BRITISH MEDICAL JOURNAL
`
`18 DECEMBER 1976
`
`1469
`
`PAPERS AND OR:IGINALS
`
`Prednisone in MOPP chemotherapy for Hodgkin's disease
`
`CHARLOTTE JACOBS, CAROL S PORTLOCK, SAUL A ROSENBERG
`
`British Medical3Journal, 1976, 2, 1469-1471
`
`Summary
`High remission rates have been produced by MOPP
`(mustine, vincristine, procarbazine, and prednisone)
`chemotherapy in patients with advanced Hodgkin's
`disease, but the prednisone component has caused
`adverse effects in patients who have undergone radio-
`therapy. The remission rates and length of remission
`were reviewed in 211 patients with Hodgkin's disease who
`received chemotherapy either with or without prednisone.
`In contrast to the findings of a British study, there were
`no significant differences in remission rates or length of
`remission between patients who had received prednisone
`and patients who had not. There were differences between
`the British prospective study and this retrospective one,
`but it is difficult to know what accounted for the sub-
`stantial differences in the findings.
`
`Introduction
`When combination chemotherapy with mustine, vincristine
`(Oncovin), procarbazine, and prednisone (MOPP) was first used
`to treat Hodgkin's disease, prednisone was included because it
`was thought to be an effective agent without bone marrow
`toxicity.' High complete remission rates (81 %) have been
`reported after treatment with MOPP in which prednisone 40
`mg/m2 was given for 14 days in cycles 1 and 4.2 But Castellino
`et al3 described seven patients who had had mantle irradiation
`and who developed pneumonitis or pericarditis shortly after
`completing either cycle 1 or cycle 4. It was thought that sub-
`clinical radiation injury to the lungs or heart might be activated
`by rapid withdrawal of high-dose steroids. Consequently, at
`Stanford, we eliminated prednisone from the regimen in those
`
`Division of Oncology, Department of Medicine, Stanford University
`School of Medicine, Stanford, California 94305
`CHARLOTTE JACOBS, MD, fellow in oncology
`CAROL S PORTLOCK, MD, acting assistant professor
`SAUL A ROSENBERG, MD, professor of medicine and radiology
`
`patients who had received mediastinal irradiation. A recent
`prospective study by the British National Lymphoma Investiga-
`tion group compared MOPP (with prednisone at 25 mg/M2 on
`days 1 to 14 in every cycle) with the same combination without
`prednisone (MOP) in patients with stage IV Hodgkin's disease;
`a highly significant difference in complete remission rates was
`found.4
`We report here a retrospective analysis of 211 patients with
`Hodgkin's disease who received MOP(P), comparing the
`complete remission rate and disease-free survival in those
`patients who did and did not receive prednisone.
`
`Patients and methods
`From June 1968 and December 1975 257 patients with advanced
`Hodgkin's disease were treated at Stanford Medical Centre with
`MOPP as initial treatment for stage IV disease or for relapse after
`initial radiation therapy. Fourteen patients were excluded from the
`study because they were still being treated. Thirty-two patients were
`eliminated because we had insufficient data on their use of prednisone
`or insufficient follow-up data.
`All biopsy specimens were reviewed at Stanford and classified
`according to the histopathological criteria of the Rye conference.5
`Before starting chemotherapy patients were evaluated to assess the
`extent of disease with physical examination, chest x-ray examination,
`bone marrow biopsy, lymphography, and biopsy of appropriate
`extranodal tissue or staging laparotomy.
`The chemotherapy administered was MOPP, as described by
`DeVita et al2: intravenous mustine 6 mg/M2 on days 1 and 8, intra-
`venous vincristine 1-4 mg/M2 on days 1 and 8 (not to exceed 2 mg per
`injection), oral procarbazine 100 mg/M2 daily for 14 days, and oral
`prednisone 40 mg/r2 daily for 14 days on the first and fourth cycle.
`The MOPP cycle was repeated every 28 days, blood counts permitting.
`In a non-randomised fashion prednisone was either (a) given in cycles
`1 and 4 as described above; or (b) omitted from all cycles because of
`previous mantle irradiation; or (c) given only in cycle
`because of
`corticosteroid intolerance or because the patient received less than
`four cycles of drugs.
`After six cycles the patients' remission status was assessed by repeat
`examination or biopsy, or both. No second-look laparotomies were
`performed. The length of complete response was calculated from the
`date of completing MOPP treatment to the first objective evidence of
`relapse. Curves for the probability of disease-free survival were calcu-
`lated by the methods of Kaplan and Meier.
`Tests for significance
`between disease-free survival curves were performed with the method
`of Gehan.7
`
`ALVOGEN, Exh. 1019, p. 0001
`
`

`

`BRITISH MEDICAL JOURNAL
`
`18 DECEMBER 1976
`
`Results
`The complete remission rate for those patients who received
`prednisone in cycles 1 and 4 was 90 3%/, compared with 93 3% in
`those who received no prednisone but completed at least four cycles
`of MOP (P=0 52) (table III). The complete remission rate for all
`patients who received some prednisone was 8157,/ compared with
`7780o
`for those who received no prednisone (P=0-66). The first
`group of patients had a high complete remission rate because, by
`definition, it excluded patients who relapsed before completing four
`cycles of treatment.
`
`TABLE iII-Effect of prednisone on complete remission rate
`
`Prednisone in cycles 1 and 4
`No prednisone in 4 cycles
`Some prednisone
`No prednisone
`
`No of
`
`No of
`patients
`113
`45
`157
`54
`
`Complete remissions
`'4
`No
`90-3
`93-3
`81-5
`77-8
`
`102
`42
`128
`42
`
`.P
`value
`0 52
`
`f
`a
`
`0-66
`
`O/o of
`patients
`100.
`190
`80 ----
`70
`60
`50
`40
`30
`20
`10
`
`&----
`
`o-O Prednisone in cycles I and 4
`&----No prednisone
`*- -* Any prednisone
`
`0
`Years free of disease
`Effect of prednisone on length of remission.
`
`2
`
`3
`
`4
`
`5
`
`The length of remission in complete responders in all groups was
`comparable, with a 60%o probability of being disease free 30-60
`months after completing chemotherapy (see figure).
`Because there were significant differences between the groups in
`numbers of patients aged under 20, sites of disease (nodes and lung),
`and previous irradiation, we analysed the complete response rate and
`length of remission of these subgroups separately. There were no
`significant differences in either complete response rate or length of
`remission between any of the subgroups when comparing those who
`did and did not receive prednisone.
`
`Discussion
`Since the introduction of MOPP chemotherapy prednisone
`has been used routinely in the drug combination. When
`Castellino et al3 associated radiation pneumonitis or pericarditis
`with prednisone withdrawal, however, prednisone was eliminated
`from the regimen in those patients who had had mantle irradia-
`compared
`recently
`tion
`Stanford. A British
`study4
`at
`prospectively complete remission rates in 90 patients with stage
`IV Hodgkin's disease and found a 44°, complete remission rate
`in those who were given MOP without prednisone and an 80%
`complete remission rate in those given MOPP with prednisone
`(oral prednisone 25 mg/M2 was given on days 1 to 14 of every
`cycle).
`We found no differences in either complete remission rate or
`length of remission between patients who received prednisone
`in cycles 1 and 4, those who received no prednisone, and those
`who received some prednisone. Because this was a retrospective
`analysis with some patient selection we analysed the complete
`response rate and remission duration for all subgroups of
`unequal size. Like others,8 9 we found that prior irradiation had
`
`1470
`
`Two comparisons were made. Patients who received prednisone in
`cycles 1 and 4 were compared with those who received no prednisone
`but completed at least four cycles of MOP. This comparison eliminated
`patients who received fewer than four cycles of therapy, thus making
`the complete remission rate seem higher. To include all patients we
`therefore compared two other groups. Patients who received some
`prednisone (including those who received the drug in cycles 1 and 4
`or only in cycle 1) were compared with those who received no
`prednisone, regardless of the number of cycles of MOP. The complete
`response rate and length of remission were compared for the major
`groups as well as for all subgroups in which there was a significant
`difference in the numbers between the prednisone and no-prednisone
`groups.
`Although the patients who received prednisone were comparable to
`those who received no prednisone in most respects, there was some
`patient selection. Significantly more patients in the prednisone groups
`had lung disease while more patients who did not take prednisone
`had lymph node involvement as the most advanced site of disease. The
`groups were otherwise comparable with respect to more advanced
`sites of disease. Significantly more of those who had no prednisone
`had received irradiation, usually because mantle irradiation was a
`reason for withholding prednisone. Finally, there were more patients
`in the four-cycle prednisone group who were under 20 years of age,
`although other age groups were comparable. Tables I and II show the
`details of the patients.
`
`TABLE I-Characteristics of patients who received prednisone in cycles I and 4
`and patients who received no prednisone but completed 4 cycles of chemotherapy
`
`Patients taking
`prednisone
`
`Patients taking
`no prednisone
`
`No
`
`113
`
`44
`69
`
`21
`65
`27
`
`78
`21
`5
`9
`
`29
`39
`9
`5
`29
`2
`69
`44
`
`X4
`100
`
`38-9
`61-1
`
`18-6
`57-5
`24-0
`
`69-0
`18-6
`4-4
`8-0
`25-7t
`34-5
`8-0
`4-4
`25-7
`1-8
`61-it
`38-9t
`
`No
`45
`
`16
`29
`
`3
`32
`10
`
`35
`6
`2
`2
`
`19
`9
`3
`4
`9
`1
`44
`1
`
`100
`
`35-6
`64-4
`6-7
`71-1
`22-2
`
`77-8
`13-3
`4-4
`4-4
`42-2t
`20-0
`6-7
`8-9
`20-0
`2-2
`97-8t
`2-2t
`
`No of patients
`Sex:
`Female
`Male
`Age:
`<20
`20-40
`>40
`Histology:
`Lymphocyte predominance
`Nodular sclerosis
`Mixed cellularity
`Lymphocyte depletion
`Unclassified
`Site*:
`Nodes
`Lung
`Liver
`Osseous
`Bone marrow
`Other
`Prior irradiation
`No prior irradiation
`
`*Most advanced site, in order listed.
`tP <0-05.
`
`TABLE II-Characteristics of patients who received some prednisone and those
`who received no prednisone, regardless of number of cycles of chemotherapy
`
`Patients taking
`prednisone
`
`Patients taking
`no prednisone
`~~l
`
`No
`
`I
`
`33
`
`38
`
`41
`
`9
`
`23
`
`4 4
`
`10
`
`153
`1
`
`39-5
`
`16-6
`
`58-6
`
`24-8
`
`1-3
`
`19-1
`
`3-8
`
`5-7
`
`24-2t
`
`33-8
`
`10-8
`
`5-7
`
`24-8
`
`1-3
`
`75-21
`
`24-8t
`
`No
`'I
`157
`
`62
`95
`
`26
`92
`39
`
`2
`110
`30
`
`69
`
`38
`53
`17
`
`93
`
`92
`
`118
`39
`
`No of patients
`Sex:
`Female
`Male
`Age:
`<20
`20-40
`>40
`Histology:
`Lymphocyte predominance
`Nodular sclerosis
`Mixed cellularity
`Lymphocyte depletion
`Unclassified
`Site*:
`Nodes
`Lung
`Liver
`Osseous
`Bone marrow
`Other
`Prior irradiation
`No prior irradiation
`
`*Most advanced site, in order listed.
`tP <0-05.
`
`ALVOGEN, Exh. 1019, p. 0002
`
`

`

`BRITISH MEDICAL JOURNAL
`
`18 DECEMBER 1976
`
`no effect on either the complete response rate or the length of
`remission within each subgroup. Similarly, the sites of disease
`(nodes and lung) and the patients' ages (under 20) did not
`significantly influence either complete response rates or the
`length of remission between the prednisone and no-prednisone
`groups.
`Although our data do not agree with those of the British study
`there are some major differences between the two studies. Our
`study was a retrospective analysis comparing groups of patients
`treated over different times. Most of those patients receiving
`prednisone were treated before 1974 or had had no mediastinal
`irradiation. A prospective randomised study of strictly com-
`parable patients is always to be preferred in judging the value of
`a treatment, but we did evaluate the effect of patient selection
`by analysing each subgroup and found no significant differences
`in the complete response rate or length of remission between
`those who did and did not receive prednisone.
`A possible explanation for the different findings of the British
`study is that good partial responses might have been converted
`into clinical complete responses by prednisone. Whether or not
`these apparent complete responses last will be known only after
`three to five years. The value of chemotherapy for Hodgkin's
`disease must be measured not only by the complete remission
`rate but also by the length of the remissions. Current studies
`indicate that about 60 0 of the patients should remain in complete
`remission for at least five years and probably indefinitely.9 10
`The unusually low complete response rate of 440), in the
`British group who had no prednisone is disturbing. The rate is
`significantly lower than that reported by most other groups.9 10
`Since the report of the British study was a preliminary one, it
`does not provide information on the amount of myelosuppressive
`
`1471
`
`drugs actually given in the two treatment groups. Their results
`could be explained if more mustine and procarbazine had been
`given to the prednisone group because of higher peripheral blood
`counts, which might be expected in that group.
`The British study used prednisone in every cycle of their
`treatment programme. This may have brought out differences
`that are not as apparent when the steroid is used for only two
`cycles. But our results with a regimen without prednisone are
`quite comparable to those in the British patients who received
`prednisone in every cycle. Furthermore, most of these complete
`responses to MOP have produced durable remissions for at least
`five years. This suggests that eliminating prednisone does not
`reduce the efficacy of the MOPP regimen.
`
`These studies were supported in part by grants CA-08122 and
`CA-05838 from the National Cancer Institute, National Institutes of
`Health, Bethesda, Maryland, USA.
`
`References
`IFrei, E, et al, Cancer Research, 1966, 26, 1284.
`2 DeVita, V T, et al, Annals of Internal Medicine, 1970, 73, 881.
`3Castellino, R A, et al, Annals of Internal Medicine, 1974, 80, 593.
`4Report from the British National Lymphoma Investigation,
`Medical Journal, 1975, 3, 413.
`5Lukes, R J, et al, Cancer Research, 1966, 26, 1311.
`6Kaplan E L, and Meier, P,_Journal of the American Statistical Association,
`1958, 53, 457.
`7 Gehan, E A, Biometrika, 1965, 52, 203.
`8 Moore, M R, et al, Cancer, 1973, 32, 52.
`9 Portlock, C S, et al, Proceedings of the American Association of Cancer
`Research and American Society for Clinical Oncology, 1976, 17, 248.
`' DeVita, V, et al, Proceedings of the American Association of Cancer Research
`and American Society for Clinical Oncology, 1976, 17, 269.
`
`British
`
`New technique for investigating bacterial flora of
`female periurethral area
`
`W BRUMFITT, J M T HAMILTON-MILLER, M BAKHTIAR, J COOPER
`
`British Medical journal, 1976, 2, 1471-1472
`
`Summary
`The bacterial flora of the female periurethral area was
`studied by impression cultures taken with polystyrene
`sponges, the results being recorded by photographic
`contact printing. With this technique it is possible to
`observe the preferential colonisation of different areas
`by different organisms and to detect persistent colonisa-
`tion by pathogens. In assessing the possible aetiological
`importance of these results, and especially in comparing
`them with the findings of other workers, it is essential to
`use correct anatomical nomenclature.
`
`Department of Medical Microbiology, Royal Free Hospital, London
`NW3 2QG
`W BRUMFITT, FRCP, professor
`J M T HAMILTON-MILLER, MRCPATH, senior lecturer
`M BAKHTIAR, MSC, research assistant
`J COOPER, MB, clinical assistant
`
`Introduction
`The role of bacterial colonisation of the regions surrounding the
`female urethral meatus in the initiation of urinary tract infections
`has long been a source of speculation. Several attempts have been
`made to isolate pathogenic strains of bacteria from patients
`subject to relapse or reinfection by swabbing various sites
`within and around the vestibule,'-6 but the conclusions drawn
`have varied. A major reason for this may well be the lack of
`standardisation of both microbiological technique and anatomical
`nonmenclature. These two factors combined constitute such a
`problem that it seems doubtful whether any of the reported
`studies could be repeated by other workers. We therefore draw
`attention to the official definitions (according to anatomy texts)
`of the terms "vestibule" (the whole area inside the labia
`minora), "introitus" (synonymous with the vaginal orifice), and
`"perineum" (the area between the thighs from the coccyx to the
`pubis). In gynaecology and obstetrics, however, the perineum
`is commonly referred to as the region between the posterior
`commissure of the labia majora and the anus.
`The confusion that has arisen through imprecise nomen-
`clature includes "introital" used apparently synonymously with
`"vaginal vestibular"' (we have been unable to find a definition
`"vaginal,"5 and "peri-
`of the term "vaginal vestibule"),
`urethral."' Even as simple a word as periurethral has been
`defined in more than one way. (Bailey et
`a14 termed as
`
`ALVOGEN, Exh. 1019, p. 0003
`
`