Preoperative chemotherapy for wilms tumor

PREOPERATIVE

CHEMOTHERAPY

R. BRUCE

BRACKEN,

M.D.

WATARU

W. SUTOW,

M.D.

NORMAN

JAFFE,

ALBERT0

AYALA, M.D.

LUIS GUARDA,

FOR WIIAI~

I

‘> )Fi

M.D. M.D.

From the Departments of Urology, Pediatrics, and Pathology, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas

ABSTRACT -Preoperative chemotherapy was administered to 19 children with Wilms tumor judged clinically to be unresectable at M. D. Anderson Hospital between January 1, 1962, and September 1, 1980. After 2 to 4 doses of vincristine, marked reduction in tumor size occurred in 16 patients. After chemotherapy 16 tumors could be resected completely, another required irradiation to reduce the tumor, and only 2 tumors could not be excised. Pathologically the most dramatic changes occurred in the undifferentiated interstitial stroma, followed next by changes in the nodular blastema. Diferentiated elements were apparently not affected. No serious complications were attributed to the preoperative drug treatment. This experience suggests that in selected instances preoperative chemotherapy can effectively facilitate the therapy of Wilms tumor.

Five to 15 per cent of Wilms tumors are too large for primary surgical excision. 1,2 Chemotherapy used preoperatively in 19 patients who had unresectable primary tumors produced sufficient tumor shrinkage to permit 15 (79 per cent) to undergo uncomplicated nephrectomy. This experience leads us to conclude that preoperative drug treatment has a definite role for patients with initially unresectable Wilms tumor. Material

I

and Methods

Between January 1, 1962, and September 1, 1980, 156 patients with Wilms tumor were seen at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston. In 19 of these patients the consulting surgeon considered the tumor to be too large for safe, primary, surgical resection (Fig. 1). In addition to giving 1. Wilms tumor on left considered too fm safe nephrectomy because it crosses midline from costal margin to pubis, extends into true pelvis and is fixed to adjacent structures. FIGURE

large

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TABLE I. Results of preoperative Case Age No. (MO.)

Sex

1

36

M

2

81

F

3 4 5

69 28 48

F M M

6

46

M

7

99

M

8

12

M

9

26

M

10

48

F

11

13

F

12

8

M

13

36

M

14

41

F

15

38

F

16

64

M

17

66

F

18

54

F

19

52

M

Description of Tumor (Side) 15cm. mass, crosses midline, nonvisualizing kidney (L) 12-cm. mass, fixed (L) 11-cm. mass (L) 12-cm. mass (L) 16-cm. mass, crosses midline (R) LO-cm. mass, vena caval thrombus, fixed, extends across midline (R) 15cm. mass (It)

Crosses midline, extends into pelvis, fixed (R) 23-cm. mass, extends into pelvis, fixed (L) Fixed, nonvisualizing on IVP crosses midline (L) 15cm. mass, extends across midline fixed (L) 15cm. mass (L) 8-cm. mass fixed (L) Nonvisualizing kidney, mass fills LUQ (L) Crosses midline, enters pelvis; kidney nonvisualizing on IVP (L) 16cm. mass, fixed, nonfunction on IVP (R) 22-cm. mass, crosses midline (L) lo-cm. mass, IVC, thrombus extending to R atrium (R) 13-cm. mass, crosses midline (R)

chemotherapy

Metastases

in 19 children

Drug

No.of Courses

Palpable Tumor Shrinkage Achieved

Current

Status

Yes

NED

None

Yes

NED 94 months

None None None

Yes

NED 53 months NED 62 months NED 67 months

V

2

Yes Yes

None

None

V

None

V

3 tumor nodules opposite kidney Tumor R kidney

v x 2, ACIxl, preop. XRT V

15 years

Yes; WC tumor thrombus persisted and not resected

DOD 9 months

Palpable mass reduced to 7 cm. but tumor unresectable No palpable decrease in size; sonographic evidence of necrosis No Yes

DOD 27 months

NED 5 months

DOD 21 months

Yes

NED 36 months

V

Yes

V

Yes

Died of intestinal obstruction with NED in 3 months DOD 8 months

V

Yes

NED 36 months

Both lungs and mediastinum

V

Yes

NED

Both lungs

V

Yes

NED 92 months

Both lungs

V

Yes

DOD 4 months

Both lungs

V

Yes

DOD 2 months

Both lungs

V, ACT

Liver

V

L kidney 5cm. mass Both lungs

2

2

the clinical impression of unresectability, 11 tumors measured 12 cm. or greater in diameter and 6 tumors weighed more than 600 Gm., even after chemotherapy. The tumors in 9 patients extended across the midline to the opposite side of the .abdomen, and 7 were judged to be fixed to adjacent structures. In 6 patients the ipsilateral kidney failed to visualize on intrave-

14 years

Yes; IVC thrombus completely eliminated

DOD 5 months

No: tumor

DOD 3 months

KEY: V = vincristine; ACT = actinomycin D; XRT = radiation therapy; NED = no evidence = intravenous pyelogram; LUQ = left upper quadrant; DOD = died ofdisease.

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with Wilms tumor

unresectable

of disease;

IVC = inferior

vena cava; IVP

nous pyelography, 2 tumors descended into the true pelvis, and in 2 patients vena caval tumor thrombi extended cranially to the level of the hepatic veins. In addition, 7 patients had hematogenous metastases and 3 had smaller neoplasms in the opposite kidney. Patients consisted of 11 boys and 8 girls who ranged in age from eight to ninety (median

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forty-one) months. Twelve tumors arose in the left kidney and 7 in the right. Preoperative chemotherapy consisted, generally, of vincristine used alone. In patients where tumor shrinkage was slow or insufficient, actinomycin D was added. Vincristine was given intravenously, 1 mg./M2 (in infants) to 1.5 mg./M2 (in older children) every five to seven days.3 Eight patients had two treatments, 8 had three, and 1 had four. The interval between initiation of chemotherapy and surgery ranged from ten to thirty-two (median seventeen) days. Surgery was planned to follow the last chemotherapy treatment by four to five days to avoid vincristine-induced ileus. Actinomycin D was administered intravenously to 2 patients in the standard dose of 15 mg./ Kg. body weight daily for five days. The tumor of one of these patients (Case 9) (Table I) failed to change in size after 2 doses of vincristine followed by one five-day course of actinomycin D. However, radiation therapy reduced the size of this tumor sufficiently to permit a safe and uncomplicated nephrectomy. The other patient (Case 18) had bilateral pulmonary metastases and a vena caval tumor thrombus that extended to the right atrium. She received 4 doses of vincristine combined with actinomycin D over a ninety-day period prior to surgery. The drugs shrank her tumor and completely eliminated the vena caval thrombus. Response to chemotherapy was assessed clinically by inspection and palpation and recorded by photographs (Fig. 2). Additional radiologic and sonographic studies were used to document tumor shrinkage in some patients. Serial intravenous pyelograms showed that 2 initially nonvisualizing kidneys visualized after chemotherapy and that tumor masses in 2 other patients shrank considerably. Sonography documented tumor shrinkage in 2 patients and showed marked tumor necrosis in 1 patient in whom tumor shrinkage per se did not occur. Pathologic material from 16 of the 17 nephrectomies was reviewed.

FIGURE 2. Illustrates dramatic response tumor on left to 2 doses of vincristine.

continuity with the nephrectomy was necessary to remove the tumor completely in 2 of these patients, but en bloc splenectomy, partial pancreatectomy, and partial hepatectomy were unnecessary. A vena caval tumor thrombus that extended to the right atrium was eliminated completely by 4 courses of vincristine and actinomycin D. The tumors of 3 patients did not shrink after chemotherapy. However, chemotherapy caused marked necrosis in the tumor of 1 (Case 8), as documented by sonography and proved at pathologic examination. Nephrectomy in this patient was performed without the benefit of tumor shrinkage. The tumor in Case 9 failed to shrink in response to preoperative treatment with vincristine and actinomycin D; however, tumor reduction that facilitated nephrectomy occurred when radiation therapy was utilized. In Case 19 the tumor failed to respond to vincristine administration, and could not be resected. Neither myelosuppression nor ileus sufficient to delay surgery nor evidence of neurotoxicity was noted. Preoperative chemotherapy did not delay routine postnephrectomy treatment, which was started one to fourteen (median seven) days after surgery. Postoperative treatment delays were related to convalescence from surgery rather than to the consequences of preoperative chemotherapy. No long-term ill effects attributable to preoperative drug administration have been seen in any of the long-term survivors.

Results Marked reduction in tumor size occurred after preoperative chemotherapy in 16 of 19 unresectable tumors (84 per cent). This shrinkage enabled uncomplicated nephrectomies to be done in 15 of the responding patients, but one patient’s tumor remained unresectable in spite of marked tumor reduction. Partial colectomy in

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FIGURE 3. (A) Small isolated blastematous nodules in background of microcystic changes secondary to vacuolization of stromal histiocytes (right), alternating with areas fibroblastic proliferation (left). Tubule seen at bottom (original magnijication x 60). (B) Low-power view of Wilms tumor demonstrating ; small isolated blastematous nodules in benign, loose i stroma containing jibroblasts and histiocytes (original magnijication x 60). (C) High-power view of two I nodules of blastema undergoing necrosis shown by numerous pyknotic nuclei; microcystic stromal changes accompanied by fibroblastic and histiocytic prohferation also prominent (original magn$cation - _

of

-x130).

Ten of 19 patients (53 per cent) are living with no evidence of disease five months to fifteen years after starting therapy (Table I). Of the 9 without metastases, most would have been classified as Stage III. Five are long-term survivors (fifty-three months to fifteen years). Tumor deaths occurred in 4 of 7 patients with Stage IV disease and in 1 of 3 patients with Stage V. One patient with Stage V disease died of intestinal obstruction, and at postmortem examination was found to be tumor-free. Histopathologic

Changes

We reviewed the pathologic material from 16 of the 17 nephrectomy specimens. Tumor extension beyond the renal capsule was demonstrated histologically in 7 patients, metastases to regional lymph nodes in 2, and vascular invasion in 3. All specimens disclosed histologic features characteristic of Wilms tumor, including blastematous components and admixture of epithelial and stromal elements. In none was there evidence of anaplastic change (unfavorable histology). Unfortunately, no tissue was examined from the two unresectable tumors.

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The most dramatic chemotherapeutic change affected the stroma. The interstitial tissue showed a complete lack of cytologic malignancy. The stroma ranged from an edematous fibrovascular background with numerous histiocytes to a fibroblastic tissue with numerous capillaries (Fig. 3A, B). Wide areas of loosely and poorly cellular stroma were present. The blastematous elements appeared to be reduced in size and transformed to smaller nodules (Fig. 3B); although most were viable, some disclosed evidence of necrosis (Fig. 3C). In one specimen, an extrarenal vein containing a large tumor thrombus showed these destructive changes (Fig. 4). Various degrees of necrosis and hemorrhage were present in 12 specimens. All had vascular changes predominantly involving the mediumsized arteries. A severe necrotizing process had occurred in the arterial wall, particularly the intima, accompanied by fibrinoid necrosis, acute inflammatory change (Fig. 5), and secondary thrombosis. The epithelial elements, whether in the form of tubules or of glomeruloid structures, were well preserved and exhibited no significant

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artery displaying FIGURE 5. Medium-sized fibrinoid necrosis of its wall. Neutrophils seen infiltrating wall and within lumen (original magnijkation X 60).

FIGURE4. Lumen of vein containing tumor thrombus; note same regressive tumor changes seen elsewhere (original magnijkation x 60).

necrosis. A well-differentiated rhabdomyoblastic component, containing fibers showing definite cross-striations, was prominent in 5 tumors5

allowed surgery within a median of seventeen days (range ten to thirty-two) from start of chemotherapy. The timing of surgery was related entirely to the schedule of vincristine therapy3 and was not increased by time necessary to recover from drug toxicity. Furthermore, the start of the postoperative treatment (median seven days postoperatively) was dictated by the patients’ postsurgical status alone, as there was no persistent toxicity from chemotherapy. Preoperative chemotherapy used in these patients did not alter the timing, dosage, or choice of postoperative chemo- or radiation therapy.‘,6*8*g Perhaps in the future the decision of which chemotherapeutic agent(s) to use postoperatively may be determined by the effect preoperative chemotherapy had on the primary tumor. Ten of 19 patients (53 per cent) are alive without evidence of disease five months to fifteen years after treatment. One death was due to intestinal obstruction. In 2 of the patients with nonmetastatic disease who died, failure to excise completely all intra-abdominal disease may have contributed to this demise. This implies that complete resection provides an advantage for the patient with advanced nonmetastatic Wilms tumor and supports preoperative measures that facilitate nephrectomy. The benefits of reducing the size of large Wilms tumors before surgery include decreasing the operative risk, difficulty, blood loss, and operating time; providing a better chance for complete en bloc excision; reducing the necessity for resecting portions of adjacent organs; and reducing chance for tumor rupture. In the past, radiation therapy has been used to reduce tumor volume, but this has now

Comment Nephrectomy is a fundamental part of successful multimodal treatment for Wilms tumor. 1*2~8gPreoperative chemotherapy given to 19 patients with unresectable tumors induced sufficient tumor shrinkage to permit an uncomplicated nephrectomy in 15 (79 per cent). In the opinion of the consulting surgeons, the tumor shrinkage greatly facilitated surgery and reduced the necessity for en bloc excision of adjacent organs. No difficulties attributable to drug treatment were encountered during surgery. Tumor rupture did not occur.* Histopathologic evaluation indicates that the interstitial undifferentiated stroma is usually the first element to disappear after chemotherapy. Next in line, the blastematous nodules become reduced in size and some actually undergo total necrosis. Differentiated elements appear to be more resistant to drug treatment, as indicated by the lack of necrosis in tubules or glomeruloid structures as well as in 5 tumors exhibiting well-differentiated rhabdomyoblastic differentiation.5 The changes in the arteries of these tumors are difficult to evaluate. They may be the result of a direct action of the drug on the arterial wall or they may occur secondarily following necrosis of the tumor tissue. Chemotherapy produced a marked and rapid tumor shrinkage in 16 patients and extensive necrosis without shrinkage in another child’s tumor. The beneficial effects of drug treatment

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largely been abandoned because of the deleterious late effects of irradiation in young children and because both the treatment and posttreatment periods may be prolonged, delaying surgery unduly. ‘J Tumor response to irradiation also may be s10w.~*’ The administration of preoperative chemotherapy overcomes some of the drawbacks of irradiation and also has inherent advantages. Preoperative treatment with vincrinstine achieves rapid tumor reduction in over 80 per cent of patients. Thus the surgery need not be unduly delayed. No short- or long-term serious toxicity has resulted from the drug regimens described here. Postoperative therapy is neither compromised nor delayed. The form of systemic therapy employed is active against either recognized or suspected metastatic deposits while it shrinks the primary tumor. The argument raised against preoperative chemotherapy is that, in 5 per cent of patients, the preoperative diagnosis of Wilms tumor may be incorrect, and in such children anticancer treatment prior to nephrectomy cannot be justified.1*2~6~8*gHowever, when patients have unresectable tumors or metastases, the diagnosis is usually obvious and the chance for a diagnostic error is minimaL Even in the unlikely event of a mistaken diagnosis, the lack of serious sequelae from preoperative chemotherapy suggests that much less harm may come from drugs than from any radiation therapy. Conclusion Preoperative chemotherapy for Wilms tumor produces consistent, significant, and rapid

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tumor reduction without troublesome toxicity. Such treatment is presumably active against both obvious and occult metastases as well as against the primary tumor. Furthermore, neither surgery nor postoperative treatment needs to be delayed or altered because of the drug therapy given prior to surgery. Preoperative chemotherapy, in our opinion, should be given to patients with Wilms tumors that are unresectable, to those who have extensive tumor thrombi in the vena cava, to those who may require the en bloc excision of adjacent viscera, and probably to those with tumor involving both kidneys. 231 Bethesda Avenue Cincinnati, Ohio 45267 (DR. BRACKEN) References 1. D’Angjo GJ, et al: The treatment of Wilms’ tumor. Results of the National Wilms’ Tumor Study, Cancer 38: 633 (1976). 2. Lemerle J, et al: Preoperative versus postoperative radiotherapy, single versus multiple courses of actinomycin D, in the treatment of Wilms’ tumor, ibid. 38: 647 (1976). 3. Sullivan MP, Sutow WW, Cangir A, and Taylor G: Vincristine sulfate in management of Wilms’ tumor, JAMA 262: 381 (1967). 4. Beckwith JB, and Palmer NF: Histopathology and prognosis of Wilms’ tumor. Results from the First National Wilms’ Tumor Study, Cancer 41: 1937 (1978). 5. Bannayan GA, Huvos AG, and D’Angio GJ: Effect of irradiation on the maturation of Wilms’ tumor, ibid. 27: 812 (1971). 6. Perez CA, et al: Treatment of Wilms’ tumor and factors affecting prognosis, ibid. 32: 669 (1973). 7. Waeeet ..,- .1.. and KOOD CE: Wilms’ tumor: oreouerative radiotherapy and chemotherapy in the management of massive tumors, ibid. 26: 338 (1970). 8. Jenkin RDT: The treatment of Wilms’ tumor, Pediatr. Clin. North Am 23: 147 (1976). 9. Green DM, and Jalfe N: Wilms’ tumor: model of a curable pediatric malignant solid tumor, Cancer Treat. Rev. 5: 1 (1978). &

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