Cancer of the larynx: A new staging system and a re-appraisal of prognosis and treatment

J

Chron Dis 1977. Vol. 30. pp. 277-305.

Pergamon

Press.

Printed

in Great

Britain

CANCER OF THE LARYNX: A NEW STAGING SYSTEM AND A RE-APPRAISAL OF PROGNOSIS AND TREATMENT* ALVAN R. FEINSTEIN,? CAROL R. SCHIMPFF,~ JOSEPH F. ANDREWS, JR* and CAROLYN K. WELLS’. Departments

of Medicine and Epidemiology. Yale University School 333 Cedar Street. New Haven. CT 06510 (Rrceiurd

iv reriscd fbrm 22

of Medicine.

Sqvr,nhrr 1976)

Abstract-In an inception cohort of I92 patients with carcinoma of the larynx. we have examined the prognostic role of the diverse clinical manifestations that were present before the first therapeutic decision. Subsequent survtval was found to be most prominently related to the types of symptoms, anatomic topography. and associated major c&morbid ailments. These symptomatic, anatomic. and co-morbid aspects of classification were combined to form a new composite 4-category staging system that produces a more quantitatively distinctive prognostic gradient than the conventional TNM anatomic arrangements. The Composite S ~A-C Stage Delta is demarcated by either extra-laryngeal anatomic spread or major co-morbidity or both. The remaining three stages depend on symptomatic patterns. SSA-C Stage Gamma contains patients with pharyngo-esophageal or ‘external’ symptoms. SAPC Stage Beta is demarcated by respiratory, systemic, or regionally ‘referred’ symptoms. SA-C Stage Alpha is reserved for patients with only local or cord symptoms. The S-yr survival rates. regardless of therapy. in the four stages were: Alpha. 36141 (88”“); Beta. 35/58 (6O”J; Gamma. 17/39 (44”,,) and Delta. 8/54 (IS”,,). Although the SAPC stages produced important prognostic gradients wrthin the same TNM stage. survival rates within the same SA-C stage were not substantially affected by differences either in TNM stage or in the duration of symptoms before treatment. In addition to showing distinctive trends in the rates of subsequent metastasis and deaths due to cancer. the SAPC stages were associated with a prognostic gradient for other forms of death, due to non-neoplastic disease. The choice of treatment was related to the SAPC stage in which a patient was encountered. Surgery was selected most often for patients in stages Beta and Gamma. whereas radiotherapy was chosen most often for the Alpha and Delta stages. Withm the Alpha and Beta S--A-C stages. the outcomes of radiotherapy seemed at least as successful as those of surgery: but in stages Gamma and Delta. surgery seemed superior to radiotherapy. These analyses mdtcate that caretul htstory takmg and attentton to the patrent’s total clinical state provide crucial data for estimating prognosis and evaluating treatment in patients with laryngeal cancer. *From the Cooperative Studies Program Support Center and the Department of Medicine of the West Haven Veterans Administration Hospital, and the Departments of Medicine and Epidemiology of the Yale University School of Medicine. Supported in part by Grant Number ROI HS 00408-07 from the National Center for Health Services Research, HRA. -FProfessor of Medicine and Epidemiology, Yale University School of Medicine, New Haven, Connecttcut; Senior Biostatistician. Cooperative Studies Program Support Center. Veterans Administration Hospital, West Haven, Connecticut. $Formerly Research Assistant, West Haven Veterans Administration Hospital. ijFormerly Assistant Resident in Medicine, Yale-New Haven Hospital. New Haven. Connecticut. TLecturer in Epidemiology, Yale University School of Medicine, New Haven. Connecticut. 277

278 ALVAN R. FEINSTEIN.CAROL R. SCHIMPEE.JOSEPHF. ANDREWS,JR and CAROLYN K. WELLS CANCER of the larynx has been classified in various ‘staging’ systems for at least 90 yr, ever since ‘extrinsic’ and ‘intrinsic’ tumors were first distinguished by either Krishaber [l] or Isambert [2]. The methods of staging have depended on such morphologic constituents as histologic type 133, fixation of involved structures [4], dissemination to cervical structures [SJ, and topographic extensiveness beyond the neck [6]. During the past two decades, national and international committees have tried to achieve uniform standards of classification by delineating the morphologic elements into categories [7] and arranging the categories into several systems of staging [S-lo]. Regardless of morphologic delineations or patterns of arrangement for staging, all of these systems are similar in their restricted attention only to the anatomic features of topography and histology. The process of classification has not been extended beyond the domain of morbid anatomy to include such important biologic features as the cancer’s rate of growth, its functional effects on the patient, or the presence of associated diseases that might alter the patient’s clinical course. In the past few years, new systems of taxonomy have been developed for classifying these additional phenomena in the clinical biology of neoplasia. The phenomena have been shown to be important indexes of behavior and prognosis in cancers of the lung, rectum, and breast [l 1, 121. In the research reported here, we wanted to determine whether these biologic phenomena had similar importance for the staging and outcome of cancer of the larnyx.

METHODS

The general methods for collecting and analyzing data in these epidemiologic assessments of cancer therapy have been reported in detail elsewhere [13]. The description here is limited to a summary of the particular tactics most germane to patients with cancer of the larynx. 1. Selection

13f populations

We began by assembling the medical records of all patients at the Yale-New Haven Hospital and the West Haven Veterans Administration Hospital who had received a diagnosis of cancer of the larynx during the years 1953-1962. The year 1953 represented the opening date of the VA Hospital. The year 1962 represented the latest year for which 5-yr follow-up data could be assembled when the research was most actively in progress, during 1968. The search for suitable patients included the diagnostic lists of the Medical Record Room, Tumor Registry, and Necropsy Service of both hospitals. This search yielded the names of 315 patients, all but one of whom had records available for analysis. Of these 314 patients, 5 were excluded from further analysis; in 4. there was no histologic proof of cancer, and in 1, the cancer was not discovered until necropsy. For each of the remaining 309 patients, a ‘zero time’ was established, based on the first antineoplastic therapy directed at the laryngeal cancer. In patients who had received no antineoplastic therapy, zero time was the date of the therapeutic decision not to give such treatment. If no such decision had been made. an appropriate alternate date was chosen. according to principles described elsewhere [I 31. After this choice of zero time. a complete chronology of data was assembled for each patient, including all details of the prc-zero interval, of the patient’s state at zero time, and of subsequent events during the post-zero interval for at least 5 yr beyond zero time.

Cancer

of the Larynx

279

After the complete data were assembled for these 309 patients, 107 patients were excluded from the subsequent analyses in order to preserve prognostic validity and morphologic specificity. Sixty-seven of the excluded patients were not members of an ‘inception cohort’ [14]: in 53 of these patients. the zero-time antineoplastic treatment had been planned and given at a hospital other than the two hospitals under survey, and in I4 patients, the zero-time treatment occurred either before or after the selected secular interval of 1953-1962. Of the 242 patients who constituted an ‘inception cohort’. 49 were excluded for morphologic reasons. In 16 of these patients, the histologic type of the cancer was not epidermoid (or squamous); in 30 patients, the cancers did not involve the anatomic limits of laryngeal structure, as defined by the American Joint Committee for Cancer Staging and End Results Reporting [S]; and in 3 patients, the cancer could not be ‘staged’ because laryngoscopy had not been performed before zero time. One additional patient, who had become lost-to-follow-up one month after a laryngofissure. was excluded because he was the only patient for whom S-yr survival information was unknown.

This report is concerned with the remaining 192 patients. They all had epidermoid carcinoma of the larynx, examined with direct or indirect laryngoscopy before zero time, first managed at one of our two hospitals during the period from 1953 to 1962, and followed for at least five years after zero time. 2. Collectiorl

of‘ data

The information contained in the medical record for each patient was extracted onto a special form. Supplementary data were obtained as necessary by communication with such sources as other hospitals, physicians, tumor registries, patients. and patients’ families. The data for the pre-zero interval included basic demographic properties, an account of all symptoms and their durations, a description of pertinent physical findings, and a summary of co-morbid ailments. as well as the conventional results of laryngoscopy, roentgenography, and pertinent laboratory tests. The details of the therapy and associated observations at zero time were noted. The data for the post-zero interval included accounts of new symptoms and signs, additional courses of treatment for the laryngeal cancer. new co-morbid diseases, and the patient’s ‘final state’, 5 yr later. In patients who had died, notation was made of the clinical mode of death [ 131 and of the necropsy data. if available. 3. Yreliminur~~ classification

of data

Before any of the clinical data could receive formal classification, certain imperfections required a consistent method of management. One of these problems. whose general management has been described elsewhere [ 131, occurs when disagreements have been reported about the existence or duration of clinical manifestations. A second problem deals with the diagnostic attribution of symptoms. Not all of the symptoms in a patient with laryngeal cancer will be due to the cancer. and a decision must be made about which disease is responsible for each of the existing symptoms. For these decisions, the attribution of a symptom was regarded as definite when the symptom seemed unequivocally due either to the carcinoma or to an associated co-morbid disease. The attribution was uncrrtain when the symptom might be caused by the cancer, by some other disease, or by both. The classification of the patient’s symptomatic state at zero time was based only on the ‘cognate’ symptoms that were attributable or questionably attributable to cancer of the larynx. The ‘co-morbid symptoms that were clearly attributable to some other disease were excluded.

280

ALVAN

R. FEINSTEIN,CAROL

4. Taxonomic

R. SCHIMPFF. JOSEPH F. ANDREWS. JR and CAROLYN K. WELLS

classijkation

a. Toponymy and staging of symptoms. The different types of cognate symptoms associated with a cancer of the larynx can be classified toponymically according to their presumptive mechanisms and effects. The ‘cord symptoms’ of hoarseness, or changes in quality or volume of the voice, are presumably attributable to the lesion on the vocal cord. Certain ‘other local symptoms’, such as irritation of the throat, fullness of the throat, or hemoptysis can be attributed to physical or inflammatory effects of the tumor locally. ‘Respiratory symptoms’, such as a change in cough, stridor, and wheezing. are probably due to obstruction of the airway, although more extensive difficulties may be present. ‘Systemic’ symptoms, attributable to debility or other ‘toxic’ effects of the tumor, include anorexia, significant weight loss,* and malaise, weakness or fatigue. Symptoms such as otalgia and neck pain can be regarded as ‘referred symptoms’. ‘Pharyngo-esophageal symptoms, such as odynophagia and dysphagia, generally imply surrounding inflammation, or direct spread of the cancer. ‘External symptoms’ occur with a patient’s complaint of a mass in the neck, or with other appropriate manifestations distant from the neck. After exploring the prognostic effects of various toponymic categories of symptoms, alone or in combination, we decided to classify patients’ symptoms into three symptomatic stages: Stage 1 : Primarq~ symptoms. Such patients could have any of the cited ‘cord or ‘local’ symptoms, but none of the symptoms listed below in Stages 2 and 3. Stage 2: Obtrusive symptoms. Such patients could have any of the ‘respiratory’, ‘systemic’, or ‘referred’ symptoms, but could not have any of the deleterious symptoms cited in Stage 3. Primary symptoms might or might not have been present. Stage 3: Deleterious symptoms. Such patients have at least one of the ‘pharyngoesophageal’ or ‘external’ symptoms, with or without primary symptoms or obtrusive symptoms. b. Anatomic extensiveness. For classifying the anatomic dissemination of the cancer, we had originally hoped to use one of the several existing systems of anatomic staging, of which the ‘TNM’ method of the American Joint Committee (AJC) [S, 91 is most common in the United States. The ‘TNM’ classification, however, had a major disadvantage. Although the main reason for ‘staging’ is to separate patients according to a prognostic gradient, a descent down the individual ‘TNM’ categories (as will be demonstrated later) does not produce a progressive monotonic gradient in survival. To avoid this difficulty, we classified our population into three simple anatomic groups. Stage 1: Localized. Tumor confined to one vocal cord without fixity of either cord. No evidence of Stages 2 or 3. (In the AJC recommendations, data obtained with special radiologic studies may be used for determining the extensiveness of the tumor in the larynx. Because such films were not available for many of the *Significant weight loss was defined as a non-deliberate loss of IO?, of more from the patient’s customary weight; if the percentage could not be calculated, a loss of 20 lb or more was accepted as significant. If weight loss was the patient’s chief complaint, it was accepted as ‘significant’ even when the absolute values or percentages of loss were slightly below the figures just cited.

Cancer of the Larynx

patients in our series. and because

‘XI

edema and local intlammation may confuse the radiographic anatomy if the films are taken after biopsy of the larynx. WC decided to record the status of laryngeal anatomy only on the basis of the findings at direct or indirect laryngoscopy.) Stugr 2: Intrnnediute. Any other involvement confined to the larynx. but beyond the limits cited for Stage 1 ; or tumor extending to pharyngeal. hypopharyngcnl or tracheal structures. No evidence of Stage 3. Stu(lc~ 3: Distunt. Fixed or palpable suspicious neck nodes, or roentgcnographic or biopsy evidence of cancer beyond the structures cited in Stage 2. (Since the AJC criteria do not contain specifications for distinguishing the palpable non-fixed cervical nodes that are suspected of metastasis and cited in Stages Nl b and N2h, we coded such nodes as metastatically suspicious if their palpable surface area was at least 9 cm’.) c. Proyrzostic~ co-n~whidity. During the extraction of data, associated co-morbid diseases had been recorded whenever present. As noted elsewhere [IS]. such diseases can affect the diagnostic analysis of symptoms in a patient with cancer. and can also alter the patient’s clinical outcome. In this investigation. WC rcscrved the term pmy~o.stic co-rnorhidity for associated ailments. present at zero time. that might be expected to impair the patient’s prognostic anticipations for life. Such ailments included: significant cardiac disease. which was often cited as a deterrent to surgery; far advanced, active tuberculosis; disseminated carcinoma of the lung: severe emphysema; physiologically advanced old age; and other types of poor health not specifically due to effects of the laryngeal cancer. d. Para-mcwhidit~~. In addition to the problems that are clearly due to associated diseases, certain functional effects of a cancer (or of co-morbid ailments) arc not identified by any of the symptomatic. anatomic, or co-morbid categories that have just been described. Anemia was the main functional effect noted here as ~MY~-~u~~~of 37 or less. or ;I hidit!,. The criteria for anemia were. in men. a hematocrit hemoglobin of 11.9 or less; and in women. a hematocrit of 34 or less. or ;I hcmoglobin of 1I .4 or less. e. A~lti-neoplastic therapy. A co~~~‘.s~ of anti-neoplastic treatment was classified. as defined elsewhere [ 131, as a sequence of one or more anti-neoplastic therapeutic modalities given in response to a single group of clinical and morphologic manifcstations. The anti-neoplastic agents could be surgical, radiologic, or chemical. Among the surgical ingredients of a course of treatment were excisional biopsy (which was regarded as ‘surgery’ if no subsequent operation was performed). partial laryngectomy (which refers to such operations as laryngofissure and hemi-laryngcctomy), and total laryngectomy. In addition to or instead of laryngeal surgery. patients could have had unilateral or bilateral radical neck dissection, and such para-laryngeal operations as pharyngectomy. partial glosscctomy. partial csophagectomy, and thyroidectomy. Radiotherapy had been given by beam irradiation. or by implantation of solid substances such as radon seeds and radioactive gold. Chemotherapy had been given with diverse cytotoxic agents. Our coding system was arranged to indicate all, components of each course of therapy, as well as the changes in patients’ condition and time elapsed between each course.

282

ALVAN R. FEINSTEIN.CAROL R. SCHIMPFF.JOSEPHF. ANDREW% JR

and

CAROLYN K. WELLS

f. Subsequent outcome. Each patient’s post-zero course was coded to cite not only the clinical, anatomic, and therapeutic changes just noted, but also the duration of survival after zero time, and (when pertinent) the clinical mode of death and the necropsy findings. g. Citation ofsurvival. In many publications, the survival results of patients with cancer of the larynx have been reported with diverse ways of defining both the original (or ‘baseline’) cohort population and the subsequent outcome. In the data reported here, all the cited patients had been followed for at least 5 yr; and (for reasons to be discussed later in the text) all patients who entered the cohort at zero time were maintained as members of the cohort, regardless of their mode of death. We could therefore list the results of the entire group of 192 patients as simple 5-yr survival rates, in which each patient was directly observed and counted.. 5. Hollerith

coding system and computer

analysis

In order to allow the results to be analyzed with electronic methods of data processing, a format was established for coding the data onto punched Hollerith (IBM) cards [16]. The instructional criteria for using the Hollerith format occupy 20 pp. of single-spaced typing, and will be made available on request by interested readers. The coded data were key-punched, subjected to double verification with keypunching, and verified again by ‘spot checks’ of printed ‘listings’ of the cards. The cards thus prepared were then analyzed via electric sorter or with various tabular programs on the 7094-7040 IBM direct coupled digital computer system and on the IBM 370/158 system at the Yale University Computer Center. (We are grateful to Mr. Victor Latvis, of the West Haven Veterans Administration Cooperative Studies Program Support Center. for his assistance in the computer programming activities.) RESULTS

A. Development

of new composite

stages

1. Survival and baseline variables of classijcation. In Table 1, the 5-yr survival rates are reported according to the nine baseline variables of classification. The categories of partition for sex, symptom and anatomic stages, co-morbidity, and para-morbidity were described previously. For age, the patients were divided at the median value of 62 yr. The patients with known values for pre-zero duration of symptoms were divided into four quartiles, each containing 47 members. The survival rates are listed for the categories of each partition, together with a survival gradient, which is the difference between the highest and lowest rates in each partition. As shown in Table 1, the 5-yr survival rate for the entire population of 192 patients was 50%. The rates were essentially the same for each category of age and sex. For pre-zero duration of symptoms, the overall gradient of survival was small (12%); the highest rate of 5-yr survival (57%) occurred in the category of patients with the longest pre-zero duration of symptoms. A survival gradient of 17% was noted for the two categories of smoking; 24% for the two categories

Cancer TABLE

2x3

of the Larynx

1. FIVE-YEAR SURVIVAL RATES ACCORIWK~ TO NINE BASELINF VARIABLES OF CLASSIFICATION

No.of Variable

Categories

Total population Sex

Age Pre-zero duration of symptoms* Smokingt Symptom stage Anatomic stage Prognostic co-morbidity Paramorbidity

TBaseline tBaseline

data data

Men Women Below 62 yr 62 or more < 3.1 months 3.26.2 months 6.3-17.8 months > 17.9 months Non-smoker Smoker Primary Obtrusive Deleterious Localized Intermediate Distant Absent Present Absent Present unknown unknown

No. of patients

192 178 14 95 97 47 41 47 47 9 182 4x 6X 76 44 110 38 172 20 174 IX

5.yr survivors

96 x9 7 48 4x 24 21 23 27 6 90 37 38 31 32 59 5 93 3 91 5

Survival Yl, gradient

50 50 >

50 > 51 51 45 49 I 57

0”,,

I I’” I 2”,I

50 I7”,, 67 > 77 56 49”,, 2x I 13 54 60” () I .3 I

15 39”,, 53 > 2x 24”,, 52 1

for 4 patients. for 1 patient.

of para-morbidity; 39% for prognostic co-morbidity; and 49y0 for the three symptomatic stages. The largest survival gradient, 6076, was noted for the anatomic categories. The overall results found with these single variables of classification thus indicated that the anatomic, symptomatic, and prognostically co-morbid stages showed the most distinctive separations of the population. These three variables were therefore used to provide the categories that were combined into the composite stages that will be described later. 2. Survival in anatomic and symptomatic stages. Before any combinations were formed, we examined the survival curves for the anatomic and symptomatic staging systems. In Fig. lA, survival rates are shown at a series of time intervals up to 5 yr for patients in the three anatomic stages. Corresponding results are shown in Fig. 1B for the three symptomatic stages. The graphical data show that each type of staging-anatomic or symptomatic--was associated with a distinctively different survival curve for the members of the three different stages. 3. Symptomatic-anatomic distributiorl oj’patirnts. The gradients noted separately in the anatomic and symptomatic stages might have arisen co-incidentally if one form of staging were merely a reflection of the other. To determine whether the two forms of staging were ‘independent’, their concomitant results were next considered. In Table 2, the 192 patients are listed according to their conjunction of symptomatic and anatomic stages at zero time. The wide distribution of cases,

284 ALVAN R. FEINSTEIN, CAROL R. SCHIMPFF, JOSEPH F. ANDREWS. JR and CAROLYN K. WELLS 8. Symptomatic

I

I

6mor I

I

2 TIME

FIG. I. Survival

curves

I

I

3

4

1

1

6mosI

5

(years1

I

,

2

3

TIME

for anatomic

stages

and for symptomatic

stages

Stages

4

5

(years)

described

in text.

spanning all nine groups in the mixture of symptomatic and anatomic categories, indicates the absence of a substitutable correlation between the structural anatomic form of the cancers and their symptomatic effects on clinical function. 4. Survival in combined symptomatic-anatomic cateyories. In Table 3, the 5-yr survival rates are shown for patients in each of the nine categories indicated in Table 2. A generally declining prognostic gradient is noted horizontally within each symptomatic group as the anatomic stage becomes progressively worse. A similar gradient is noted vertically in anatomic stages I and II as the symptomatic stage becomes progressively worse. (In anatomic stage III, the number of cases in symptomatic groups I and II is too small for conclusions about a progressive gradient.) The presence of these ‘double gradients’ in both the symptomatic and anatomic directions demonstrates that the two types of staging are distinctively important, and that both types of stages must be considered for effective classification of patients with laryngeal cancer. Since nine categories of symptomatic-anatomic staging are too cumbersome for general use, our next step was to combine some of the groups shown in Tables 2 and 3, while preserving the co-existence of symptomatic and anatomic demarcations. The strategy used for the combination [ 17, 181 was to join groups that were ‘biologically coherent’ and that had similar survival rates. With this strategy, the nine symptomatic-anatomic groups were clustered into four composite symptomatic-anatomic categories. Anatomic groups I and II were combined within the three symptomatic groups to form the composite groups A, B, and C. The three symptomatic groups were combined within anatomic group 111 to form the composite group D. The pattern of clustering is shown in the table that follows. Anatomic Symptomatic stage I II III

stage

I

II

III

A B C

A B C

D D D

Cancer

285

of the Larynx

TABLE 2. DISTRIBLT~ON OF PATIENTS AT ZERO TIME

Anatomic Symptomatic stage I Primary II Obtrusive III Deleterious Total

I Localized

stage

II Intermediate

III Distant

Total

21

24

3

48

21

44

3

68

42 110

32 3x

76 192

-J 4il

TABLE 3. FIVE-YEAR SURVIVAL IN SYMPTOMATICAW ANATOMIC STAGES

Anatomic

stage

Symptomatic stage

I Localized

II Intermediate

I Primary II Obtrusive III Deleterious

17.!21 (8 I ‘I”) 14/21 (67”“) I:2

20j24 (84”“) 23i44 (52”,,) 16142 (38”,>) 59/l 10 (54”J

Total

y;z (7j”l”)

III Distant o/3 (O”,,) ‘I:3 (33”,,) 4132 (13”,,) S/38

(I 3”,,)

Total 37148 (77:;)) 38/68 (56”6) 21176 (28”,,) 961192 (5036)

These new categories were called composite symptomatic-anatomic stages, or S-A stages. The survival rates for patients in S-A stages A, B, C, and D show distinctive prognostic gradients at diverse time periods up to 5 yr. For .5-yr survival, the rates were as follows in each stage: A, 37/45 (829:,); B, 37165 (57”!); C. 17/44 (39%); and D, 5/38 (13%). 5. _Eficts of’ prognostic co-morbidity. Having completed the combination of symptomatic and anatomic stages, we next examined the effects of prognostic comorbidity. As shown in Table 4, the 5-yr survival rates for each S-A stage were higher i’n patients without co-morbidity than in patients with co-morbidity. The numbers in each S-A stage were too small for statistical significance, but the differences were highly ‘significant’ (xL = 10.9; P < 0.001) for the 54 vs lSo/;, survival rates in the totals. 6. Creatiorl of composite S-A-C stages. Since these results indicated that a satisfactory staging system should not ignore the existence of important co-morbid diseases, our next step was to combine the co-morbid and non-co-morbid S-A categories that seemed to have comparable prognostic outcomes. The pattern of combination, shown in the table that follows, created four composite symptomatic-anatomic-co-morbid (S-A-C) stages, called Alpha, Beta. Gamma and Delta.

286 ALVAN R. FEINSTEIN, CAROL R. SCHIMPFF. JOSEPH F. ANDREWS, JR and CAROLYN K. WELLS TAHLE 4. EFFECT OF PROGNOSTIC CO-MORBIDITY ON 5 yr SURVIVAL RATES Composite symptomaticanatomic stage

Patients with prognostic co-morbidity

Patients without prognostic co-morbidity

A

36141 (@‘%,I 35158

B

D Total

S-A-C

A B C D

(82’2,) 37165 (57%) 17144 (39”,,) 5;‘3x (13”:) 96,092 (50’:“)

stages

Without prognostic co-morbidity

SPA stage

37/45

114 (25”,,) 217 (29”<,) o/5 (o”,,) o/4 (Olj”) 3120 (15’:“)

(60:,,) 17139 (44” ,,) 5134 (15”“) 931172 (54%)

C

Total

Alpha Beta Gamma Delta

With prognostic co-morbidity Delta Delta Delta Delta

The survival rates at 6 months and at annual intervals to 5 yr are shown in Fig. 2 for patients in the four S-A-C composite stages, and illustrate the distinctive prognostic gradients among these four groups. The 5-yr survival rates in the four stages were: Alpha, 36/41 (88%); Beta, 35/58 (60%); Gamma, 17/39 (44%); and Delta, 8/54 (15%). 7. The role of chronomrtry. Although early detection and prompt treatment is a general maxim of care for patients with cancer, the only quantitative method

I

6mor FIG. 2. Survival

curves

I

for patients

2 3 TIME (y0,arrl in composite

4 S-A-C

5 stages described

in text.

Cancer

of the Larynx

TABLE 5. FIVE-YEAR SURVIVAL RATES ACCOKIXNG AND CHRONOMETRY

Composite S--A-C stage Alpha Beta

Total

Duration 63.1 months 919 (1000”) 8/12 167”,,1

of pre-zero

2x7 TO SA-C

symptoms*

3.2X1.2 months

6.3-17.X months

617

IO/l I (91”,,) 5:1 I (45”J 7;14 (50” ,J I,,1 I (9”J 23141 (49”J

1 l/19 (W,) 5;9 (56” ,J I#7 ( 14” ,,) ‘7,47 (57”J

in whom

pre-zero

(X6”,,) 1 I!16 (69”,,1 3’8 (38” ,J I,‘16

(28”“)

16”,3

24147 (5 1“‘0)

21147 (45”,,3

*Does not include data for 4 patients of symptoms was unknown.

STAGES

> 17.9 months IO/l2

(X3”,,)

Totals 35.39 (90”“) 35:5x (60”,,) 17’39 (44” ,,I

(,g 95:lb (.51”,,) duration

for contemplating the ‘earliness’ of detection in patients with laryngeal cancer is to note the pre-therapeutic duration of appropriate symptoms. The data on these durations, which were available in 188 of the 192 patients, were partitioned into 4 quartiles of chronometry, as shown in Table 5. For patients in the same S-A-C stage, the duration of symptoms before zero time seemed to have little or no effect on the 5-yr survival rates. Patients discovered ‘late’ (with symptoms for 17.9 months or more) generally fared as well as those discovered ‘early’ (with symptoms for no more than 3.1 months). In fact, an inverse relationship seemed to exist between the duration of symptoms and the likelihood that the patients would be encountered in the worst (Delta) S-A-C stage. Thus, among the 47 patients with the shortest duration of symptoms, 18 (3832) were found in the Delta stage. As the duration of symptoms increased in the next three chronometric groups, the percentage of Delta patients fell respectively to values of 34. 23, and 15%. The results suggest that prompt diagnostic detection after onset of symptoms may reflect the biologic behavior of laryngeal cancer. The unfavorable behavior of invasive tumors may produce symptoms that lead to their being detected sooner than the more favorable tumors that grow slowly and non-invasively. 8. E&crs qf other pr-e-zero cariahles. Our next step was to determine whether important additional prognostic gradients would be created within the composite S-A-C stages by any of the other pre-zero variables under consideration. The variables that were cross-tabulated with the S-A-C stages were age, sex, smoking, and paramorbidity. Like pre-zero duration of symptoms, none of these variables produced additional distinctive prognostic gradients in the population under study. 9. Surnnzury of the new S-A-C staging system. Since no further prognostic distinctions were added by the variables just cited. we decided to accept the four composite S-A-C stages as an adequate system for prognostic stratification for the laryngeal cancers of the observed patients. The constituents of these stages can be represented as follows:

288

ALVAN

R. FEINSTEIX.CAKOI.

S-A-C

R. SCHIMPFP.

stage

JOSEPH

Symptomatic

Alpha Beta Gamma Delta

Primary Obtrusive Deleterious

F. ANDREWS. JR and CAROLYN K. WELLS

Anatomic Not distant Not distant Not distant All others

Prognostic co-morbidity Absent Absent Absent

The stages can be biologically summarized as follows. All patients with either anatomic evidence of distant dissemination (to regional lymph nodes or other structures beyond the larnyx) or with major prognostic co-morbidity, or both, are in the worst (Delta) stage. The remaining patients, who lack prognostic co-morbidity or distant anatomic dissemination, are then divided into three groups according to their symptomatic manifestations. The deleterious group forms Stage Gamma; the obtrusive group, Beta; and the primary group. Alpha. In the latter three groups. the amount of anatomic spread within the laryngeal structures is not crucial. as long as the tumor appears anatomically absent from regional lymph nodes or more distant sites. B. Cornparisorz with comzntional

morphologic

stqes

In the conventional methods of staging, a laryngeal cancer can be classified according to three aspects of its anatomic morphology: an individual TNM category; a clustered TNM stage, based on combinations of individual TNM categories; and an anatomic source, based on the apparent origin of the cancer in, above, or below the glottis. In the sections that follow, all three of these morphologic forms of staging are examined and compared with the S-A-C stages. 1. Irdiuidual TNM catryories. In the most recent revision of the TNM staging system 193, the topographic extensiveness of the laryngeal tumor was cited in five categories (Tla, Tl b, T2, T3, and T4). Distant metastasis was cited as absent or present (MO and Ml). Although the basic TNM classification contains six citations for lymph nodes (NO, Nla, N lb, N2a, N2b, and N3), all acts of TNM staging for nodes really depend on three categories. The absence of nodes or nodal metastases (NO. Nla, N2a) is cited in one group; suspiciously metastatic but nonfixed nodes (Nl b, N2b) are in the second group; and fixed nodes (N3) are in the third group. To avoid problems in multiple numerical designations, we labelled these three nodal categories respectively as N,, N,, Nc. With our 192 patients classified according to these individual TNM citations, the 5-yr survival rates showed the results that appear in Table 6. For the TNM categories, the clear prognostic gradients noted previously both in the individual symptomatic and anatomic stages, and also in the composite SA and S-A-C stages, became more diffuse and less discernible. A progressive gradient was not found in the different T stages, and a particularly striking contradiction was that patients in stages T2N,MO and T3N,MO had better long-term survival results than patients in stage Tl bN,MO. In the composite S-A-C stages developed here, all patients in the TNM groups N,, N,, and Ml were assigned to Stage Delta. The remaining patients, in the TNM groups N,4M0, all had cancers that were apparently confined to the larynx. The distribution and survival rates of this ‘TNM-localized’ group are shown in

Cancer TAHL~

6. SUKVIVAL

0

N

A

0

I

Pts

I yr

la lb ’ ; 4

51 32 17 21 33

47 (92”J 29 (9 I”,,)

B

1 2

c

3 4 Ia lb i 2

Any

Subtotals

3

I5 (XX”,,,

,

4

1;

Any

5

INDIVID~IAL

alive

3 yr

20 (95”,,) 22 (67” ,I,

0 I 1 2 8 4 1 I

43 I9 I4 I5 I3

(X4”,,) (59” ) (x2”::) (71-J (42” I,)

5 4’ 37 (73”,,) I9 (59”,,, I4 (82” , I3 (62”::) X (24”,,)

I 0 2 6

(I OO”,,,

I 0 2 2

( I OO”,,,

(O”,,, (loo”,,, (75”,,)

IO”,,, (lOo”,,) (25”J

I (ION,,) 0 (O”,,) 1 (5O”J I (l3”J

0 I 0 l 4

(0”“) (loo”,,, (O”,,) (50”,,) (3l”J

0 0 0 0 2

(O”,,) (O”,,, (o”,,l (0” I>) ( 15” ,I)

0 0 0 0 2

0 (O”,,,

0 (O”,,)

(O”,,) (O”,,, (o”,,, (0” .)

(IS’,,)

0 (o”,,,

for MO groups Tla Tlb T2 T3 T4 N, NH N,

Grand

No. and (percentage)

No. of

1

TNM

TO

T

Ia lb 0

2X9

KATES ACCOKDING CATFGOKIES

Categories M

of the Larynx

total

55 34 I9 25 54

47 3I I5 23 32

(X5”“) 19 I “,,) (79”J (92”,,, (59”,,,

43 (7X”“) ‘0 (59”J I4 (74”,,) I7 (6X”,,, IX (33”,,,

37 20 I4 14 II

(67”,,) (59” ,,) (74”,,, (56”,,,

(20” ,

I54 I2 21

I33 (X6”,,) 9 (75”J 6 (29”,,)

105 (6X”,,) 5 (42”J 2 (IO’~,,)

91 (59”::) 3 (‘5” ,

192

I48 (77”,,)

I I3 (5X”,,)

96 (50”,,)

2 (b::,

Table 7. according to the concomitant distinctions of ‘T’ stages and the composite S-A- C stages, Alpha through Delta. In horizontal transit through the T stages within each S-A-C stage, we once again note the absence of a monotonic prognostic gradient. In vertical descent through the ,%A-C stages, however, prognostic gradients are readily apparent within each T stage, despite some reversals due to small numbers of cases. The SAPC gradient is particularly evident within the largest TNM subdivision, T 1aN,,,MO.

TAI~LI7. FIvL-Y~AK SUKVIVAL KAT~S FOK COMPOSITE SAPC CANCER Composite stage Alpha Beta Gamma Delta Totals

TNM TIL~N,~MO IX;20 (9O’:J I5122 (68”,,) 2,‘4 (SO?“) 2 .‘5 (4ou;J 37/:5l (73:;)

Tl bN,MO IO/l3 (77”;) 6/l 1 (55”J 3/4 (75”“) o/4 (0”;;) l9/32 (59YJ

stage

TZN,MO 4/4 6/6 316 l/l 14117

STAGES II\: PATIENTSWITH ‘TNM LOCALIZED

T3N,MO

(IOO~,,) 3;3 (loo’j,,) 6:l I (5O’:J 4 7 (low,,) (X2’/,) 13, 21

(IOO”,,) (55”,,) (57”,,) (62”~

T4N,AM0 I I (lOO”&) 2.‘8 (25”/,) 51.18 (2x”,;) 0’6 (O”/,) 8.‘33 (24”;)

Totals 36141 3 5/5X l7/39 3116 911154

(XX”);) (60”:,) (44Y;J (19”,,) (59”“)

290

ALVAN R. FENSTEIN, CAROL R. SCHIMPFF. JOSEPH F. ANDREWS. JR and CAROLYN K. WELLS

These results demonstrate that the individual categories of the TNM ‘localized stages (i.e. N, and MO) do not themselves provide a distinctive prognostic gradient, and further, that the composite S-A-C stages can create distinctive gradients when imposed upon the TNM stages. 2. Clustrred TNM stuges. For more general usage, the many individual TNM categories shown in Tables 6 and 7 have been clustered [9] into four main stages as follows: Stage I: TlN,MO Stage II: T2N,MO Stage III: T3N,MO;

T4N,MO; N,MO Stagr IV: NcMO; M 1 The results obtained with our cohort of 192 patients, arranged according to the composite S-A-C and clustered TNM staging systems, are shown in Table 8. The TNM results show several obvious disadvantages in comparison to the SAPC staging system : (a) The TNM population was not well distributed. Of the 192 patients, 83 (43%) were in TNM Stage I and only 17 (9%) were in Stage II. (b) The TNM stages did not provide a progressive gradient. The total 5-yr survival rate was higher in TNM Stage II than in Stage I. (c) Within the same TNM stage, the S-A-C stages created a distinctive prognostic gradient, particularly evident in TNM Stages I and III. Even for the relatively small numbers of patients under study, the Alpha and Beta survival differences were statistically significant within TNM Stage I (2’ = 3.88; P < 0.05). 3. The ‘old’ TNM systrm. The TNM categories and stages cited in the foregoing sections had been published by the American Joint Committee in July, 1972, as a new revision of an ‘old’ TNM staging system that was issued a decade earlier [8]. When the research reported here was being performed, we had classified our patients according to the old TNM system. The analyses had been completed and a manuscript was being prepared for publication when we learned that a new set of classifications and analyses would be necessary because a revised TNM system had been issued. TABLE 8. FIVE-YEAR SURVIVAL RATES ACCORDING TO COMPOSITE SSAPC OR CLUSTERED TNM STAGES Composite

Clustered TNM

S-A-C stages Alpha Beta Gamma Delta Total

I

II

28133 (85%) 21133

(100%) 616

(64%) 518 (63Y;) 219 (22’14) 56183 (67%)

414 (100%)

stages

III

IV

36141

414 (IOVX:,) 8/19

316

(42%) 9125

(50%) I/l (loo”,‘) 141;; (82”)“)

(36%) 3/18 (17”‘) 2416: (36%)

Total

(88%) 35158 -

(60%) 1l/39

2126

(44%) 8154

(8%) 2126

(15%) 961192

(8%)

(50%)

Cancer

291

of the Larynx

To save space, we shall not show the detailed results obtained with the old TNM classifications. In summary, the old TNM categories and clustered stages produced an analogous set of inconsistencies in survival rates when the data were arranged as shown in Tables 6-8. In the clustered old TNM stages, our population’s 5-yr survival rates were as follows: Stage I, 36/50 (72%); Stage II. 55/104 (53%); Stage III, 2/4 (50%); and Stage IV, 3/34 (9”/,). Comparison of these results with the data of Table 8 shows that the new TNM staging system creates a substantial rearrangement of the way the same population would have been previously classified, but neither the new nor the old TNM system has produced a satisfactory progressive survival gradient from one stage to the next. 4. Anatomic source. Another morphologic method of classification consists of designating the cancer according to its apparent source in the larynx. Detailed criteria for these categories are presented in the AJC pamphlet [9]. Our classifications can be summarized as follows. The tumor was regarded as ylottic if it involved the true vocal cords or the anterior commissure, but none of the supraglottic or subglottic structures. The tumor was regarded as supraglottic if it involved such locations as the arytenoid cartilage, laryngeal ventricle, ventricular band, or ary-epiglottic fold but none of the glottic or subglottic structures. A suhglottk tumor would have involved such locations as the cricoid cartilage or thyroid cartilage. but none of the glottic or supraglottic structures. If only one of these anatomic locations is involved, the tumor may be regarded as originating in that part of the larynx, even though extra-laryngeal involvement may be present in cervical lymph nodes or elsewhere. If more than one laryngeal location is involved. however, an exact anatomic source for the tumor cannot be determined. Hence, when two or more of these three laryngeal locations was involved, we regarded the tumor as mised. In our series of 192 patients, none of the tumors could be designated as subglottic; 73 were glottic, 55 were supraglottic, and 64 were mixed. Table 9 shows the 5-yr survival rates for these three anatomic categories, together with the associated S--A--C stages and chronometric categories. For chronometric designations. the TARLIZ 9. FwF.-Y~AK SURVIVAL RATES ACCORDING TO COMWSITE S-A-C ‘ANATOMIC SOI'RCE'

Composite S--A-C stages Alpha Beta

‘Long’*

13/14 (93”;) 12115 (80%)

IO/13 (779”) 6115 (40%)

215 (40”“) 27134 (79%)

l/3 (33%) l/6 (17:“) I8137 (49%)

Gamma Delta Total

Supraglottic

Glottic ‘Short’*

STAGI:S. CHRONOMI:TRY. ~YI)

Totalt

‘Short’

24/29t (83%) 18130 (60%) l/3 (3370) 3/l 1 (277,)) 46173-b (63%)

*‘Short’ = pre-zero symptoms for < 6.2 months; tVertica1 totals include 4 patients (2 ‘glottic’, symptoms was unknown.

‘Long’ 2 /?

Mixed Totalt

‘Short’

‘Long’

Total+ 10; IO

212

(100”,,) (I oo”;,) 418 (SW’,,) 7121 (33”,,) 3i24t (13”J 16/55t (29”,,)

(1%

)

(12:

5/c

x.:ti

W’,,)

(7.+,,)

I.'3

(33”“) I,‘10 (lo”“) 9124 (3X”,)

) (loo”,,)

X:12

(67”,,) l/8 (13”J 25139 (64”,,)

13,x

(65”J 9/15 (6o”J 2.19t (1 1'2 34:64t

(53”J

‘long’ = pre-zero symptoms for > 6.2 months. and 1 ‘mixed’) for whom duration

1 ‘supraglottic’.

of

292

ALVAN R. FEINSTEIN, CAROL R. SCHIMPFF, JOSEPH F. ANDREWS, JR and CAROLYN K. WELLS

patients were divided into two groups, according to a ‘short’ and ‘long’ boundary, which was 6.2 months, the median duration of pre-zero symptoms in the population of 188 patients for whom the duration was known. In the totals, the 5-yr survival rates were substantially higher (63%) for glottic tumors than for supraglottic tumors (29%); but most of the patients with glottic tumors were in the favorable Alpha and Beta stages, whereas most of the patients with supraglottic tumors were detected in Stages Gamma and Delta. Thus, of the 73 patients with glottic tumors, 59 (81%) were detected in Stages Alpha or Beta, whereas only 10 (18%) of the 55 patients with supraglottic tumors were in these two stages. When total results are compared within the same S-A-C stage, the survival rates are similar for the glottic and supraglottic groups. The ‘mixed’ group showed overall 5-yr survival rates and proportionate S-A-C stage distributions that were midway between the glottic and supraglottic groups, although survival rates were generally similar within the same S-A-C stages. The relative prognostic importance of biologic behavior can be compared in Table 9 by noting that the supraglottic tumors, despite their generally unfavorable survival rates, seemed to have the shortest symptomatic durations of the cancers in these three anatomic-source categories. The median duration of pre-zero symptoms was 4.2 months for the supraglottic group, 6.4 months for the glottic group. and 10.1 months for the mixed group. The neoplastic rate of growth thus seemed most rapid in the supraglottic cancers. When survival rates are examined in relation to duration of pre-zero symptoms, the glottic patients seemed to fare much better with short durations, and the supraglottic and mixed groups had better survivals with long durations. In the totals, the differences are statistically significant (by chi-square test) for the opposite results of ‘short’ and ‘long’ durations in the glottic group and in the mixed group. These contradictory findings re-affirm the importance of considering a tumor’s biologic behavior rather than morphology alone when cancers are evaluated. A location on the vocal cords enables glottic tumors to produce vocal symptoms that can lead to ‘prompt’ discovery; whereas mixed tumors, growing more slowly, may not create such distinctive symptoms and may not provoke the patient to seek medical attention until the symptoms have lasted longer. 5. Quantitatioe evaluation qf six staging systems. The anatomic-source groups just cited will not receive further attention here because they are seldom used as a separate classification for laryngeal cancer. We are thus left with six different systems that might be applied for staging. These systems are: the old version of the conventional TNM clustered stages; the latest. revised TNM stages; the simple anatomic and symptomatic arrangements described earlier in this text; and the composite S-A and S-A-C systems that have been newly developed. Some of the various qualitative merits of these six systems of staging have already been discussed in the text, but the individual application of each staging system to the same group of patients also allows the systems to be compared for certain quantitative attributes. The statistical standards used for these quantitative appraisals have been discussed elsewhere [17]. Each standard is associated with a score or rating that can be directly compared among the systems. The desirable properties of these numerical scores are as follows: a monotonic (progressively falling) gradient in survival rates; a large gradient between the lowest

Cancer

293

of the Larynx

and highest survival rates; a well-spaced proportionate distribution of the population among the stages; a high score for distribution of patients and for linear trend in survival rates; a low score for the number of congruent errors produced if each patient is predicted to have survived or died according to the majority result in that stage; a high value in the chi-square score for the survival rates; and a high score for the amount of survival ‘variance’ that was reduced by the staging system. Table 10 shows the scores achieved when each of these staging systems was applied to the same group of 192 patients. The composite S-A-C system had the best results in all of the desired quantitative features. It was lowest in congruent error score, and highest in total gradient, distribution score, linear trend score, conventional chi-square score, and variance reduction score. The clustered TNM systems were inferior to the S-A-C composite systems in all of these features; and inferior to the SA system in all but one of the features. The new TNM system was superior to the old TNM system in all of the quantitative scores listed in the bottom five rows of Table 10, but achieved this superiority at the major cost of sacrificing a monotonic gradient in survival rates. For these reasons, the S-A-C staging system was selected as the reference classification for all subsequent analyses here. The S-A composite system. which is also substantially better than the TNM groupings, can be used by readers who prefer to avoid the co-morbidity component of S-A-C staging. C. Corrclution

qf symptom

and lrsiom

In the final arrangement of SAPC stages, the Delta group is demarcated either by prognostic co-morbidity or by evidence of tumor beyond the larynx (or by both). The Alpha, Beta, and Gamma stages, however, are demarcated only by symptomatic manifestations, without regard to the topographic stage of the tumor

TABLE 10. STATISTICAL FVALUATION OF SIX SYSTEMS 0~ STAGING FOK PATENTS WITH LARYKCXAL

Property evaluated

Symptomatic

Monotonicity of survival gradient Total gradient (5yr survival rates) Proportionate First stage distribution Second stage 01 Third stage i Fourth stage population Distribution score Linear trend score Number of congruent errors Conventional chi-square score Variance reduction score *The survival

gradient

Anatomic

System

of staging

Old clustered TNM

New clustered TNM

Yes

Yes

Yes

49:‘” 25”:, 35”” 40”;

60% 23”,“, 57”,;, 20:,,

87.8 30.0 62

19.2 28.2 68

63”,, 26”;, 54” 11 2” o l8”,, 80.0 32.5 6X

30.2 0.158

30.3 0.158

33.1 0.172

No

* 43”,, 9°C) 34”” I 4” (1 98. I 33.6 56 40.8 0.212

Composite SA

TANCEK

Composite SA- C

Yes

Yes

69”, 23”, 34”;, 23”,, ‘0”

73”,, ‘I”,, 30”,, Xr’,, W,, I I I.0 52.x 53

Il0.i 42.6 5x 42.8 0.223

is 59”/, from Stage I to Stage IV and 74”,, from Stage II to Stage IV.

53.3 0.278

294

ALVAN R. FEINSTEIN. CAROL R. SCHIMPFF. JOSEPHF. ANDREWS,

JR and

CAROLYN K. WELLS

within the larynx. The emergence of symptoms in this crucial staging role was a surprising event that warranted further attention. The principal reason for the ‘surprise’, of course, is that symptoms have not hitherto been deliberately catalogued and analyzed prognostically. Despite many reported tabulations of the symptoms noted in association with laryngeal cancer, the symptoms have seldom been organized into a demarcated set of taxonomic categories, and survival rates have almost never been specifically examined for patients in those categories. Because survival results have conventionally been reported only according to the anatomic findings noted at laryngoscopy (or in the excised surgical specimens), anatomic methods of staging have become the ‘conventional wisdom’ not because symptomatology has been useless, but because it has been ignored. In Table 2, we showed the relationships of the gross staging categories of symptoms and anatomic lesions for patients in our case series. A more detailed examination of these relationships is shown in Table 11. The symptom constituents are listed for each of the three main stages of symptoms; and the laryngeal lesions are classified in two different ways: according to glottic location and according to their topographic extensiveness within the larynx, irrespective of any nodal or metastatic involvement beyond the larynx. The data of Table 11 show a distinct correlation between the symptoms and the anatomic findings. For example, symptoms referable to the vocal cord were cited by lOOo/ of patients with glottic tumors, but only by 69% of those with supraglottic tumors. On the other hand, other types of ‘local’ symptoms were noted by 71% of the patients with supraglottic tumors but only by 25% of patients with glottic tumors. Pharyngo-esophageal symptoms occurred in 7% of the glottic group but in 65% of the supraglottic group. In the ‘mixed group’, the occurrence rates of the cited symptoms were midway between the rates for the glottic and supraglottic groups. The occurrence rate of such ‘referred symptoms’ as otalgia and neck pain rose progressively from 5 to 40% as the topographic lesion advanced from group Tl a to T4. From these data and from the results shown earlier, the following conclusions may be drawn: (a) The changing occurrence rates of symptoms in relation to different anatomic lesions demonstrates that patients are capable of discriminating (and reporting) subjective sensations that have important significance, both anatomically and prognostically. (b) A particularly important prognostic distinction arises from the manifestation of ‘obtrusive’ symptoms. The respiratory stridor, wheezing, ear pain, weight loss, or other symptoms that are characteristic of this category are major prognostic harbingers that cannot be discerned from anatomic examination. (c) Similarly, the pharyngo-esophageal and ‘external’ manifestations that constitute the deleterious group of symptoms have major prognostic importance, although the occurrence of these symptoms cannot always be noted by anatomic examination. For example, as shown earlier in Table 2, these deleterious manifestations appeared in 2 of the 44 patients whose tumor appeared to be anatomically localized at laryngoscopy, and in 42 of the 110 patients whose anatomically intermediate tumor showed no pre-therapeutic evidence of spread beyond the larynx.

13

55

64

55

36

20

‘6

55

192

Supraglottic

Mixed

Tla

Tlb

T2

T3

T3

Total

No. of patients

Glottic

Location Or T stage

(90% 34 (94%) 20 OOV”) 25 (96”,,) 43 (78”;,) 173 (90”“)

73 (100%) 38

Cord

(4%

(4& x (40”“) II (42”“) 34 (62” I,)

(2&

(4&

(25%) 39 (71%

18

Other local Total

51 (93”“) 185 (96”“)

(loo”,,)

(9% ) 3;” (97’:“) 20 (loo’:“) 26

63” (90”)

(14$ 7 (35’5”) 10 (38”“) 22 (40”“) 57 (30”,,)

(24’;“)

25 (45X) 20 (31’2”) 13

12

Systemic

Cl& (16%) (@&)

symptoms

AND

22 (40”“) 42 (22”“)

(35’:,,)

(3& Ii” (277”) 3 (5%) 5 ( 14”lJ 3 (15”“) 9 (W”) 22 (40%) 17 (47%) II (55’11”) 14 (54”“) 33 (60”“) 97 (5 1”“)

(5& 3i;”

(4%

Respiratory

symptoms

(757”) 31 (56:a) 19 (53%) 14 (7OY”) 22 (85:“) 44 (804”) 130 (68”“)

(748;)) 48”

(5;;)

Total

Deleterious

(19Y”) 8 (40’:“) 9 (35”“) 38 (69”“) 68 (35”,,,)

( 11%) I

6

(Wo)

(65%) 21

(7;) 36

c

Pharyngo-esophageal

SYMPTOMMANIFESTATIONSAT ZERO ~ME

uoh,

Referred

Obtrusive

I 1. CWIRELATION OF ANATOMIC FINDINGS

Primary

TAHLF

(14”“)

(3F ) 27”

(IZ”,,)

(20’;“) 3

(240~ 13

External

sympjoms

(42’:“) 42 (76”“) 76 (40”“)

(45%) 8

Total

z -

296 ALVAN R. FENSTEIN. CAROL R. SCHIMPFF,JOSEPHF. ANDREWS. JR and CAROLYN K. WELLS

The advantage of classifying patients at zero time according to a symptomatic staging, therefore, is that the symptoms correlate reasonably well with the intralaryngeal anatomic findings, while adding important prognostic ‘dimensions’ that cannot be detected from anatomy alone. The currently available non-surgical procedures of diagnosis do not establish the true extent of the disease; and morphologic information does not indicate the virulence or rate of tumor growth. Symptoms and their durations thus provide an index of biologic behavior that cannot be otherwise identified. D. Therapy

and post-therapeutic

survival rates

Because the S-A-C staging system had been developed for the entire population without regard to therapy, the contents of the staging categories were chosen independently. The selections had no opportunity to be affected by any prejudices that might be caused by the data analyst’s knowledge of treatment. The S-A-C staging system could thus be used to examine the outcome of the patients and the possible accomplishments of treatment. In this section, the outcome will be presented according to the customary index of assessment: 5-yr survival rates. Other aspects of the post-therapeutic course will be presented in the subsequent section. 1. Categories qf therapy. The 192 patients under survey had received a complex array of diverse agents and sequences that produced 73 different patterns of therapy. The most frequent pattern, a single course of beam radiotherapy and no other treatment thereafter, had been given to 47 patients. The next most frequent pattern, in 18 patients, consisted of a laryngectomy and unilateral radical neck dissection, performed simultaneously, without subsequent therapy. The third most frequent pattern, in 15 patients, was laryngectomy alone, without further treatment. No other distinct pattern of treatment occurred more than 7 times, and individually unique patterns occurred in each of 53 patients. Most of the distinctions among these patterns of treatment were due to diverse choices and permutations in the sequence of different ancillary agents, such as beam radiotherapy, solid irradiation, paralaryngeal surgery, and chemotherapy. In order for this diversity of treatment to be analyzed, some form of simplification was necessary. For this purpose, we classified treatment into five main groups. The name of each group and the criteria of designation are as follows: (a) Surgery, one-course: In the first course of treatment the laryngeal tumor was surgically excised. Although the first course of treatment may also have included radiotherapy. chemotherapy, or surgical excision of other structures, no other antineoplastic treatment was given subsequently as a separate course of therapy. (b) Surgery, augmented: After surgical excision of the tumor in the first course of treatment, the patients received a distinctively separate course of antineoplastic therapy at a later date. (c) Radiotherapy, one-course: In the first course of therapy these patients received radiotherapy and possibly other forms of antineoplastic treatment, but no surgical excision of the laryngeal tumor. No antineoplastic therapy was given thereafter. (d) Radiotherapy, augmented: After receiving radiotherapy without laryngeal surgery in the first course of therapy, these patients at a substantially later date

Cancer

of the Larynx

297

received a subsequent course of antineoplastic therapy, which may or may not have included laryngeal surgery. (e) No prirwry therapy: These patients received none of the four modes of treatment just cited. They may or may not have received chemotherapy or palliative treatment directed at sites other than the primary tumor. These five therapeutic groups could be condensed into three by combining the two surgical categories into a single group called irritial stlryer~:, and by similar combination of the two radiotherapy groups into a single category called irzitiul rcrdiothrrupy. 2. Orrrdl results. The 5-yr survival rates in the three principal groups were as follows:

therapeutic

57”; (52/9 I ) Initial surgery Initial radiotherapy 5OY, (44/8X) No primary therapy O”~,,(O/13) Within the four subgroups of patients who received primary anti-neoplastic treatment, the highest survival rates were 66 ‘>‘,in the 62 patients who received surgery, one-course; and 59:< in the 53 patients who received radiotherapy, one-course. For the surgery-augmented and radiotherapy-augmented groups. the respective values were 380<1(= 1l/29) and 370/, (= 13/35). None of these statistics can be meaningfully interpreted. however, without consideration of the way the patients were chosen for therapy. Because treatment was not assigned by randomization. the pre-therapeutic condition of each patient would obviously affect the doctor’s choice of treatment. The association between the pre-therapeutic stage of the patients and the initially selected treatment is shown in Table 12, which demonstrates the patterns of bias in selection of therapy for patients with cancer of the larynx. Radiotherapy was most commonly selected for patients at the extremes of the ‘good’ and ‘bad’ stages. It was chosen for 59’:; of patients in Stage Alpha and 52% of those in Stage Delta. Surgery was most commonly chosen for patients in the intermediate stages, being given to 57”,, of those in the Beta stage and 67”;) of those in the Gamma stage.

TABLL

12. DISTRIBUTION OF PATIENTS AKORIXW TO S-A-C STAGES AND INITIAL TREATMLNT

Composite SPA-C stage

Initial surgery

Initial radiotherapy

COMPOSITE.

No primary thcrapq

Total

(5”J

(loo”,,)

I0 ( 1Xi’,,) 13

(14 )

(7”J

(1CQ”,J

Alpha Beta Gamma

(3;s ) 33O (57”J 26 (67’:“)

Delta ($“, Total

192l’

298

ALVAN R. FENSTEIN, CAROL R. SCHIMPFF,JOSEPHF. ANDREWS. JR and CAROLYN K. WELLS

Because of these selective features in the choice of therapy, its results must be evaluated according to the pre-therapeutic stage of the patients, and not just according to the treatment itself. 3. Results within S-A-C stages. The results of treatment for patients in different S-A-C stages are shown in Table 13. For patients in the Alpha stage, the results were excellent, regardless of the pattern of surgery or radiotherapy. For patients in the Delta stage, the results were generally poor regardless of therapy. although the surgical survival rates appeared higher than those of radiotherapy. Radiotherapy seemed somewhat better than surgery in the Beta stage, but somewhat worse in the Gamma stage. Another noteworthy feature of Table 13 is the further element of selectivity in treatment indicated by the results for the two forms of surgery and radiotherapy. The overall results of the surgery-augmented group (387” survival) are significantly worse than those of surgery, one-course (66% survival). This difference reflects the frequent choice of additional modes of treatment when a patient does poorly after the initial surgery. Similarly, the total survival results in the radiotherapyone-course group (59%) are significantly better than those of the radiotherapyaugmented group (37%). The survival data in the Beta stage are particularly interesting. Although surgery was the first choice of treatment for a majority (57%) of these patients, the survival rates for both the one-course-surgery and surgery-augmented groups were lower than for the corresponding radiotherapy groups. The proportion of patients who received or required augmented therapy was the same for both types of initial therapy. Thus, a subsequent course of treatment was given to 12 (36:/h) of the 33 patients who initially received surgery, and to 9 (367;) of the 25 patients who initially received radiotherapy. The data therefore suggest that in the Beta stage, as in the Alpha stage, radiotherapy was probably a preferable first approach to treatment. In the Gamma and Delta stages, these therapeutic results were reversed. Patients who received initial surgery had better outcomes, with or without subsequent treatment, than the patients who initially received radiotherapy.

TABLE 13. FIVE-YEAR SURVIVAL RATES ACCORDING Composite S-A-C stage Alpha Beta Gamma Delta Total

Surgery, one-course 10/11 (91%) 15121 (717”) 13120 (65%) 3/l 0 (30%) 41162 (66%)

Surgery, augmented 515

(loo?;) 2112 (17%) 216 (337”) 216 (33’:/,) 1II29 (38%)

TO COMPOSITE S-A-C

Radiotherapy. one-course IS/18 (83%) 13116 (Z (40%) l/14 (7%) 31153 (59%)

STAtitS AND MODE OF THERAPY

Radiotherapy, augmented

No primary therapy

Cl& 519 (56”/,,) O/6 (o”,,) 2114 (14”,,) 330.5 (37’1,,)

($,f,,

O/2 (O”,,) O/IO (011,,) O/13 (0” ,,I

Total 36141 W”,,) 35158 (60’:,,) 17139 (44”“) 8/54

(15”,,) 96/I 92 C50<‘,,)

Cancer

E. The post-therapeutic

of the Larynx

‘99

course

In addition to 5-yr survival rates, a physician prognosticating for a patient at zero time would want to know about other aspects of the clinical course after the initial therapeutic intervention. The additional information would include the quality of the patient’s life, particularly with respect to physical or psychological debility; the likelihood of subsequent metastasis: the need for further therapy: and the risk of death due to ailments other than laryngeal cancer. Since the necessary details are not consistently reported in patients’ medical records, we were unable to analyze the quality of life after treatment. The remainder of the data to be presented here will show the association between the SAPC stage at zero time and the other cited aspects of the post-therapeutic clinical course. 1. Subsequent rnetastases and subsequent therap!!. For 188 of the 192 patients, satisfactory evidence was available to demonstrate whether new symptomatic or anatomic evidence of metastasis had occurred after zero time in each patient’s 5-yr clinical course. In relation to the initial S-A-C stages, new evidence of metastasis later appeared as follows: Alpha, 2/41 (5”;,): Beta, 16155 (29”,,); Gamma. 1l/39 (287;); and Delta, 22/53 (42%). The S-A-C stages thus served not only to indicate the existence of metastases at zero time. but also to predict the likelihood of new metastases thereafter. The results associated with subsequent courses of treatment are difficult to evaluate, because the new courses of therapy can be ordered for diverse reasons. In some patients the treatment may have been prompted by local or distant anatomic spread or by adverse clinical effects, but in other patients, with no evidence of deterioration, the purpose may have been prophylactic rather than remedial. Furthermore, the only patients subjected to subsequent treatment are those who have lived long enough to receive it and who seem capable of enduring it. Because of all of these problems and because our investigation was concerned mainly with prognostication at zero time, we decided not to report the survival results for different aspects of subsequent treatment. Of the 179 initially treated patients in our cohort, 64 (36”/,) received a subsequent course of therapy. With respect to zero time stage, the rates of subsequent anti-neoplastic treatment were: Alpha, 11140 (28%); Beta, 21/58 (36%); Gamma, 12/37 (32”J; and Delta, 201’44 (450,). 2. Mode ofdeath. On the basis of the clinical information. each death was classified in one of two categories. In order to allow the decisions to be made from information that would be available for all patients, necropsy data were /lot used for these classifications. A cancer death seemed definitely or probably due to the laryngeal cancer and its immediate complications; and a I~o~~-cu~Ic~~ death seemed clearly due to some other ailment. Although no post-operative deaths occurred among the 192 patients, such deaths would have been classified as associated with the cancer. Because a mode of death was established for each patient in this series. and because each patient had been followed for at least 5 yr, the mortality results could be reported in a simple, direct approach, without recourse to the more complex forms of ‘life-table’ or ‘relative survival’ analyses that are used when patients are lost to follow-up or when causes of death are not distinguished. The 5-yr death rates due to cancer and non-cancer causes could be shown directly

300

ALVAN R. FEINSTEIN.CAROL R. SCHIMPFF.JOSEPH F. ANDREWS,JR

and CAROLYN

K. WELLS

TABLE 14. COMPOSITL S-A-C STAGY AND FATALITY RATES AT 5yr FOK c..%NCkKAND NON-CANCER (‘AUSES OF DEATH Number and percentage of patients who died

S-A-C stage Alpha Beta Gamma Delta Total

No.of patients (N) 41 58 39 54 192

Cancer deaths (C)

1 Wo) I6 15 34 66

(28”/“) (387;) (63”:) (34?J

Non-cancer deaths (D) 4 7 7 12 30

(lo:,,) (12”“) (IX”,,) (22”,,) ( I6”;,)

Fatality ‘Determinant’ case5 [C:(N L O)]

Y’,, 3 I I’,) 47”,, 8 I “(, 41”,,

rates for ‘Co-morbid’ cases ID/‘(N - Ul IO;:, 17, 29”,, 60’!<, 24Y,

for all patients. As items of interest, two additional fatality rates could be calculated. The rate for ‘determinant’ cases would indicate the proportion of cancer deaths in patients who did not die of co-morbid causes. The rate for ‘co-morbid cases would indicate the proportion of non-cancer deaths in patients who did not die of cancer. The results, presented in Table 14, show monotonic trends in all four of the cited rates, helping to confirm the importance of a biologic, rather than purely anatomic, staging system for laryngeal cancer. Furthermore, since death is not always due to the cancer, the mode of death, rather than death alone, should always be contemplated when treatment is evaluated for its effect on survival rates (or fatality rates). Because either disseminated cancer or co-morbidity could have been responsible for patients being categorized in the Delta stage, the two groups were separated and their results were examined individually. Of the 54 patients in the Delta stage at zero time, 20 had prognostic co-morbidity at zero time. Nine of these 20 co-morbid patients (45%) died of cancer causes; of the remaining I I patients, 8 (73%) died of non-cancer causes. The other 34 patients in the Delta group did not have prognostic co-morbidity at zero time. Of these 34 patients. 25 (74’;o) had cancer deaths during the next 5 yr; and 4 (44?;) of the other 9 patients died of non-cancer causes. Thus, the monotonicity of the gradients shown in the totals of Table 14 for both cancer deaths and non-cancer deaths would be unaffected by the inclusion or exclusion of prognostically co-morbid patients in the Delta group.

DISCUSSION

Perhaps the most common instruction that students receive in medical school is the exhortation to take a careful history from the patient. In textbooks, lectures, discussions, and conferences, medical students are constantly urged to pay attention to a patient’s history and to respect its fundamental importance. Despite these exhortations, however, the history of patients with cancer appears to receive no scientific attention after the diagnosis of cancer is established. Except for a few systemic symptoms that are included in recent classifications of Hodgkin’s disease [20], the staging systems for cancer are entirely morphologic. A patient’s prognosis is estimated and therapy is evaluated according to the histologic appearance and

Cancer

of the Larynx

301

anatomic spread of the tumor. Its functional behavior, as manifested by symptomatic effects on the patient, is ignored. The scientific disregard for patients’ symptoms probably arises from the belief that the data are unreliable because of possible inaccuracies in the patient’s description of symptoms. in the doctor’s performance of history-taking, or in the way that the history is reported in medical records. Nevertheless, cancer of the larynx is the fourth cancer [ll. 121 that we have intensively analyzed on the basis of medical-record data. In all four cancers, the recorded information has been imperfect, but with assiduous techniques of assembling and interpreting the data [13], the information has been adequate for analysis. Furthermore, in cancer of the larynx--as in cancers of the lung, breast, and rectum--the symptomatic data, when suitably classified, denoted crucial prognostic distinctions that could not be discerned from any conventional forms of morphologic staging. The general belief that symptomatology is scientifically unreliable seems especially ironic in view of the striking inconsistencies found on the few occasions when observer variability has been examined for morphologic data. In several non-laryngeal cancers [21-241, major discrepancies were noted in the interpretations given by different histopathologists to the same specimen, or in repeated independent readings of the same specimen by the same observer. We know of no investigations of histopathologists’ consistency in designating either the cell type of laryngeal cancer or the extent of anatomic spread in surgically removed specimens. The only tests that seem to have been conducted for morphologic observers of laryngeal cancer are comparisons of the pre-operative anatomic assessments, as noted by the clinician at laryngoscopy. with the subsequent findings noted by the pathologist in the surgically removed specimens. The results were summarized by Olofsson rt al. [25] as follows: We have been surprised and disappointed by the extremely poor correlation between the clinical preoperative assessment. and the histopathologic findings in the laryngectomy specimens.. (There is) a well known tendency of these tumours to invade deeply beneath intact mucosa.

Similar difficulties have been reported by McGavran 1261, Tucker [27]. Norris and Peale [28], Goldman [28A], and Kirchner and Som [29]. The routine use of pre-operative radiography does not seem to have improved the situation. Olofsson et ul. [30] have pointed’ out that the ‘faulty assessment of tumours in the vertical plane. (has continued) despite the support of the radiological examination’. The main current hope for getting better morphologic assessments seems to be microlaryngoscopy, but the problems of consistency in these observations have also not been checked. When not wholly overlooked, the possibility of using patients’ symptoms as a prognostic guide has been deliberately dismissed. After developing a questionnaire format for recording symptoms as well as morphology in patients with laryngeal cancer, McKinnon rt al. [31,32] decided not to analyze ‘symptoms and other

items of history’ because of ‘the high error rate involved in taking medical histories’ and because ‘their further analysis is unlikely to add new information to the understanding of these disease processes’. We do not wish to defend the occasional or frequent inadequacies of the data recorded for patients’ mation appears no more unreliable than the traditionally

histories, but the inforrespected morphologic

302

ALVAN R. FEINSTEIN.CAROL R. SCHIMPFF,JOSEPHF. ANDREWS. JR and CAROLYN K. WELLS

citations. Furthermore, many of the defects in data for patients’ symptoms could be eliminated or reduced if physicians began to recognize the value of the data and began to give greater attention to better methods of soliciting, recording, and coding the information [13,33]. In addition to exhortations about history-taking, medical students regularly receive advice about the importance of establishing a correct diagnosis. This advice presumably applies not merely to the identification of a cancer, but also to suitable diagnosis for a patient’s other ailments. Nevertheless, the identified co-morbidity that may be found in association with a cancer has also been constantly neglected in the analysis of prognosis and treatment. Co-morbidity has never been noted as a feature to be classified in describing a patient’s condition at zero time; and the only acknowledgment that co-morbidity seems to have received in cancer staging is the peculiar statistical practice of retrospectively excluding the ‘non-determinant’ patients who later die of causes unrelated to the cancer. Even with the crude demarcations of present or absent in our classification of zero-time prognostic co-morbidity, it was found to have occurred in 20 (10%) of our 192 patients and to have major prognostic importance. In the remaining 172 patients of our series, other co-morbid ailments were often present, but were not severe enough to be designated as prognostic co-morbidity. With a more refined classification of degrees of prognostic severity for co-morbidity [34], a more specific gradient of prognosis might have been noted for this important zero-time feature that is discerned not in the morphology of the cancer, but in the total clinical state of the affected patient. The categories currently demarcated in the S-A-C system are neither definitive nor sacrosanct. They emerge from the study of a single case series; and (like the stages of a TNM system) they may require modification after additional patients are studied at our own institutions and elsewhere. The main point to be noted from this analysis is not the specific demarcations we have used for the patients’ symptomatic and co-morbid features. Instead, we would emphasize the major importance of symptoms and co-morbidity in any quantitative contemplations of prognosis and treatment for cancer of the larynx. The statistics used for these evaluations depend on what happens in patients, not on the morphologic features of a cancer alone; and the patients’ clinical events must have an appropriately prominent role in the data that are counted to create the statistics. Careful attention to the ‘whole patient’, which includes symptoms and associated ailments as well as the anatomy of the ‘main disease’, has long been regarded as a basic necessity of art in medical humanism. This attention is also a basic necessity of science in clinical statistics. In contemplating the results of therapy, our findings should be interpreted cautiously. The improvements of a new system of staging can help remove some, but not all, of the bias that may occur when treatment has been deliberately selected rather than randomly assigned. Furthermore, if these same patients were to be treated today, the outcomes might be different because of the many technologic advances since the era of 1953-1962. Surgical procedures are now accompanied by better anesthesia and medical support; radiotherapy has become more potent and precise; and chemotherapy has acquired a large array of powerful new agents.

Cancer of the Larynx

303

Nevertheless, newer therapeutic regimens would hardly be likely to improve the outcome of patients in S-A-C Stage Alpha. These patients seemed to be having excellent results even with the more ‘primitive’ treatments used more than a decade ago. The main concern about such patients today is that they be properly recognized as members of the Alpha stage and spared from treatment that may do more harm than good. It seems reasonable to conclude that surgical excision of the larynx is not a desirable first course of treatment for such patients. Patients in Stage Beta also seemed to fare at least as well with radiotherapy as with surgery in the first course of treatment. Without direct controlled comparative trials of these procedures, the apparent superiority (or equivalence) of radiotherapy cannot be proved. In the absence of such trials, radiotherapy would also seem to be a preferable first choice for the Beta group. In the Gamma and Delta stages, surgery seemed superior to other forms of therapy. Because the patients’ survival rates in these two stages are relatively low with LU~J’ form of therapy, the quality of life that occurs after laryngectomy or other surgical procedures should be included as an important consideration when the therapeutic decisions are made. Regardless of whether future therapeutic decisions depend on randomized clinical trials or on results found in the type of ‘historical’ survey presented here. clinicians will have problems in determining the similarity between patients reported in the literature and a new patient for whom treatment is to be chosen. Because cancer of the larynx is not a common disease. the acquisition of a suitably large number of patients will require that multiple institutions collaborate in randomized trials or that a large span of calendar time be used for the ‘admission period’ included in an historical survey. With either method of assembly, the patients will form a heterogeneous mixture that must be divided into reasonably homogeneous. reproducibly specified subgroups if the reported results are to be clearly identifiable and applicable to future patients. The TNM anatomic classifications have not offered a ‘stable’ system for achieving prognostically homogeneous or clinically reproducible subgroups. Diverse investigators [35~~38] have arranged the elemental T, N, and M categories into at least eight different patterns of clustered stages; and even the basic constituents of the individual T. N. and M categories have been revised on several occasions [9.39]. These diverse alterations and revisions have presumably been intended to improve the prognostic sensitivity of the anatomic staging system. but no arrangement of anatomic categories can provide homogeneous or reproducible results if crucial prognostic phenomena are omitted from the classification c171. In this research. we have demonstrated two basic prognostic ‘dimensions’ symptom type and prognostic co-morbidity-that can greatly augment the precision of staging for cancer of the larynx. The new system is easy to apply: it provides much sharper prognostic distinctions than designations based only on morphology; and it requires no subtle and possibly inconsistent decisions about the cancer’s intra-laryngeal topography. Because of these advantages, the S-A--C system would readily lend itself to general clinical application, particularly for identifying prognostically comparable patients when different forms of therapy are evaluated. The TNM categories could be used by surgeons and radiotherapists

304

ALVAN R. FEINSTEIN, CAROL R. SCHIMPFF. JOSEPH F. ANDREWS. JR and CAROLYN K. WELLS

for supplementary stage.

classification of the anatomic lesions treated within each S-A-C

Acknowledymmt-We are grateful to Dr. John A. Kirchner, Professor of Otolaryngology, Yale University School of Medicine, for providing access to the case records of the patients reported here and for his constructive comments on the manuscript.

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