Table 2.

Loss of LRC^a/SV^b and time factor.

Anatomical site	Loss of LRCa [references]	Loss of survival	Time factor (Gy/d) and lag (Tkc, weeks)	Comments
Mixed Location	Daily (%) 1–2 [52] Weekly (%) 9 (as in Fowler’92) [40]; 12 (as in Fowler’92) [43]; 14 [8]; 21 (as in Fowler’92) [51]; 15–25 (as in Fowler’92) [42]	3-year OSd: ↓ 9–13% [43,44] 5-year OSd: ↓ 10–43% [40,46,51,54] 5-year CSSe: ↓ 20% [51] ↓ 30% median OSd in larynx (19% for salivary gland, p = 0.06) [55] 5-year DSSf: ↓7% [50] (*)	γ/α2Gy (Dprolif)g: 0.612 [41]; 0.58 (during gap, ≈0.76; during days with RT, 0.2; during weeks 3–4, 0.85; and > 4 weeks, 0.75) [49] Kh: 0.6, >1, 0.66 [9,42,45] Tkc: 4 wks ± 1 [9]; lag not possible < 2 weeks [41]; lag 29 days [45]; ≥2 weeks [49]	LRCa: Try to maintain OTTk < 45–50 days [35,41]. In any case, avoid OTTk ≥60 days (LRCa and/or OSd) [37,43] Delays ≥5 days must be avoided (LRCa and/or OSd) [44,46,52] No prognostic significance: No. of consecutive treatment days missed [43] and gap position [44,52]. In adjuvant radiotherapy, may be significant early gaps in R0l and late gaps in R1m pts and total n° of gaps in both [52]. No adverse effect if break in the first 3 weeks [54] TCPn significantly correlated with OTTk and gap duration [49] Impossible to establish if weekends scored as gaps is important [49] Induction chemo not negate to avoid interruptions [46] OTTk protraction significantly affected LRCa only in G1-2 tumors [47], especially in laryngeal subgroup [50] (*) ↓ 12% preservation of voice in laryngeal cancer [50]
Larynx	Daily (%) 0.68 [29]; 0.9/1.6 (*) [28]; 1.2 (*) [23]; 1.3 [17]; 1.4 (as in Cox’92) [22] Weekly (%) 2.2 [32]; 8.4 (*) [23]; 12 (as in Fowler’92) [26]; 12 (as in Fowler’92) [22]; 20 (as in Fowler’92) [7]; 5–12 TCP [15]	5-year OSd: ↓ 33% [16] 5-year DSSf: ↓ 17% [16] 5-year DFPo: ↓ 15–20% [28]	γ/αi: 0.7 (adjusted for stage and subsite: 0.8) [22]; 0.76 [23]; 0.89 [29]; 1.2/1.63 (***) [27]; 1.76/2.69 (**) [28] γ/α2Gy (Dprolif)g: 0.69 [23] γ/α2.5Gy (Dprolif)j: 0.64 (adjusted for stage and subsite: 0.73) [22] Kh: 0.35 [17]; 0.4 [0.74 as in Withers’88) [19]; 0.56 (as in Withers’88) [7]; >0.5 [26]; 0.5–0.6 [31]; 0.6–0.8 [25]; 0.8 [15] Tkc: Lag ≤ 3 weeks [31]; 20 days [25]; 32/34 days (***) [27]	LRCa in T1-2N0 glottis cancer: Try to maintain OTTk < 40–47 days [10,16–18]. In any case, avoid OTTk > 60 days [33]. LRCa in any other site: Try to maintain OTTk < 45–50 days [7,11,33] For OTTk schemes ≤4 weeks, try to avoid delays > 4 days [24] A single gap is potentially damaging for LRCa, especially for T1N0 tumors [28]. It may be related to gap position (in the first 19 days of radiotherapy or >29 days, but not between [30]; >28 days in T2N0 [12]) or maybe not: Any gap results in the same amount of OTTk prolongation, and, hence, OTTk is more important than the position of the gap [28,29]. In any case, avoid gaps ≥3 days for LRCa and OSd [12,28] (*) ↓ 0.6%/day and 4.2%/week LRCa in hypopharynx ± larynx patients. γ/αi for hypopharynx, 0.3 Gy/d (Dproliff, 0.25 Gy/d) [23] (**) ↓ LCp 0.9%/day for OTTk extension as a whole and 1.6% for gaps ≥ 3 days; γ/αi, 1.76 or 2.69, depending on the mathematical model used [28] (***) γ/αi 1.2 or 1.63, and Tkc, 32 or 34 days, when 4 or 3 centers, respectively, are analyzed [27] The hazard rate for LCRa failure ↑ 0.067%/day of interruption [18] One NSq study showed a ↓ 12%/week LRCa (as in Fowler’92) [19] NSq lag phase; however, best estimate of Tkc is 21 days [15]
Nasopharynx		The hazard rate for DFSr failure ↑ 2.9%/day of interruption [57]	Kh: 0.09 (as in Withers’88) [56]	An OTTk delay ≥ 3 weeks is significantly deleterious [56] The position of the gap (beginning or end) is NSq[57] The hazard rate for LCRa failure ↑ 3.3%/day of interruption [57] LRCa: One NSq study showed a ↓ 5.9%/day [58]
Oropharynx	Daily (%) 0.7 [65]; 1/1.25 (*) [64]; 1 TCP [62] Weekly (%) 14 (as in Fowler’92) [61]; 20 (as in Fowler’92) [60]	OSd: ↓ 17% [63] 5-y OSd: ↓ 19–21% [65]	γ/α2Gy (Dprolif)g: 0.68 [62] Kh: 0.34 (as in Withers’88) [59]; 0.53/0.73(*) [64]	For LRCa, avoid OTTk > 50–55 days [61–63] If ERTs + BTt, avoid OTTk >7 weeks and interval RTEs-BTt > 20 days for LRCa and 5-years OSd [65] G-1 tumors may perform worse than G-2/3 tumors [61,62] (*) LRCa lost of 1% or 1.25% per day for T2N+ or T3N+ tumors, respectively. Kh: 0.53 or 0.73, for an assumed non-significant lag of 30 days or without lag, respectively [64]
Oral cavity	Weekly (%) 9–14 (as in Fowler’92) [66]			Try to keep OTTk ≤40 days [66]

^aLRC, loco-regional control.

^bSV, survival (any kind, see Section 2).

^cTk, time-lag to kick off accelerated proliferation of tumor clonogens.

^dOS, overall survival.

^eCSS, cancer-specific survival.

^fDSS, disease-specific survival.

^gγ/α_2Gy (D_prolif). (See Section 2).

^hK. (See Section 2).

ⁱγ/α. (See Section 2).

^jγ/α_2.5Gy (D_prolif). (See Section 2).

^kOTT, overall treatment time.

^lR0, complete surgical resection.

^mR1, incomplete surgical resection (microscopic disease).

ⁿTCP, tumoral control probability.

^oDFP: disease-free progression.

^pLC: Local control.

^qNS: non significant.

^rDFS: disease-free survival.

^sERT, external radiotherapy.

^tBT, brachytherapy.