Contemporary RT Literature
General RT principles
Prior to a review of the more contemporary ATC literature, several important RT concepts merit discussion; these include 1) the dose-volume relationship, 2) inherent radiosensitivity and the impact of FXN, 3) dose escalation, 4) chemosensitization, and 5) the strong association of extensive ETE/ATC disease with likely occult DMs. The dose-volume tenet of RT refers to the observation that larger aggregates of disease require higher total doses of RT for effective sterilization. For most other head and neck cancers, doses of 50 Gy, 60–65 Gy, and 70–75 Gy of SF/RT are required for 95% control of a microscopic, a 2-cm, and a 4-cm tumor, respectively. Although similar data are not available for ATC, especially given the potential for ATC to develop acquired resistance, effective doses may be higher; in any case, larger aggregates require higher doses, regardless. Notably, despite being one of the most important predictors of the degree of response, the volume of irradiated disease for most study populations remains poorly defined, is rarely stratified, and includes a spectrum of disease extending from presumed R1 microscopic disease (ie, after GTR) to presumed bulky disease (represented by the proportion of patients with R3 disease). With rare exception, only patients with IT/ATC were observed to achieve an R0 resection, and reported LTS has been almost exclusively for this cohort. Although the strategy is controversial, most authors, including Sugino, continue to recommend postop RT for small, completely resected iATC, given the risk for regional recurrence.[7,18,24] It also remains controversial whether “mixed ATCs” have a more favorable prognosis, which probably is related more to the volume and extent of the ATC component relative to that of the more well-differentiated elements. Finally, it should be emphasized that the extent of disease, specifically the extent of ETE/palpable disease, not only influences the ability of surgery and of RT to secure LC, but it also has an impact on any prospects for LTS/NED, as extensive disease is known to be highly associated with occult DMs.[6,7]
Radiosensitivity is a measure of the inherent susceptibility of cells to damage by RT. Radiosensitivity varies throughout the cell cycle and with the availability of oxygen (required for cell kill). Increasing FXN may improve cell kill by allowing for reassortment and reoxygenation; however, if overall RT time is protracted, it will then facilitate accelerated repopulation as a result of cellular mutations and survival of resistant clones, phenomena typically observed after the first 3 to 4 weeks of RT. Hyperfractionation (HPFXN/RT), giving smaller doses with multiple fractions per day but the same total dose over same amount of time, in concept decreases late toxicity, or conversely, allows for an increase in total dose with the same amount of late effects. However, only accelerated HPFXN/RT (HART) gives the same total dose over a shorter period of time and most efficiently compensates for cellular repopulation. However, the efficacy of HART may be limited by the tolerance of the early-responding normal tissues, such as esophagus and skin. Although in concept late-responding tissues should be relatively spared, if the FXN dose is too high or the time between fractions is too short, then there may be insufficient time for repair of normal tissues or there may be depletion of stem populations, which will prove detrimental. On the other hand, high-precision RT, using advanced technology, may allow higher doses to be delivered to tumor, and relatively less to critical structures if the latter are not in too close proximity to the target.[29-31] CM entails the concomitant use of RT and a chemotherapy agent that has been shown to be effective against a tumor—and ideally with different toxicities than those anticipated with RT. Different mechanisms of action include synergistic DNA damage or inhibition of repair of RT damage or of tumor repopulation.
Review of the contemporary RT literature
In the 1980s, several institutions investigated novel “dose-intensifying” approaches in an effort to address the challenges both of treating measurable volumes of ATCs and of the observed rapid proliferation of recurrent or persistent disease over time. Such strategies included using twice-a-day treatment (BID HPFXN/RT), typically along with condensed overall treatment times (HART), as well as employing CTX as a radiosensitizer (CM). Often, both tactics were used: preoperative (preop) or postop RT with either HPFXN/RT or HART, 1.2–2.0 Gy BID with CM—or a similar RT regimen interdigitated with CTX (sequential CM); notably, however, total doses were rarely escalated. Additionally, revolutionary improvements in technology, including 3-dimensional (3D) radiotherapy and, more recently, intensity-modulated radiation therapy (IMRT), have facilitated the delivery of higher total tumor doses, approximating 66 to 70 Gy,[19,29] while still remaining within the tolerance of nearby critical structures—a feat unattainable with earlier technologies. Moreover, several contemporary authors, recognizing the need for a GTR, pursued a preop RT approach. Such an approach is especially relevant for the 50% of initially R3 tumors. Some authors who have adopted a preop approach have reported some of the highest ms and lowest DcLF (death with a component of local failure) in the RT literature.[20,25,32]
The details of seven contemporary studies are included in Tables 1 and 2. These reports come from several, notably international, centers, including Memorial Sloan-Kettering Cancer Center, Princess Margaret Hospital, Royal Marsden Hospital,[22,35] MD Anderson Cancer Center, Gustave-Roussy, Lund University in Sweden, and the Institute of Oncology in Slovenia. As can be seen, these treatment regimens are distinctly different with regard to total dose, FXN schedule, the use of CM, and the sequencing of treatments, as well as, importantly, the prognostic variables of different study groups. Many of these series are institutional reports of unique strategies, without controls [32,36]; none were randomized, and only two were prospective.[25,32] Three institutions reported on the use of preop RT, generally split course, with an initial dose of 30–46 Gy prescribed for R3 tumors in the hope of changing the patient’s resectability status. Importantly, a change in resectability was recorded for 23%, 40%, and 70%, respectively.[20,25,32] Several authors performed comparative analysis: patients were categorized by intent of treatment, performance status, resectability status, or whether or not they had DMs.[20,25] Notably, Besic’s entire study population was entirely devoid of DMs. With regard to treatment parameters, CTX was concomitant with RT in two series,[32,33] sequentially alternated with RT in another, inconsistently used in three,[19,20,34] and avoided in two.[22,35] Similarly, FXN schedules included HPFXN/RT or accelerated HPFXN,[20,22,25,35]
while some authors reported outcomes on “hybrid distribution,” citing various percentages of HPFXN/RT and SF/RT courses (notably, less than half used HPFXN/RT).[19,20] Finally, with rare exception,[19,34] the extent of RT fields was similar (mastoid to carina). Other important RT treatment variables, including total dose and technique, varied significantly between studies and often within a study, although most noted a tendency for dose escalation over time. Although 3D treatment planning was introduced in the 1980s, almost all of these contemporary studies relied on simple anteroposterior/posteroanterior (AP/PA) fields with electron boosts; only Bhatia and Posner comment on the use of 3D and IMRT treatment planning for ATC.[19,29] As noted, the lack of stratification of study populations according to important prognostic variables is a serious omission, specifically the lack of stratification according to tumor size or resection status. Such numerous variations confound comparative analyses of these contemporary studies, other than on a speculative basis.
Tables 1 and 2 include important metrics pertaining to the evaluation of the merits of RT in the treatment of ATC. First, it should be emphasized that the LC statistics as reported in the literature have typically defined LC as no evidence of progression, as opposed to disappearance, of disease for the lifetime of the patient or the length of study. Thus, in any attempt to evaluate the ability of a given regimen to optimally sterilize disease, LC rates need to be evaluated in the context of ms, since otherwise they often appear over-inflated. The s/rCCR (no clinical evidence of disease at or near the completion of all local therapies) metric seems advantageous as a more valid, though not necessarily complete, assessment of “durable control.” At times this metric was calculated after personal review of patient lists or by extracting information from the text. The s/rCCR metric takes into account both the contribution of a successful initial surgery (%iGTR) and the observed r/CCR. This metric also needs also be assessed in the context of the percentage of patients who show progression of local disease during the course of RT (%r/POLD), as well as those who have local recurrence after attempted resection, prior to commencing RT (%s/POLD); we have included both of the latter values in Tables 1 and 2. Also, acknowledging the current, still realistic goal of using multimodal therapy to prevent death by an uncontrolled primary, DcLF is cited. Of particular importance is the identification not only of the number of LTSs, but also of the patient, tumor, and treatment variables specific to these small cohorts of patients, since these give the prospects for durable tumor control. Additionally, prognostic variables (ie, %DMs and %IT/ATC) and surgical outcomes (GTR, gR2) have been tabulated, since these are relevant to survival statistics and to the efficacy of treatment in relation to the observed toxicities. Other cited metrics/outcomes include %pRTb, which defines the pre-RT bulk of disease (ie, combines the percentage of patients with initially unresectable tumors [iR3] and gR2 irradiated tumors).
Seven representative international studies
On overview, most of these series reported on study populations with very locally advanced tumors, notably with a high percentage of bulk tumor irradiated (pRTb ranging from 70% to 100%), while the delivered total doses (with the exception of Bhatia) were only moderate (40 to 60 Gy). Similarly, many included a high proportion of unresectable R3 tumors, typically 40% to 60%. Not unexpectedly, those studies with a high percentage (> 25%) of initial DMs cite poor survival outcomes even for short-term survival, with ms of 2 to 3 months, in accord with the historical literature. Notably, for populations with a high percentage of either initial DMs or R3 tumors, it remains challenging to decipher outcome statistics, given the competing causes of death (the DMs, an uncontrolled primary, or its associated occult DMs). Finally, given the small numbers of patients, seriously underpowered statistics, and varied risk factors, conclusions remain speculative and difficult to validate, although themes emerge.
Princess Margaret Hospital. Although principles of radiobiology support the use of HPFXN/RT in the hope of preventing rapid tumor repopulation, and despite the validation of HPFXN/RT in selected other head and neck cancers, there still is not a uniform consensus in the ATC literature regarding its superiority. Several authors have reviewed the subject, but the imbalance of other treatment variables confounds analysis.[32,37]
In a subgroup analysis, Wang specifically compared results between patients with a favorable prognosis (group A) who were treated with HPFXN/RT and patients in the same group who were treated with SF/RT; the patients all received the same total dose of 60 Gy, and none received CTX. Wang noted a trend for improvement in ms (10 vs 14 months) favoring the use of HPFXN/RT, although this was not significant, likely because the analysis was underpowered. There was no apparent improvement in LC. On more detailed review, the most significant advantage of HPFXN/RT was seen between the 6th and 9th months, when the survival of those treated with HPFXN/RT was nearly twice that of those treated with SF/RT; however, both regimens quickly failed after 1 year. With the use of HPFXN/RT, there was an increase in skin toxicity but, importantly, not esophageal toxicity. Of note, none of the 60% of patients treated with aggressive 60 Gy SF/RT (nor any of the 40% treated with HPFXN/RT) showed r/POLD, despite the fact that most of those irradiated had a significant volume of disease. By current standards, it is unreasonable that even 60 Gy, one of the highest doses reported in these series, would effectively sterilize any measurable amount of tumor, which was present in more than half the patients (pRTb, 52%). Median survival was seemingly prolonged, especially for group A patients treated aggressively with a hybrid of high-dose SF/RT and HPFXN/RT, compared with historical controls (10 vs approximately 5 months).[10,15] Although more died with DMs (70%), there was still a disappointingly high 62% DcLF. These results suggest that the HFXN/RT treatment paradigm, despite the fact that fewer than half the patients were treated with HFXN/RT, may appear better than historical treatment with lower-dose, nonstandardized SF/RT; nevertheless, it is still seemingly inadequate (with regard to durable control) for a population with relatively few (13%) initial DMs as the competing mode of death, although many were still destined to develop occult DMs. A relatively high total dose may have postponed progression, as evidenced by the comparison of ms; however, it did not ultimately prevent it. Additionally, even in group B patients, who were treated for palliation with a short HYPO/FXN/RT regimen (> 3 Gy/2 weeks), there was no suggestion that this scheme had an impact on control; r/POLD was 23%, rRR was only 18%, and there was no r/CCR and high DcLF. Nevertheless, compared with historical controls, aggressive treatment worked better than a palliative approach, and ms nearly doubled in aggressively treated patients. A comparative analysis may be confounded by differences in patient populations; nevertheless, results for some remain encouraging, compared with the decree that no treatment has made any difference for any patient with ATC. In 2006, Wang commented that HPFXN/RT was well tolerated and that he and his colleagues at Princess Margaret Hospital are now exploring BID FXN with IMRT technology (although they are changing the treatment fields from hyoid to suprasternal notch) for patients with good performance status and without DMs.
Memorial Sloan-Kettering. One of the most successful HPFXN/RT schedules was reported by Kim, notably for a population devoid of DMs, although only 19 patients were included. The reported high LC of 68% seems especially significant given the context of relatively improved 12-month ms, as does the impressive 67% r/CCR despite a high 90% pRTb. These results suggest a quite effective radiation regimen, although notably the four LTSs when treated had only minimal (likely resected) disease. Interestingly, this is one of the highest r/CCR percentages reported. CM (10 mg/m2 doxorubicin(Drug information on doxorubicin) once weekly) was used, but despite the HPFXN/RT regimen, RT was not accelerated.
Lund University. Tennvall prospectively reviewed the impact of increasing preop therapy and increasing HPFXN/RT (over 10 then 7 then 3 weeks), in three consecutively treated cohorts of “generally R3” patients, all of whom were prescribed a total dose of 46 Gy. Local control, but not ms or %DcLF or resectability, improved with the sequential regimens. None of the patients who received entirely preop HPFXN/RT and who went on to resection had a local recurrence. Notably, toxicity for the entire population, including those who received a preop dose of 46 Gy given at 1.25 Gy BID, was deemed acceptable, with 7% experiencing grade 3/4 toxicity and no reports of operative morbidity. It is noteworthy, however, that although overall LC (60%) was one of highest reported, and although DcLF was low at 24%, these outcomes are overshadowed by a poor ms of < 4 months; the latter finding is likely explained by the high percentage of marginally R3 tumors in an elderly population. This very short ms limits the ability to evaluate the durability of LC with this specific regimen. Also, although after some component of preop RT, over 60% of these “marginally resectable” patients were able to achieve a GTR, nearly 40% of patients had gross disease remaining after all therapies, including 27% left with R3 disease. There were five patients who achieved NED/LTS status; four of the five patients had ETE/ATC and had been treated with CM and attempted resection. Although the ms was not different from that seen in historical controls—perhaps because 60% had received split-course RT and because treatment was of an elderly population—this regimen did result in significantly fewer patients succumbing to an uncontrolled primary, as well as in LTS/NED in several patients, all of whom had documented ETE/ATC.
Royal Marsden Hospital. Two authors reported on the exclusive use of accelerated HPFXN/RT (HART), though with quite different FXNs and total doses, and with markedly different conclusions as to efficacy. Mitchell, with a subsequent update by Dandekar, reported on an elderly population having significant DMs (65%).[22,35] Treatment was one of the most aggressive regimens reported, both with regard to fraction size (1.8 + 2.0 Gy BID) and total dose (60.8 Gy [median, 57 Gy] over 3 weeks), although without CTX. The RT scheme was rigorous, conceivably to compensate for a low resectability rate of only 30% to 40% and a very high pRTb of 90% to 100%. Although the 60% rRR was reasonable, the 20% r/CCR was rather low, reflecting the considerable bulk of tumor. Despite such bulk, there was 75% LC and only 12% DcLF, suggesting improvement in sterilization. Again, however, this conclusion was undermined by a ms too low (2.5 months) for adequate assessment of durability. Surprisingly, 12% to 15% showed POLD during treatment. Furthermore, acute toxicity in this elderly population was high; while it likely was not warranted, this regimen was abandoned in favor of one that actually used lower doses, although it was still HART. Importantly, as was well elucidated by Dandekar, there is a serious question regarding the efficacy of an aggressive regimen when patients who have multiple poor prognostic variables succumb from disease before they even recover from the acute effects of the aggressive regimen.
Gustave-Roussy. De Crevoisier reported quite different results in a population with more favorable prognostic variables (younger, high resectability, fewer DMs; and 13% with IT/ATC, only 66% pRTb) using a less aggressive HART program, although treatment extended over 5 months. This prospective, generally postop strategy consisted of a sequential CTX/HART RT/CTX regimen; total dose was initially 40 Gy (for 73% of the study population) then later was escalated to 55 Gy. For the overall population of 30 patients, an exceptionally high 63% s/rCCR was reported; half of this was accounted for by successful GTR (s/CCR) and half by the degree of response of gR2 to RT (r/CCR). Nine of 20 patients (45%) who had an initial incomplete resection or no surgery (including four patients with initial R3 disease and five with gR2) demonstrated an r/CCR, and five of these sustained LC, suggesting durability of the response to RT. All seven who achieved LTS/NED had been taken to surgery, and notably more than half (four patients) had initial ETE/ATC. Remarkably, two had measurable disease irradiated (not GTR), including one who initially had R3 status. Validation of the data has been criticized, with note being made of a high percentage of “mixed tumors.” However, on personal review of the 13 patients with “pure ATC,” we found that there were two LTSs, all of whom had ETE. Furthermore, although not acknowledged, a ms of 7 months for those six patients with DMs is notably high, even though the numbers are very small. Compared with the regimens used in historical controls,[6,10,15] this regimen holds promise, with doubling of ms and half the DcLF seen in the historical literature. Although all LTSs had advanced ETE/ATC, they otherwise had relatively favorable prognostic variables, with few DMs and lesser amounts of bulky disease.
Institute of Oncology (Slovenia). Besic reported on a study population entirely devoid of DMs, categorized according to initial resectability, and treated initially with either primary CM or primary resection followed by CM. Each population had comparable “hybrid distribution” of SF/RT and HPFXN/RT, and each was treated with a similar total median dose of 45 Gy (subsequently escalated to 64 Gy). Each also had a similar “hybrid distribution” of sensitizing CTX (cisplatin + doxorubicin). Reported ms was surprisingly the same—7 months—despite an inherently more favorable tumor status for the group A patients, who were treated initially with surgery (followed by postop CM), compared with the tumor status of the group B patients, who were initially R3 patients treated primarily with CM. Importantly, a subgroup of 12 of the group B patients (23%), upon reevaluation after receiving 20 to 50 Gy (typically 30 Gy), were able to go for resection (23% change in resectability), and a GTR was secured for 13% of the initially R3 patients (58% of those who went for resection). Notably, this subgroup of 12 patients who were able to be taken for resection after only rather low preop doses, and who then returned for the complete dose, showed an exceptionally high ms of 14 months and 50% 1YS. Additionally, they showed a low 18% DcLF, comparable to that reported for initially resected group A patients, and this was despite a high 100% pRTb. They also demonstrated LC, which proved to be durable LC, given the protracted ms of 15 months. Nevertheless, probably because of occult DMs associated with their R3 status, none were NED/LTS. De Crevoisier also reported on the re-evaluation of R3 patients after treatment with 30 to 40 Gy, citing a 40% change in resectability status for the 10 initially R3 patients, with all 4 of those whose status changed to resectable attaining a GTR and 1 becoming a LTS. This change in resectability status after a moderate preop dose remains attractive for a population typically presenting with marginally resectable tumors.
The evaluation of LTS/NED for these seven different treatment regimens is especially enlightening since it reflects the potential for achieving durable control with local therapies. On review of Tables 1 and 2, one may note that the range for LTS/NED (over 2 years) ranges from 7% to 30% for the different patient subgroups; surprisingly, LTS/NED was not predicted solely by those reporting outcomes for populations devoid of DMs. In contrast to the historical literature, four authors reported that some patients who initially had ETE/ATC became LTS/NED, especially those who were able to secure a GTR after a rigorous MMS—and invariably who did not have initial DMs.[19,25,32,36] Importantly, both De Crevoisier and Bhatia reported that a few patients (2 and 2, respectively) irradiated with gross postop disease (not GTR) were also LTS/NED. De Crevoisier cited LTS/NED status for a patient who initially had an R3 tumor that later became resectable (GTR) after preop RT and another patient who was left with gR2 disease. The most favorable results—37% LTS/NED, reported by De Crevoisier—likely reflected not only effective treatment but also more favorable patient and tumor parameters. Although Besic reported a fair 7-month ms (notably the same in resectable and unresectable patients), it remains a matter of speculation whether more favorable results, with respect to LTS, would have been obtained if patients had been treated exclusively with HPFXN/RT and CM, as opposed to fewer than half of patients having been so treated. Besic currently advocates an initial preop approach for most patients, with the exception of those with IT/ATC, noting the possibility of evaluating the effectiveness of CTX and reintroducing surgery when possible. In 2005, she recommended weekly doxorubicin and vinblastine(Drug information on vinblastine), specifically with HPFXN/RT to a dose of 45–64 Gy, with subsequent re-evaluation for resection.
MD Anderson. More recently, Bhatia reported results in series of patients treated at MD Anderson with a variety of RT schedules, 24% of whom were treated with IMRT. The overall population had a high (43%) rate of DMs and a correspondingly low ms of only 3 months. Three patients (16%) demonstrated s/POLD prior to RT. Although rRR was not reported specifically for group A patients who were treated aggressively, 16% (5/31), achieved LTS/NED status; none had DMs, all had ETE/ATC (not IT/ATC), and, importantly, this number included two patients irradiated with gR2. Furthermore, all had completed a median dose of 66 Gy and CM (cisplatin and paclitaxel(Drug information on paclitaxel)).There was a suggestion of a dose response above 50 Gy. Toxicities included 23% of patients requiring hospitalization; IMRT and 3DRT toxicities were 31% and 20%, respectively (not significant); two patients demonstrated late esophageal stricture. Bhatia makes reference to the fact that use of IMRT allows for dose escalation while reducing toxicity. Interestingly, on multivariate analysis, the use of CTX was shown to impact survival. She, and others, have considered biologically targeted therapies as potential radiosensitizers, and also as holding promise for control of systemic disease.[19,38]
Conclusions regarding the contemporary RT literature
In 2005, Chen published an analysis of the most recent SEER database (1983-2002), categorizing 261 ATC patients into three groups (akin to Union for International Cancer Control [UICC] staging) on the basis of tumor extent: 1) those 36% of patients who presented with DMs, with an anticipated survival of < 3 months; 2) the < 15% who had IT/ATC , including the < 10% with iATC, with ms of 9 months; and 3) the majority, 42%, who presented with various degrees of ETE/ATC, with ms of 6 months and 16% 2-year overall survival. In particular, Chen noted that postop RT had an impact on the survival of those with group 3 disease (those who had ETE), but not on the survival of those with DMs, nor of those with IT/ATC (this last finding is controversial, however, because of the small numbers), while surgery benefited both those with IT/ATC and those with ETE/ATC.
In summary, in contrast to the historical literature,[6,10,15] which reports on SF/RT and typically involves a single-modality approach to the treatment of ATC tumors, the more contemporary series have investigated novel MMS (including HPFXN/RT, sensitizing CTX, and dose escalation) to overcome the biological aggressiveness of ATC, yet still set within the confines of anatomical dose-limiting constraints. This review of several very specific treatment paradigms supports the hypothesis that although the overall survival reported for ATC has not changed in the last 20 years, significant advances have improved the quality of life for selected affected patients; less fortunate patients, specifically those with initial DMs or tremendous tumor volume, never taken to surgery, may be better treated with a more gentle approach, including purely palliative measures. Although the effort of shifting through different outcome scenarios and searching for a logical thread may be fraught with misconceptions and statistical errors, the exercise reveals interacting, sometimes competing, dynamics variables that need to be examined and that may be instrumental in prospectively directing individual patient care: resectability, medical risks, bulk residuum, significance of DMs, duration of therapy, anticipated incurred toxicities, as well as cause of death. More concrete recent discoveries include: acknowledgement of the feasibility of HPFXN/RT prescribed to nearly 60 Gy and combined with CTX in the preop setting; recognition of the chance (23%, 40%, or 70%) that an initially unresectable tumor may become resectable after CM, with a corresponding likelihood (13%, 40%, or 60%, respectively) of securing a GTR; and the shrinking, by approximately half, of the risk of death from local disease (with more than 70% succumbing to DMs, and less than 30% to uncontrolled local disease). This last development gives hope that at least a few, though perhaps as many as 10% to 30%, of patients who have no DMs at diagnosis and who have the vigor to endure aggressive multimodal therapies, may be able to achieve LTS/NED status.
Additionally, given that relatively archaic technology was used in most of these studies (there has been only one published report, and a preliminary report at that, of the incorporation of IMRT into the treatment paradigm), to some degree the risk-benefit ratio may be redefined and the efficacy of RT improved; nevertheless, dose escalation will likely still be limited by the tolerance of the esophagus, 60 to 66 Gy. In any case, an aggressive strategy, with its inherent toxicities, should be undertaken only in patients with at least 3 months estimated survival, specifically those without DMs. Other technical advances, such as PET/CT scanning, may further improve patient selection, helping not only to identify those with ATC who have documented metastatic disease, but also helping incorporate external beam RT earlier into the treatment paradigm of patients who present with mixed histologies that include a component of ATC. In conclusion, an aggressive sequential MMS needs to be thoughtfully considered in relatively high-performance patients who are without DMs and whose tumor shows an early therapeutic response to first-line therapy (whether resection or preoperative CM), with consideration especially given to incurred toxicities and realistic expectations for quality of life.