Is the published literature a reliable guide for deciding between alternative treatments for patients with early cervical cancer?

Is the published literature a reliable guide for deciding between alternative treatments for patients with early cervical cancer?

In, .I Rudro,ron On300 Numbers of treatment arms One - I eluded was adequately reported in only 37% for single and 59% for multiple series studies...
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0 Oncology Intelligence IS THE PUBLISHED LITERATURE A RELIABLE GUIDE FOR DECIDING BETWEEN ALTERNATIVE TREATMENTS FOR PATIENTS WITH EARLY CERVICAL CANCER? P. ZOLA,

M.D.,’ T. VOLPE, M.D.,’ G. CASTELLI, M.D.,’ P. SISMONDI, M.D.,’ A. NJCOLUCCI, M.D.,* F. PARAZZINI, M.D.* AND A. LIBERATI, M.D.*

‘1st Obstetric and Gynecology Clinic, University of Torino; and *Mario Negri Institute for Pharmacological

Research, Milan, Italy

The quality of the methodology and reporting of studies on the treatment of early cervical cancer published in English and French language over the period 1975-1985 were examined using an explicit, predefined protocol aimed at assessing their internal validity and generalizability. One hundred and fifty-two articles reporting results on over 40,000 patients treated with surgery, radiotherapy, or the combination of the two, were examined. The astonishing lack of formal comparative studies together with the poor quality of those actually carried out were the two major findings of our study. More than half of the reviewed papers (54%) were single series studies. Among the remaining 46% only a few formally compared the two treatments (i.e. surgery vs. radiotherapy), the remainder dealing with comparisons of specific surgical or radiothempeutic techniques. With reference to study quality, the existence of a pre-specified research protocol could not be ascertained in most studies. A description of patients’ characteristics and information on the source population were deficient in most papers reviewed, information on the two aspects was in fact satisfactorily reported in only 7% and 47% of the papers, respectively. Finally, the lack of standardization of follow-up methods (i.e. type and modalities) and of information on treatment compliance were two other severe methodological deficiencies. In view of this poor quality and of the intrinsic difficulty of drawing firm scientific conclusions from non-experimental investigations, the reliability of this literature remains highly dubious. Another possible caveat is that what is published is a biased sample of the overall evidence because of the well known tendency of authors to write about and editors to publish positive results more frequently than negative ones. Cervix neoplasms, Clinical trials, Follow-up studies, Research design, Publication bias.

INTRODUCTION The question whether carcinoma of the uterine cervix should be treated with surgery, radiotherapy, or the combination of the two, is still unsolved ( 12). The lack of properly designed and conducted randomized control trials and the relatively good prognosis of patients with early stages of the disease makes it impossible to decide which treatment should be taken as standard. Treatment results in oncology are traditionally assessed using “objective” criteria such as disease-free or absolute survival. Only recently, however, has attention to patients’ quality of life become of interest for clinicians. This stems from the realization that if differences in prognosis from alternative treatments are likely to be small, the psychosocial impact of treatment may become an essential endpoint (2).

In the treatment of cervical cancer, the present therapeutic controversy focusses not mainly on cure rateswhich do not seem to differ substantially when surgery or radiotherapy is used (12)-but mostly on the relative merits of the two treatment options in terms of tumor control or frequency of complications. Although, to our knowledge, surgery and radiotherapy have been formally tested in only four randomized control trials (6, 7, 9, 1 l), most clinicians are so strongly in favor of one of the two alternatives that it is nearly impossible to set up a randomized study. Both sides of the controversy claim the support of part of the published scientific literature, made up mostly of small, non-comparative studies (accepted for publication very likely more on the basis of the results than the soundness) that of adequately sized experiments aimed at testing of the comparative yield of the two strategies. To draw researchers’ and clinicians’

Reprints requests to: Alessandro Liberati, M.D., Mario Negri Institute for Pharmacological Research, 62 Via Eritrea, 20 157 Milan, Italy. Acknowledgements-We thank Peg Hewitt for her useful suggestions in the preparation of this manuscript. This work was

supported by grants from the Italian Association for Cancer Research (AIRC), the Italian Ministry of Education and the Italian National Research Council Special Project “Oncology” grant no 86.00720.44. Accepted for publication 29 September 1988. 785

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attention to this unsatisfactory situation, we attempted a systematic review of all original articles reporting results of primary treatment of patients with early cervical cancer treated with surgery, radiotherapy, or the combination of the two, published between 1975 and 1985. Our aim was not to produce an additional narrative review with its own therapeutic recommendations, but to assess the quality of this research and possibly document the need for further and more carefully planned investigations in the field. In interpreting the results of this study the reader is cautioned that the items chosen to assess quality of published reports are not founded on any absolute measure of quality, but represent judgmental approximations whose real utility still has to be established. Nevertheless, although only a crude attempt to measure research quality, they are useful in calling attention to deficiencies of published studies.

METHODS

AND MATERIALS

Conduct of the study Articles eligible for this evaluation were retrieved by searching MEDLINE with specific Medical Subject Headings (MeSH) terms (human, cervix neoplasms, follow-up studies, random allocation, comparative study), by inspecting the bibliographies of original and review articles and by scanning the pertinent Index Medicus volumes under the heading “Cervical Cancer”. Only papers referring to the primary treatment of Stage IA and B and IIA and B cervical cancer treated with surgery, radiotherapy, or the combination of the two, and reporting results in terms of survival were eligible for this study. Studies where cases with in situ or advanced carcinoma were reported together with elegible patients were included only if results of different groups were presented separately. Initially, 296 articles in English and French over the period January 1975-January 1985 were retrieved. After a careful evaluation of their eligibility based on reading each full paper, 144 (49%) were excluded for the following reasons: 10 were review articles without original data, 30 did not report information on survival, 37 dealt only with frequency of complications, 16 with surgical or radiation techniques, 18 were about prognostic factors, 11 were about epidemiology or diagnostic methods, 15 reported results on patients with advanced disease and, finally, 7 because of more than one of the above reasons. In the present report 152 articles have therefore been examined. A full reference list is reported in the Appendix 2. At least two and sometimes three of the authors independently reviewed and scored the original articles by completing the itemized check-list displayed in Appendix 1. As soon as the papers had been read by two or three people, meetings were held to resolve differences. This happened 8% of the time, because one person usually missed an important point picked up by the other reader.

March 1989. Volume 16, Number 3

The scoring system For this study we used a modified version of the quality score originally developed by Chalmers et al. (5) for randomized control trials in general, and adapted to the particular requirements of cancer trials by Liberati et al. ( 13) As no study included in this review was randomized and data were collected before the study plan was set up (i.e. most studies were retrospective), the scoring system was substantially simplified and re-adjusted to take account of the greater intrinsic difficulty of a thorough quality assessment in this type of research. All items referring to the use of techniques of random allocation and blinding were eliminated, as were those exploring the appropriate use of statistical tests, sample size calculations, and multivariate analysis. The quality assessment eventually carried out in this study was based on the following 11 items: (a) type and frequency of follow-up; (b) treatment adherence; (c) withdrawals; (d) methods of their analysis; (e) information on patients’ characteristics; (f) information on patients elegible but not included (i.e. reject log); (g) description of the therapeutic regimen(s); (h) timing of reported events; (i) comparisons with other series; (j) quality of internal comparisons (when the study had more than one arm); (k) information on side-effects seriousness and incidence. The meaning of all items is displayed in Appendix 2. In view of the importance of various items, results are presented separately for “single-arm” and “comparative”, studies. Differences of sample sizes of various studies were compared using the Kruskal-Wallis test with the SPSS package. RESULTS Some general characteristics of the 152 papers are listed in Table 1. Almost half of the papers (45%) had been reported in gynecology journals, 26% in radiation therapy, and 23% in oncology journals. The United States was the most frequent country of origin (57%) compared to Europe (35%) and the vast majority of the studies reported the experience of individual institutions. Almost half of the papers were published before or during 1980. Table 2 and Fig. 1 report on the sizes and the number of treatment arms of studies considered in this review. More than half of the papers (54%) reported results of studies on a single series without any comparison based on historical or concurrent patient series. In 56 papers (37%) two treatment arms were compared and in 14 (9%) comparisons included three treatment groups. In no case were patients allocated at random to various therapies. The median number of patients was 180 (range 5-2803) for all 152 studies and the total was 44,376. The median number of patients for studies presenting a single series was 155 (range 5-2803) and 193 (range 7-1684) for multiple series studies. Direct comparisons of the efficacy of surgery and radiotherapy were infrequent even among multiple series studies. Although we found 70 articles re-

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Alternative treatments for patients with early cervical cancer 0 P. ZOLA et al.

Table 1. Some general characteristics of the I52 studies included in the review

Journal specialty Journal type Gynecology Oncology General Medicine Radiotherapy Surgery Unknown Country of study USA UK Europe Other Year of publication Before 1980 During/After 1980

RadioSurgery therapy no. no. 15 I

1

16 11 2 21 1

Combined treatments no. 38 17 1 13 1 2

Table 2. Information

Combined treatments no.

No.

(%)

5 12 6

17 9 16 15

10 15 23 25

27 29 51 46

(18) (19) (33) (30)

Two

19 4

43 13

20 39

82 56

(54) (37)

Three

-

13

14

(9)

Surgery no.

Total

(W)

69 (45) 35 (23) 3 (2) 40 (26) 1 (1) 4 (3)

14 7 2

33 3 12 9

40 2 29 1

87 (57) 5 (3) 48 (32) 12 (8)

12 11

32 25

31 41

75 77

(49) (51)

results on more than one patients series, only 26 (37%) presented data of the comparative efficacy of surgery and radiotherapy. The remaining 44 compared two surgical or radiotherapeutic techniques. The expected association between sample sizes and the number of treatment arms was not particularly evident in our study (see Fig. 1) and differences-possibly because of the small number of studies with more than two arms-were not statistically significant (Kruskal-Wallis test = 4.27, p = 0.11). Table 3 sets out results of quality assessment by individual item, separately for studies with single or multiple series. Information on follow-up type and schedules was adequate in 5 (6%) and 5 (7%) of single and multiple series studies, respectively. Analysis of treatment adherence (compliance) was inadequate in 47 (57%) of single and 55 (79%) multiple series studies. The retrospective nature of this type of reports made it particularly difficult to assess whether or not all patients originally treated were eventually included in the analysis. Some information on withdrawals was given most of the time (in 68 of single (76%) and 57 (81%) of multiple series studies). When information was sought on the way dropouts were handled in the analysis (i.e. according to the intention to treat principle or discarded), we found that 60 (78%) of single series and 57 (83%) of multiple series studies had this information. Greater concern for the reliability of these studies arises when considering the items aimed at exploring mechanisms through which patients were sampled and selected. Information on patient characteristics was satisfactorily reported in only a small proportion in both single (7%) and multiple (7%) series. A major warning signal on their intrinsic validity is the unsatisfactory information on how eligible patients were actually selected for inclusion. A log of patients potentially elegible for the study but not inporting

Radiotherapy no.

Total No.

on types of studies

Numbers of patients 550 so-99 100-300 >300 Numbers of treatment arms One

-

I

eluded was adequately reported in only 37% for single and 59% for multiple series studies. Among less crucial but still important elements of the presentation of results, the therapeutic regimen under study was adequately described most of the time: 88% and 77% of single and multiple series studies, regardless of the treatment modalities. Conversely, an adequate description of the timing of events (i.e. time of death) was rarely provided. The distribution of prognostic factors was discussed in relation to others reported in the literature in about two thirds of the papers. Information on imbalances in the distribution of prognostic factors between patient groups was adequately presented and dealt with in about half (46%) without significant differences between the treatment modalities considered. Finally, reporting of sideeffects was generally poor. Among single and multiple series studies only 13% of reviewed papers reported their frequency and seriousness. Although the small number of studies in some subgroups prevents from any definite comparison, the quality of individual items did not seem to differ substantially between single and multiple arm studies, even

ARtIS

No

(X)

TWO No (X1

15

(16)

1I

ONE


TOTAL Fig. 1. Distribution

02 c:ooj

THREE No (W) 26

(20)

56 (100)

14 (100)

152

of study size by number of treatment arms.

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March 1989, Volume 16, Number 3

Table 3. Quality distribution of individual items Single series studies Surgery

(A) Follow-up schedules Adequate Partial Inadequate (B) Information on treatment adherence Adequate Partial Inadequate (C) Withdrawals Adequate Inadequate (D) Analysis of withdrawals Adequate Inadequate Not evaluable (E) Patients’ characteristics Adequate Partial Inadequate (F) List of non-eligible patients Adequate Partial Inadequate (G) Therapeutic regimen description Adequate Inadequate (H) Timing of events Adequate Partial Inadequate (I) Comparisons with other series Yes No (L) Quality of internal comparisons Adequate Inadequate Not evaluable (M) Discussion of side effects Adequate Partial Inadequate

Radiotherapy

No.

(%)

No.

(W)

3 1 15

(16) (5) (79)

2 41

(5) (95)

16 3

(84) (16)

12 4 27

(28) (9) (63)

12 7

(63) (37)

33 10

12 6

(67) (33)

32 8

: 14

(5) (21) (74)

5 4 10

10 2

Both

Multiple series studies Total

Surgery

No.

(%)

No.

(%)

No.

(%)

No.

(%)

No.

(%)

5

(6)

1

(29)

2

(14)

2

(4)

5

(7)

1

(1)

20

(100)

76

(93)

3

(75)

12

(86)

4::

(ii;

6;

(::i

3

(15)

(50)

2

(85)

(38) (5) (57)

2

17

31 4 47

2

(50)

12

(14) (86)

8 3 41

(15) (6) (79)

12 3 55

(17) (4) (79)

(77) (23)

17 3

(85) (15)

62 20

(76) (24)

3 1

(75) (25)

11 3

(78) (22)

43 9

(83) (17)

57 13

(81) (19)

(80) (20)

16 3

(84) (16)

60 17 5

(78) (22)

2 2

(50) (50)

13 1

(93) (7)

42 9

(8) (19)

57 12

(83) (17)

2: 56

(4:; (68)

2 2

63

1

31

11

(26) (21) (53)

17 2 24

(40) (5) (55)

8 3 9

(40) (15) (45)

30 9 43

(37) (11) (52)

18 1

(95) (5)

38 5

(88) (12)

16 4

(80) (20)

72 10

(88) (12)

2 14 13

(11) (21) (68)

6 19 18

(14) (44) (42)

3 8 9

(15) (40) (45)

11 31 40

(13) (38) (49)

1 3

(25)

16 3

(84) (16)

25 18

(58) (42)

14 6

(70) (30)

55 27

(67) (33)

2 2

not applicable

3 27 13

Total

(%)

(15) (30) (55)

(16) (32) (52)

Both

No.

(5) (23) (72)

3 6 10

Radiotherapy

(7) (63) (30)

5 14 1

after allowance for imbalances due to differences in the quality of studies exploring different treatment modalities.

DISCUSSION The key message of this quality evaluation is that the published literature on the treatment of early cervical cancer, at least in the last 10 years, is of very limited use

(25) (70) (5)

11 47 24

(13) (57) (30)

(50) :

(8)

(50)

6

(Ii’, (43)

2

(50)

6

(43)

33

(63)

41

(59)

2

(50)

:

,:;;

1:

,::i

2:

(Xi’

4

(100) -

13 1

(93) (7)

37 15

(71) (29)

54 16

(77) (23)

2 2

(14) (36) (60)

6 19 27

(12) (37) (51)

8 25 37

(11) (36) (53)

(50) (50)

9 5

(64) (36)

38 14

(73) (27)

49 21

(70) (30)

2 1

(67) (33)

5 9

(36) (64)

25 27

(36) (64)

32 37 1

(46) (54)

1

(25)

3

(75)

1 12 1

(7) (86) (7)

7 29 16

(13) (56) (31)

9 41 20

(13) (59) (28)

(25) 5

2; 25

(44) (48)

3: 33

,rz; (47)

in addressing the key question relevant for a practicing clinician: “What is the treatment with the best risk/benefit profile for a typical Stage I or II patient?’

The inherent quality of more than 20 years of research, summarized in the 10 years of published literature is remarkably poor. More important than our analysis of quality assessment, though, poor quality is indicated by the scarcity of formal comparative studies of surgery and

Alternative treatments for patients with early cervical cancer 0 P.

radiotherapy and the prevailing use of uncontrolled methods indicated by the lack of randomized controlled trials (RCT). A potential treat to our conclusion is that we cannot be certain that our search was complete. While interested readers can check the thoroughness of our work against the reference list reported in the Appendix, it is worth stressing that the purpose of our work was mostly qualitative and that it is quite unlikely that we systematically missed papers of better quality. Although there are those still in favor of the use of historical controls in cancer research (8, lo), (especially for situations where it may be impossible, impractical, or even unethical to use concurrent randomized series), there is now enough agreement that only RCT can produce unbiased estimates of the comparative yield of alternative treatments (15). To our knowledge only four RCTs comparing surgery and radiotherapy in the treatment of early cervical cancer have so far been conducted, yielding conflicting results. Their execution covered a long time span (the first patient was treated in 1945 and the last in 1975) when the methodology of RCTs was still in its infancy. Thus, the whole sample of these studies, which amounted to a total of 626 patients treated with surgical or radiotherapeutic techniques, is not fully comparable to those in current use. (6, 739, 11) Although the relatively good prognosis of early cervical cancer may at least partly account for a relaxed research effort and the subsequent lack of formal comparative studies, the consequence of this is the present uncertainty on the relative merits of different treatments, especially as regards their consequences on patients’ quality of life. This situation of sparse and unrigorous research efforts cannot be explained by pessimism concerning the possibility of a therapeutic breakthrough. These breakthroughs have been scant in most types of cancer over the last 30 years (1) and yet the number of RCTs conducted in breast ( 18), ovarian ( 16, 17), colorectal(3) and lung (4, 14) cancers indicates that the method has indeed been accepted as the standard to solve therapeutic uncertainties. Intense research in cervical cancer has demonstrated the efficacy of early detection strategies in reducing mortality and morbidity, and from this viewpoint the weakness we found on the therapeutic side of investigation is even less understandable. Looking more narrowly at our findings, several comments are required. Our first goal was an explicit assessment of the scientific quality of published experiments. Our experience with the simplified version of the scoring system originally devised to measure the quality of RCTs (their general principles of design and conduct are fairly well standardized today) was not fully satisfactory. There are basic issues, such as the definition of patient characteristics, their eligibility criteria, why the treatment was given or not, patients’ inclusion or exclusion from the analysis, etc., which in post-hoc retrospective studies (such

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as those we dealt with in this quality assessment) could not be meaningfully assessed from the published reports. The absence of a protocol, prepared before data are acquired, gave rise to certain defects in these studies. Exactly what measures were taken for what kind of patients for what indications was often unclear from the article. Decisions about which patient to include, and which to reject were often unassessable and were probably based on highly subjective judgments. Withdrawals may be poorly documented or even undocumented, with possible major bias in the results. It was often natural to wonder whether the results had been selected among many possible end-points. It was clear that the critical knowledge for judging study validity and generalizability was the selection mechanism for study inclusion (not explained in the articles). Most of the papers we reviewed showed poor quality as regard information on patients’ selection mechanisms and inclusion criteria. The relatively good score for most papers on information on drop-outs must, on the other hand, be interpreted carefully as the items were scored positively if the article reported what was done, and not if what was done was done correctly. Equally poor was the reporting on how follow-up was conducted and treatment compliance assessed. This suggests poor quality in terms of absence of efforts to control for biases in outcome ascertainment. Other common failures such as poor reporting on timing of relevant events and on side effects seriousness and frequency, though less serious as concerns their influence on results, further stress the limited contribution this literature makes for practicing physicians. A final comment seems worthwhile on the representativeness of the published literature vis-a-vis the entire evidence ever produced in the field of cervical cancer treatment. Here again reference to RCTs may clarify the issue. That positive studies (i.e. studies where one treatment is shown to be significantly superior to its alternative) tend to be over-represented in the literature is a widespread belief, recently supported by convincing empirical evidence ( 19). In the realm of prospective studies with a clear protocol established in advance, such as RCTs typically are, responsibility for “result-dependent publication” lies probably more with editors than with authors as, once a study is terminated, authors are interested in publishing their results because they recognize that a carefully planned and conducted study is informative regardless of its statistical significance. In this context, the number of unpublished studies, though difficult to quantify, can be conceptualized as a finite factor of published ones. In the realm of a literature consisting mostly of retrospective studies, publication bias is not quantifiable, is much more serious and cannot be eliminated by a prospective registration system such as been recently advocated for RCTs ( 19). Authors’ result-dependent censorship (the fact that the decision to write a paper based on retrospective data is often the result of a suspicion, or even

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an informal observation, of a positive outcome of a series) is therefore an inherent limitation of this type of research. In this situation, the amount of unpublished information, besides being unknown, does not correspond to a finite number of studies but to the entire patient population treated. There is thus no way in which one can even guess at the degree of unrepresentativeness of the published literature.

CONCLUSIONS A systematic quality assessment of the literature on the treatment of early cervical cancer published over the period 1975- 1985 indicated that the literature is of limited help in deciding the best treatment for patients. Truly

March 1989, Volume 16, Number 3

comparative studies were exceptions and, even with a systematic attempt, the overall quality of this literature was difficult to judge. The latter difficulty was complicated by the impossibility-contrary to what can be done in the framework of RCT’s (10, 13)-of distinguishing different dimensions of research quality such as its internal validity, generalizability and reliability ( 19). If, as we think, many questions still remain to be answered for the treatment of patients with cervical cancer, a profound change seems to be called for in the way therapeutic research is conducted. As for many other solid tumors where it is reasonable to think that therapeutic benefits, if any, are likely to be small, even for cervical cancer the planning of largescale trials with careful consideration of relevant endpoints may be a model against which to weigh the clinical relevance of research to come.

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6.

7.

8.

9. 10.

Bailar, J. C. III; Smith, E. M. Progress against cancer? N. Engl. J. Med. 314:1226-1232; 1986. Barofsky, 1. Quality of life assessment. Evolution of the concept. In: Ventafiidda, V., van Dam, F. S. A. M., Yancik, R., Tamburini, M., eds. Assessment of quality of life and cancer treatment. Amsterdam: Excerpta Medica; 1986: ll180. Buyse, M.; Zeleniuch-Jacquotte, A.; Chalmers, T. C. Adjuvant therapy of colorectal cancer: why we still don’t know. JAMA 259, 3571-3578; 1988. Carter, S. K. Chemotherapy of lung cancer. Sem. Oncol. 9(Suppl. 1):40-55; 1982. Chalmers, T. C.; Smith, H. Jr.; Blackburn, B.; Silverman, B.; Schroeder, B.; Reitman, D.; Ambroz, A. A method for assessing the quality of a randomized control trial. Controlled Clin. Trials 2:3 l-49; 198 1. Churches, C. K.; Kurrle, G. R.; Johnson, B. Treatment of carcinoma of the cervix by combination of irradiation and operation. Am. J. Obstet. Gynecol. 118:1033-1040; 1974. D’Argent, M.; Guillemin, G. La place de la lymphadenectomie ilio-pelvienne dans le traitement du cancer du co1 u&in. J. Int. Chirurgie 10:345; 1950. Diehl, L. F.; Perry, D. J. A comparison of randomized concurrent control groups with matched historical control groups: Are historical controls valid? J. Clin. Oncol. 4: 11141120; 1986. Fletcher, G. H. Textbook of radiotherapy. Philadelphia: Lea and Fibiger; 1973. Gehan, E. A. Randomized or historical control groups in

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APPENDIX

cancer clinical trials: Are historical controls valid? J. Clin. Oncol. 4:1024-1025; 1986. Kielbinska, S.; Tarlowska, L.; Fraczek, 0. Studies of mortality and health status in women cured of cancer of the cervix uteri. Comparison of long-term results of radiotherapy and combined surgery and radiotherapy. Cancer 32:245252; 1973. Lansac, J.; D’Argent, D.; Lefloch, 0.; Jerbaulet, A.; Granjepont, M. C.; Magnin, G. Cancer du co1 uterin. Encycl. Med. Chir. Paris Gynecologie 600:AlO-GlO; 1979. Liberati, A.; Himel, H. N.; Chalmers, T. C. A quality assessment of randomized control trials of primary treatment of breast cancer. J. Clin. Oncol. 4:942-95 I; 1986. Mulshine, J. L.; Glatstein, E.; Ruckdeschel, J. C. Treatment of non-small-cell lung cancer. J. Clin. Oncol. 4: 1704- 17 15; 1986. Pocock, S. J. Clinical trials. A practical approach. Chichester: John Wiley; 1983. Richardson, G. S.; Scully, R. E.; Nikrui, N. A.; Nelson, J. H. Jr. Common epithelial cancer of the ovary (first of two parts). N. Engl. J. Med. 3 12:4 15-424; 1985. Richardson, G. S.; Scully, R. E.; Nikrui, N.; Nelson, J. H. Jr. Common epithelial cancer of the ovary (second of two parts). N. Et@. J. Med. 312:474-482; 1985. Rutqvist, L. E.; Wallgren, A.; Nilsson, B. Is breast cancer a curable disease? A study of 14,73 1 women with breast cancer from the Cancer Registry of Norway. Cancer 53: 1793- 1800; 1984. Simes, R. J. Publication bias: The case for an international registry of clinical trials. J. Clin. Oncol. 4: 1529-l 54 1; 1986.

1

Criteria used to score the articles

A) Follow-up schedules When the paper reported on type and frequencies of different follow-up examinations (routine physical Adequate (RPE) examinations only or RPE plus other laboratory and/or diagnostic tests) When only one of the two above items was reported Partial When no information was reported Inadequate B) Info on treatment adherence (compliance) When authors reported the exact number of patients who completed the planned treatment together Adequate with the reasons for withdrawal for those who did not complete the therapy When authors reported the information in a qualitative way without the exact figures Partial

Alternative treatments for patients with early cervical cancer 0 P.

Inadequate C) Withdrawals Adequate Inadequate

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When no information was reported When the article stated that no patient was lost to follow-up or gave the precise number of patients withdrawn from the analysis When no information was reported

D) Analysis of withdrawals When no patient was excluded from the analysis even if follow-up was incomplete Adequate When exclusions were weren’t explained Inadequate E) Patients’ characteristics When information on patients age, stage, diagnostic work-up, histology and tumor size was all reported Adequate When information on age and stage only was reported Partial When information on age and stage was missing even if other data on patients characteristics are Inadequate presented F) List of non-eligible patients When the paper reported information on the overall background from which patients studied were Adequate selected. Two ways of reporting were acceptable: either the authors said that “all consecutive patients were enrolled” or they reported the actual number of patients potentially elegible but not enrolled When no information was reported Inadequate G) Therapeutic regimen description G. 1.) Surgical papers When the operative technique(s) were described together with the extent of lymphoadenectomy Adequate When no information was reported Inadequate G.2.) Radiotherapy papers When there was a full description of type of energy employed, source, times, fractioning and fields Adequate When some of the above information was missing Inadequate H) Timing ofevents If follow-up was completed for all patients, an article was scored “adequate” when percent survival and/or disease-free at three and five years were reported. If results were based on actuarial estimates the following rules were adopted: When the article presented a life table with number of patients at risk at three intervals (one, three Adequate and five years) When a survival curve without the number of patients at risk was reported Partial When only survival percentages at three or five years were reported without any curve Inadequate 1) Comparison with other series When the authors discussed their results with a view to understanding the extent to which differences Yes in the distribution of prognostic factors accounted for differences from results in other reported series Otherwise No L) Quality of internal comparison When authors discussed their results taking into account differences in the distribution of prognostic Adequate factors (i.e. lymph node involvement, tumor size, histology, etc) in different series When authors did not make such analysis or did it using non relevant prognostic factors Inadequate N.B. This item applied only to multiple series studies M) Discussion of side-eflects When the article reported on types of side-effects and number of patients who suffered them Adequate When only a qualitative evaluation was reported Partial When the issue was not discussed Inadequate

APPENDIX 2 A 1. Abbes, M.; Chauvel, P.; Paillaud, F.; Paschetta, V.; Prat, P. P.; Juillard, G.; Richelme. H.; Cronier, C. A propos de 241 epitheliomas des cols u&ins a

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