(MAID) RTOG institutional participation in chemotherapy studies must be in accordance with the Medical Oncology Quality Control guidelines stated in the RTOG Procedures Manual.

7.1.1 Preoperative Chemotherapy

Patients will receive a maximum of six cycles of MAID chemotherapy. Three cycles will be administered preoperatively interdigitated with radiation therapy and three cycles will be

administered postoperatively. The postoperative chemotherapy (Section 7.1.3) should be instituted between 21-35 days following surgery. Delays beyond 35 days will be considered a major protocol deviation.

7.1.1.3.1 Suggested Hydration: Four hours prior to the ifosfamide administration, begin hydration of with D5'NS, 2400 cc/day at 100 cc/hr until six hours following the completion of the continuous infusion of ifosfamide.

7.1.1.5 G-CSF: 5 mcg/kg/day administered as a subcutaneous injection starting on day 5 (24 hours after completion of the administration of the chemotherapy) and continuing daily until white blood cell count recovers (post nadir granulocyte or ANC count of >10,000) even if the G-CSF is given concurrently with the radiation therapy. While patients receiving G-CSF, white blood cell counts and differenitial counts should be checked at least twice weekly until the G-CSF is discontinued.

7.1.2 Drug Mixing

Both mesna and ifosfamide can be mixed together in one liter D5W and administered via peripheral line. Both doxorubicin and DTIC can be mixed together in 1 liter NS and administered via a central line (should be protected from light).

7.1.3 Postoperative Chemotherapy

Patients who have had stable disease, or a minor or major clinical response to chemotherapy (including radiation therapy) will receive three cycles of treatment in the postoperative period. Postoperative chemotherapy should begin between 21-35 days after surgery. Each cycle of chemotherapy will include mesna, doxorubicin, ifosfamide, DTIC and G-CSF exactly as given in the preoperative period.

7.2 Mesna (Mesna )

7.2.1 Dose Formulation: Mesna is available as an injectable sterile preservative-free aqueous solution. The colorless solution is supplied in clear glass ampules containing 4 and 10 ml of a 100 mg/ml solution. Mesna may be further diluted in 5% dextrose, 5% dextrose and 0.45% normal saline or normal saline to a final concentration of 1 to 20 ml. Mesna should be given as a continuous intravenous infusion via a peripheral line.

7.2.2 Mechanism of Action: Mesna is a uroprotective agent used to prevent hemorrhagic cystitis induced by the oxasphosphorines (Ifosfamide, cyclophosphamide). It has no intrinsic cytotoxicity, no antagonistic effects on radiotherapy or chemotherapy. Mesna binds with acrolein, the urotoxic metabolite produced by the oxasophosphorines to produce a non-toxic thioether, and slows the rate of acrolein formation by combining with 4-hydroxy metabolites of oxasophosphorines.

7.2.3 Drug Availability: Mesna is commercially available in 4 and 10 ml ampules containing 100 mg/ml.

7.2.4 Storage: Intact ampules are stored at room temperature. Diluted solutions are physically and chemically stable for 24 hours under refrigeration.

7.2.5 Side Effects: At the doses used for uroprotection, mesna is virtually non-toxic. However, adverse effects that have been attributable to mesna include: nausea, vomiting, diarrhea, abdominal pain, rash, lethargy, headache, arthralgia, myalgias, fatigue, and bad taste in mouth.

7.3 Doxorubicin (Adriamycin, Rubex)

7.3.1 Dose Formulation: Doxorubicin is available as a red powder for injection in 10, 20, 50, 100 and 150 mg vials. Five, 10, 25, 50 or 75 ml of preservative-free normal saline to the 10, 20, 50, 100 or 150 mg vials respectively to produce a solution containing 2 mg /ml. Doxorubicin should be given as a continuous intravenous infusion via a central line.

7.3.2 Mechanisms of Action: Doxorubicin is an anthracycline antibiotic. It causes intercalation between adjoining nucleotide pairs in the DNA helix causing inhibition of DNA and DNA-dependent RNA synthesis. Free radical generation is responsible for cardiac toxicity. Doxorubicin also inhibits topoisomerase II.

7.3.3 Drug Availability: Doxorubicin is commercially available.

7.3.4 Storage: Adriamycin RDF or Rubex intact vials are stable protected from light at room temperature Adriamycin PFS vials must be refrigerated. Reconstituted solutions are stable for 24 hours at room temperature and 48 hours under refrigeration. The Adriamycin RDF 150 mg multidose vial as stable after reconstitution for 7 days at room temperature or 15 days if refrigerated and protected from sunlight.

7.3.5 Side Effects:

7.4 Ifosfamide (Ifex)

7.4.1 Dose Formation: Ifosfamide is available as a white crystalline powder in 1 and 3 gram single dose vials. When the 1 and 3 gram vials are reconstituted with 20 and 60 ml of sterile water respectively, each vial will contain 50 mg/ml. The solution's pH is approximately 6. Ifosfamide should be given as a continuous intravenous infusion via a peripheral line.

7.4.2 Mechanism of Action: Ifosfamide is an alkylating agent which is activated by hepatic microsomal enzymes to reactive alkylating substance. The reactive metabolites, ifosfamide mustard and aldophosphamide, are capable of covalent binding and cross-linking of DNA and cellular proteins.

7.4.3 Drug Availability: Ifosfamide is commercially available.

7.4.4 Storage: The intact, unreconstituted vials are stored at room temperature. The sterile reconstituted solution is stable for 1 week at 30-C or 3 weeks at 5-C. Ifosfamide liquifies at temperatures above 35-C.

7.4.5 Side Effects:

7.5 Dacarbazine (DTIC)

7.5.1 Dose Formulation: The drug is available in vials containing 100 mg, 200 mg or 500 mg of Lyophilized drug. The 100, 200 and 500 mg vials are diluted with 9.9, 19.7 and 49.5 nl of sterile water respectively, resulting in a concentration of 10 mg/ml. Protect the drug from direct light. Do not freeze. Discard if the solution turns pink/red. The drug can be further diluted in 50-500 ml of 5% dextrose or normal saline. DTIC should be given as a continuous intravenous infusion via a central line.

7.5.2 Mechanism of Action: DTIC is classified as an alkylating agent. Activity may be the result of a least 3 mechanisms: (1) alkylation; (2) antimetabolite activity as a purine precursor; and (3) interaction with sulfhydryl (SH) groups in proteins. Dacarbazine appears to be more active in G2 phase but is not particularly cell cycle phase specific.

7.5.3 Drug Availability : DTIC is commercially available. If there is any difficulty in obtaining DTIC for protocol use, please contact June Brouillette at Bayer Corporation (203/812-2355).

7.5.4 Storage: Store vials under refrigeration and protected from light. In solution, dacarbazine is stable for 96 hours if refrigerated and protected from light, 24 hours if not refrigerated but protected from light. When further diluted in 500 ml D5W or NS, it is stable for 24 hours if refrigerated, and 8 hours at room temperature and protected from light.

Photodegradation: The manufacturer of dacarbazine states that the drug dose not decompose when left at room temperature under normal lighting conditions for eight hours.

Note:A change in color of solution from pale yellow to pink is indicative of decomposition of the drug.

7.5.5 Incompatibility: Metabolism of dacarbazine may be inducted by phenytoin or phenobarbital. Toxicity may be enhanced if given concomitantly with allopurinol, azathioprine, or mercaptopurine. Dacarbazine is physically incompatible with hydrocortisone sodium succinate and heparin.

7.5.6 Side Effects:

7.6 Filgrastim (r-metHuG-CSF, Neupogen) (4/28/97)

7.6.1 Dose Formulation: G-CSF is available in preservative-free vials containing either 600 mcg of G-CSF in 2 ml buffered sterile solution or 480 mcg in 1.6 ml of solution. Each 1 ml contains 300 mcg of G-CSF, a preservative-free solution containing 0.59 mcg acetate, 50 mg mannitol, 0.004% Tween 80, 0.035 mg sodium, and 1 ml water for injection, USP pH 4.0.

G-CSF will be administered subcutaneously. Injection sites should be rotated. If the volume to be injected is > 1.5 ml, the dose should be divided in half and both doses should be given at the same time in two sites. Patients will be instructed in self-administration. Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.

7.6.2 Mechanism of Action: Filgrastim is a human granulocyte colony-stimulating factor (G-CSF) produced by recombinant DNA technology. G-CSF regulates the production of neutrophils with the bone marrow. Endogenous G-CSF is a glycoprotein produced by monocytes, fibroblasts and endothelial cells. r-met HuG-CSF is a 175 amino acid protein manufactured by recombinant DNA technology. It is produced by Escherichia Coli bacteria into which has been inserted the human granulocyte colony stimulating factor gene. Phase III clinical trials have demonstrated that G-CSF significantly reduces the incidence of febrile neutropenic episodes. With discontinuation of therapy, neutrophil counts returned to baseline, in most cases within 4 days.

7.6.3 Drug Availability: G-CSF is available from Amgen, Inc. (9/8/98)

7.6.3.1 G-CSF is being supplied free-of charge for this study by Amgen, Inc. and is available through Oncology Gherapeutics Netwok (OTN). Filgrastim orders from U.S. sites only will be accepted. To obtain a supply of G-CSF, complete the Filgrastim (G-CSF) Drug Request Form supplied in Appendix VI and fax or mail to:Oncology Therapeutics Network (OTN) Clinical Shipments Fax: (650) 952-1588; this number should be used for clinical shipping requests. General Phone: (800) 370-2508.

Orders will be shipped (refrigerated) Monday through Thursday for next day delivery. The initial shipment will be delivered by 10:30 a.m., subsequent shipments will be delivered by 3:30 p.m. Orders received on Friday will be shipped the following Monday, unless the institution specifically requests Saturday delivery on the Drug Request Form and can guarantee accepting the delivery. Emergency shipments will be made on the same day with next day delivery when the drug request is received by 12 noon PT by OTN.

7.6.3.2 Reorders will be sent directly to OTN, ATT: Clinical Shipments, fax (650) 952-1588. The contact person is Fadia Alaraj, telephone (800) 370-2508.

7.6.3.3 For this study, G-CSF is supplied in 480 mcg/1.6 ml vials. Initial order quantities will be 100 vials/patient; reorder quantities will be in 10 vial increments. Unused drug at the site upon termination of the study will be returned to OTN with a completed Return Medication Packing Slip (Appendix VII) included identifying for which study the drug was originally shipped.

7.6.4 Storage: Unopened vials should be stored in a refrigerator at 2-8°C (36-46°-F). Do not freeze. Avoid shaking.

Prior to injection, G-CSF may be allowed to reach room temperature for a maximum of 24 hours. Any vial left at room temperature for greater than 24 hours should be discarded. G-CSF is stable for at least 1 year when stored at 2-8°C.

7.6.5 Side Effects:

Musculoskeletal: Mild to moderate medullary bone pain in 20% to 25% of patients.

Dermatologic and Hypersensitivity: Redness, swelling, itching, and pain may occur at the injection site. Transient, generalized rash has been reported occasionally. Anaphylactoid and allergic reactions have been reported rarely.

Hematologic : Leukocytosis occurs occasionally.

Other: Less frequently reported side effects include transient supraventricular arrhythmia, splenomegaly, and vasculitis. Transient increases in serum concentrations of uric acid. LDH, alkaline phosphatase and leukocyte alkaline phosphatase have been reported after cytotoxic chemotherapy.

7.7 Drug Dose Modification The doses of chemotherapy will be attenuated as noted below. The most severe toxicity should determine the degree of attenuation.

7.7.1 Hematology Toxicity

7.7.1.1 Ifosfamide, Doxorubicin and DTIC doses are to be modified based both on the nadir (day 14) counts of the previous cycle and counts obtained on day treatment is given. No new treatment course may begin unless the patient's granulocyte count is > 1500/ml and platelet count is >100,000/ ml. If these are not present on day 22, then repeat counts weekly; if after 2 weeks the patient's counts are not adequate for therapy, contact Dr. Ettinger.

Absolute Neutrophil Count (Reduce doses only if ANC is <1000 for > 5 days)

In the event that dose adjustments are needed for both ANC and platelets, patients are to receive the lower dose.

Treatment should be delayed for one week until Day 1 ANC is >1500 and the platelet count is >100,000. If after one week the counts have recovered, the patient should proceed with the next course of treatment based on the previous course's nadir counts. However, if the counts have not recovered in two weeks, the Study Coordinator should be contacted. Patients and investigators need to be attentive to the possibility of fever and infection so that these complications can be promptly and appropriately managed.

When a dose reduction is made for a decreased ANC or platelet count and the reduced dosage results in no toxicity, the next course should be given at intermediate-dose rather than full-dose, e.g., if a 30% dose reduction results in no toxicity, the next course should start at 80% dose rather than 100% (i.e. 70% dose increased to 80% of dose, and 80% dose would be increased to 100%).

Dose reductions are not based on a single nadir count. The ANC must remain <1,000 for >5 days before a dose reduction is made.

If chemotherapy must be withheld due to hematologic toxicity. CBC and platelet counts should be obtained weekly until the counts reach the lower limits for treatment as outlined. The treatment schedule will then proceed in the usual sequence.

7.7.2 Gastrointestinal Toxicity (Ifosfamide, Doxorubicin, DTIC)

Nausea and/or vomiting should be controlled with adequate antiemetics. If Grade III nausea/vomiting occurs in spite of antiemetics, the dose should be reduced by 25% for the next course. If tolerated, increase back to 100% dose as soon as possible.

If on Day 1 of any treatment cycle the patient has mucositis, the treatment should be withheld until the mucositis is cleared. If acute Grade III mucositis occurs at any time, the dose should be given at 75% dose when the mucositis is completely cleared.

7.7.3 Hepatic Toxicity: give the following percent of previous course's dose based on the patient's bilirubin the day of treatment.

7.7.4 Neurotoxicity: Ifosfamide doses will be modified for neurotoxicity as outlined below:

7.7.4.1 Mild Somnolence (sleeping constantly but easily aroused and oriented): Decrease dose of narcotics or antiemetics; continue ifosfamide with no change in dose.

7.7.4.2 Moderate Somnolence (difficult to arouse or disoriented when finally awakened); discontinue IFOS until toxicity clears and then reinstitute at same dose. If moderate somnolence recurs, again discontinue IFOS and reinstitute at a 25% dose reduction for the rest of the course. If the same symptoms recur at the reduced dose, again hold until symptoms resolve and restart at a 25% further dose reduction. If symptoms recur after a 50% reduction, discontinue permanently.

7.7.4.3 Visual Hallucinations, Confusion, Catatonia: Hold IFOS, reinstitute at 25% reduced dose with next course minimizing any other psychoactive medications. If symptoms recur, decrease IFOS dose by another 25% with the subsequent course. If symptoms recur after a 50% dose reduction, discontinue permanently.

7.7.5 Cardiac Toxicity

Doxorubicin should be withheld if EKG abnormalities or congestive heart failure develops. Non-invasive ventricular function studies should be performed if available. If EKG abnormalities improve, Doxorubicin may be reinstituted, but it should not be reinstituted if congestive heart failure or ventricular dysfunction are present. Patients whose MUGA scan drops to less than 50% should be removed from the study.

7.7.6 Genitourinary

Cystitis: IFOS-related gross or microscopic hematuria correlates with the concentration of drug metabolites in the bladder. Adequately hydrate patients and ensure frequent voiding. Should Grade 2 hemorrhagic cystitis occur, discontinue IFOS. Reinstitute IFOS at a 50% reduced dose when hematuria has cleared. If Grade 2-3 bladder toxicity occurs at the 50% dose reduction, discontinue IFOS permanently. IFOS may be escalated to full dose after dose reduction with subsequent courses if no hematuria occurs at the 50% dose reduction.

7.7.6.1 Nephrotoxicity: Give the following percent of the previous course's dose for nephrotoxicity based on renal function on the day of treatment:

7.7.7 Miscellaneous Toxicity

7.7.7.1 Skin Ulceration/Phlebitis: Doxorubicin may cause chemical phlebitis, even when administered by continuous infusion through side-arm of a rapidly running intravenous infusion. Chemical phlebitis is not an indication to stop any drug. Doxorubicin must be administered through central line (not merely a long line).

7.7.7.2 Extravasation outside a vein will cause skin necrosis; stop the infusion immediately if extravasation is suspected.

7.7.7.3 Fever and Flu-like Syndrome associated with DTIC administration may be avoided with oral acetaminophen.

7.7.7.4 Alopecia: IFOS and Doxorubicin cause total alopecia.

7.7.7.5 For any Grade 3 or 4 toxicity not mentioned above, the treatment should be withheld until the patient recovers completely or to Grade 1 toxicity. The treatment should then be resumed at 50% dose (permanent dose reduction). For Grade 1 or 2 toxicities, no dose reduction should be made.

Patients who show progressive disease at the primary site during the preoperative period, will not receive post-operative chemotherapy. If progressive disease is noted after any preoperative cycle, the patient will be offered surgical therapy immediately. Patients who develop systemic metastatic disease will be considered treatment failures and will be removed from the study. They may be treated with other forms of palliative chemotherapy.

7.9 RTOG/Adverse Drug Reaction Reporting

7.9.1 The following guidelines for reporting adverse drug reactions (ADRs) apply to any research protocol which uses commercial anticancer agents. The following ADRs experienced by patients accrued to these protocols and attributed to the commercial agent(s) should be reported to the Investigational Drug Branch, Cancer Therapy Evaluation Program, within 10 working days:

7.9.1.1 Any ADR which is both serious (life threatening, fatal) and unexpected.

7.9.1.2 Any increased incidence of a known ADR which has been reported in the package insert or the literature.

7.9.1.3 Any death on study if clearly related to the commercial agent(s).

7.9.1.4 Acute myeloid leukemia (AML). The report must include the time from original diagnosis to development of AML, characterization such as FAB subtype, cytogenetics, etc. and protocol identification.

7.9.2 The ADR report should be documented on the FDA form 3500 (Appendix V) and mailed to:

7.10 ECOG/Adverse Drug Reaction Reporting

7.10.1 All toxicities should be coded according to the RTOG Common Toxicity Criteria and the RTOG Acute Radiation Morbidity Scoring Criteria (Appendix IV).

ECOG suggests ADRs to be reported on the Adverse Reaction (ADR) Form for Investigational Drugs (#391RF). The form must be signed by the treating investigator. However, the MedWatch (FDA Form #3500) is also acceptable for reporting ADRs on commercial arms. All ADR reports must be accompanied by copies of supporting documentation. In addition, your institution's Investigational Review Board must be notified.

7.10.2 This protocol contains COMMERCIAL AGENTS only: Mesna, Doxorubicin, Ifosfamide, Dacarbazine (DTIC), and G-CSF. Events indicated below must be reported in the manner specified.

For:

7.10.3 Call the ECOG Coordinating Center within 24 hours of the event. Submit original written ADR form to the ECOG Coordinating Center within 5 working days of the event. In addition, a copy must be mailed to the Investigational Drug Branch (IDB) within 10 days and your institutional Review Board (IRB) must be notified.

The ECOG Coordinating Center will call the RTOG office to report ADR telephone calls and will forward ADR reports to RTOG.

1 To be completed within 30 days of diagnosis of AML/MDS that has occurred during or after protocol treatment. A copy is to be sent to ECOG and to the NCI, accompanied by copies of the pathology report and when available, a copy of the cytogenetic report.

2 To be submitted to ECOG within 30 days of diagnosis of a new primary cancer during or after protocol treatment, regardless of relationship to protocol treatment. Not for use for reporting recurrence or metastatic disease. A copy of pathology report should be sent, if available.

7.10.4 Non-Treatment Related Toxicities: If a toxicity is felt to be outside the definitions listed above and unrelated to the protocol treatment, this must be clearly documented on the data forms which are to be submitted to the ECOG Coordinating Center according to the Data Submission Schedule. This does not in any way obviate the need for reporting the toxicities described above.

8.1 Biopsy may be by incisional biopsy or core needle biopsy. Sufficient tumor must be obtained to determine the diagnosis of soft tissue sarcoma and the tumor grade. The biopsy should be done in such a way as to permit excision of the biopsy site at the time of formal resection. If needle biopsy is done, care must be taken to tatto or otherwise identify the biopsy site so that it may be excised at the time of resection.

8.2 Resection of the sarcoma will occur following combined preoperative radiation and chemotherapy. The resection should be done with a goal to have negative margins. Quality assurance for surgical resection will be provided by assessment of the specimen by surgical pathology (see Section 10.0). Absence of tumor on ink will be accepted as a negative margin.

8.3 The surgeon and radiation oncologist will consult after diagnosis and prior to the institution of neoadjuvant therapy. Plans for neoadjuvant therapy and subsequent surgery can be made. Following neoadjuvant therapy the surgeon, radiation therapist and medical oncologist see the patient again. Definitive plans for resection are made at this time. If deemed necessary, plastic surgery may be consulted at this time.

8.4 Definitions of operative procedures will be made following pathologic evaluation of the resected specimen (no more than two weeks post operation). The definitions include:

8.4.1 Amputation (For type of resection see 8.4.2.1 - 8.4.2.4. This applies to amputations as well).

8.4.2 Non-amputation and the margins achieved (4/28/97)

8.4.2.1 Intralesional Resection - grossly positive margin - visible tumor left behind.

This procedure is not acceptable as a biopsy or a therapeutic resection for the purposes of this protocol.

8.4.2.2 Marginal Resection - All gross disease removed; less than compartmental or muscle group excisions; microscopically positive margins. These patients will receive postoperative radiation and continue in protocol (see Section 6.3).

8.4.2.3 Wide Excision - Microscopically negative margins, less than compartmental or muscle group excision (for lesion within a specific muscle group), all gross disease removed. Margins are microscopically negative.

8.4.2.4 Radical Excision - Entire anatomic compartment and negative microscopic margin.

8.4.2.5 Periosteum - If periosteum is resected in extremity sarcomas, consideration should be given for internal fixation.

The surgical treatment necessary to resect the tumor with negative margins should be used. These definitions noted above will be recorded in the surgical form.

8.6.1 All lesions of the trunk and extremities will be treated with conservative resection (minimal wide excision) and neoadjuvant chemoradiation. Any biopsy site should be excised en bloc with the definitive surgical specimen. Surgical resection should remove as wide a margin of tissue around the tumor as possible without compromising function. Dissection should always be done through grossly normal tissue planes and should be done beyond the fascial plane adjacent to the tumor. If the tumor is close to or displaces major vessels or nerves, these need not be removed if the adventitia or perineurium is removed and the margin is not involved pathologically. Frozen section at the time of surgery should be done from the closest margin and must be confirmed as being free of tumor. If postoperative pathology evaluation reveals positive soft tissue margins other than bone, nerve or large blood vessels, this margin should be resected if possible. If bone, major blood vessel or nerve is microspocially positive, additional radiation should be given as noted in the protocol. In general, lymph node dissection is not recommended but a sampling can be performed if regional lymph nodes are clinically enlarged or if the primary tumor is over a major node station. Elective node sampling may be performed in patients with epitheloid sarcoma, or clinically positive lymph nodes. Primary tumors overlying major lymph node stations may best be treated with surgical resection including node dissection. Marker clips (titanium) should be placed to help guide the radiation oncologist. Closed wound suction drainage should be used in all anatomic regions (Davol, Hemavac, etc.). The drains should exit the skin close to the edge of the surgical incision. External compression for extremity resections with ace wraps or compression dressings is advised.

8.6.2 State clearly in the operative note what type of surgical procedure was performed, and from where the frozen section of the margins was taken.

8.6.3 Because all patients will have had neoadjuvant radiation and chemotherapy and radiation, special care must be given to skin flaps. Use of muscle flaps, pedicled myocutaneous flaps, and even free flaps is encouraged to fill dead space and used if there is any concern about the viability of the wound flaps.

8.6.4 In general, the following principles should be followed in postoperative management of these patients:

8.6.5 Resectability will depend upon the judgment of the operating surgeon. For the extremities, resection must be limb salvage procedure. For other anatomic area it must be judgment of the operating surgeon that he/she may reasonably expect to obtain negative margins. Extremity patients who are not resectable without amputation, may be amputated. Unresectable tumors elsewhere may be palliated with additional chemotherapy or radiation therapy.

8.7.1 Per Protocol - Surgery completed by day 80 after start of treatment

8.7.2 Minor Variation - Surgery completed > day 80-day 94 after start of treatment

8.7.3 Major Deviation - Surgery completed > day 95 after treatment start.

Not applicable to this study.

10.0 PATHOLOGY (4/28/97)

10.1 Assessment of Pre-treatment Biopsy Specimen

10.1.1 Central Pathology Review

a) Recuts of all histology slides, a representative paraffin tissue block and a copy of the surgical pathology report must be mailed with a Pathology Submission Form to:

b) Immunohistochemistry slides should be made available upon request. A small sample should be snap-frozen and saved in tissue bank (see Section 10.4). A small sample should be also fixed in glutaraldehyde for possible electron microscopy and should be sent upon request.

c) For ECOG institutions: Recuts off all histology slides and a copy of the surgical report must be mailed to the ECOG Pathology Coordinating Office (PCO). If ECOG institutions submit paraffin blocks, they will be returned to the contributing institution and slides will be requested. ECOG members will send pathology material to the ECOG PCO:

Note: A copy of the completed ECOG Pathology Material Submission Form No. 638 will be sent to the ECOG Study Chair and to the ECOG Coordinating Center by the PCO. The ECOG PCO will log the materials and route them to RTOG Headquarters.

10.1.2 Type of Specimen

10.1.3 Histopathologic Assessment

10.2.1 Central Pathology Review

a) Recuts of all histology slides, the surgical pathology report, and a representative paraffin block and a Pathology Submission Form should be submitted to RTOG Pathology Coordinator per Section 10.1.1a.

10.2.2 Gross Parameters of Tumor

10.2.3 Handling of Gross Specimen

10.3.1 Additional biologic studies will be performed on the paraffin sections including immunohistochemistry for p53 protein, multi-drug resistance protein (p-glycoprotein), and proliferation marker (e.g. Ki-67). DNA content may be determined by image analysis.

10.4.1 Many informative biological studies can be done with snap-frozen tissue samples. These include molecular biologic studies of oncogenes and tumor suppressor genes, including frozen-section immunohistochemistry (e.g. for MDM2 protein), polymerase chain reaction and DNA sequencing techniques. Frozen tissue may also be put in tissue culture or used in flow cytometry for determination of DNA content. Many additional studies will be possible. Details and methods will be determined as the study progresses.

11.2.1 Measurement of Response

Response to preoperative chemotherapy and radiation will be measured by comparing tumor size at time of registration for the protocol with measurements taken 0 to two weeks prior to surgical resection. Response will be measured through evaluation of the MRI change, CT change or change in physical examination. In addition pathologic response will be recorded at the time of pathologic review of the resected specimen (see pathology section).

• Complete response (CR) - Disappearance of all measurable tumor as measured by MRI, CT or physical examination (PE). This is the order of preference of items for measurement.

• Partial response (PR) - 50% or greater decrease in product of perpendicular dimensions as measured on MRI, CT or PE. This is the order of preference of items for measument.

• Minor response (MR) - A measurable decrease of the product of perpendicular dimensions as measured on MRI, CT or PE of 25% - 50%. This is the order of preference of items for measurement.

• Stable disease (SD) - Stable disease is defined as a < 25% decrease in size or < 25% increase in size of the measured lesion.

• Progression (P) - Progression is defined as an increase in size of the lesion by >25% as defined by the product of the perpendicular dimensions on MRI, CT or PE. This is the order of preference of items for measurement.

11.2.2 Record of Timing of Therapies

Modification of chemotherapy dose associated with toxicity is noted in Section 7.7. Delays in institution of chemotherapy, radiation therapy (RT) or surgery should be recorded. We anticipate 21 days between cycles of chemotherapy. Ideally there will be 2 days between the completion of chemotherapy and the institution of the preoperative radiation doses in the treatment arm. Surgery should be completed by day 80 of protocol (time from first chemotherapy to time of surgery). Delay from day 80 to 94 will be considered a minor variation. Delay beyond day 94 will be considered a major deviation. Chemotherapy should be instituted between 21 days and 35 days following surgery. Delay beyond 35 days following surgery will be considered a major deviation.

Wound complications are to be reported. They will be categorized as noted below. These categories will also apply to the control or preoperative radiation therapy arm of the protocol.

11.3.1 Category 1: This is a minor wound complication such a minor skin separation or delayed drain removal. This category of complication does not result in delayed institution of post operative chemotherapy (see Section 11.2.2).

11.3.2 Category 2: This represents a more serious problem which seriously delays the institution of adjuvant chemotherapy. Included would be a major infection, but a complication in which limb loss is not threatened.

11.3.3 Category 3. This represents a very serious infection or vascular complication in which limb loss, major soft tissue loss or skin loss is threatened.

Recurrence represents the time when recurrent or persistent disease is noted. This must be biopsy proven.

Time to recurrence represents the time from registration to time that recurrence is biopsied.

Survival represents the time from registration to the time of death.

Patients will be followed until death. Followup must include MRI or CT scans as indicated. Every effort should be made to obtain an autopsy to document the extent of disease at the time of death.

11.9.1 Musculoskeletal sarcomas are imaged using standard spin echo (SE) sequences in planes designed to demonstrate both the compartmental and longitudinal extent of the lesion. The number of slices, slice thickness, image gap, image matrix and field-of-view will vary depending on the size and location of the lesion and cannot be specifically defined in the protocol. In each case, the primary determinant of the slice thickness and matrix/field-of-view combination is the requirement that the entire tumor be imaged with sufficient surrounding tissue to include compartmental margins, adjacent joints and draining nodal groups. Sufficient resolution must be maintained to define the relationship of the tumor to vessels and nerves passing nearby. Similarly, the number of slices and slice gap will vary with larger tumors requiring more slices and, occasionally, slice gapping to fully evaluate the tumor. Rapid acquisition gradient echo and turbo spin echo sequences may be substituted for standard spin echo sequences when they are available, provided that identical sequences are used prior to and following contrast injection.

11.9.2 Intravenous Gd-DTPA is administered at 0.1 mmol/kg body weight. Both the pre-and post-contrast T1 weighted sequences are multi-slice sequences covering the entire tumor. Image sequences are obtained immediately following infusion and at 1, 3, 5 and 10 minutes following the infusion. The post infusion images are reviewed and the regions of greatest enhancement identified. The signal value in this area is measured on each sequence and compared with subcutaneous fat (which should not enhance) in an area away from the tumor. The ratio of fat to tumor is them plotted relative to time from injection.

11.9.3 Suggested standard sequences:

12.2.1 Dosimetry data must include complete and final information for patients receiving post operative RT. These include completed T5, T6 as well as T8 (boost films). Patients who do not receive post operative RT, do not require T8 films. All dosimetry data will be submitted directly to RTOG, including ECOG members.

12.3.1 Note: ECOG institutions should send all radiation oncology material directly to RTOG.

12.3.2 For ECOG institutions - originals of completed forms must be sent by the institutions to the:

ECOG Coordinating Center
Frontier Science
ATTN: Data
303 Boylston Street
Brookline, MA 02146-7648

The RTOG case number as well as the ECOG case number should appear on every form. Investigators should retain a copy of their records. The ECOG Coordinating Center will forward the date-stamped originals to RTOG Headquarters. ECOG members should send forms directly to RTOG. RTOG forms should be used. DO NOT use ECOG data forms except for the ECOG Pathology Material Submission Form NO. 638, the ECOG Second Primary Cancer Form No. 630 and the Adverse Reaction (ADR) Form for Investigational Agents 391RF.

12.3.3 ECOG will attach a forms appendix to their members' version. It will be the responsibility of the institutions to copy the attached forms and to maintain a supply of available forms for data submission.

The following are the study endpoints. They will be analyzed in detail at the completion of this study.

13.1.1 Initial Response to the Preoperative Chemoradiation

Both the clinical and the histopathologic responses will be assessed. See Sections 10.2.4 and 11.2.1 for details.

13.1.2 Local Recurrence and Distant Metastasis

The local recurrence rate and the distant metastasis rate within two years of surgery will be reported.

13.1.3 Toxicity

Both acute and late toxicity within the first two years after registration will be summarized.

13.1.4 Wound Complications

Wound complications will be divided into three categories as listed in Section 11.3.

13.1.4 Treatment Delivery

The treatment delivery will be divided into three phases: preoperative, surgical and postoperative. The number of patients who completed each phase per protocol will be reported. Both dose and timing variations will be recorded.

13.1.5 Survival

Absolute survival as well as local and distant disease-free survival will be studied, but by the time of the initial treatment paper most patients will still be alive.

This is an intergroup study. From a survey of RTOG member institutions, we project that 30 patients can be accrued in about one year. All the ratios, such as the initial response rates, local recurrence rates and wound complications rates, can be estimated with a standard deviation of no more than 0.09. All patients will be followed until death as is usually done in RTOG, but the initial treatment paper will be prepared after the last patient has been followed for two years.

Semi-annual reports will be prepared and published in the RTOG Meeting Reports until the initial treatment paper is submitted to a peer-reviewed journal. In general, these reports will contain information about the patient accrual rate, data quality, compliance rate of treatment delivery, distribution of important prognostic baseline variables and the frequencies and severity of the toxicities.

In conformance with the National Institute of Health Revitalization Act of 1993 with regard to inclusion of women and minority in clinical research, the possible difference in any of the above endpoints between men and women, or whites and non-whites, will be investigated.

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