A critical analysis of response criteria in patients with prostatic cancer treated with...

A CRITICAL ANALYSIS OF RESPONSE CRITERIA IN PATIENTS WITH PROSTATIC CANCER TREATED W I T H CIS-DIAMMINEDICHLORIDE PLATINUM I1

ALAN YAGODA, MD,* ROBIN C. WATSON, MD,? RONALD B. NATALE, MD,$ WINSTON BARZELL, MD,f PRAMOD SOGANI, MD,J: HARRY GRABSTALD, MD,J:

A N D WILLET F. WHITMORE, MDJ:

Cis-diamminedichloride platinum I1 (DDP), 50-70 mglm’ iv, q 3w was administered to 25 patients with Stage D adenocarcinoma of the prostate. Since the assessment of tumor regression in a disease-oriented phase I1 sttidy demands a clear end-point of response, case selection was restricted to patients who had objectively measurable lesions, i .e., nodes, skin, lung and liver metastasis. Partial remission occurred in 3 (12%) and stabilization of disease in 1 patient. Responders lived 53 weeks vs. 20 weeks for nonresponders. In the dosage and schedule used in this protocol, DDP was not an active agent in the treatment of prostatic cancer. Various patient characteristics are examined and correlations made between remission rates and survival in this study vs. 4 other response schemata. A critical analysis of patient selection, “lead time”-diagnosis to chemotherapy, and the definitions of the terms “measurable” lesions, “evaluable” parameters, “objective response”, stabilization of disease and response criteria employed in the 4 schemata are also discussed.

Cancer 44:1553-1562, 1979.

HE EFFICACY of anti-neoplastic drugs in T the treatment of prostatic cancer is difficult to evaluate since this tumor frequently lacks objective, measurable lesions, such as lung, liver, skin, subcutaneous and nodal m e t a ~ t a s e s . ~ ~ ~ ” ~ ~ ~ ~ ~ ~ ~ ~ ~ The majority of‘ patients entered into most Phase I1 prostatic cancer trials have poorly measurable, so- called “evaluable” lesions, i .e . , rectal or pelvic masses, pleural effusions, lymphangitic spread of pulmonary metastases, or abnormal lymphangiograms, intravenous pyelograms, ro- entgenographic skeletal surveys and/or radionuclide bone or liver scans. Additional parameters used to assess response include

From the *Solid Tumor Service, Department of Medicine, ?Department of Diagnostic Radiology, and the $Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.

Supported in part by Public Health Service Grant CA- 05826 from the National Cancer Institute, National In- stitutes of Health, Department of Health, Education and Welfare.

8 Fellow, Medical Oncology. Address for reprints: Alan Yagoda, MD, 1275 York

Avenue, New York, NY 10021. T h e authors- thank Mrs. Marjorie Freilich-Den for

technical assistance. Accepted for publication November 20, 1978.

improvement of abnormal laboratory values- serum acid (SAP) and alkaline (ALKP) phosphatases, liver function tests, carcino- embryonic antigen (CEA), hemoglobin and platelets, and improvement of symptoms-pain intensity and analgesic requirements, weight loss and performance status (PS).1”q11.173R834” The potential inaccuracies in physician assessment of objective changes in “evaluable” lesions and in the subjective interpretations by both physicians and patients of favorable symptomatic benefit can be misleading47 and may result in aberrant response rates. A recognition of these problems has led some in- vestigators to devise various schemata to define remissions and these new categories of response hinder attempts to compare published response rates of clinical trials in prostatic cancer which use single or combination drug therapies. In some studies, complete (CR), partial (PR) or minor (MR) remissions simply denote any temporary decrease in pain or improvement in performance status (usually found in poly-drug regimens which include corti~osteroids)~*’~ and/or any decrease, or transient normalization, or reduction of >50% from pretreatment abnormal SAP levels. Compounding this confusion is

0008-543X/79/1100/1553 $1.00 0 American Cancer Society

1553

1554 CANCER November 1979 VOl. 44

TABLE 1 . Eligibility for Protocol

Adenocarcinoma of the prostate, histologically confirmed

Measurable lesions-nodes, lung, liver, cutaneous, subcutaneous

PS 2 3 0 WBC >2500/mm3 Platelets > 100,000/mm3 Estimated survival >3 weeks Ccr >50 muminute No major auditory deficiency (<50 db loss at 6000-8000 Hz)

the exclusion in some clinical trials of an increasing SAP or ALKP level as evidence of tumor progression (PROG) or cessation of response.

On the other hand, stabilization (STAB) or PROG, particular in bone is difficult not only to quantitate but also to interpret. New areas of sclerotic or osteoblastic lesions in a bone survey can be an indication of either progression or regression of tumor,13 and while bone scans qualitatively monitor metastatic activity, quantitative improvement can be produced by factors other than reduction in tumor s i ~ e . ’ ~ , ~ ~ Since the predominant metastatic pattern of prostatic cancer is to osseous sites, and progression in bone is evi- denced only after major alterations in x-rays or scans, many patients seem to achieve STAB. Stabilization of osseous metastases coupled with minor or transient improvement in symptoms or laboratory abnormalities frequently is interpreted as confirmation of remission and many clinical trials now publish “objective” response rates which include CR, PR, MR and STAB categories based upon such considerations. For example, 3 Phase 11-111 trials of the National Prostatic Cancer Project (NPCP) report “objective responses” in 35% (38/110),40 29% (27/94)“j and 37% ( 18/49)16 of patients, respectively. Yet, only 7 of 110,4” 2 of 9416 and 3 of 4916 patients, respectively, achieved PR status. The remaining “objective responders” showed STAB or the absence of noticeable progression of disease. The validity of these responses was then supported statistically by the findings of an increased survival in “responders” vs. “nonresponders.”

Since the assessment of response in patients with prostatic cancer who have poorly measurable parameters may be regarded as subjective, the true estimation of CR and PR rates as defined in the standard disease- oriented phase I1 trial-which normally

demands a clear end-point of response’-is lacking. Carcinoma of the prostate does metastasize to the lungs, pleura, liver, breasts, lymph nodes, cutaneous and subcutaneous areas.6,20~21,26,28,30~41,46 Although patients with such measurable parameters comprise only a small percentage of cases, the most reliable information concerning the incidence of tumor regression with chemotherapeutic agents can be obtained in such cases.

Approximately 8 patients with objectively measurable prostatic cancer are seen annually at Memorial Sloan-Kettering Cancer Center (MSKCC) and are selected for disease- oriented phase I1 trials. This report sum- marizes our experience between 1175- 1/78 with cis-diamminedichloride platinum I1 (DDP) in 26 patients (24 from a disease- oriented Phase I1 trial and 2 from a previously reported drug-oriented Phase I protoc01’~) with prostatic cancer who fulfilled the criteria outlined in Table 1 .

MATERIALS AND METHODS

All patients had an initial history, complete physical examination and biopsy proven carcinoma of the prostate confirmed by the MSKCC Department of Pathology. Each ac- cessible lesion was measured by two or more perpendicular diameters and, except for 3 patients, was reevaluated at designated intervals by the same observer (AY). Quan- titative changes in liver size were evaluated by the technique used at MSKCC48 which utilizes 3 to 8 measurements obtained at 5 cm intervals from the xiphoid. The sum of all measurements below the costal margin at each of these points was recorded.

Laboratory tests included a complete blood and platelet count, a 12 channel screening profile, serum creatinine and a 24 hour creatinine clearance (Ccr). Samples for the determination of the SAP were always col- lected prior to a rectal examination and measured by a modification of the Bodansky method.2 In addition, many patients had evaluations of the CEA, 5’nucleotidase, and various coagulation factors. Routine ro- entgenographic and radionuclide studies included chest x-rays, intravenous pyelograms, bone surveys, and liver and bone scans. In selected patients, lymphangiograms, stereo- scopic chest x-rays and pelvic computerized transaxial tomograms (CT scans) were per- formed. AII x-rays were evaluated inde-

No. 5 DDP I N PROSTATIC CANCER . Yagodu et al. 1555

pendently (RCW). Appropriate diagnostic tests were always obtained prior to the administration of each dose, except for scans, skeletal surveys and CT scans which were re- peated after every second or third dose. Except in 3 cases, PS, weight, intensity of pain and analgesic usage were evaluated by one observer (AY).

DDP was diluted with sterile water and administered iv in 10-20 minutes after a 1 hour infusion of 500-1000 ml of D5W. Hos- pitalized patients received an additional 1-3 liters of iv fluid for 12-24 hours thereafter. Some patients with borderline renal function (Ccr < 60 ml/minute) received mannitol 12.5 g iv at the time of DDP administration and sufficient fluids to maintain a diuresis of 125 mlfhour for 6 hours. High doses of anti- emetics were routinely used but were inef- fective in reducing nausea and vomiting.

Previous experience at MSKCC4S with DDP in other solid tumors indicated rapid responses so that an adequate trial was defined as 1 dose, with or without hematologic de- pression and 3 week survival, if active progression of disease was found. Otherwise patients were continued on therapy until PROG was noted, renal or auditory toxicity occurred, or nausea and vomiting resulted in patient refusal to continue DDP therapy.

The response criteria used in Phase I1 studies at MSKCC are outlined in Table 2. Although mixed responses, such as regression of objective parameters with progression of osteo-

TABLE 2. Response Criteria

CR Complete disappearance of all measurable, radiologic and biochemical abnormalities.

PR Soft tissue lesions->50% decrease in the sum of the products of 2 or more perpendicular diameters of all lesions for > 1 month.

Abdominal or pelvic masses->75% decrease by physical examination and/or >50% by CTT in the sum of the products of 2 or more perpendicular diameters for > 1 month.

Hepatomegaly->50% decrease in the sum of all available measurements by physical examination and >50% decrease in all biochemical abnormalities and filling defects on scan for > I month.

( In addition, if pretreatment SAP or CEA are abnormal, a >50% decrease is required.)

25-50% decrease in tumor size or biochemical abnormalities for > I month or >50% for <1 month.

(25% decrease or increase in tumor size or biochemical abnormalities for >3 months.

>25% increase in tumor size or biochemical abnormalities, or a mixed response.

MR

STAB

PROG

TABLE 3. Patient Characteristics ~ ~~

Pro- gressors PWSTAB (n = 21) (n = 4)

Age (years) 5 1-60 61-70 7 1 + Median

2 80 60-70 40-50 530

Performance status

Prior chemotherapy Prior hormonal therapy

Diagnosis to hormone

Hormone to protocol (months)

(months) Prior orchiectomy

(months)

(months)

Diagnosis to orchiectomy

Orchiectomy to protocol

Prior to radiation therapy Radiation to protocol

Increased SAP (>0.8 U/dl) Increased CEA (>5.0 ng/ml) Hemoglobin (g/dl)

(months)

210.5 510.4

Platelet (< 175,000/mm3) Natural history

Symptoms to diagnosis

Diagnosis to metastases

Diagnosis to protocol

Protocol to survival (weeks)

(months)

(months)

(months)

6 12 3

66

5 8 7 1 9

18

4

21 12

1

30 16

2 12* 8t

\

15 6 5

125

1

26 20

1 2 1

65

2 1 1 0 2 4

1

4

13

27 4

1 2 I f

4 0 0

5

30

48 53

* 20 patients evaluable. t 11 patients evaluable. $ 2 patients evaluable. 5 19 patients evaluable.

lytic lesions on skeletal surveys andfor a rise in the SAP were evaluated separately, patients with such findings were assigned to the PROG category. Duration of response was measured from the initiation of protocol until PROG occurred. Subjective changes (PS) were evaluated by the Karnofsky scale. Leukopenia was defined as a WBC <4,500/ mm3 and thrombocytopenia as a platelet count < 175,000fmm3.

Patient Characteristics

Twenty-five of 26 patients received an adequate trial. Information from the in-

1556 CANCER Nouember 1979 VOl. 44

adequately treated patient who died 11 days after the first dose was excluded from all subsequent data. The characteristics of 25 adequately treated patients are outlined in Table 3. Although the median age was 65 years, 28% were 560. The median PS for all patients was 60. The original tumor was poorly differentiated or anaplastic in 11 of 18 patients. Some form of endocrine therapy had been given to 22/25 patients and 82% had achieved remission. Eleven patients (44%) had prior chemotherapy trials, mostly with combination regimens; adriamycin (3), 5-fluorouracil (3), hydroxyurea (2) and alkylating agents (9).

Twenty patients had “indicator” lesions: 12 had palpable lymph node, or penile, breast, and other cutaneous and subcutaneous masses, 5 of whom had hepatomegaly and 3 pulmonary metastases; 6 had pulmonary or extrapleural lesions, 4 of whom had hepatomegaly; and 2 had malignant hepatomegaly, one of whom was previously untreated and had an abnormal lymphangiogram and a large prostatic mass.

Although patients were carefully selected for measurable, objective disease, reexamina- tion of x-rays and scans, and the subsequent course and postmortem findings resulted in 5 patients being reclassified as “evaluable.” Two patients had large rectal and prostatic masses easily evaluable by CTT, 1 with a SAP of 10 Uidl, and both exhibited hepatomegaly, although biopsy proof of liver metastases was lacking. One patient had only a grossly abnormal lymphangiogram. The remaining 2 patients on follow-up were found not to have the originally suspected pulmonary and hepatic metastases, and their “evaluable” disease was confined to symptoms, abnormal skeletal surveys and scans, and SAP levels of 26 and 1.6 U/dl, respectively. Discrete osteoblastic rib lesions superimposed on the lung fields have been erroneously interpreted as evidence of parenchymal pulmonary disease.3 While pulmonary metastases have been found at postmortem in 25% to 47% of patients2”26 with prostatic carcinoma, they are microscopic in two thirds of the cases.3

Serum oxalacetic transaminase was elevated in 50% of patients, ALKP in 88%, lactic dehydrogenase in 7 1 % and 5‘nucleotidase in 38% (5115). The SAP was elevated in 60% (14124) of patients, the hemoglobin was 5 12.4 gldl in 68% (17/24) and 1 patient had hypercalcemia. The CEA was 25.0 ng/ml (median 11.6, range 6.5-346) in 9 (64%) pa-

tients, 2.5-4.9 in 3 and <2.4 in 2. Liver scans were grossly abnormal in 5 patients, equivocal in 2 and negative in 5. One patient who had biopsy proven hepatic metastases and an enlarged liver by physical examination never had a liver scan. Bone scans were abnormal in 21/24 and skeletal surveys in 20/23 patients.

RESULTS

PR status was achieved in 3 (12%) patients for 3, 2.5, and 2 months, respectively. One (4%) patient showed STAB for 8 months. T w o responders had received extensive prior irradiation, chemotherapy and endocrine ma- nipulation while the third responder had had limited irradiation and hormonal therapy. One patient who had been reclassified into the “evaluable” disease group is categorized as achieving STAB because of marked pain relief, weight gain and stabilization of osseous lesions, SAP, ALKP and CEA levels. He illustrates the difficulty in evaluating and interpreting poorly measurable disease parameters. Two other patients had transient decreases in the SAP (26 to 18 and 1.13 to 0.56 U/dl). Dramatic relief of bone pain was noted in 8 (32%) additional cases 1-4 days after DDP administration, mostly in patients who had mixed responses or STAB of <3 months duration. If pain relief, osseous lesions, ALKP and SAP levels were the only measurable parameters, 48% of patients would have been categorized as having achieved STAB. Twenty-one patients have expired as of 6/78 and 2 of the remaining 4 are terminal.

There was no significant difference between responders vs. progressors with respect to age, prior chemotherapy, limited or extensive irradiation, and ALKP or SAP levels. However, significance was found for PR/ STAB patients, all of whom had an orchiectomy and a hemoglobin level 2 10.5 g/dl prior to DDP administration, and a longer interval from diagnosis to metastases (30 vs. 1 month for PROG) and diagnosis to protocol (48 vs. 26 months for PROG).

Prognostic significance of various parameters was also examined (Table 4) in a format similar to that used by the NPCP3’ but additional information was added, namely, the intervals from symptoms to protocol and from diagnosis to protocol for each param- eter (Table 4). Although patients 7 1 years of age had a shorter survival from protocol,

No. 5 DDP IN PROSTATIC CANCER . Yugodu et ul. 1557

TABLE 4. Prognostic Factors: Patient Status Prior to initiation of Protocol

Symptoms to diagnosis Diagnosis to protocol Protocol to follow-up

No. No. No. pts. Months* (Range) pts. Months* (Range) pts. Weeks* (Range)

Age (yrs) 51-60 61-70 71+

Diagnosis to protocol (yrs)

<1 1-3 >3

2 80 60-70 40-50 5 3 0

None Orchiectomy Hormones Hormones

Performance status

Endocrine therapy

+ orchiectomy

6 11 13 3 4 14

3 1 1 1 9 9 12

7 2 8 7 7 12 1 12

3 1 1 1 6 13

13 8

(1 -20) (0-59) (0- 16)

(1-59) (0- 16) (0-20)

(0-20)

(12)

(1) (6-20)

(1-59)

(1-14)

( 1 -59)

(0- 16)

7 19 14 26 4 55

7 17 9 34 8 36 1 20

3 1 1 21 6 26

15 42

(1-64) (1-57)

(40- 108)

(1-57) (11-67)

(9- 108) (20)

(1-17)

( 18-44)

(1 1 - 108)

7 14 4

3 12 10

7 9 8 1

3 I 6

15

20 25 5

24 22 23

36 29 18 9

24 28+ 24

15

(5-91) (8-62+) (3-36)

(8-91) (5-62) (3-55+)

(3-57+) (18-91)

(4-52) (9)

(20-91) (28 + ) (9-57)

(3-55+)

Orchiectom y 14 3 (0-19) 16 41 (11-108) 16 19 (4-55+) No orchiectomy 9 12 (1-20) 9 20 (1-44) 9 24 (9-57+)

None 13 2 (0-59) 14 25 (1-67) 14 24 (3-91) 1 4 14 (3-20) 4 39 (10-44) 4 26 (5-57+) 2 + 7 10 (1-16) 7 28 (18-108) 7 21 (4-55+)

Prior chemotherapy trials

Prior RT None 9 1 (0-59) 9 17 (1-48) 9 20 (8-91) 1 port 5 6 (0-16) 6 43 (23-108) 6 17 (3-36) 2+ ports 8 12 (2-20) 10 36 (19-64) 10 30 (5-57+)

10.5-12.4 9 12 (1-20) 10 29 (1-48) 10 33 (9-91)

Hemoglobin (g/dl) >12.5 8 2 (0-12) 8 27 (16-67) 8 24 (3-62)

.................................................... >10.5 17 6 (0-20) 18 27 (1-67) 18 29 (3-91) <10.4 6 13 (1-16) 7 30 (11-108) 7 8 (4- 18)

Platelets ( X IO3/mm3) >125,000 18 7 (0-16) 20 30 (1-108) 20 22 (3-91) < 125,000 5 16 (1-20) 5 4 0 (1 -44) 5 24 (5-40+)

Serum acid phosphatase

Normal 10 3 (0-16) 10 26 (1-67) 10 23 (3-91) Abnormal 13 12 (1-59) 14 36 (1-108) 14 22 (4-62+)

<5 ng/rnl 4 2 (1-14) 5 30 (1-57) 5 56+ (27+-91) CEA

>5 n g h l 8 10 (0-20) 9 28 (11-53) 9 23 (8-55+) Response

None 19 12 (0-59) 21 26 (1-108) 21 20 (3-90) PWSTAB 4 5 (2-16) 4 48 (2-57) 4 53 (36-55+)

* All values are medians.

they had longer intervals from symptoms to III/IV histology. Prior chemotherapy and protocol and from diagnosis to protocol than radiation were not of prognostic significance. younger patients. Patients with a PS 280 did Although patients starting on protocol with a survive longer, but probably had been placed hemoglobin 2 10.5 g/dl survived longer than on protocol earlier (shortened “lead time”) patients with a level of 510.4, survivals were than patients with a lower PS. Of note, all similar from initial diagnosis to death in both patients who had a PS of 540 had had grade groups. Patients with platelet counts <125

1558 CANCER November 1979 Vol. 44

X 103/mm3 had a shorter survival from protocol but a significantly shorter interval from symptoms to protocol than patients with counts >125 X 103/mm3, possibly reflecting a longer period for bone marrow invas_ion by tumor. The reason for a significantly longer interval from symptoms to protocol for patients who presented with an elevated SAP at the time of chemotherapy is unclear.

Of particular interest is the longer survival and significantly longer interval from diagnosis to protocol for PIUSTAB vs. progressors. Although the duration of response is only 2-3 months, the survival differences for responders vs. nonresponders is considerable, 53 vs. 20 weeks, suggesting a slower growing pattern of disease in the former. However, it is also possible that DDP did influence survival.

Doses and Toxicity

There were 69 doses, median 3, administered to 25 adequately treated patients. Seven (28%) patients had 1 dose, 7 (28%) 2 doses and 1 1 (44%) 3 to 8 doses. In early trials,Ig dosages were determined in mg/kg and subsequently have been converted to mg/m2; thus, the initial doses were 60-77 mg/m2 in 14 patients, 50-59 mg/m2 in 6 patients and 49 mg/m’ in 5 patients. The median total dose for 23 patients was 141 mg or 62 mg/m2 administered every 3 weeks. In early trials, dose schedules of DDP were also different, i e . , one patient received 18 mg/m2/day for 8 consecutive days, another received 18 mg/m2/wk for 4 consecutive weeks and 4 patients were initially given low doses with subsequent escalation until myelosuppression o c c ~ r r e d . ’ ~

Nausea and vomiting occurred in 18 (72%) patients and was severe in 7 (28%). A decrease in auditory acuity was noted in 3 patients, transient tinnitus after each dose in 1, diarrhea in 2 and a pruritic rash in 1. Leukopenia, median 2.6 x 103/ml (range 0.8-4.4 X 103/ml), was noted in 9 patients and unexplained thrombocytopenia (range 27-140 x 103/ml) in 5. However, some episodes of thrombocytopenia were caused by an acute exacerbation of chronic dis- seminated intravascular c o a g ~ l a t i o n . ~ ~ Nine (36%) patients showed unexplained transient BUN (median 32 mg/dl, range 22-55) or creatinine elevations which returned to pretreatment levels 2 to 8 weeks later.

DISCUSSION

DDP in the dose and schedule used in this protocol was not an active agent in prostatic cancer. Review of published re- ports of DDP used singly in prostatic cancer found 34 of 43 adequate trial^.'^,^^,^^ Rossof et al.35 had 1 (8%) PR in 12 cases given 75 mg/m2 iv q 3w. In patients with “measurable” and “evaluable” lesions, Merrin23*24 noted PR in 43% (9/21) lasting 3-14 mos, median 5.8, with DDP 1 mg/kg in a 6 hour infusion q.w. for 6 weeks, then q 3w thereafter. The average total dose was 527 mg/ patient. DDP, 50 mg/m2, and ADR, 50-60 mg/m2 q 3-4 wks produced 9 (53%) of 17 PR for 1-18 mos, median 5 months.25*59~32~43 However, some response consisted only of “control of pain and laboratory abnormalities.”25 Samson et ~ 1 . ~ ’ gave DDP, bleomycin and vinblastine to a patient with prostatic cancer without response.

Patients in the present study had many “negative response parameters” described by Johnson et a1.16 and Schmidt et ~ 1 . ~ ’ as “predictors of a poor response to chemotherapy or standard therapy.” These parameters included: extensive prior irradiation (48% of cases had >2,000 rads) and chemotherapy (44%); low PS (72% <80); anemia (68% had a hemoglobin <12.5 g/dl and 24% C10.5 g/dl); hepatomegaly (52%); and no orchiectomy (36%). In fact, many patients in the present series would be un- acceptable for NPCP protocols because of prior irradiation or chemotherapy. While these factors may be labelled as “negative response parameters,” in the present experience at least, they were not associated with any apparent difference in response or survival. Another factor which may affect response to chemotherapy is the presence of soft tissue and nodal metastasis. Patients who display such lesions are considered to have more advanced disease, and therefore have a lower PS, a shorter survival time than patients with nonmeasurable lesions and less responsiveness to chemotherapy.l0 On the other hand, whether soft tissue lesions are uniquely responsive to chemotherapy5 or simply easier to follow is uncertain. In any event Eagan et al.,11J2 DeWys et al.9J0 and Schmidt et al.38 found no difference in response rates in patients with “measurable” vs. “evaluable” disease parameters. Differ-

No. 5 DDP IN PROSTATIC CANCER * Yugoda et al. 1559

TABLE 5. MSKCC Responses (PR,* STAB,t Progt) in 25 Adequately Treated Patients Re-evaluated According to the Criteria of 4 Other Schemata

MSKCC NPCP ASS ECOG Kane et a]. ~ ~~ ~~ ~~

I* 3* 3*

1$ 1$ 1-4 = 20% I t = 23% PR 3% = 12% I $ = 4% = 1 1 %

3* 2* I t

2$ 3$ STAB I t = 4% I t = 24% I t = 21% = 20% 4$ = 18%

PROG 21$ = 84% 18$ = 72% 1st = 68% 12$ = 60% 13$ = 59%

Not evaluable 0 0 6$ 5$ 3.4 Survival (weeks)

PWSTAB mean 50 48 51 34 37 median 54 52 54 33 36 range 36-52 15-91 15-91 15-52 8-52

PROG mean 24 21 27 15 17 median 20 16 23 19 20 range 3-91 3-62 5-62 3-62 3-91

Objectively measurable lesions, except for hepatomegaly >5 cm, were excluded and response was judged

ences in survival have been described in patients who have bone and soft tissue lesions (3%-5 months) vs. bone metastasis (7- 11 months) only. Age has also been shown to adversely affect survival4* and 28% of patients in the present series were younger than 60- years-old. However, Eagan et al. l1 found no difference in response rates to drugs based on age.

Although there were only 25 adequately treated patients in the present study, the presence of measurable parameters makes it unique compared with other disease-oriented trials. Correlations were made between patient characteristics and remission rates in this study and 4 other response schemata- the NPCP,3s*40 the ECOG (Eastern Coopera- tive Oncology Group),’O the ASS (Ancillary Scoring System),llslzJe and Kane et ul.“ For comparison, all objectively measurable lesions found in patients in the present series, except for hepatomegaly of >5 cm,l0 were excluded and responses were judged only on the basis of “evaluable” lesions. Assign- ment of patients from the present series into the other schemata was difficult because of 1) the unfamiliarity with the four other sys- tems; 2) the different and, at times, imprecise definitions employed for malignant hepatomegaly; and 3) the absence, in some cases, of available information from our data base used for response criteria in the four schemata. Although such considerations limit meaning-

only on the presence of “evaluable” lesions. See text.

ful comparisons and illustrate the conflicting definitions of the term, “objective response,” it does not denote the superiority of one set of criteria over another.

An important difference between the response criteria in the present study and in the NPCP scheme is the relationship of the SAP to PROG. The NPCP does not consider an increase in serum acid or alkaline phosphatases alone indicative of progression of disease or cessation of a response. Prostatic cancer is recognized to be composed of a nonhomogeneous population of cells; some of which produce acid phosphatase. How- ever, until decreases in the SAP can be ac- curately quantitated with the percentage of cell destruction, responses which are mixed or solely based on changes in the SAP probably deserve to be included in the PROG category. In Table 5, the news ECOG cri- teria1° of PROG was used: an increase in tumor size during the first 2 weeks was regarded as delayed tumor cell death and not considered evidence of PROG, rather a new baseline for future assessment of drug re- s p o n ~ e . ~ The new1’ numerical values of the

was used also in Table 5 . In some ~ c h e m a t a , ~ ~ ~ ” DDP toxicity which can adversely affect PS, weight and appetite has pre- vented attainment of PR status and increased the number of patients assigned to STAB.

Perusal of all published studies of the 4

1560 CANCER November 1979 Vol. 44

groups has found >50%40 and up to 91%17 of patients have only “evaluable” lesions and results indicate a heavy reliance on subjective changes. Some patients who have shown mixed responses or STAB of < 3 months duration and who are listed as progressors in the present series, generally fall into the PR or STAB group in other schemata. Regardless, within each of the 5 schemata, survival is longer in responders and slow progressors than in the nonresponders and rapid progressors. Table 5 illustrates than when stringent criteria are ap- plied to evaluation of response, PR and STAB rates are low and effects of chemotherapeutic agents on survival may only reflect the re- arrangement of patients by, as yet unknown, selection factors.

The goal of Phase I1 protocols is to measure anti-tumor activity of a drug or drug combination in the context of a specified dosage and schedule. Unless the natural history of the cancer under study is known7 anti-tumor activity can best be defined in patients who have measurable lesions. “Extended” Phase I1 and Phase I11 studies attempt to minimize known prognostic variables affecting survival by patient stratification and unknown variables by randomization. Thus, Phase I11 trials can include patients with “measurable” and “evaluable” parameters and examine not only response rates but more importantly, survival. Unfortunately, prognostic factors which may influence survival in patients with prostatic cancer are largely still unknown. Al- though Schmidt et al.,3n Paulson et ~ l . ’ , ~ ~ and DeWys et ~ 1 . ~ have begun to define probable “good” and “poor” prognostic features as re- lated to response to chemotherapeutic agents, Whitmore has pointed out the extreme vari- ability in the natural history of this tumor.45 In addition, the behavior of the disease may be changing; Murphy et ~ 1 . ’ ~ analyzed 3 decades of experience with this tumor at a cancer center and found a statistically significant lower age at diagnosis (65.4 vs. 69.3 years) and a longer survival from initial diagnosis for all clinical stages. Newer diagnostic techniques and therapy are influencing the “natural history” of this tumor making it difficult to draw firm conclusions concerning the effect of any modality of therapy, in- cluding chemotherapy, on survival. For example, although older s t ~ d i e s ~ , ~ ’ , ~ ~ indicate a 7 to 10 month survival in patients with prostatic cancer after failure of estrogens or

orchiectomy, survival from endocrine relapse to death may now be longer possibly because closer patient observation has led to earlier recognition of relapse. Aggressive therapeutic approaches now involve imme- diate cessation of hormonal therapy and initiation of chemotherapy. Thus, the shortened “lead time” (diagnosis to chemotherapy) may explain the 40 weeks survival found by Kane et a P 7 for nonresponders vs. 20 weeks in the present series and the 10-25 weeks in the trials by Eagan et al.,” DeWys et al.,” and the NPCP.40 In fact, the 40 weeks survival for nonresponders which has been noted by Kane et al.I7 is similar to the duration of survival described for responders (CR, PR, MR, and STAB) in the present trial and in the studies of Eagan et al.” and the NPCP.’6j4”

In addition to the effect of a shortened “lead time” on the results of Phase 111 trials is the inclusion of patients who achieve STAB in the “objective response” categories.I6 While STAB may represent a response, it cer- tainly does not represent an objective response in patients with poorly measurable disease parameters and a review of published clinical trials indicates that most patients who achieve STAB have “evaluable,” not “measurable” lesions. Patients who show STAB may have tumors containing a large population of slow- growing cells and if these patients present for protocol studies with only evaluable parameters ( i e . , bone, SAP and symptoms), recognition of progression of disease will be both difficult and delayed. As stated by DeWys et ~ 1 . ’ ~ “judgments about effectiveness of therapy and decision about the continuation of therapy may not always be made optimally”; thus, some patients are continued on protocol, being categorized as obtaining STAB until grossly evident progression of disease occurs. In randomized trials, the relatively long survival of patients considered as achieving STAB is at best poor evidence of the efficacy of treatment and statistical confirmation that patients with slow-growing tumors survive longer than those with fast growing tumors is hardly proof of therapeutic benefit.8

Critical analysis of disease-oriented Phase I1 trials, i e . , the present study and Kane et al.,I7 and of extended Phase 11-111 trials, i e . , ECOG,’” NPCP” and Eagan rt al.” in patients with prostatic cancer suggest the following: 1) currently employed categories of response may not be appropriate for evaluating re-

No. 5 DDP IN PROSTATIC CANCER * Yugodu et ul. 1561

missions in this tumor; 2) symptoms and other “evaluable” lesions, particularly in bone are too imprecise for quantitative assessment of remission; 3) hepatomegaly in this age group may be due to nonmalignant medical dis- orders and requires histologic proof of tumor involvement; 4) chemotherapy trials of short duration may underestimate remissions in slow-growing disease and may require pro- longed drug administration before beneficial effects are obtained; 5) all patient characteristics should be listed since prognostic factors which influence remission are as yet unknown; and 6) the presence of soft tissue lesions may indicate more advanced disease, less responsiveness to chemotherapy, shorter

survival and, theoretically a small and distinct subset of the prostatic cancer population. However, until better criteria are available to document response in this tumor, patients with objectively “measurable” disease might profitably be excluded from Phase 111 trials and be evaluated only by rigid prospective criteria already established for Phase I1 studies. Although the number of patients with prostatic cancer who have “measurable” lesions are few, the use of gray scale transrectal ~ l t r a s o n o g r a p h y ~ ~ , ~ ~ and of CT scans may per- mit accurate assessment of previously considered “evaluable” lesions thereby increasing the number of cases with “measurable” parameters available for clinical study.

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