life better, so should be considered standard for these patients
 * Comment: Oncolink at UPenn
 * QoL; 2009 PMID 19546404 -- "Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial." (Nout RA, et al. J Clin Oncol. 2009 Jul 20;27(21):3547-56. Epub 2009 Jun 22.)
 * QoL evaluated by EORTC QoL-C30, PR-25, and OV-28 questionnaires. 348 patients (81%) evaluable for QoL. Median F/U 2 years
 * Outcome: VBT better social functioning (SS), and significantly improved diarrhea, fecal leakage, need to stay close to the toilet, and limitation of daily activities due to bowel symptoms (SS). No difference in sexual functioning (~40%)
 * Conclusion: EBRT patients significantly worse diarrhea and bowel symptoms, and worse social functioning
 * 2010 PMID 20206777 -- "Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial." (Nout RA, et al. Lancet. 2010 Mar 6;375(9717):816-23.) Median F/U 3.75 years
 * Outcome: 5-year vaginal recurrence VBT 1.8% vs EBRT 1.6% (NS); 5-year loco-regional relapse 5.1% vs 2.1% (NS); isolated pelvic recurrence 1.5% vs 0.5% (NS); DM 8.3% vs 5.7% (NS). 5-year OS 85% vs 80% (NS).
 * Toxicity: Acute G1-2 at completion of RT VBT 13% vs EBRT 54%
 * Conclusion: VBT is effective, with fewer toxic effects
 * Editorial (PMID 20206759): Agree that VBT should be the standard of care for these patients
 * Long-term QoL, 2015 PMID 26530748 -- "Long-term impact of endometrial cancer diagnosis and treatment on health-related quality of life and cancer survivorship: results from the randomized PORTEC-2 trial." de Boer SM, et al. Int J Radiat Oncol Biol Phys. 2015 Nov 15;93(4):797-809.
 * QoL evaluated by EORTC QoL-C30 and Impact Of Cancer (IOC) version 2 questionnaires at 7 and 10 years. 202 out of 265 patients (76%) evaluable at 7 years, and 80 out of 119 (67%) at 10 years.
 * Outcome: Persistence of higher bowel symptoms in EBRT arm -- fecal leakage 10.6% vs 1.8% (SS), diarrhea 8.4% vs 0.9% (SS), limitations due to bowel symptoms 10.5% vs 1.8% (SS), and bowel urgency 23.3% vs 6.6% (SS). Trend for more urinary urgency (39.3% vs 25.5%, p=0.05). Sexual activity not differ.
 * Conclusion: EBRT had long-lasting impact on bowel symptoms.
 * 10-year, 2018 PMID 30356126 -- "Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy." Wortman BG, et al. Br J Cancer. 2018 Oct;119(9):1067-74. Median F/U 116 months (9.6 years).
 * Outcome: 10-year vaginal recurrence VBT 3.4% vs EBRT 2.4% (NS). Pelvic recurrence VBT 6.3% vs EBRT 0.9% (SS), but mostly combined with distant metastasis. Isolated pelvic recurrence 2.5% vs 0.5% (NS); distant metastasis 10.4% vs 8.9% (NS). 10-year OS 69.5% vs 67.6% (NS). L1CAM, p53-mutant, and substantial LVSI were risk for PR and DM.
 * Conclusion: VBT is standard adjuvant for high-intermediate risk. EBRT had better pelvic control in unfavorable risk.

 * MRC ASTEC and NCIC CTG EN.5 (1996-2005) -- EBRT vs Observation
 * Two randomized trials merged in 1998 to pool results and facilitate data monitoring. 906 Stage I-IIA endometrial CA patients, with intermediate or high risk features (one or more of the following: IA-IB Grade 3, IC Grade 1-3, serous papillary or clear cell type, FIGO stage IIa). PLND not required; women with positive pelvic LN eligible for ASTEC but not EN.5. Para-aortic LN+ excluded. Peritoneal washings could be negative, positive, or not done. Arm 1) EBRT 40-46 Gy daily vs. Arm 2) observation. BT allowed by institutional preference (ASTEC HDR 8/2 or LDR 15/1, EN.5 per institution), BT given in 51% of observation arm vs. 5% of EBRT arm
 * Patient characteristics: 30% PLND; 84% endometrioid; IA 3%, IB 20%, IC 77%; Grade 1 26%, Grade 2 42%, Grade 3 31%. Brachy given to 52% patients in both arms
 * 2007 ASCO Abstract -- "Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: Results of the randomised MRC ASTEC and NCIC CTG EN.5 trial." (Orton J, et al. J Clin Oncol. 2007 Jun 20;25(18_suppl):5504.) Median F/U 3.8 years
 * 5-year outcome: OS 84% both groups (NS), DSS 89% (NS); small difference in isolated vaginal/pelvic recurrence with brachytherapy
 * Morbidity: EBRT 56% vs. no EBRT 24%; Grade 3+ toxicity rare
 * Conclusion: EBRT alone not indicated due to no benefit on OS/DFS, but higher toxicity
 * RT; 2009 PMID 19070891 -- "Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis." (ASTEC/EN.5 Study Group, Lancet. 2009 Jan 10;373(9658):137-46. Epub 2008 Dec 16.) Median F/U 4.8 years
 * Outcome: 5-year OS OBS 84% vs EBRT 84% (NS), DSS 90% vs 89% (NS), Recurrence 15% vs. 15%, Isolated vaginal or pelvic recurrence OBS 6% vs. EBRT 3% (SS)
 * Subset analysis: No difference in intermediate risk, high risk, no PLND, and PLND for both OS and DSS
 * Toxicity: Any acute toxicity OBS 27% vs. EBRT 57%, Grade 3 <1% vs. 3%; Any late toxicity 45% vs. 61%, any Grade 3-4 3% vs. 8%
 * Updated Meta-analysis (GOG99, PORTEC1, ASTEC/EN.5): HR 1.04 for benefit of RT (0.84-1.29, NS)
 * Conclusion: Adjuvant EBRT cannot be recommended as part of routine treatment for women with intermediate/high risk early stage endometrial CA. There is no benefit on OS or DFSS, and absolute benefit for isolated local recurrence is small and not without toxicity
 * ASTEC PLND; 2009 PMID 19070889 -- "Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study." (Kitchener H, Lancet. 2009 Jan 10;373(9658):125-36. Epub 2008 Dec 16.)
 * Please see the Lymphadenectomy section
 * Comment; 2010 PMID 19897230 -- "ASTEC lymphadenectomy and radiation therapy studies: are conclusions valid?" (Creasman WT, Gynecol Oncol. 2010 Mar;116(3):293-4. Epub 2009 Nov 7.)
 * Two different questions, but due to overlap don't answer either one

 * PORTEC 1 (The Netherlands) (1990-1997)
 * Randomized. 715 patients with Stage IB (G2-3) or IC (G1-2), specifically no IC G3. TAH/BSO with washings, not allowed to have lymphadenectomy. Allowed adenocarcinoma and variants (including papillary serous and clear cell).
 * Randomized to postoperative EBRT 46 Gy vs no further therapy. Fields: superior border at L5/S1.
 * 5-years, 2000 PMID 10791524 — "Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma." Creutzberg CL et al. Lancet. 2000 Apr 22;355(9213):1404-11. Median F/U 4.3 years
 * 5-year outcome: LRF: 4% vs 14% (SS); 73% of recurrences in vagina. DM unaffected (7%). OS same (80% vs 84%, NS) with ~50% deaths due to other causes
 * Salvage: Most LR salvaged, which may explain why the survival is similar in both arms despite a difference in LR. 3-year OS after vaginal relapse 69% vs. 13% for pelvic or DM.
 * Toxicity: RT 25% vs. 6% (SS); excess of secondary cancers of the GI tract, which is associated with endometrial cancer.
 * Prognostic: Age < 60 was good prognostic, IBG2 also had low LRR of < 5%; suggesting omission of RT in these subgroups. Age ≥ 60 with ICG1-2 or IBG3 had more LRR in control group (5% vs 18%, p-value not reported), but similar DM and EC death.
 * Conclusion: EBRT reduces LR but has no impact on survival. Don't recommend if <60 or if IB G2
 * Side effects, 2001 PMID 11728684 -- "The morbidity of treatment for patients with Stage I endometrial cancer: results from a randomized trial." (Creutzberg CL, Int J Radiat Oncol Biol Phys. 2001 Dec 1;51(5):1246-55.) Median F/U 5 years
 * Late complications: RT 26% vs. control 4% (SS). Most grade I (65%). Grade 3-4 complications 3% vs. 0%
 * By site: GI 20% (3% severe); GU 8% (no severe); bone 2% (no severe); vagina 1% (no severe)
 * Time course: ~50% Grade 1-2 resolved over time (2-3 years), but not in Grade 3-4 complications
 * Technique: 4F box lower risk; 4F 21% vs. AP/PA 30% vs. 3F 36% (p=0.06)
 * Conclusion: Severe complications 3%, mild complications 20%. RT use requires careful consideration, since no survival benefit
 * Comment: Reporting done differently between the 2 arms, special form for acute RT toxicity. Also, surgeons don't report large midline scar as a complication while transient erythema is one
 * Vaginal Relapse / Salvage, 2003 PMID 12713981 — "Survival after relapse in patients with endometrial cancer: results from a randomized trial." (Creutzberg CL et al. Gynecol Oncol. 2003 May;89(2):201-9.) Median F/U 6.1 years
 * See also at: Radiation Oncology/Endometrium/Recurrence
 * 8-year outcome: LRF: RT 4% vs. control 15% (SS), majority failures after surgery only in vagina; DM 10% vs. 6% (NS); OS RT 71% vs. control 77% (NS)
 * 39 pts with isolated vaginal relapse; 31 of these treated with curative intent (usually RT+brachy). CR obtained in 31 of 35 (89%), with long term control in 24 of 31 (77%). Total long term control rate is thus 24/35 (68%).
 * Survival after 1st relapse at 3 yrs: 51% (control group) vs 19% (RT).
 * Survival after vaginal relapse 73%, after pelvic relapse 8%, after DM relapse 14%.
 * Vaginal salvage: 5-year OS: control group better 65% vs. RT group 43% (SS).
 * Conclusion: Limit pelvic RT to pts with ≥ 15% risk of recurrence
 * Stage IC G3, 2004 PMID 15051771 — "Outcome of high-risk stage IC, grade 3, compared with stage I endometrial carcinoma patients: the Postoperative Radiation Therapy in Endometrial Carcinoma Trial." Creutzberg CL et al. J Clin Oncol. 2004 Apr 1;22(7):1234-41.
 * Analysis of 99 IC G3 registered but ineligible patients, treated per same protocol. Median F/U 6.9 years
 * 5-year outcome: OS: IB-C G1-2 83-85%, IB G3 74%, IC G3 58%; DM rate 3-8%, 20%, and 31%
 * Conclusion: IC G3 at high risk of DM and cancer-related death
 * 10-years, 2005 PMID 15927414 -- "Postoperative radiotherapy for Stage 1 endometrial carcinoma: long-term outcome of the randomized PORTEC trial with central pathology review." (Scholten AN, Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):834-8.)
 * Central pathology review for 569 patients (80%). Poor reproducibility for G1 vs. G2
 * 10-year outcome: LR: 5% vs. 14% (SS); OS 66% vs. 73% (p=0.09), cancer-related deaths 11% vs. 9% (NS)
 * Poor prognosis for LR: at least 2 of Age ≥ 60, Stage IC (≥ 50% invasion), and Grade 3. 10-year LRR of this group 4% (RT) vs 23% (no RT) (p-value not reported).
 * Conclusion: In view of significant LR control benefit, RT indicated if high-risk features.
 * Comment : Since ~50% deaths due to competing causes, overall survival not a good metric. Number of events even less than GOG-99, since high risk IC G3 disallowed. Trial not really powered to show survival difference.
 * 15 years, 2011 -- Outcome and QOL PMID 21444867 -- "Long-Term Outcome and Quality of Life of Patients With Endometrial Carcinoma Treated With or Without Pelvic Radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) Trial." (Nout RA, J Clin Oncol. 2011 May 1;29(13):1692-700. Epub 2011 Mar 28.) -- Mean f/u 13.3 yrs
 * 15 yr LRR 5.8% (RT) vs 15.5% (no RT); OS 52% vs 60%, NS.
 * Pts treated with RT had significant increases in urinary incontinence, diarrhea, fecal leakage, and more limitations in daily activities.
 * Conclusion: EBRT for endometrial cancer is associated with long-term urinary and bowel symptoms and lower functioning. "Despite its efficacy in reducing locoregional recurrence, EBRT should be avoided in patients with low- and intermediate-risk EC."
 * 15-year outcome of HIR and second cancers, 2011 PMID 21640520 — "Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma." (Creutzberg CL, et al. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e631-8.)
 * High-intermediate risk (HIR) was 2 of: grade 3, age ≥ 60, and deep invasion.
 * Outcome: Median F/U for alive patients 13.3 years. 15-year failure-free survival 50% (RT) vs. 54% (no RT) (NS), 15-year distant metastasis 9% vs 7% (NS), second cancers 22% vs 16% (NS). For HIR, 15-year OS 41% vs 48% (NS), 15-year EC death 14% vs 13%. Multivariate analysis: Grade 3, age ≥ 60, and deep invasion were prognostic for LRR and EC death.

 * GOG 99 (1987-1995) — pelvic EBRT vs no additional treatment
 * Randomized. 392 patients, treated with TAH/BSO, selective PLN and PALND. Originally included "intermediate risk" — stages IB, IC, and II (occult), any grade, with negative LN. Excluded clear cell and papillary serous adenoCA. Revised during the course of study to define "high intermediate risk (HIR)" group expected to have 25% recurrence risk based on increasing age, G2-3 tumor, LVI, or outer 1/3 myometrial invasion: 1) ≥ 70 yrs old with only 1 other risk factor, 2) ≥ 50 yrs old with 2 risk factors; 3) any age with 3 risk factors. Others were considered "low intermediate risk (LIR)". Randomized to Arm 1) no additional treatment (NAT) vs Arm 2) postoperative pelvic EBRT. Fields: superior border at L4/L5 interspace, lateral borders 1 cm beyond pelvis, posterior border at posterior border of S3, anterior border at symphysis pubis. Dose: 50.4 Gy. No brachytherapy allowed.
 * 1998 Abstract — "A phase III randomized study of surgery vs surgery plus adjunctive radiation therapy in intermediate-risk endometrial adenocarcinoma (GOG No. 99)." (Roberts JA, et al. Gynecol Oncol. 1998 Jan;68(1):135.) Median F/U 56 months (4.7 years).
 * Outcome: 2-year progression-free interval 88% (NAT) vs 96% (RT) (SS). Loco-regional recurrences 17 vs 3 patients (p-value not reported). 36-month OS 89% vs 96% (NS).
 * 4-years, 2004 PMID 14984936 — "A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study." (Keys HM, et al. Gynecol Oncol. 2004 Mar;92(3):744-51.) Median F/U 5.7 years
 * Outcome: 2-year recurrence rate: 3% vs 12% (SS). 2-year isolated LR 2% vs 7%. 4-year OS 92% vs 86% (NS). In HIR subgroup (34%): 4-year recurrence 13% (RT) vs 27% (NAT) (SS).
 * Conclusion: Strong benefit for adjuvant EBRT in high intermediate risk group
 * Comment : OS not primary survival, not powered for it. Primary end-point DFS, which was significantly better with RT

 * Norwegian Radium Hospital -- VBT alone vs VBT + EBRT
 * Randomized. 540 patients with surgical Stage I. All patients had TAH/BSO (no lymphadenectomy) + postoperative brachytherapy 60 Gy to the surface of the vagina (~40 Gy LDR @ 0.5cm and ~ 24 Gy HDR @ 0.5 cm). Then randomized to no further treatment vs pelvic RT 40 Gy (central shielding after 20 Gy)
 * Preliminary, 1976 (1968-1972) PMID 821824 — "Postoperative external pelvic irradiation in carcinoma of the corpus stage I: a controlled clinical trial." Onsrud M, et al. Gynecol Oncol. 1976 Jun;4(2):222-31.
 * Outcome: 5-year OS 90% (BT) vs 88% (BT+EBRT) (NS). Loco-regional recurrence 7.2% (4.6% vagina, 2.5% pelvic wall) vs 2.1% (all vagina). Distant metastasis 5.1% vs 9.9%. In BT alone arm, recurrence rate 4.1% (≤ 50% myometrial invasion) vs 12.7% (> 50% myometrial invasion).
 * 9-years, 1980 (1968-1974) PMID 6999399 — "Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients." Aalders J et al. Obstet Gynecol. 1980 Oct;56(4):419-27.
 * 9-year outcome: OS BT alone 90% vs BT+EBRT 87% (NS). EBRT decreased LR (7% vs 2%) but there were more distant mets (5% vs 10%, borderline SS). Similar recurrence rate in both groups, but more deaths in XRT group.
 * Subset analysis: Improved OS for BT+EBRT in IC Grade 3 (82% vs. 72%); probably due to improved local control (LR 5% vs. 20%) with comparable DM (14% vs. 15%). IC G1-2 had no difference in OS, LR, and DM.
 * Poor prognosis: Age ≥ 60, Stage IC, Grade 3, LVI+
 * Conclusion: No benefit for EBRT after vaginal BT, except for Stage IC G3 patients
 * Long-term outcomes, 2013 PMID 24019546 — "Long-term outcomes after pelvic radiation for early-stage endometrial cancer." Onsrud M, et al. J Clin Oncol. 2013 Nov 1;31(31):3951-6.
 * Outcome: Median F/U 20.5 years. Median OS 20.5 years in both groups. Age < 60 years had higher death in EBRT arm, but not in ≥ 60 years subgroup. Secondary cancer 24.5% (BT) vs 30.5% (BT+EBRT) (SS), with median time of 15.0 years. Patients aged < 60 years had higher secondary cancer after EBRT (39.7% vs 25.6%, SS), but not in ≥ 60 years. Third cancer were also more common after EBRT (7% vs 2%)
 * Toxicity: 4 treatment-related deaths, all in EBRT arm (1 before EBRT, 3 after surgery for radiation-induced ileus). Grade 3-4 events 0 (BT) vs 2.9% (BT+EBRT). Grade ≥ 2 complications 4.5% vs 27.4%.
 * Conclusion: Addition of EBRT had no survival benefit. On the other hand, EBRT decreased survival and increased secondary cancer for those aged < 60.

Risk of Vaginal Relapse
 * In PORTEC: risk of vaginal relapse in surgery only arm was IBG2 5%, IBG3 14%, ICG1 10%, and ICG2 13% (personnal communication in PMID 16814156)
 * In ASTEC/EN.5: risk of isolated vaginal or pelvic relapse: observation (50% received BT): 6% vs. EBRT 3%
 * Rosewell Park (PMID 19944453): 3.4% in "high risk" patients treated with VB alone
 * PORTEC2 editorial (PMID 20206759): Without any radiotherapy the risk of vaginal relapse is 10-14% based on GOG92 and PORTEC

Retrospective

 * SEER; 2012 (UNC) (1988-2006) PMID 21640502 -- "The influence of radiation modality and lymph node dissection on survival in early-stage endometrial cancer." (Chino JP, Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):1872-9.)
 * SEER database. 56,360 pts with Stage IA or IB (using FIGO 2009 staging), negative lymph nodes if sampled. 70% were low risk, 26% intermediate, and 3% high. 42% underwent lymph node dissection. 17% had RT: 9.4% WPRT alone, 4.6% VB alone, and a combination in 3.7%.
 * RT was used less frequently over the later years of the study, decreasing from 25% in 1988 to 16% in 2006. (The drop was from a decrease in the use of WPRT. The use of VB alone and combination EBRT+VB remained stable.) The use of LND increased: 16.2% to 59.5%.
 * In low-risk disease, LND was associated with higher survival; RT was not. In intermediate-risk, both LND and RT were associated with higher survival; there were no differences between RT modalities. In high risk, both LND and RT were associated with increased survival; VB alone was inferior to WPRT if LND was not performed.
 * Conclusion: "Both WPRT and VB alone are associated with increased survival in the intermediate-risk group. In the high-risk group, in the absence of LND, only WPRT is associated with increased survival. LND was also associated with increased survival."

 * Roswell Park; 2010 PMID 19944453 -- "Adjuvant vaginal brachytherapy alone for high risk localized endometrial cancer as defined by the three major randomized trials of adjuvant pelvic radiation." (McCloskey SA, Gynecol Oncol. 2010 Mar;116(3):404-7. Epub 2009 Nov 27.)
 * Retrospective. 87 patients (out of 464), Stage I-IIA endometrial CA, high risk by PORTEC (n=37) or GOG 99 (n=77) or Aalders (n=14), treated with VB alone. PLND in 46%. ICG3 16%; LVI+ 18%. Median F/U 4.3 years
 * Outcome: locoregional recurrence 3.4% (1 vaginal recurrence, 1 pelvic recurrence, and 1 vagina+pelvis recurrence)
 * Conclusion: VB alone reasonable for high risk localized endometrial CA

 * SEER Registry; 2006 (1988-2001) PMID 16434629 -- "Frequency and effect of adjuvant radiation therapy among women with stage I endometrial adenocarcinoma." (Lee CM, JAMA. 2006 Jan 25;295(4):389-97.)
 * Population-based. 21,249 patients with Stage IA-IC on TAH/BSO and pathologic staging, N0 endometrial adenocarcinoma. Adjuvant RT in 19% (62% EBRT, 18% BT, 26% EBRT+BT). Median F/U 3.8 years.
 * Outcome: 4-year OS 86% (3% dead due to endometrial CA, 10% dead due to other causes)
 * Adjuvant RT improved OS in Stage IC G1 (SS) and IC G3-4 (SS)
 * Conclusion: Statistically significant improvement in survival in Stage IC disease

 * U.Chicago; 1999 (1986-95) PMID 10214841 PDF -- "External pelvic radiation therapy in stage IC endometrial carcinoma." (Weiss MF, Obstet Gynecol. 1999 Apr;93(4):599-602.)
 * Purpose: to evaluate the results of patients treated with EBRT alone without VB.
 * Retrospective. 61 pts with Stage IC. EBRT alone to a median dose of 48.6 Gy (range: 43.2-50.4 Gy). No pts received VB.
 * Median f/u 69.5 months. 5-yr DFS 86.7%, OS 97.6%. No pt had a local / vaginal recurrence.
 * Conclusion: local control was excellent with EBRT without VB

Adjuvant RT +/- Chemo

 * EORTC 55991 (1996-2006) -- RT vs sequential RT→Chemo
 * Randomized. Terminated due to slow accrual. 372 patients. Initially, surgical Stage I; later amended to include occult II, IIIA (positive peritoneal fluid only), or IIIC (positive LNs only) with high risk features. Typically 2 or more of grade 3, deep myometrial invasion, DNA non-diploidy). PLND optional. Pelvic RT 44 Gy (vaginal BT optional, given in 41%) +/- 4 cycles of chemo (several regimens allowed). 25% didn't receive full chemo
 * 2007 ASCO Abstract -- "A randomized phase-III study on adjuvant treatment with radiation (RT) ± chemotherapy (CT) in early-stage high-risk endometrial cancer (NSGO-EC-9501/EORTC 55991)." (Hogberg T, et al. J Clin Oncol. 2007 Jun 20;25(18_suppl):5503.) Median F/U 3.5 years
 * Outcome: PFS RT alone 75% vs. RT+CT 82% (SS)
 * Conclusion: RT+CT better than RT alone
 * 2010 PMID 20619634 -- "Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer-Results from two randomised studies." (Hogberg T, et al. Eur J Cancer. 2010 Sep;46(13):2422-31.)
 * Merged outcomes from EORTC 55991 (n=378) and MaNGO ILIADE-III (n=156). MaNGO trial was same format, but enrolled primarily Stage IIB and III patients
 * EORTC Outcome: 5-year PFS RT 76% vs RT→chemo 85% (HR 0.6, SS), no difference OS. Signficant OS benefit for chemo in endometrioid subset (5-year OS 69% vs 80%, SS) but not in serous and clear cell subset (NS)
 * Pooled Outcome: 5-year PFS RT 72% vs RT→chemo 80% (HR 0.6, SS), CSS 82% vs 89% (SS), OS 79% vs 84% (p=0.07)
 * Conclusion: Addition of adjuvant chemotherapy improves PFS in high risk endometrial patients, though no benefit on subgroup analysis for serous/clear cell

 * RTOG 99-05 (1999-2003)
 * Randomized. High risk endometrial CA (Stage IC G2-3, II, III). Arm 1) Adjuvant EBRT 50.4/28 (BT optional) vs. Arm 2) concurrent cisplatin 50 mg/m2 + EBRT 50.4/28, followed by cisplatin 50 mg/m2 + paclitaxel 160 mg/m2 (based on RTOG 97-08)
 * Closed due to nonaccrual.

 * RTOG 97-08 (1997-99)
 * Phase II. Post-operative chemo+RT for "high risk" endometrial adenocarcinoma (Stage IC G2-3, II, III). 45 Gy pelvic RT with concurrent cisplatin on weeks 1+5, plus vaginal brachytherapy, followed by 4 cycles cisplatin + taxol.
 * Final; 2006 PMID 16545437, 2006 — "Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer." Greven K et al. Gynecol Oncol. 2006 Oct;103(1):155-9.
 * Median f/u 4 yrs. Excellent local control. Tolerable regimen.
 * Preliminary; 2004 PMID 15093913, 2004 — "Preliminary analysis of RTOG 9708: Adjuvant postoperative radiotherapy combined with cisplatin/paclitaxel chemotherapy after surgery for patients with high-risk endometrial cancer." Greven K et al. Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):168-73.

 * Finland (1992-1996) -- pelvic EBRT vs. interdigitated chemo-RT
 * Randomized. 156 patients with Stage IA-B G3 (n=28) or Stage IC-IIIA (n=128), who underwent TAH/BSO. 80% had at least PLND. Arm 1) Pelvic EBRT split course 56 Gy (28 Gy x2 with 3 week break) vs. Arm 2) Interdigitated chemo-RT, given as chemo - RT 28 Gy - chemo - RT 28 Gy - chemo. Chemo was cisplatin 50 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 500 mg/m2 x3 courses. Brachytherapy not mentioned (not given?)
 * 2008 PMID 18534669 -- "Surgically staged high-risk endometrial cancer: Randomized study of adjuvant radiotherapy alone vs. sequential chemo-radiotherapy." (Kuoppala T, et al. Gynecol Oncol. 2008 Aug;110(2):190-5.)
 * Outcome: 5-year DFS RT 85% vs. chemo-RT 82% (NS). LRR 3% in both arms; DM 14% vs. 20%
 * Toxicity: Grade 3 bowel toxicity RT 3% vs. chemo-RT 9%
 * Conclusion: Adjuvant interdigitated chemo-RT failed to improve OS or lower recurrence rate over EBRT alone

 * GOG 34 (1977-1986) -- pelvic RT +/- doxorubicin
 * Randomized. 181 patients with high risk endometrial cancer (>50% myometrial invasion (Stage IC), cervical involvement (Stage II), pelvic or para-aortic LN+ (Stage IIIC), adnexal mets (Stage IIIA)). Surgery + RT (whole pelvis 50 Gy; if PA LN+ then PA field to top of T12 45/30). Arm 1) observation vs. Arm 2) doxorubicin
 * 1990 PMID 2298404 -- "Doxorubicin as an adjuvant following surgery and radiation therapy in patients with high-risk endometrial carcinoma, stage I and occult stage II: a Gynecologic Oncology Group Study." (Morrow CP, Gynecol Oncol. 1990 Feb;36(2):166-71.)
 * Outcome: No difference in 5-year PFS or OS
 * Toxicity: 7% SBO; treatment-related deaths DOX 25% vs. RT 2%
 * Conclusion: Due to protocol violations, small size, and loss to follow-up, unable to determine effect of doxorubicin

Adjuvant RT vs. Adjuvant Chemo

 * GOG 0249
 * Randomized. 601 patients, Stage I endometrial with high risk features, Stage II endometrial, Stage I-II serous or clear cell. Arm 1) pelvic radiation versus Arm 2) Vaginal brachytherapy followed by chemotherapy with paclitaxel 175 mg/m2 + carboplatin AUC 6 every 3 weeks x 3 cycles. Median age 63, Stage I disease 74%, endometrioid 71%, serous 15%, clear cell 5%, PLND 89%
 * Preliminary Results; 2014 SGO Abstract -- "A randomized phase III trial of pelvic radiation therapy (PXRT) versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy (VCB/C) in patients with high risk (HR), early stage endometrial cancer (EC): a Gynecologic Oncology Group trial" (McMeekin DS, Gynecol Oncol. 2014 Aug;134(2):438. SGO 2014 Late-Breaking Abstract 1A). Median F/U 2 years
 * Outcome: vaginal recurrence PXRT 5 versus VCB/C 2; pelvic recurrence 2 vs 19; distant failure 32 vs 24. RFS 82% vs 84% (NS); OS 93% vs 92% (NS)
 * Toxicity: acute toxicity more common with VCB/C
 * Conclusion: Study did not demonstrate superiority of VCB/C to PXRT
 * 2017 ASTRO Abstract -- "A phase 3 trial of pelvic radiation therapy versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy in patients with high-risk, early-stage endometrial cancer: a Gynecology Oncology Group study" (Randall M, et al. Int J Radiat Oncol Biol Phys. 2017 Dec 1;99(5):1313. ASTRO 2017 Late-Breaking Abstract)
 * to be continued ...
 * 2019 PMID 30995174 -- "Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer." (Randall ME, et al. J Clin Oncol. 2019 Jul 20;37(21):1810-8.)
 * to be continued ...

 * JGOG 2033 (1994-2000) -- adjuvant pelvic RT vs. adjuvant cisplatin/doxorubicin/cyclophosphamide
 * Randomized. 103 institutions. 385 patients with Stage IC-IIIC and >50% myometrial invasion (Stage II-III with <50% invasion ineligible). IC 61%, II 14%, IIIA 13%, IIIC 12%. Age <75. S/P TAH/BSO and surgical staging (96% PLND, 29% PALND). Arm 1) RT AP/PA 45-50 Gy. BT boost in only 6 patients (3%). Arm 2) CAP (cyclophosphamide (333 mg/m2), doxorubicin (40 mg/m2) and cisplatin (50 mg/m2) x3+ courses
 * 5-years; 2007 PMID 17996926 -- "Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: A Japanese Gynecologic Oncology Group study." (Susumu N, Gynecol Oncol. 2007 Nov 8). Median F/U
 * Outcome: 5-year PFS 83% vs 82% (NS); OS 85% vs. 87% (NS)
 * By risk: No difference in low/intermediate risk patients. High risk (IC and >70, IC G3, II, IIIA) PFS RT 66% vs. chemo 84% (SS), OS 74% vs. 90% (SS)
 * Toxicity: No difference
 * Conclusion: Adjuvant chemo useful alternative, especially in higher risk patients

 * GOG 156
 * Randomized. Stage IB-IIB. Arm 1) Adjuvant pelvic RT vs. Arm 2) Adjuvant adriamycin/cisplatin
 * Closed due to nonaccrual

 * Italy (1990-1997) -- adjuvant EBRT vs. cisplatin/doxorubicin/cyclophosphamide
 * Randomized. 345 patients. High-risk endometrial (IC G3, II G3 and >50% invasion, III). Arm 1) EBRT 45-50 Gy vs. Arm 2) cisplatin 50 mg/m2 + doxorubicin 45 mg/m2 + cyclophosphamide 600 mg/m2. Primary endpoint OS and PFS
 * 2006 PMID 16868539 -- "Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial." (Maggi R, Br J Cancer. 2006 Aug 7;95(3):266-71. Epub 2006 Jul 25.) Median F/U 8.0 years
 * Outcome: 5-year OS RT 69% vs. chemo 66% (NS); 5-year PFS 63% vs. 63% (NS). RT delayed local relapse, CT delayed DM
 * Toxicity: both well tolerated
 * Conclusion: No difference between adjuvant RT and adjuvant chemo

Carcinosarcoma

 * Mayo Clinic/Harvard; 2015 PMID 25890795 -- "Vaginal brachytherapy for early-stage carcinosarcoma of the uterus." (Brown LC, et al. Brachytherapy. 2015 Jul-Aug;14(4):433-9.)
 * Retrospective. 33 patients from 2 institutions, Stage I-II carcinosarcoma. (15 and 18 respectively). VBT 21/3 or 24/6 fractions. PLND 82%. Chemo 55%
 * Outcome: 2 year vaginal cuff control 94%, pelvic control 87%, locoregional control 81%, DFS 66%, OS 79%
 * Conclusion: Relatively high risk of local and distant relapse. Risk of pelvic recurrence comparable to women treated with pelvic radaition but no lymph node dissection. Pelvic radiation should be considered based on clinical context

Primary RT (Inoperable Patients)

 * Please see this section

Lymph node dissection

 * See Chino 2012 above (PMID 21640502)

Salvage

 * Montreal; 2006 (1997-2003) PMID 16386785 -- "Salvage treatment with high-dose-rate brachytherapy for isolated vaginal endometrial cancer recurrence." (Petignat P, Gynecol Oncol. 2006 Jun;101(3):445-9.)
 * Retrospective. 22 patients with endometrial CA, isolated vaginal recurrence. 82% EBRT + HDR, 18% HDR only. Median EBRT dose 45 Gy (44-50.4), median HDR dose 26 Gy (8-48; dose per fraction 6-8 Gy, median number of fractions 4). Median time to recurrence 1.7 years. Median F/U 2.7 years
 * Outcome: no LR recurrence, 1 patient DM; 5-year LC 100%, DFS 96%, DSS 96%
 * Toxicity: 18% Grade 3-4 GI (persistent rectorrhagia), 50% grade 3 vaginal (<1/3 vaginal length)
 * Conclusion: Recurrent vaginal endometrial CA amenable to salvage

Toxicity
IMRT vs Conventional
 * NRG/RTOG 1203 (2012 - 2015)
 * Randomized. 278 patients. Conventional radiation vs IMRT. Dose 45 Gy or 50.4 Gy, stratified. Concurrent cisplatin 40 mg/m2 weekly at physician discretion based on predefined criteria. Primary endpoint acute GI toxicity.
 * 2016 ASTRO Abstract -- "A Phase III randomized trial comparing patient-reported toxicity and quality of life (QOL) during pelvic intensity modulated radiation therapy as compared to conventional radiation therapy." Klopp AH, et al. Int J Radiat Oncol Biol Phys. 2016 Oct 1;96(2 Suppl):S3.
 * to be continued ...
 * 2018 PMID 29989857 -- "Patient-reported toxicity during pelvic intensity-modulated radiation therapy: NRG Oncology-RTOG 1203." Klopp AH, et al. J Clin Oncol. 2018 Aug 20;36(24):2538-44.
 * Outcome: EPIC-GI score decreased more in conventional vs IMRT group, at 3 weeks and 5 weeks (p=0.048). At EOT, diarrhea in 52% vs 34% (SS), with more anti-diarrheal medication use. No difference at 4-6 weeks post treatment. EPIC-GU scored also declined more in conventional vs IMRT group.
 * Conclusion: Pelvis IMRT resulted in significantly less GI and GU toxicity from patient's perspective.
 * 2019 ASTRO Abstract -- "IMRT improves late toxicity compared to conventional RT: An Update on NRG Oncology-RTOG 1203." Yeung AR, et al. Int J Radiat Oncol Biol Phys. 2019 Sep 1;105(1 Suppl):S50.
 * to be continued ...
 * 2020 PMID 32073955 -- "Improvement in patient-reported outcomes with intensity-modulated radiotherapy (RT) compared with standard RT: a report from the NRG Oncology RTOG 1203 study." Yeung AR, et al. J Clin Oncol. 2020 May 20;38(15):1685-92.
 * to be continued ...

Diarrhea
 * Lippe Hospital, Germany (2000-2006) -- selenium vs control
 * Randomized. 81 patients with uterine (88%) or cervical (12%) cancer. If pretreatment selenium <84 ug/l randomized to Arm 1) selenium 500 ug PO daily vs Arm 2) control. Primary endpoint: efficiency of supplementation
 * 2010 PMID 20133068 -- "Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology." (Muecke R, et al. Int J Radiat Oncol Biol Phys. 2010 Nov 1;78(3):828-35.)
 * Outcome: Selenium level post RT significantly higher with supplement. Grade 2+ diarrhea selenium 20% vs no selenium 44% (SS). No difference in other measures
 * Conclusion: Selenium supplementation effective in improving blood selenium status in deficient patients, and reduces RT-induced diarrhea

RT Technique

 * RTOG 1203 -- post op 3D vs IMRT
 * Chronic Toxicity; 2022''' PMID 35960897 -- "Intensity-Modulated Radiation Therapy Reduces Patient-Reported Chronic Toxicity Compared With Conventional Pelvic Radiation Therapy: Updated Results of a Phase III Trial" (Yeung AR, J Clin Oncol. 2022 Sep 20;40(27):3115-3119.)
 * 279 eligible patients. EPIC surveys and EuroQOL EQ-5D through 3 years after RT. (3-year completion rate 55%). Median F/U 3.1 years
 * Outcome: 3 year OS IMRT 92% vs 3D 97% (NS), DFS 86% vs 81% (NS), or LRF 3% vs 2% (NS)
 * GI toxicity: 1 year CRT 15% vs IMRT 6% (SS), antidiarrheal use 9% vs 1% (SS). No difference in fecal incontinence. No difference at 3 years.
 * GU toxicity: 1 year no difference. 3 years 3D worsening vs IMRT improving (SS)
 * Quality of Life: no difference at 1 year or 3 years
 * Conclusion: IMRT improves chronic GI and urinary toxicity; no difference in treatment efficacy at 3 years

3D Fields


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Radiation Oncology/Endometrium/Locally Advanced Stage

Locally Advanced Endometrial Cancer (III-IV)

Overview

 * Stage III and IV disease represents ~16% of endometrial cancer
 * Systemic chemotherapy is superior to whole abdominal radiation, based on GOG 122. However, chemotherapy alone has pelvic relapse rates of 20-40%, and 5-year OS only 50%
 * Addition of chemotherapy to pelvic radiation in two European randomized trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) improved progression-free survival and trended to improved overall survival
 * GOG 184, which evaluated incorporation of paclitaxel into the chemotherapy regimen, used postoperative radiation as a standard component
 * Retrospective multi-institutional data suggests improved OS with combination of chemotherapy and radiation therapy, delivered as a "sandwich" (chemotherapy -> radiation therapy -> chemotherapy)

Sequential chemotherapy with radiation therapy

 * Albert Einstein; 2012 PMID 22035806 -- "Phase II trial of adjuvant pelvic radiation "sandwiched" between combination paclitaxel and carboplatin in women with uterine papillary serous carcinoma." (Einstein MH, Gynecol Oncol. 2012 Jan;124(1):21-5. Epub 2011 Oct 27.)
 * Phase II. 81 patients (89% completed chemo->RT and are reported here), surgically staged UPSC, no visible residual. Stage I/II 82%, Stage III/IV 18%. Adjuvant paclitaxel 175 mg/m2 and carboplatin AUC 6 Q3 weeks x 3 cycles, followed by RT (pelvis 45/25, PA if 2+ pelvic nodes or documented PA disease, HDR vaginal brachytherapy 5 Gy x 3 at 0.5 cm), followed by chemotherapy x 3 cycles
 * Outcome: Stage I/II OS 6.3 years, Stage III/IV OS 3.0 years. 3-year OS 84% and 50%. PFS 5.4 years and 2.1 years
 * Toxicity: G3/4 non-hematologic toxicity 2.5%
 * Conclusion: RT-chemotherapy "sandwich" well tolerated and high efficacious in completely resected UPSC

 * NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III
 * NSGO-9501/EORTC-5591 (1996-2007): endometrial cancer, status post surgery, Stage I (high risk), Stage II, Stage IIIA (only positive cytology) and Stage IIIC (only positive pelvic lymph nodes). Arm 1) adjuvant RT only vs Arm 2) adjuvant chemotherapy and radiation therapy. Sequence of therapy elective. Pelvic RT. Vaginal brachytherapy ~40%. Chemotherapy several alternative regimens. 383 patients accrued.
 * MaNGO ILIADE-III (1998-2007): endometrioid cancer, Stage IIB, IIIA-IIIC (arm IIIA with cytology only excluded), serous/clear cell excluded. Arm 1) adjuvant RT only vs Arm 2) adjuvant chemotherapy and radiation therapy. Pelvic RT 45/25, PA-field as needed to L1/L2. Vaginal brachytherapy if cervical stromal involvement. Chemotherapy doxorubicin 60 mg/m2 and cisplatin 50 mg/m2 Q3W x 3 cycles. 157 patients accrued
 * Pooled Results; 2010 PMID 20619634 -- "Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies." (Hogberg T, Eur J Cancer. 2010 Sep;46(13):2422-31. Epub 2010 Jul 7.)
 * Outcome: 5-year PFS RT 69% vs RT-CT 78% (HR 0.6, SS), 5-year OS RT 75% vs RT-CT 82% (HR 0.7, p=0.07). Subset analysis shows no benefit of chemotherapy for serous/clear cell, while significant benefit for endometrioid
 * Conclusion: Addition of adjuvant chemotherapy to radiation improves progression free survival, with trend to improved overall survival

 * University of Western Ontario
 * Prospective. Stage III-IV (IIIA 21%, IIIC 70%, IVB 9%) endometrial cancer. Hysterectomy. Adjuvant paclitaxel (175 mg/m2) and carboplatin (350 mg/m2) Q3 weeks x 4 cycles, followed sequentially by pelvic RT 45 Gy (3D-CRT 58% vs IMRT 42%, EFRT 30%), followed by paclitaxel / carboplatin x 2 cycles. Para-aortic RT and HDR vaginal brachytherapy (5-7.5 Gy x 3 at 0.5 cm depth) at discretion.
 * Update; 2009 (2002 - 2006) PMID 19406459 -- "Adjuvant carboplatin and paclitaxel chemotherapy interposed with involved field radiation for advanced endometrial cancer." (Lupe K, Gynecol Oncol. 2009 Jul;114(1):94-8. Epub 2009 Apr 29.)
 * 43 patients. Most common Stage IIIC (63%), serous carcinoma (49%). Median F/U 2.5 years
 * Outcome: Local recurrence 3% (2 pelvis, 1 vagina/vulva). Overall recurrences 49% at median 1.5 years. 3-year DFS 53%, 3-year OS 68%
 * Conclusion: Low rate of local recurrence and favorable survival
 * Preliminary; 2007 (2002-2005) PMID 17084542 -- "Adjuvant paclitaxel and carboplatin chemotherapy with involved field radiation in advanced endometrial cancer: a sequential approach." (Lupe K, Int J Radiat Oncol Biol Phys. 2007 Jan 1;67(1):110-6. Epub 2006 Nov 2.)
 * 33 patients. Median F/U 1.75 years
 * Outcome: 2-year DFS 55%, 2-year OS 55%. One pelvic relapse (3%)
 * Toxicity: chemotherapy acute grade 3/4 toxicity 27%; radiation 12%. Late RT toxicity 18%
 * Conclusion: Adjuvant chemotherapy with interposed radiation well tolerated
 * Multi-Institutional; 2009 (1993-2007) PMID 19560193 -- "A multicenter evaluation of sequential multimodality therapy and clinical outcome for the treatment of advanced endometrial cancer." (Secord AA, Gynecol Oncol. 2009 Sep;114(3):442-7. Epub 2009 Jun 26.)
 * Retrospective. Three institutions (Duke, UNC, Ohio State). 109 patients. Stage III-IV disease, status post surgery. Endometrioid 48%, optimal cytoreduction 90%, chemo->RT->chemo (CRC) 41%, chemo->RT (CR) 42%, RT->chemo (RC) 17%.
 * Outcome: 3-year OS CRC 88% vs CR 57% vs RC 54% (SS), adjusted HR for OS CR 2.6 (SS) and RC 5.7 (SS)
 * Toxicity: no difference among arms
 * Conclusion: Sequential chemo->RT->chemo is associated with improved survival compared to other sequencing, with similar side effect profile

Concurrent radiation therapy with chemotherapy

 * RTOG 99-05 (1999-2003)
 * Randomized. High risk endometrial CA (Stage IC G2-3, II, III). Arm 1) Adjuvant EBRT 50.4/28 (BT optional) vs. Arm 2) concurrent cisplatin 50 mg/m2 + EBRT 50.4/28, followed by cisplatin 50 mg/m2 + paclitaxel 160 mg/m2 (based on RTOG 97-08)
 * Closed due to nonaccrual.

 * RTOG 97-08 (1997-99)
 * Phase II. Post-operative chemo+RT for "high risk" endometrial adenocarcinoma (Stage IC G2-3, II, III). 45 Gy pelvic RT with concurrent cisplatin on weeks 1+5, plus vaginal brachytherapy, followed by 4 cycles cisplatin + taxol.
 * Final; 2006 PMID 16545437, 2006 — "Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer." Greven K et al. Gynecol Oncol. 2006 Oct;103(1):155-9.
 * Median f/u 4 yrs. Excellent local control. Tolerable regimen.
 * Preliminary; 2004 PMID 15093913, 2004 — "Preliminary analysis of RTOG 9708: Adjuvant postoperative radiotherapy combined with cisplatin/paclitaxel chemotherapy after surgery for patients with high-risk endometrial cancer." Greven K et al. Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):168-73.

Pelvic RT vs. Adjuvant chemotherapy

 * JGOG 2033 (1994-2000) -- adjuvant CAP vs adjuvant pelvic RT
 * Randomized. 103 institutions. 385 patients with Stage IC-IIIC and >50% myometrial invasion (Stage II-III with <50% invasion ineligible). IC 61%, II 14%, IIIA 13%, IIIC 12%. Age <75. S/P TAH/BSO and surgical staging (96% PLND, 29% PALND). Arm 1) RT AP/PA 45-50 Gy. BT boost in only 6 patients (3%). Arm 2) CAP (cyclophosphamide (333 mg/m2), doxorubicin (40 mg/m2) and cisplatin (50 mg/m2) x3+ courses
 * 5-years; 2007 PMID 17996926 -- "Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: A Japanese Gynecologic Oncology Group study." (Susumu N, Gynecol Oncol. 2007 Nov 8). Median F/U
 * Outcome: 5-year PFS 83% vs 82% (NS); OS 85% vs. 87% (NS)
 * By risk: No difference in low/intermediate risk patients. High risk (IC and >70, IC G3, II, IIIA) PFS RT 66% vs. chemo 84% (SS), OS 74% vs. 90% (SS)
 * Toxicity: No difference
 * Conclusion: Adjuvant chemo useful alternative, especially in higher risk patients

 * Italy (1990-1007) -- adjuvant CAP vs adjuvant pelvic RT
 * Randomized. 345 patients, high risk endometrial carcinoma (ICG3 in 26%, IIG3 and myometrial invasion >50% in ~10%, III in 65%), excluded clear cell or UPSC. TAH/BSO with selective pelvic/PA LN sampling. Arm 1) adjuvant chemotherapy (cyclophosphamide 600 mg/m2, doxorubicin 40 mg/m2, cisplatin 50 mg/m2) x5 cycles vs Arm 2) Pelvic RT 45-50 Gy, upper border at L5, if PA LN+ then PA field 45/25, upper border at L1. Primary endpoint PFS and OS
 * 7-years; 2006 PMID 16868539 -- "Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial." (Maggi R, Br J Cancer. 2006 Aug 7;95(3):266-71. Epub 2006 Jul 25.) Median F/U 8 years
 * Outcome: 5-year OS chemo 66% vs RT 69% (NS), 7-year OS 62% vs 62% (NS). No difference in PFS. RT delayed local relapse, chemo delayed mets, but neither (SS).
 * Conclusion: No difference between adjuvant chemotherapy and adjuvant RT. Different patterns of failure

Whole abdominal RT vs. Adjuvant chemotherapy

 * GOG 122 (1992-2000)
 * 388 pts. Stage III-IV, all histologies. Required TAH/BSO, surgical staging, and <2cm residual tumor. Para-aortic LN allowed but no mets to chest or SCLV. Randomized to WAI (30 Gy, 20 fx, AP/PA plus boost to pelvic +/- para-aortic LN 15 Gy in 8 fx) vs chemotherapy (AP; doxorubicin + cisplatin q3w x 8 cycles).
 * 2006 PMID 16330675 — "Randomized Phase III Trial of Whole-Abdominal Irradiation Versus Doxorubicin and Cisplatin Chemotherapy in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study." Randall ME et al. J Clin Oncol. 2006 Jan 1;24(1). Median F/U 6.2 years
 * 5-year outcome: PFS raw RT 38% vs. chemo 42% (p not given), stage-adjusted 38% vs. 50% (SS); raw OS RT 42% vs. chemo 53% (p not given), stage-adjusted (despite it being ranomized trial) 42% vs. 52% (SS)
 * Recurrence locations: WAI: recurrence in 54% (pelvic in 13%, abdomen in 16%, distant 22%). For chemo: 50% recurrence (18%,14%,18%)
 * Grade 3-4 Toxicity: hematologic RT 14% vs. chemo 88%, GI 13% vs. 20%, cardiac 0% vs. 15%, neurologic 1% vs. 7%
 * Conclusion: chemotherapy improves PFS and OS for advanced disease, compared with whole abdomen RT, though with significant toxicity
 * Comment: Despite this being a randomized trial, the chemo arm was stage-adjusted during analysis. Argument was that it had worse prognosis patients (presumably the Stage IIIC, however, LN+ was not a prognostic variable in the study itself). The whole abdomen arm also had bad prognosis patients (IIIA with serosal/adnexal mets). The raw OS result are still significantly better for the chemo arm, but raw PFS was comparable in the two arms (38% vs. 42%). The statistical rationale is not justified, and thus questionable

Whole abdominal irradiation + chemotherapy

 * GOG 9001 (1990-92) - PMID 8946862, 1996 — "A phase I study of weekly cisplatin and whole abdominal radiation for the treatment of stage III and IV endometrial carcinoma: a Gynecologic Oncology Group pilot study." Reisinger SA et al. Gynecol Oncol. 1996 Dec;63(3):299-303.
 * Phase I. 10 pts. Stage III-IV, maximally debulked. Treated with whole abdomen RT + Pelvic/PA Boost + cisplatin 15 mg/m2 QW
 * Conclusion: tolerance comparable to whole abdomen alone

Whole abdominal irradiation

 * GOG 94 (1986-94) - Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer. Also included Stage I-II papillary serous or clear cell.
 * Phase II.
 * PMID 15913742, 2005 — "Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer: a gynecologic oncology group study." Sutton G et al. Gynecol Oncol. 2005 Jun;97(3):755-63.
 * PMID 16213007, 2006 — "Adjuvant whole abdominal irradiation in clinical stages I and II papillary serous or clear cell carcinoma of the endometrium: A phase II study of the Gynecologic Oncology Group." Sutton G et al. Gynecol Oncol. 2006 Feb;100(2):349-54.

 * MD Anderson; 1983 (1961-1978) PMID 6654180 -- "Treatment of intraperitoneal metastatic adenocarcinoma of the endometrium by the whole-abdomen moving-strip technique and pelvic boost irradiation." (Greer GE, Gynecol Oncol. 1983 Dec;16(3):365-73.)
 * Retrospective. 31 patients with intraperitoneal metastatic endometrial CA, residual disease <2cm, treated with whole-abdomen moving-strip technique and pelvic boost RT
 * Outcome: 5-year absolute OS 63%, corrected OS 80%
 * Conclusion: Feasible, toxicity tolerable

Radioactive Phosphorus (P32)

 * 1985 (1977-1983) PMID 4037013 -- "Intraperitoneal chromic phosphate P 32 suspension therapy of malignant peritoneal cytology in endometrial carcinoma." (Soper JT, Am J Obstet Gynecol. 1985 Sep 15;153(2):191-6.)
 * Prospective. 65 women with positive washings (clinical Stage I 80%, Stage II 14%, Stage III 7%). Adjuvant P-32
 * Outcome: 2-year PFS clinical Stage I 89%, surgical Stage I 94%; recurrences: 9% intraperitoneal, 36% intraperitoneal/distal, 55% distal
 * Toxicity: Grade 4 GI in 0% if P-32 alone vs. 29% if combined with EBRT
 * Conclusion: P-32 effective, but caution if P-32 combined with EBRT

 * 1981 PMID 7315922 -- "Prognostic significance of peritoneal cytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal radiopharmaceuticals." (Creasman WT, Am J Obstet Gynecol. 1981 Dec 15;141(8):921-9.)
 * Prospective. 23 patients with clinical Stage I, but positive washings on TAH/BSO (IIIA), treated with intra-abdominal P-32
 * Outcome: 3 recurrences, none in abdominal cavity
 * Conclusion: intraperitoneal P-32 efficacious if positive washings

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Radiation Oncology/Endometrium/Brachytherapy

Endometrial Brachytherapy

Overview

 * Treat upper proximal 3–5 cm for endometrioid, treat entire vagina for clear cell and UPSC
 * For ICRT only: LDR dose 50-60 Gy at 0.5 cm depth over 72 hrs (70-80 cGy/hr). HDR dose 21 Gy (7 Gy x 3 at 0.5 cm).
 * For EBRT + ICRT: LDR dose 30 Gy. HDR dose 15 Gy (5 Gy x 3 at 0.5 cm) or 6 Gy x 3 (at surface).

American Brachytherapy Society

 * HDR Recommendations; 2000 PMID 11020575 — "The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the endometrium." Nag S et al. Int J Radiat Oncol Biol Phys. 2000 Oct 1;48(3):779-90.
 * Prescription documentation: Treatment site, radionuclide, prescribed absorbed dose, fractionation, prescription point, type of applicator, optimization points, method of optimization, number of dwell positions, relative dwell weights, isodose distribution
 * Localization: Use localization radiographs in treatment position
 * Doses: see table below
 * Dose specification:
 * Endometrioid: treat proximal 3–5 cm of the vagina
 * Clear cell and UPSC: treat entire vaginal canal
 * Prescribe to either surface or 0.5 cm depth
 * Report both surface and depth doses
 * Place optimization points on both lateral surfaces, along the curved portion of the cylinder dome, and at the apex
 * Use proper anisotropic calculations
 * Optimization:
 * Dose distribution should satisfy physician requirements, not just optimization specs
 * Dwell positions should not extend beyond target to avoid overdosing normal structures
 * High-dose heterogeneity within normal tissues is not acceptable
 * Process should not be too time-consuming
 * Treatment review (second check):
 * Dosimetry data are correct
 * Absorbed dose prescription point, absorbed dose per fraction, number of fractions are per facility protocol
 * Absorbed dose distribution plan matches the prescription
 * Reconstructed applicator geometry matches the radiograph
 * Distance from machine reference point to the most distant dwell position is consistent with treatment plan
 * Absorbed doses to normal tissues are within tolerances
 * Dwell times for the generated plan are within a range consistent with those for similar patients
 * Programmed treatment data (dwell times, locations, step sizes) match those on the plan
 * Subsequent fractions using the same plan are performed with the correct data and the current source activity, and treatment time is adjusted accordingly
 * HDR source activity for the treatment day is corrected for source decay in the treatment planning system/console computer and verified by a separate independently calculated source decay chart or method
 * Other checks for multifraction treatment
 * Use of correct applicator for each fraction
 * Reproduced applicator position
 * Doses
 * To calculate LDR equivalent, use dose-modifying factor 0.7 for late effects
 * Recommended doses in tables below (now updated for 2019 publication), depending on EBRT and prescription depth:

 * Brachytherapy Fractionation Choices; 2019 PMID 30979631 — "Compendium of fractionation choices for gynecologic HDR brachytherapy - An American Brachytherapy Society Talk Group Report." Albuquerque K et al. Brachytherapy. 2019 Jul-Aug;18(4):429-36.

 * Practice Survey; 2005 PMID 16109462 — "American Brachytherapy Society survey regarding practice patterns of postoperative irradiation for endometrial cancer: current status of vaginal brachytherapy." Small W Jr et al. Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1502-7.
 * Most common doses listed
 * Brachytherapy alone:
 * LDR: 60 Gy at surface; 47-60 Gy at 0.5 cm (mean 47.9 Gy, median 50 Gy, mode 60 Gy)
 * HDR: 7 Gy x 3 at 0.5 cm
 * Boost after EBRT:
 * LDR: 30 Gy at surface, 20 Gy at 0.5 cm
 * HDR: 5 Gy x 3 at 0.5 cm

Dose Prescriptions
Examples of HDR and LDR prescriptions see also ABS recommendations above

 * PORTEC-2 Protocol
 * For brachytherapy alone:
 * LDR 30 Gy at 0.5 cm
 * HDR 7 Gy x 3 at 0.5 cm
 * RTOG / GOG
 * RTOG 99-05 / GOG 0194
 * Boost dose: (after 50.4 Gy)
 * LDR 20 Gy at surface (at dose rate 0.8-1.2 Gy/hr)
 * HDR 6 Gy x 2 at surface (=12 Gy)
 * RTOG 97-08
 * Boost dose: (after 45 Gy)
 * LDR 20 Gy at surface (at dose rate 0.8-1.2 Gy/hr)
 * HDR 6 Gy x 3 at surface (=18 Gy)

Dose Evaluation

 * Oreboro; Sweden (1989–2003)
 * Randomized. 290 low-risk (endometrioid, Stage IA-B, Grade 1–2, <50% myometrial infiltration, diploid DNA, pLN-, washings-), Stage IA 62%, Stage IB 38%. Vaginal cylinders 20–30 mm, dose prescription 5mm depth. All received 6 fractions in 8 days, randomized to Arm 1 2.5 Gy/fractions (total 15 Gy) or Arm 2) 5.0 Gy/fx (total 30 Gy). Colpometric measurements of vaginal shortening pretreatment and at 5 years
 * 2005 PMID 16029797 -- "Intravaginal high-dose-rate brachytherapy for stage I endometrial cancer: a randomized study of two dose-per-fraction levels." (Sorbe B, Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1385-9.)
 * Outcome: CSS 98.5% (NS), OS 95.3% (NS), no distant mets. Recurrence 1.4% (NS), 0.7% pelvic (NS) and 0.7% vaginal (NS)
 * Toxicity: no vaginal shortening for 2.5 Gy/fx group (pre vs. post) compared with 25% vaginal shortening (mean 2.1 cm) for 5.0 Gy/fx group. Also more vaginal atrophy and mucosal bleeding in 5.0 Gy/fx group
 * Conclusion: Recommend six fractions of 2.5 Gy/fx in low-risk endometrial Ca

Placement

 * Mt. Vernon; 2002 (UK) PMID 11932216 -- "The influence of applicator angle on dosimetry in vaginal vault brachytherapy." (Hoskin PJ, Br J Radiol. 2002 Mar;75(891):234-7.)
 * 30 patients. Dosimetric evaluation of "natural" insertion angle vs. horizontal insertion angle (determined by a level). Prescription 5.5 Gy at 0.5 cm depth. ICRU rectal and Bladder points used
 * Outcome: Mean change in angle of 19.7 degrees, resulting in mean absolute dose reduction of 1.3 Gy to rectum, but increase of 0.5 Gy to bladder
 * Conclusion: Vaginal BT should be performed in "corrected" horizontal position to reduce bowel dose at expense of bladder dose

Retrospective
With pelvic radiotherapy:
 * Wake Forest, 1990 - PMID 2380095 — "Role of intracavitary cuff boost after adjuvant external irradiation in early endometrial carcinoma." Randall ME et al. Int J Radiat Oncol Biol Phys. 1990 Jul;19(1):49-54.
 * Retrospective. 157 pts. Treated with surgery + external beam RT. Compared pts with or without vaginal cuff boost of 30-50 Gy surface dose.
 * No difference in local control (but higher risk features in the group receiving brachy).
 * Conclusion: Adding vaginal cuff boost to EBRT does not improve local control

Brachytherapy alone:
 * Meta-Analysis; 2000 PMID 10869750 -- "Post-operative high dose rate brachytherapy in patients with low to intermediate risk endometrial cancer." (Pearcey RG, Radiother Oncol. 2000 Jul;56(1):17-22.)
 * Literature review. 13 series, 1800 cases. Wide range of fractionation schedules; BED calculated using LQ model
 * Outcome: vaginal control rate 99%. No threshold for tumor control, moderate dose (BED10 ~50 Gy) appeared tumoricidal with control rate at least 98%. 3 series using 21/3 showed 0% toxicity and 98-100% control rate
 * Toxicity: BED3 >100 Gy predicted for late complications
 * Conclusion: HDR brachytherapy yields high local control and extremely low morbidity using modest dose fractionation schedules
 * Eltabbakh, Roswell Park - PMID 9226326 — "Excellent long-term survival and absence of vaginal recurrences in 332 patients with low-risk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal staging lymph node sampling: report of a prospective trial." Eltabbakh GH et al. Int J Radiat Oncol Biol Phys. 1997 May 1;38(2):373-80.
 * 303 pts. Stage 1B, Grades 1–2, treated with hysterectomy only without lymph node staging, then LDR brachytherapy to 30 Gy to 0.5 cm depth. 10, 20, and 30-year DFS were >95% (median 8 yr f/u).

HDR Dose Models

 * Ohio State; 2000 PMID 10661360 — "A simple method of obtaining equivalent doses for use in HDR brachytherapy." (Nag S, Int J Radiat Oncol Biol Phys. 2000 Jan 15;46(2):507-13.)
 * Microsoft Excel based program that applies the LQ formula to calculate BED for various fractionation schemes, and reconverts it to "standard" (2 Gy/fx) fractionation

Toxicity

 * Please see the ''Vagina toxicity page

Other References

 * "Endometrial Cancer" (Potter R, Gerbaulet A, Haie-Meder C) chapter from the "GEC ESTRO Handbook of Brachytherapy" Gerbaulet, Alain; Pötter, Richard; Mazeron, Jean-Jacques; Meertens, Harm; Limbergen, Erik Van, eds. (2002). Leuven, Belgium: European Society for Therapeutic Radiology and Oncology. OCLC 52988578.
 * Gynecol Oncol 2015 Review PMID 25555710 — "The role of vaginal cuff brachytherapy in endometrial cancer." Harkenrider MM, et al. Gynecol Oncol. 2015 Feb;136(2):365-72.
 * Good review of brachytherapy


text:
Sound Synthesis Theory

Contents
Introduction

A Foundations

1. Sound in the Time Domain

2. Sound in the Digital Domain

3. Time-domain Analysis

4. Frequency-domain Analysis

B Synthesis

5. Oscillators and Wavetables

6. Additive Synthesis

7. Subtractive Synthesis

8. Modulation Synthesis

9. FM Synthesis

10. Physical Modelling

11. Granular Synthesis

12. Vocal / Formant Synthesis

13. Sampling / PCM Synthesis

C Appendices

i. Synthesis Software and Tools

ii. Links and Bibliography

Special Pages

 * Book Policy
 * Page Listing

Authors
Damien Karras

声音合成原理Teoría de la Síntesis de Sonido

title: Sound Synthesis Theory


text:
Sound Synthesis Theory/Introduction

=Introduction=

This book covers a sub-field of Music Technology called sound synthesis. Although the tone is generally aimed at musicians and people with little prior knowledge of music systems, there may be some mathematical concepts and programming techniques that are not familiar. The book focuses on synthesis from a digital perspective rather than an analogue one, since it aims to demonstrate the theory of digital synthesis rather than applications to a specific medium or piece of software.

What is sound synthesis?
Sound synthesis is the technique of generating sound, using electronic hardware or software, from scratch. The most common use of synthesis is musical, where electronic instruments called synthesizers are used in the performance and recording of music. Sound synthesis has many applications both academic and artistic, and we commonly use synthesizers and synthesis methods to:

 * Generate interesting and unique sounds or timbres incapable of being produced acoustically.
 * Recreate or model the sounds of real-world acoustic instruments or sounds.
 * Facilitate the automation of systems and processes (text-to-speech software, train station P.A.s)

Background and history
One of the earliest musical synthesizers was Thaddeus Cahill's Teleharmonium, presented to an audience of about nine hundred in 1906. This massive instrument defined a fundamental synthesis technique called additive synthesis which used combinations of pure tones to generate its sounds. Other early synthesizers used technology derived from electronic analog computers, laboratory test equipment, and early electronic musical instruments. However, it was not until the late 1960s that technology had developed far enough for synthesizers to be a commercial success, most notably with Robert Moog's modular and mini-modular analogue synthesizers.

Since the late 1980's, most new synthesizers have been completely digital. At the same time analogue synthesis has also revived in popularity, so in recent years the two trends have combined in the appearance of virtual analog synthesizers, digital synthesizers of which model analog synthesis using digital signal processing techniques. Digital synthesizers use digital signal processing (DSP) techniques to make musical sounds. Some digital synthesizers now exist in the form of 'softsynth' software that synthesizes sound using conventional PC hardware. Others use specialized DSP hardware.

title: Sound Synthesis Theory/Introduction


text:
Sound in the Digital Domain

Digital systems (e.g. computers) and formats (e.g. CD) are clearly the most popular and commonplace methods of storing and manipulating audio. Since the introduction of the compact disc in the early 1980's, the digital format has provided increasingly greater storage capacity and the ability to store audio information at an acceptable quality. Although analogue formats still exist (vinyl, tape), they typically serve a niche audience. Digital systems are ubiquitous in modern music technology. It must be stressed that there is no argument as to whether one domain, be it analogue or digital is superior, but the following provides some desirable features of working with audio in the digital domain.

 * Storage. The amount of digital audio data capable of being stored on a modern hard drive is far greater than a tape system. Furthermore, we can choose the quality of the captured audio data, which relates directly to file size and other factors.

 * Control. By storing audio information in digital, we can perform powerful and complex operations on the data that would be extremely difficult to realise otherwise.

 * Durability. Digital audio can be copied across devices without any loss of information. Furthermore, many systems employ error correction codes to compensate for wear and tear on a physical digital format such as a compact disc.

Digital <-> Analogue Conversion
Acoustic information (sound waves) are treated as signals. As demonstrated in the previous chapter, we traditionally view these signals as varying amplitude over time. In analogue systems, this generally means that the amplitude is represented by a continuous voltage; but inside a digital system, the signal must be stored as a stream of discrete values.

Digital data stored in this way has no real physical meaning; one could describe a song on a computer as just an array of numbers; these numbers are meaningless unless there exists within the system a process that can interpret each number in sequence appropriately. Fig. 2.1 shows an overview of the process of capturing analogue sound and converting it into a digital stream of numbers for storage and manipulation in such a system. The steps are as follows:

1. An input such as a microphone converts acoustic air pressure variations (sound waves) into variations in voltage.

2. An analogue to digital converter (ADC) converts the varying voltage into a stream of digital values by taking a 'snapshot' of the voltage at a point in time and assigning it a value depending on its amplitude. It typically takes these 'snapshots' thousands of times a second, the rate at which is known as the sample rate.

3. The numerical data is stored on the digital system and then subsequently manipulated or analysed by the user.

4. The numerical data is re-read and streamed out of the digital system.

5. A digital to analogue converter (DAC) converts the stream of digital values back to a varying voltage.

6. A loudspeaker converts the voltage to variations in air pressure (sound).

Although the signal at each stage comes in a different form (sound energy, digital values etc.), the information is analogous. However, due to the nature of the conversion process, this data may become manipulated and distorted. For instance, low values for sample rates or other factors at the ADC might mean that the continuous analogue signal is not represented with enough detail and subsequently the information will be distorted. There are also imperfections in physical devices such as microphones which further "colour" the signal in some way. It is for this reason that musicians and engineers aim to use the most high-quality equipment and processes in order to preserve the integrity of the original sound throughout the process. Musicians and engineers must consider what other processes their music will go through before consumption, too (radio transmission etc.).

Sampling
Sound waves in their natural acoustic form can be considered continuous; that is, their time-domain graphs are smooth lines on all zoom factors without any breaks or jumps. We cannot have these breaks, or discontinuities because sound cannot switch instantaneously between two values. An example of this may be an idealised waveform like a square wave - on paper, it switches between 1 and -1 amplitude at a point instantaneously; however a loudspeaker cannot, by the laws of physics, jump between two points in no time at all, the cone has to travel through a continuous path from one point to the next.

Sampling is the process of taking a continuous, acoustic waveform and converting it into a digital stream of discrete numbers. An ADC measures the amplitude of the input at a regular rate creating a stream of values which represent the waveform in digital. The output is then created by passing these values to the DAC, which drives a loudspeaker appropriately. By measuring the amplitude many thousands of times a second, we create a "picture" of the sound which is of sufficient quality to human ears. The more and more we increase this sample rate, the more accurately a waveform is represented and reproduced.

Nyquist-Shannon sampling theorem
The frequency of a signal has implications for its representation, especially at very high frequencies. As discussed in the previous chapter, the frequency of a sine wave is the number of cycles per second. If we have a sample rate of 20000 samples per second (20Khz), it is clear that a high frequency sinusoid such as 9000 Hz is going to have less "snapshots" than a sinusoid at 150 Hz. Eventually there reaches a point where there are not enough sample points to be able to record the cycle of a waveform, which leads us to the following important result:

The sample rate of a system defines the maximum representable frequency, which is half the sample rate.

Why is this? The minimum number of sample points required to represent a sine wave is two. It may seem apparent at this time that using just two points to represent a continuous curve such as a sinusoid would result in a crude approximation - a square wave. And, inside the digital system, this is true. However, both ADCs and DACs have low-pass filters set at half the sample rate (the highest representable frequency). What this means for input and output is that any frequency above the cut-off point is removed and it follows from this that the crude sine representation - a square wave in theory - becomes filtered down to a single frequency (i.e. a sine wave). From this, we have two mathematical results:

$$F_{s} \ge 2 f_{max}$$ and $$F_{N} = \frac{F_{s}}{2}$$

Where $$F_{s}$$ is the sample rate, $$f_{max}$$ is the highest frequency in the signal. $$F_{N}$$ is the highest possible frequency that can be represented with $$F_{s}$$, and is known as the Nyquist frequency. Frequencies over the Nyquist frequency do not exist due to the presence of filters to block them; without such processes there would be frequency component foldover, otherwise known as aliasing.

Sampling accuracy and bit depth
It has been established that the higher the sample rate, the more accurate the representation of a waveform in a digital system. However, although there are many reasons and arguments for higher sample rates, there are two general standards: 44100 samples per second and 48000 samples per second, with the former being most commonplace. The main consideration for this is the fact that the human hearing range extends, at maximum, to an approximate limit (that varies from person to person) of 20000 Hz. Frequencies above this are inaudible. Considering the example of 44.1 Khz, we find that the Nyquist frequency evaluates to 22050 Hz, which is more than the human hearing system is capable of perceiving. There are other reasons for this particular sample rate, but that is beyond the scope of this book.

There is one more important factor to consider when considering the sampling process: bit depth. Bit depth represents the precision with which the amplitude is measured. In the same way that there are a limited amount of samples per second in a conversion process, there are also a limited amount of amplitude values for a sample point, and the greater the number, the greater the accuracy. A common bit resolution found in most standard digital audio systems (Hi-Fi, Compact Disc) is 16 binary bits which allows for a range of 65536 ($$2^{16}$$) individual amplitude values at a point in time. Lower bit values result in a greater distortion of the sound - a two bit system ($$2^2$$) only allows for four different amplitudes, which results in a massively inaccurate approximation of the input signal.

title: Sound in the Digital Domain


text:
Sound Synthesis Theory/Sound in the Time Domain

=Sound in the Time Domain=

The appearance and behaviour of sound waves
The metric (acoustical) definition of sound is variation in pressure waves and density caused by the propagation of the waves through a medium. Between about 25Hz, and 18kHz, human hearing systems sense these waves as they cause the ear drum to move. This mechanical movement is transduced into electrochemical signals in the cochlea as nerve impulses, and sent to the auditory region of the brain for analysis. Sound waves, being variation in air pressure over time, may be represented as a varying voltage or a stream of data over time. This is a 'time/amplitude' representation of sound, also known as the amplitude time line. The amplitude represents the molecular displacement caused by the changes in air pressure. In the digital domain, amplitude is typically represented as a value between 1 and -1 where 1 and -1 represent maximum positive and negative amplitudes of the signal, and 0 represents zero amplitude.

The waveform in Fig. 1.1 is called a sine wave or sinusoid. Sine waves can be considered the fundamental building blocks of sound. The figure demonstrates that the amplitude varies over time, but that pattern of variance repeats periodically.

The waveform in Fig. 1.2 is more complicated than the sinusoid in 1.1. There are peaks and troughs of different amplitudes, and, although the pattern does repeat itself over time (see if you can find it) it is harder to spot. In the same way that a sine wave behaves in a simple way and sounds simple, this sound behaves with greater complexity and also sounds more complex. For this reason, detailed, complex sounds that change over time often have no discernible features when viewed this close up- there may be no repeating pattern or behaviour which we can use to tell us something about the sound.

In Fig. 1.3 we are given a look at a sound over the course of about 2 seconds rather than 2 milliseconds. From this perspective, we can see the way the overall sound amplitude changes over time; in particular, the parts with high amplitude can easily be seen as drum hits - they appear suddenly and drop in amplitude very quickly as one would expect from striking a drum head. It may have been very difficult to tell what kind of instrument was being played if this sound was viewed over the range of a few milliseconds. From this, we should conclude that the short time interval and long time interval perspectives both show different types of information and that selecting the right perspective to suit one's needs is important.

Sinusoids, frequency and pitch
As indicated in Fig. 1.1, the sine wave has a periodic form that repeats every $$T \,$$ seconds which is known as the period, cycle. The wave also has a positive maximum amplitude, $$A \,$$ and a negative maximum amplitude, $$-A \,$$. The frequency, $$f \,$$, of a sine wave is the number of cycles per second and is measured in Hertz (Hz). We can obtain the frequency from wavelength from the following equation:

$$f = \frac{1}{T} \,$$

Furthermore, we can express a sine wave with the following mathematical form (with angles in radians). This form may be useful to programmers interested in creating their own controllable sine functions in code:

$$p(t) = Asin \left (\frac{2 \pi t}{T} \right ) = Asin(2\pi f t)$$

Psychometrically, higher frequencies (eg above 1.5kHz) are often associated with words such as 'brightness', whereas lower frequencies (eg below 200Hz) are often associated with 'depth' or 'bass'. The intermediate range may be associated with the term 'warmth'. For example, an instrument such as an electric guitar played clean may be called 'bright' or 'sharp' whereas an acoustic double-bass may be referred to as 'dark' and 'warm'. Being psychometric, terms like these are not objective quantities we can measure precisely, but are often used in describing the timbre, or tone color of a particular sound. The various amplitudes of frequencies present in a sound, and their evolution over time are the major factors associated with timbre, and there are infinite shades of timbre that can be achieved through combinations of different frequencies that make up a sound. In psychometric terms, human hearing associates whole number frequency ratios with pitch, and associate particular frequencies with particular notes in the standard Western scale:

Fig. 1.4. The relationship between wavelength, frequency and note name.

Note that this table covers the range of an octave. The frequency doubles and the wavelength halves.

Construction and deconstruction of sinusoids
Using Fourier analysis, sine waves can be considered the fundamental components of sound, since a single sine wave is a single frequency. Within Fourier analysis, combining sinusoids of different frequency, amplitude and phase can recreate the frequency spectrum of any sound. Similarly, complex sounds may be analyzed in terms of frequencies, amplitudes and phase.

Fig. 1.5 demonstrates the appearance of two sine waves summed together. The characteristics of both waves are combined in the resultant waveform. This technique is the basis of additive synthesis which is covered later in the book. Furthermore, in the way that the sound is constructed, it is possible to filter out the two component frequencies from the whole; this is typically done by analysis of the waveform in the frequency domain, which is covered in the subsequent chapter.


text:
Sound Synthesis Theory/Sound in the Digital Domain

=Sound in the Digital Domain=

Introduction
Digital systems (e.g. computers) and formats (e.g. CD) are clearly the most popular and commonplace methods of storing and manipulating audio. Since the introduction of the compact disc in the early 1980s, the digital format has provided increasingly greater storage capacity and the ability to store audio information at an acceptable quality. Although analogue formats still exist (vinyl, tape), they typically serve a niche audience. Digital systems are ubiquitous in modern music technology. It must be stressed that there is no argument as to whether one domain, be it analogue or digital is superior, but the following provides some desirable features of working with audio in the digital domain.

 * Storage. The amount of digital audio data capable of being stored on a modern hard drive is far greater than a tape system. Furthermore, we can choose the quality of the captured audio data, which relates directly to file size and other factors.

 * Control. By storing audio information in digital, we can perform powerful and complex operations on the data that would be extremely difficult to realise otherwise.

 * Durability. Digital audio can be copied across devices without any loss of information. Furthermore, many systems employ error correction codes to compensate for wear and tear on a physical digital format such as a compact disc.

Digital <-> Analogue Conversion
Acoustic information (sound waves) are treated as signals. As demonstrated in the previous chapter, we traditionally view these signals as varying amplitude over time. In analogue systems, this generally means that the amplitude is represented by a continuous voltage; but inside a digital system, the signal must be stored as a stream of discrete values.

Digital data stored in this way has no real physical meaning; one could describe a song on a computer as just an array of numbers; these numbers are meaningless unless there exists within the system a process that can interpret each number in sequence appropriately. Fig. 2.1 shows an overview of the process of capturing analogue sound and converting it into a digital stream of numbers for storage and manipulation in such a system. The steps are as follows:

 * 1) An input such as a microphone converts acoustic air pressure variations (sound waves) into variations in voltage.
 * 2) An analogue to digital converter (ADC) converts the varying voltage into a stream of digital values by taking a 'snapshot' of the  voltage at a point in time and assigning it a value depending on its amplitude. It typically takes these 'snapshots' thousands of times a second, the rate at which is known as the sample rate.
 * 3) The numerical data is stored on the digital system and then subsequently manipulated or analysed by the user.
 * 4) The numerical data is re-read and streamed out of the digital system.
 * 5) A digital to analogue converter (DAC) converts the stream of digital values back to a varying voltage.
 * 6) A loudspeaker converts the voltage to variations in air pressure (sound).

Although the signal at each stage comes in a different form (sound energy, digital values etc.), the information is analogous. However, due to the nature of the conversion process, this data may become manipulated and distorted. For instance, low values for sample rates or other factors at the ADC might mean that the continuous analogue signal is not represented with enough detail and subsequently the information will be distorted. There are also imperfections in physical devices such as microphones which further "colour" the signal in some way. It is for this reason that musicians and engineers aim to use the most high-quality equipment and processes in order to preserve the integrity of the original sound throughout the process. Musicians and engineers must consider what other processes their music will go through before consumption, too (radio transmission etc.).

Sampling
Sound waves in their natural acoustic form can be considered continuous; that is, their time-domain graphs are smooth lines on all zoom factors without any breaks or jumps. We cannot have these breaks, or discontinuities because sound cannot switch instantaneously between two values. An example of this may be an idealised waveform like a square wave - on paper, it switches between 1 and -1 amplitude at a point instantaneously; however a loudspeaker cannot, by the laws of physics, jump between two points in no time at all, the cone has to travel through a continuous path from one point to the next.

Sampling is the process of taking a continuous, acoustic waveform and converting it into a digital stream of discrete numbers. An ADC measures the amplitude of the input at a regular rate creating a stream of values which represent the waveform in digital. The output is then created by passing these values to the DAC, which drives a loudspeaker appropriately. By measuring the amplitude many thousands of times a second, we create a "picture" of the sound which is of sufficient quality to human ears. The more and more we increase this sample rate, the more accurately a waveform is represented and reproduced.

Nyquist-Shannon sampling theorem
The frequency of a signal has implications for its representation, especially at very high frequencies. As discussed in the previous chapter, the frequency of a sine wave is the number of cycles per second. If we have a sample rate of 20000 samples per second (20 kHz), it is clear that a high frequency sinusoid such as 9000 Hz is going to have fewer "snapshots" than a sinusoid at 150 Hz. Eventually there reaches a point where there are not enough sample points to be able to record the cycle of a waveform, which leads us to the following important requirement:

Why is this? The minimum number of sample points required to represent a sine wave is two, but we need at least slightly more than this so that we're not dependent phase (samples at exactly twice the sine wave frequency, the samples may fall on the peaks of the sine wave, or on the zero crossings). It may seem apparent at this time that using just two points to represent a continuous curve such as a sinusoid would result in a crude approximation - a square wave. And, inside the digital system, this is true. However, both ADCs and DACs have low-pass filters set at half the sample rate (the highest representable frequency). What this means for input and output is that any frequency above the cut-off point is removed and it follows from this that the crude sine representation - a square wave in theory - becomes filtered down to a single frequency (i.e. a sine wave). From this, we have two mathematical results:

$$F_{s} > 2 f_{max}$$ and $$F_{N} = \frac{F_{s}}{2}$$

Where $$F_{s}$$ is the sample rate, $$f_{max}$$ is the highest frequency in the signal. $$F_{N}$$ is the Nyquist frequency. Frequencies over the Nyquist frequency are normally blocked by filters before conversion to the digital domain when recording; without such processes there would be frequency component foldover, otherwise known as aliasing.

Sampling accuracy and bit depth
It has been established that the higher the sample rate, the more accurate the representation of a waveform in a digital system. However, although there are many reasons and arguments for higher sample rates, there are two general standards: 44100 samples per second and 48000 samples per second, with the former being most commonplace. The main consideration for this is the fact that the human hearing range extends, at maximum, to an approximate limit (that varies from person to person) of 20000 Hz. Frequencies above this are inaudible. Considering the example of 44.1 kHz, we find that the Nyquist frequency evaluates to 22050 Hz, which is more than the human hearing system is capable of perceiving. There are other reasons for this particular sample rate, but that is beyond the scope of this book.

There is one more important factor to consider when considering the sampling process: bit depth. Bit depth represents the precision with which the amplitude is measured. In the same way that there are a limited amount of samples per second in a conversion process, there are also a limited amount of amplitude values for a sample point, and the greater the number, the greater the accuracy. A common bit resolution found in most standard digital audio systems (Hi-Fi, Compact Disc) is 16 binary bits which allows for a range of 65536 ($$2^{16}$$) individual amplitude values at a point in time. Lower bit values result in a greater distortion of the sound - a two bit system ($$2^2$$) only allows for four different amplitudes, which results in a massively inaccurate approximation of the input signal.