Treatment of patients with unresectable stage IIIA and IIIB non-small-cell lung cancer with conventionally-fractionated radiation therapy (ie, total doses of 50 to 60 Gy, using one fraction per day), which was standard
ABSTRACT: Treatment of patients with unresectable stage IIIA and IIIB non-small-cell lung cancer with conventionally-fractionated radiation therapy (ie, total doses of 50 to 60 Gy, using one fraction per day), which was standard practice in the 1970s and early 1980s, resulted in good short-term palliation but few long-term survivors. Local control was poor, and the majority of patients also rapidly developed symptomatic metastatic disease outside the chest. In the past 15 years, a number of approaches to improve this situation have been defined in prospective clinical trials. They include radiation therapy with altered fractionation schemes that allow either higher overall doses or shortened treatment times, the use of systemic chemotherapy to address microscopic metastatic disease, and the use of a variety of agents, some but not all with intrinsic cytotoxic activity, to act as radiation sensitizers. These strategies have resulted in modest but significant improvements in local and systemic disease control, but at a cost of increased toxicity, including myelosuppression, esophagitis, and pneumonitis. Further advances in treatment will require better (ie, more active) cytotoxic agents and better ways of limiting radiation effects to the target volume of tumor. [ONCOLOGY 11(Suppl 9):43-50, 1997]
As the twentieth century draws to a close, the epidemic of lung cancer continues its lethal course throughout the world, and will lead to death in 10% of all persons now living. In the United States, about 180,000 new cases of lung cancer were expected in 1996, with an estimated overall mortality rate of 85%. Roughly 75% of new cases will be non-small-cell lung cancer (NSCLC). While in past years lung cancer was predominantly a disease afflicting men, with squamous cell the most common histology, recent years have seen a trend toward equality in the numbers of cases in men and women and a shift to adenocarcinoma as the most common histology.
During the 1970s, standard therapy for patients with "locally advanced" NSCLC was treatment with radiation therapy alone, generally in doses ranging from 50 to 60 Gy over 5 or 6 weeks. This treatment gave reasonable palliation, with about 60% to 80% of patients having marked symptomatic improvement in cough and hemoptysis. A few patients were cured, however, and overall 5-year survival averaged about 5%. Five-year survival rose to 10% in carefully selected patients who had excellent performance status and few, if any, symptoms, (ie, those whose tumors were discovered incidentally, perhaps on a chest x-ray before elective surgery). At the time, local disease control was considered reasonably good, in the range of 60% at these doses. Many of these reports cited freedom from local progression, however, not durable local control. With the short survival of many patients and the difficulty of distinguishing between local tumor progression and postradiation pulmonary fibrosis, such estimates appear to have been significantly in error. Local control as assessed by bronchoscopic examination and biopsy following radiation therapy is more in the range of 20% with these or similar dose/fractionation regimens.
Spurred by the high incidence of lung cancer and its great lethality, clinical investigators in single institutions and cooperative research groups have made great efforts over the past two decades to improve these dismal figures, and we have seen modest but real progress. This review will consider three areas of development: improved imaging and stage classification of patients with so-called locally advanced non-small-cell lung cancer, improvements in radiation therapy dose delivery (physics) and fractionation (radiation biology), and integration with many different rationales of radiation and cytotoxic chemotherapy.
Patients with stage III NSCLC are heterogeneous in overall clinical status and stage. Performance status and weight loss are highly significant prognostic factors both for the ability to tolerate treatment and for survival. The otherwise healthy patient with an incidental diagnosis of stage IIIA disease based on a chest x-ray done before elective surgery will likely fare far better than the symptomatic patient who has significant weight loss.
The importance of substaging patients with stage III NSCLC has been increasingly recognized in recent years. Until the New International Staging Classification was adopted in 1986, stage III included patients with locally advanced primary and/or nodal disease and those with extrathoracic metastases. The 1986 system established stage IV for patients with extrathoracic visceral disease, and subdivided stage III. Stage IIIA includes patients with potentially resectable disease, and IIIB encompasses those with direct mediastinal invasion, and/or malignant pleural effusions, and/or contralateral mediastinal nodal metastases, and/or supraclavicular metastasis, who are clearly not surgical candidates.
While this distinction is valid when comparing IIIA patients treated surgically with IIIB patients treated nonsurgically, how the prognosis of these groups is affected following either radiation alone or radiation combined with chemotherapy is controversial.[6-8] Disease bulk is generally an important determinant of the ability of radiation to achieve local control. Omitting bulk from the staging system likely obscures differences among patients treated nonsurgically. While T4 disease due to invasion of unresectable mediastinal structures and T4 disease due to the presence of a malignant pleural effusion preclude curative surgery, they are not equivalent when definitive radiation therapy is being considered. Radiation may be appropriate for mediastinal but not for pleural T4 disease. Data also suggest that the number of involved mediastinal nodal sites and/or the total number of involved nodes is prognostically important at least for surgically-treated patients.
The greatest heterogeneity within stage IIIA concerns patients with T3,N0 and T3,N1 disease. Patients with T3,N0 disease, treated surgically, can have 5-year survivals in the range of 30% to 50%, and those with T3,N1 disease will have a 5-year survival of about 25% compared with a 5-year survival of 15% or less for patients with T3,N2 disease. Current recommendations to revise the staging classification take into account some of this heterogeneity. It may be, however, that surgically- and nonsurgically-treated patients require somewhat different staging systems.
The techniques used to evaluate mediastinal nodal involvement are important in determining prognosis, particularly the percentage of long-term survivors. Computed tomography (CT) has been widely used in the past decade and is generally equal or superior to magnetic resonance imaging for assessing mediastinal node enlargement. Nonetheless, it is essential to recognize that nodal enlargement is not synonymous with nodal involvement by tumor and that a cutoff of 1.5 cm will result in about a 20% false-positive and false-negative CT scan rate. Of concern is a series of clinically-staged patients that show a tail on the survival curve suggesting that many of these long-term survivors may have been N2 radiographically but N1 or N0 histologically. Since the survival of patients with T2,N0 disease is significantly better when they are treated with resection as opposed to nonsurgical therapy, patients who are otherwise good candidates for resection deserve histologic confirmation of suspected N2 disease. Reports of clinical trials of N2 patients should also indicate the proportion with bulky disease (visible on chest x-ray), CT detectable disease, or only mediastinoscopically detectable disease. Table 1 gives a suggested revision of the staging system that considers some of these factors and suggests treatments by substage.
Because of the wide range of prognoses for patients with stage IIIA and IIIB NSCLC, determining at the outset whether an individual should be treated aggressively with some expectation of cure or whether palliation of symptoms with minimal treatment duration and toxicity is more appropriate is essential. Such initial triage must consider stage-based prognosis, co-morbid conditions, and the preferences of patients, which may well differ from those of their physicians. These considerations will lead to treatment that is more appropriate for the individual patient (and his or her family) and to more rational use of costly medical resources as well.
In the 1970s the Radiation Therapy Oncology Group (RTOG) conducted a series of trials that attempted to define the appropriate radiation dose, its fractionation, and volume parameters. While these trials were well conceived and implemented for their time, they were conducted without technology now considered standard (like CT-based treatment planning), routine use of custom-shaped field blocking, and selection of patients with favorable prognostic features (good performance status and minimal weight loss.) Many of the early RTOG trials also allowed the use of posterior spinal cord shields, which resulted in underdosing of the anterior mediastinal nodes.
RTOG 73-01 randomized 376 patients among 4 fractionation schema, 40 Gy given in 2 sessions of 20 Gy in 5 fractions separated by a 2-week break, and continuous course treatment (2 Gy per fraction, 5 days a week to total doses of 40, 50, or 60 Gy). Survival at 2 yearsbut not at 5 yearswas better for the higher-dose radiation groups. Freedom from local progression at 3 years was reported as 67%, 58%, and 48% for patients receiving 60 Gy, 50 Gy, and 40 Gy, respectively, in the continuous radiotherapy groups and as 49% for patients in the 40-Gy split-course radiation group. Unfortunately, freedom from progression is not synonymous with local control, and when disease relapses systemically, patients may not be assessed carefully for local control. Thus, these figures for absence of local progression greatly overestimated the actual probability of local control.
Curran et al looked critically at the relapse patterns of patients with stage IIIA and IIIB non-small-cell lung cancer who had been treated for cure with radiation therapy as a single modality during the 1980s at the Fox Chase Cancer Center (Philadelphia). While distant failure is often considered the most common mode of failure in such patients, these data show that local and distant failure occur equally (Figure 1). Local control (or, rather, failure to observe local progression) was achieved in, at best, 50% of patients, with no differences in either survival or patterns of failure for patients with stage IIIA and IIIB disease.
A more critical assessment of local tumor control was provided by Le Chevalier et al, who randomized patients either between radiotherapy alone or preceded and followed by chemotherapy and assessed all patients bronchoscopically. Rates of tumor clearance were poor17% for the combined modality arm and 15% for the radiotherapy arm (65 Gy). Radiation therapy, delivered in daily fractions of 1.8 to 2.5 Gy to total doses of 60 to 65 Gy over 6 or 7 weeks, is clearly not adequate to provide good local control for patients with stage IIIA/B non-small-cell lung cancer. Considering that such doses are rarely able to control bulky tumors at other sites (eg, head and neck, cervix, breast), this should come as no great surprise.
The poor results with conventional radiation therapy in patients with non-small-cell lung cancer have led to several new approaches for improving local control. These fall broadly into two categoriesthose that seek to better define and target volume to allow higher radiation doses to the tumor while sparing normal tissues and those that alter radiation fractionation to exploit biologic differences between tumor and normal tissues.
The ability to deliver higher radiation doses, whether by conventional, hyperfractionated, or accelerated fractionation, depends critically on the ability to limit the dose to normal tissues like lung, heart, esophagus, and spinal cord. The high-dose volume should conform closely to tumor volume, which is usually extremely irregular (anatomic rather than geometric) in shape. In the past, simple parallel-opposed beam arrangements did this rather poorly. More recent treatment planning and delivery systems, however, allow the tumor and normal tissues to be modeled accurately in three dimensions, ie, multiple coplanar and non-coplanar beams allow a steeper gradient between the dose to tumor and the dose to normal tissue.
The first step in the accurate delivery of radiation therapy is the correct delineation of a target volume. Over the past two decades, the methods of obtaining this delineation have progressed from conventional radiographs or linear tomograms (rarely obtained with the patient in the precise treatment position) to routine use of simulation, CT scan-based treatment planning, and the frequent use of immobilization devices that aid CT scanning, treatment planning, and treatment delivery.
This approach is often applied to both the central axis plane and several off-axis planes. Current treatment planning computers present a full three-dimensional visualization of target and normal tissue volumes as well as dose distributions. When such planning methods were applied retrospectively to patients treated with conventional planning techniques, gross miss of tumor volume can be demonstrated in about one third of cases.
A second component of improved treatment planning and delivery is to reduce reliance on simple opposed-beam arrangements, which treat large volumes of tissue (both tumor and normal) with uniform doses. Past treatment protocols have generally relied on such beam arrangements, either anterior-posterior or oblique, to deliver most or all of the dose to the primary tumor and mediastinal lymph nodes.
Current planning approaches emphasize the use of multiple noncoaxial and often noncoplanar beams to minimize beam overlap in nontarget tissues. Although this results in a greater volume of normal tissue receiving low radiation doses, less normal tissue is treated to doses that exceed tolerability levels. Dose-volume histograms clearly demonstrate the potential advantages of such techniques over traditional planning.
While no prospective studies yet confirm the theoretical superiority of such conformal therapy, several institutions have reported encouraging pilot results. The RTOG is instituting a prospective phase II trial of conformal therapy.
Graham et al at Washington University (St. Louis) have demonstrated a reduction in the radiation dose to normal lung and heart tissue using multiple coplanar beams. With conventional treatment plans, treating the target volume with doses greater than 65 Gy was generally not possible, but escalating the radiation dose to 70 to 75 Gy is possible with conformal techniques.
Leibel et al at Memorial Sloan-Kettering Cancer Center (New York) reported a reduced radiation dose to the ipsilateral lung of 11% and to the contralateral lung of 51% using conformal techniques. They were also able to escalate doses to 72 Gy with acceptable pulmonary and esophageal toxicity. The survival of these patients appeared promising, with a median of 16.5 months and a 2-year survival of 33%.Hazuka et al at the University of Michigan (Ann Arbor) have reported on their 10-year experience with developing and implementing conformal treatment techniques for lung
cancer. They have been able to escalate doses to 84 Gy as long as elective irradiation of nodal sites was avoided and the margin of normal lung kept to a minimum. Retrospective dose analysis showed benefit to those patients who received 67 Gy or more. However, this may have been due to selecting patients with more reasonable target volumes for the higher-dose treatment.
Progress in dose-escalated conformal therapy is unlikely as long as large volumes of radiographically normal lymph nodes are routinely treated prophylactically. While earlier RTOG studies suggested a benefit for prophylactic treatment of supraclavicular and contralateral hilar nodes, more recent analysis has failed to confirm this and suggests that the target volume should be confined to radiographically demonstrable tumor, the ipsilateral hilum, and the paratracheal nodes.
The typical use of radiation therapy in daily fractions, 24 hours apart for 5 days, is based more on logistic and social conditions than radiologic ones. There is no reason to believe that the optimal interval between fractions should coincide with the period of the earth's rotation about its axis. Four general approaches have been used to alter fractionation.
In hyperfractionation, the size of individual fractions is reduced from the normal 1.8 to 2.0 Gy to 1.1 to 1.2 Gy and two daily fractions are given within a separation of 6 hours. Total tumor dose is increased over what would be given normally. The rationale behind this strategy is that reducing the fraction size will result in protecting the late-responding normal tissue while maintaining cytotoxicity against tumor cells. However, this will come at the expense of an increased incidence of acute reactions in rapidly dividing normal cells like the oral or esophageal mucosa.
The RTOG 83-11 trial evaluated this approach in sequential randomized phase II studies and found a total dose of 69.6 Gy optimaldoses of 74.4 or 79.2 Gy did not improve survival and caused greater toxicity. This regimen was then compared prospectively with a "standard" 60 Gy for 6 weeks and induction chemotherapy with cisplatin (Platinol) and vinblastine (Velban) followed by standard RT. The median survival of patients was 11.4 months with standard radiation, 12.3 months with hyperfractionated radiation, and 13.8 months with the combined modality approach. At 3 years' follow-up, however, standard radiation led to 9% survival, hyperfractionated radiation 14%, and the combined modality, 13%. Thus, increasing radiation dose intensity appears to have merit.
Another approach for administering radiation therapy has been to shorten the overall radiation treatment time. Two reasons for using this approach are the intrinsic rapid potential doubling time of some lung tumors and the accelerated repopulation of surviving tumor cells following induction chemotherapy. In the United Kingdom, Sanders and Dische  developed a regimen they termed continuous hyperfractionated accelerated radiotherapy (CHART) which delivered three fractions of 1.4 to 1.5 Gy per day for 12 consecutive days (including weekends), to a total dose of 50.4 to 54 Gy. Patients with unresectable non-small-cell lung cancer had a 2-year survival of 34% compared with 12% for historical controls. A recently completed multi-institution phase III trial confirmed their results, with a 2-year survival for patients treated with CHART of 30% compared to 20% for those who received a standard regimen of 60 Gy in 6 weeks (P = .006). The majority (80%) of patients in this trial had a squamous histology, and greater benefit for CHART was seen in patients with T3 and T4 tumors than in those with T1 or T2 disease. This may reflect more advanced nodal disease in those with T1 or T2 primary lesions who have unresectable disease.
With some modifications in fractionation, a recent Eastern Cooperative Oncology Group (ECOG) phase II trial (ECOG 4593) has tried to duplicate these results. Weekend treatments have been omitted, and the mid-day fraction, which is given through oblique or lateral portals that exclude the spinal cord (and, if possible, the esophagus), has been increased to 1.8 Gy. A total of 57.6 Gy is delivered over 12 treatment days, typically every 15 days. As in the British CHART regimen, the chief acute toxicity has been esophagitis, usually beginning several days after treatment is completed (thus avoiding treatment breaks) and lasting for 2 or 3 weeks. Although about one third of patients required liquid or soft-solid diets and narcotic analgesics, parenteral feeding has only rarely been necessary. Late esophageal strictures have not been reported, but further follow-up is probably warranted. Median survival has not been reached and uncorrected 1-year survival is 65%.
The RTOG has also investigated a strategy of concurrent boost therapy, in which 1.8 Gy is given to the primary tumor, known nodal metastases, and electively treated nodes. Then a 0.7- to 0.8-Gy boost is given immediately to areas of known gross disease. In phase II studies, this approach has not proven to be strongly superior to standard treatment and is not being pursued actively at present.
In summary, these regimens of altered fractionation based on increased knowledge of both tumor and normal tissue kinetics and radiobiology have demonstrated improved survival in two large, prospectively randomized trialsindicating that despite the high propensity for distant spread of stage III non-small-cell lung cancer, strategies to improve local control are worthwhile.
The discouraging survival results and the high rate of systemic failure for treatment regimens of radiation therapy alone have led to an effort to combine systemic treatment, either chemotherapy or immunotherapy, with local radiation. While such attempts are often considered in the aggregate, and several meta-analyses have either considered all combined modality trials together or divided them primarily according to the chemotherapeutic agents used, there are at least four conceptu
ally distinct modes of combining radiation and chemotherapy.
This sequence uses radiation to treat known locoregional disease and chemotherapy to treat both systemic micrometastases and the remaining tumor cells not killed by radiation. It presumes no particular interaction between the modalities and makes no particular demands on timing, although one would expect that chemotherapy would begin soon after radiotherapy has been completed. Potential advantages are the avoidance of the toxicity of concurrent therapy to normal tissues and thus less chance that therapy will be interrupted. Disadvantages include delay of systemic therapy for several months while radiation therapy is being administered and the possibility that postradiation fibrosis may reduce drug delivery within the irradiated volume.
Another relatively noninteractive mode of combining radiation and chemotherapy is to give chemotherapy before radiation. This sequence avoids the delay in beginning systemic treatment and overcomes the theoretical concern regarding reduced drug delivery to irradiated tissues. An additional advantage may be the ability to reduce the radiation target volume in those who respond to induction chemotherapy. Data from patients with small-cell lung cancer support this reduction of field size, but this approach has not yet been shown effective for patients with non-small-cell lung cancer. Since radiation toxicities, both early and late, generally depend on both the radiation dose and the volume, reducing the target volume should allow the administered radiation dose to be increased for the same level of toxicity. A potential disadvantage is that drug-resistant cells will proliferate during initial chemotherapy with some data suggesting that this rapid proliferation is an obstacle to subsequent control by conventionally fractionated radiation therapy.
Concurrent Radiation and Chemotherapy
Concurrent administration of radiation and chemotherapy at the beginning of treatment avoids the potential delays that occur with the previous two schedules. In small-cell lung cancer, Murray et al have shown that patients treated with combined radiochemotherapy regimens wherein less than 6 weeks elapsed between the start of radiation and the initiation of chemotherapy achieve better survival rates than regimens in which the treatment lapse was longer. Whether this is also true for patients with non-small-cell lung cancer remains to be determined. The price paid with concurrent regimens is an increase in acute toxicities, primarily hematologic and esophageal, which may cause an interruption in treatment or a reduction in dose intensity.
The above method of combining radiation and chemotherapy relies primarily on the independent cytotoxicity of each modality. The chemotherapeutic regimens (drug, dose, and schedule) would logically be those shown to have activity in patients being treated for metastatic disease. An alternate strategy is to use lower chemotherapy doses given frequently (weekly or daily) to exploit the observations of in vitro and a variety of animal studies that show a number of the chemotherapeutic agents active against non-small-cell lung cancer also increase the sensitivity of cells to radiation. Such agents include cisplatin and carboplatin (Paraplatin), the taxanes, etoposide (VePesid), gemcitabine (Gemzar), and topoisomerase I inhibitors like topotecan (Hycamtin) and irinotecan (Camptosar). While the ability of these agents to sensitize cells to radiation is certain, the selectivity of this sensitization for tumor cells may be questionable. Without such selectivity, a parallel increase in the radiation sensitivity of tumor and normal tissues would not necessarily represent a therapeutic gain. The direct cytotoxic effect of many of these agents given in modest weekly or daily doses has not been well studied, although recent data on weekly paclitaxel (Taxol) show substantial single-agent activity comparable to that reported with dosing schedules of every 3 or 4 weeks.
Over the past decade a large number of prospective trials have been conducted comparing radiation therapy as a single modality to combinations of radiation and chemotherapy in patients with stage IIIA and IIIB non-small-cell lung cancer. Most of these have been flawed because of the clinical rather than surgical staging of the mediastinum. Several have also been so small that only a very large difference in outcome would have been detected with statistical significance. With these caveats, however, a case can be made that these trials have demonstrated a modest but reproducible benefit for combined modality therapy.
Table 2 summarizes the larger trials that compared radiation therapy with induction chemotherapy followed by radiation therapy.[28,29] No prospective trials of radiation with or without only postradiation chemotherapy have been reported. While not all of the trials showed a survival benefit, especially the smaller ones and those that did not use cisplatin-based chemotherapeutic regimens, the trials reported by Dillman et al  for the Cancer and Leukemia Group B, Le Chevalier et al , and Sause  for ECOG and RTOG, which together enrolled nearly 1,000 patients, showed a modest but consistent improvement in both median survival and time points beyond the median to at least 3 years.
When patterns of failure have been examined in these trials, the greatest difference has been in the rate of distant relapse. The relatively poor local control was not influenced by the use of induction chemotherapy. In the trial reported by Le Chevalier et al  local complete response, assessed bronchoscopically, was 15% with and 15% without chemotherapy.
Asking whether, in the presence of chemotherapy of some effectiveness particularly in those who respond to chemotherapy, radiation needs to be added at all is logical. This theory was
tested in two prospective trials (Table 2). The Southeast Cancer Study Group randomized patients to treatment with single-agent vindesine, thoracic irradiation, or both, and found survival equally poor in all groups . The trial included patients with poor nutritional and performance status and used drug and radiotherapy regimens that would now be considered suboptimal. Kubota et al treated patients with one of four cisplatin-containing regimens and randomized responders to observation or thoracic irradiation in doses from 50 to 60 Gy . While there was little difference in median survival, long-term survival strongly favored the inclusion of radiation therapy due to a marked reduction in local failure (5 of 15 vs 15 of 16).
A large number of trials have compared radiation therapy with concurrent chemotherapy, using either intermittent high-dose chemotherapy or lower doses of single agents or combinations administered daily or weekly during radiotherapy. The larger of these trials are summarized in Table 3.[30-34] While little benefit appears to accrue from giving either single-agent cisplatin every 3 weeks or carboplatin/etoposide every 2 weeks, there is more suggestion of benefit for weekly or daily chemotherapy during radiation therapy. Analysis of patterns of failure in trials by Schaake-Koning et al and Jeremic et al indicates that using chemotherapy in this fashion improved local tumor control without altering distant failure rates. The trial by Trovo et al, similar in design to that of Schaake-Koning et al but with a more dose-intense radiation therapy schedule, failed to show improvement in either local control or survival.
It is doubtful that foreseeable improvements in either radiation therapy or chemotherapy will lead to high cure rates for patients with unresectable stage IIIA and IIIB non-small-cell lung cancer. A reasonable intermediate stance is to combine the benefits of induction chemotherapy with those of more aggressive radiotherapy schedules and/or concurrent chemoradiotherapy. To this end, the RTOG is currently conducting a trial that compares sequential or concurrent radiotherapy and cisplatin/vinblastine chemotherapy with a regimen of induction chemotherapy plus concurrent chemotherapy with cisplatin and etoposide. The ECOG is conducting a trial in which patients receive 2 cycles of induction chemotherapy with carboplatin/paclitaxel followed by either standard radiation (64 Gy over 7 weeks) or hyperfractionated accelerated radiation (57.6 Gy over 2½ weeks). The Cancer and Leukemia Group B is investigating a number of newer agents including vinorelbine (Navelbine), docetaxel (Taxotere), and gemcitabine in combination with cisplatin as both induction and concurrent therapy.
While enjoying the modestly improved median and long-term survival results achieved with these aggressive combined therapies, we must not lose sight of the fact that such benefits accrue to only a subset of patients with good performance status. Many patients with stage III non-small-cell lung cancer present with either tumor-related symptoms or co-morbid illness (often smoking-related cardiopulmonary disease) that renders them poor prospects for aggressive therapy of any sort. For these unfortunates, we must continue to develop palliative therapies that can effectively relieve their local and systemic symptoms with minimum cost, time, and side effects.
Finally, it must not be forgotten that lung cancer is not a common natural part of the human condition but rather a disease directly related to tobacco abuse, and the most effective way to reduce this epidemic in the 21st century will be to prevent tobacco use by children. The United States and the overseas markets are increasingly becoming the target of United States tobacco companies in their marketing of suffering and death.
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